Meeting Abstracts

Proffered papers and posters presented at the Seventh International Symposium on Hereditary Breast and Ovarian Cancer—BRCA: From the Personal to the Population


Presented by the Hereditary Breast and Ovarian Cancer Foundation in collaboration with the Program in Cancer Genetics, McGill University; Centre Mont-Royal, Montreal, QC; 8–11 May 2018


doi: http://dx.doi.org/10.3747/co.25.4243

The opinions expressed in the abstracts are those of the authors and are not to be construed as the opinion of the publisher (Multimed Inc.), the organizers of the Seventh International Symposium on Hereditary Breast and Ovarian Cancer, or the Program in Cancer Genetics, McGill University. Although the publisher (Multimed Inc.) has made every effort to accurately reproduce the abstracts, Multimed Inc. and the organizers of the Seventh International Symposium on Hereditary Breast and Ovarian Cancer, or the Program in Cancer Genetics, McGill University, assume no responsibility and/or liability for any errors and/or omissions in any abstract as published.


Proffered Papers

S1-PP1: An International Interlaboratory Study of Complex Pathogenic Variants in Hereditary Breast/Ovarian Cancer


Stephen Lincoln*, Eric Klee, Andrew Fellowes, Shimul Chowdhury§, Shazia Mahamdallie, Justin Zook#, Rebecca Truty*, Russell Garlick**, Marc Salit#,††, Nazneen Rahman, Swaroop Aradhya*, Stephen Kingsmore§, Robert Nussbaum*,‡‡, Matthew Ferber, Brian Shirts§§


ABSTRACT

The comprehensive assessment of inherited mutations in cancer susceptibility genes helps to optimize clinical decision-making. Conventional laboratory methods based on ngs focus on the detection of single nucleotide variants, small insertions/deletions, and certain copy-number changes in accessible regions of a patient’s dna. Other clinically significant alterations are invisible to these approaches, and for this reason their clinical impact is less well studied.

We investigated the prevalence of technically challenging mutations in a large (n = 80,000) patient population focusing on 19 genes (including BRCA1 and BRCA2) associated with breast and/or ovarian cancer. Technical methods beyond conventional next-generation sequencing (ngs) were used to detect and confirm the presence of dna alterations in these patients. We found that 8.6% of patients with a potentially actionable result harbored a mutation not easily detected by conventional ngs sequencing or copy number methods. No single class of mutation was responsible for this—rather, a diversity of challenges was present. Most of these mutations were individually extremely rare, although some were recurrent. Many would have clinical relevance in either a germline or somatic context.

Laboratory studies generally include few, if any, of these technically challenging variants. To help evaluate and improve methodologies across laboratories, we constructed a synthetic specimen containing 22 challenging variants in 7 cancer genes. This specimen was provided to collaborating laboratories who sequenced it using a total of 10 different ngs tests. Only 10 of the 22 challenging variants were detected by all tests, and just 3 tests detected all 22. Some but not all of these limitations were previously known.

In summary, technically challenging pathogenic variants are collectively prevalent in patients, although methods to detect these variants are not yet uniformly implemented. The clinical data and specimen described here are now available and mght help improve the assessment of cancer risk internationally.

AUTHOR AFFILIATIONS

*Invitae, San Francisco, CA, and,
Mayo Clinic, Rochester, MN, U.S.A.;,
Peter MacCallum Cancer Centre, Melbourne, Australia;,
§Rady Children’s Hospital, San Diego, CA, U.S.A.;,
Institute of Cancer Research, London, U.K.;,
#National Institute of Standards and Technology, Gaithersburg, MD,,
**SeraCare Life Sciences, Gaithersburg, MD,,
††Joint Initiative for Metrology in Biology, Stanford University, Stanford, CA,,
‡‡Volunteer Clinical Faculty, University of california, San Francisco, CA, and,
§§University of Washington, Seattle, WA, U.S.A..


Proffered Papers

S1-PP2: Pheno Analysis Is a Highly Accurate and Robust Variant Classification Algorithm With High Tolerance for Reported Clinical History Errors


Karla Bowles, Brian Morris, Benjamin Roa, Alexander Gutin


ABSTRACT

Background

Pheno analysis is a computerized statistical tool that provides very strong classification evidence used to classify variants identified in cancer-associated genes. Pheno utilizes personal and family cancer histories recorded on the test requisition form (trf) as inputs to determine whether a variant is or is not associated with strong personal and family history of cancer, and is thus likely to be pathogenic or benign. As trf information is self-reported by patients, it is expected that errors exist.

Methods

Gene-specific analyses were performed for BRCA1 and BRCA2. Pheno cases and controls are ascertained using the same trfs. Thus, trf errors are assumed to be uniform, and simulated errors were uniformly applied to cases and controls. For each trial, certain types and proportions of erroneous cancer histories were randomly introduced into trf case–control data. Pheno prevalence tables were constructed targeting ≥99.5% positive (ppvs) and negative predictive values (npvs), and 25,000 pathogenic and 50,000 benign composite variants were analyzed through two-fold cross-validations. The ppvs, npvs, and average number of probands required for Pheno to make a classification call were calculated.

Results

For all passing trials, ppvs. and npvs. were >99.5%. As trf error rates increased, the number of probands required to make a Pheno call also increased. trf errors limited to 2nd-degree relatives had smaller effects than errors including 1st-degree relatives; and errors including probands in addition to family members had the greatest impact.

Conclusions

Pheno is a highly accurate and robust variant classification algorithm with high tolerance for trf errors. As trf errors increase, Pheno utility decreases, because of larger proband numbers being required to make a Pheno call. While high trf error rates result in Pheno failure (that is, Pheno does not make a classification call), if Pheno makes a classification call, that call is accurate, regardless of the number of trf errors present.

AUTHOR AFFILIATIONS

Myriad Genetic Laboratories Inc., Salt Lake City, UT, U.S.A..


Proffered Papers

S1-PP3: Functional Assays Identify Clinically Actionable Variants in Hereditary Breast and Ovarian Cancer Predisposition Genes


Rachid Karam, Marcy Richardson, Charles Yi, Vickie Hsuan, Blair Conner, Kate Krempely, Ginger Haynes, Michelle Jackson, Ira Lu, Brook White, Tina Pesaran, Sitao Wu, Hsiao-Mei Lu, Phillip Gray, Brigette T. Davis


ABSTRACT

Introduction

Genomic testing for hereditary breast and ovarian cancer (hboc) is becoming widespread; however, the interpretation of variants of unknown significance (vus) in hboc genes remains a challenge to geneticists and patients. Here, we demonstrate an integrated dna, rna, and protein functional approach for the assessment of vus that improves the identification of clinically actionable alterations in hboc genes.

Methods

We analyzed sequence data obtained from a cohort of ∼23,000 individuals who underwent a hboc dna multigene panel test in a clinical laboratory. We then used a combination of clinical data, protein structure, and in silico analyses to select vus for specific functional analysis, depending on the type of alteration. For BRCA1 and BRCA2 missense vus, protein function was determined by measuring homology-directed recombination (hdr) efficiency and quantitative infrared Western blot analysis. For splicing variants, we performed targeted rna studies. Finally, for gross duplications, a novel dna breakpoint assay (dba) was used to detect tandem duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2.

Results

Most of the vus in hboc genes were missense (91.6%), splicing (3.2%), or gross duplications (1%). To date, 22% of the missense alterations tested using the combination of structure and functional assays (hdr assay and quantitative infrared Western blot) were reclassified from vus to likely pathogenic. For splicing alterations, targeted rna studies resulted in ∼78% reclassifications. Finally, dba allowed us to ascertain breakpoints for 44 unique gross duplications from 156 consenting probands. We determined that the duplications occurred in-tandem in 123 individuals from this cohort (79%). Among the intandem gross duplications that were eligible for reclassification, 95% were upgraded to pathogenic mutations.

Conclusions

The use of dna, rna, and protein functional assays significantly improved the overall assessment of germline variants in hboc genes, resulting in a reduction in vus classifications.

AUTHOR AFFILIATIONS

Ambry Genetics, Aliso Viejo, CA, U.S.A..


Proffered Papers

S2-PP1: BRCA2 Haploinsufficiency for Replication Stress Suppression in Primary BRCA2 Heterozygous Mammary Epithelial Cells


Haohui Duan*, Rachel Reed, Stephen Godin*, Judy Garber, Shailja Pathania*


ABSTRACT

BRCA2 is a breast and ovarian tumour suppressor that maintains genome integrity by engaging in multiple cellular processes, including repair of dna damage. BRCA2 is an important player in both dna double-strand break repair [dsbr (via homologous recombination)] and repair of stalled replication forks. Here, we report that primary BRCA2 heterozygous (BRCA2mut/+) mammary epithelial cells (mecs), though efficient in dsbr, are defective in repair of stalled forks. Stalled forks are frequent source of dna damage in replicating cells, and their inefficient repair leads to increased replication stress, a prime contributor to epithelial cancer.

Furthermore, we show that BRCA1 and BRCA2 play different roles in the repair of stalled forks—leading to differences in repair pathway choices made by BRCA1 and/or BRCA2 mutant cells. In keeping with this, we find that primary BRCA2mut/+ mecs (n = 8), and not BRCA1mut/+ cells (n = 10), are haploinsufficient for nucleotide excision repair. This would imply higher predisposition for skin lesions, including melanoma, in BRCA2 mutation carriers. Risk for melanoma is indeed higher in BRCA2 mutation carriers. We also show that there exists a difference in mutational signature in whole-genome sequences derived from BRCA1 and BRCA2 mutant tumours, in line with the differences expected if there is an increased nucleotide excision repair defect in BRCA2 compared with BRCA1 mutant cells.

Together, our findings provide the first evidence for innate haploinsufficiency for replication stress suppression in primary BRCA2mut/+ mecs and evidence for differences between how BRCA1 and BRCA2 defective cells process stalled forks. This mechanistic difference between BRCA1- and BRCA2-dependent response at stalled forks, and the crosstalk with nucleotide excision repair, potentially contributes toward differences in BRCA1 and BRCA2 mutant breast and ovarian cancer, and could also explain the differences observed between BRCA1 and BRCA2 mutant tumours’ response to different chemotherapeutics.

AUTHOR AFFILIATIONS

*University of Massachusetts Boston and,
Dana Farber Cancer Institute, Boston, MA, U.S.A..


Proffered Papers

S2-PP2: Aneuploidy and Altered Cell Fate Define the Early Pathogenesis of BRCA2-Associated Breast Cancer


Leif W. Ellisen*, Mihriban Karaayvaz*, Rebecca E. Silberman, Michelle C. Specht, Adam Langenbucher*, Elena Zarcaro*, Kenneth N. Ross*, Srinivas V. Saladi*, Kristen M. Shannon§, Paz Polak*,, Gad Getz*,, Michael Lawrence*,, Angelika Amon


ABSTRACT

Germline mutations in BRCA1 and BRCA2 confer risks for distinct breast cancer subtypes, because most BRCA1-associated cancers are estrogen receptor (er)–negative and “basal-like,” whereas those arising in BRCA2 genetic carriers are predominately er-positive (er+) and “luminal-like.” The early events that give rise to these divergent cancer phenotypes remain unknown. We thus sought to reveal the earliest steps in BRCA1/2–associated breast cancer pathogenesis through detailed cellular, molecular, and functional analysis of fluorescence-activated cell sorted populations from freshly isolated, histologically normal breast tissues of BRCA1 carriers (n = 18), BRCA2 carriers (n = 28), and matched controls (n = 28).

We observe an age-associated increase in the luminal progenitor (lp) population and increased luminal/basal cell ratio selectively in BRCA2 carriers. Correspondingly, rnaseq analysis demonstrates a prominent signature of G2/M stress and Aurora kinase activation selectively in lp cells of BRCA2 carriers compared with BRCA1 carriers and controls, associated with downregulation of genes signifying basal and bipotent cell fate. This phenotype is linked to dna damage as evidenced by increased γ-H2AX staining in the corresponding tissues. We then used a validated next-generation sequencing (ngs)–based methodology for single-cell ploidy analysis, which demonstrates polyclonal aneuploidy in >20% of BRCA2lp cells. These aneuploid events are predominantly losses and include large (>10 MB) deletions never observed in normal cells.

We conclude that the early pathogenesis of BRCA2-associated breast cancer involves selective cell-cycle deregulation and the resulting expansion of a luminal fate-shifted progenitor population that is subject to mitotic stress, triggering aneuploidy that ultimately drives malignant progression. Notably, these findings support recent data pointing to distinct patterns of genomic damage in BRCA1 compared with BRCA2-associated breast cancers and the enrichment of chromosomal losses with BRCA2. These findings have implications for breast cancer pathogenesis and prevention in BRCA1/2 genetic carriers.

AUTHOR AFFILIATIONS

*Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston,,
Koch Institute Cancer Research and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge,,
Massachusetts General Hospital, Boston,,
§Center for Cancer Risk Analysis, Massachusetts General Hospital, Boston, and,
Broad Institute of mit and Harvard, Cambridge, MA, U.S.A..


Proffered Papers

S2-PP3: Functional Analysis of the PALB2 Tumour Suppressor


Amélie Rodrigue*, Mandy Ducy, Timothy Wiltshire, Yan Coulombe*, Guillaume Marguillan, Joris Pauty*, Penny Soucy, Graham Dellaire§, Marcelo Alex Carvalho, Alvaro Monteiro#, Fergus J. Couch, Jacques Simard, Jean-Yves Masson*


ABSTRACT

One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumour suppressors such as PALB2. Inherited mutations in PALB2 are associated with a predisposition to ovarian, breast, and pancreatic cancers. In particular, it has been reported that mutations in PALB2 increase breast cancer risk up to 8- to 9-fold. PALB2 was identified as a BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination. Our group focuses on both the regulation and activities of PALB2 during the dna damage response and the effect of cancer-causing mutations.

First, we will present our work in deciphering the functions of PALB2 in dna double-strand break repair and homologous recombination. Second, predicting the functional consequences of PALB2 mutations or variants has been challenging because they can lead to different biologic effects. Using a novel crispr/Cas–based homologous recombination assay and biochemical and cellular assays, we performed a structure–function analysis of PALB2 using PALB2 truncated mutants (R170fs, L531fs, Q775X, and W1038X). These studies allowed us to uncover a PALB2 regulation mechanism by which cancer cells could drive genomic instability leading to cytoplasmic accumulation of PALB2. We have undertaken a systematic functional analysis of PALB2 variants of unknown significance (vus). We now present evidence that the cytoplasmic localization of PALB2 can be triggered by specific vus in patients. The assays presented here will be valuable tools for the functional assessment of PALB2 variants, or other homologous recombination genes, in cancer causation.

AUTHOR AFFILIATIONS

*Laval University Cancer Research Centre and,
chu de Québec–Université Laval Research Center, Quebec City, QC;,
Mayo Clinic, Rochester, MN, U.S.A.;,
§Dalhousie University, Halifax, NS;,
Instituto Nacional de Câncer, Rio de Janeiro, Brazil;,
#H. Lee Moffitt Cancer Center, Tampa, FL, U.S.A..


Proffered Papers

S3-PP1: Modulation of Base Excision Repair Influences DNA Damage Repair for BRCA2 Mutant Cancer: Implications for Chemotherapeutics


Stephen Godin, Haohui Duan, Stacy Mulei, Shailja Pathania


ABSTRACT

BRCA2 mutation carriers have a dramatically elevated risk of developing breast and ovarian cancer during their lifetime. Women who develop BRCA2-mutant ovarian cancer initially respond very favourably to cisplatin or carboplatin, the first-line treatment for ovarian cancer. However, despite the high initial response rate, 70% of women with BRCA2-mutant ovarian cancer will develop resistance to platinum agents within 5 years.

Through a screen to identify genes and/or pathways that can modulate sensitivity of BRCA2-mutant cancer to cisplatin, we identified abasic site endonuclease (ape1), a central base excision repair (ber) protein, as regulating platinum resistance in BRCA2-deficient cells. We find that loss of ape1 confers a 2- to 5-fold increase in cisplatin resistance to BRCA2-deficient cells. Moreover, loss of ape1 rescues multiple cisplatin-induced dna damage hallmarks in BRCA2-deficient cell. These include increase in nuclear aberrations and accumulation of replication-associated dna double-strand breaks. We find that ape1 influences the choice of repair pathway upon cisplatin treatment, and that cells depleted of ape1 are biased away from BRCA2-dependent repair towards alternative repair pathways that that do not necessarily require BRCA2 for repair. In line with these results, we find that patients with BRCA2-mutant ovarian cancer that expresses low levels of ape1 have a significantly worse prognosis than patients whose tumours express high levels of ape1, suggesting that ape1 regulates BRCA2-mutant cancer survival.

We expand on these findings to find that inhibition of certain other members of the ber pathway produce phenotypes similar to those with loss of ape1, suggesting that our findings are applicable to other proteins active in the ber pathway. Finally, we demonstrate that while loss of ape1 promotes resistance to cisplatin in vitro, cells deficient in both ape1 and BRCA2 remain sensitive to multiple other dna damaging agents, suggesting alternative treatment strategies for BRCA2 mutation carriers with defective ber.

AUTHOR AFFILIATIONS

University of Massachusetts Boston, Boston, MA, U.S.A..


Proffered Papers

S3-PP2: Impact of DNA Repair Defects on the Outcomes of Metastatic Resistant Prostate Cancer


Elena Castro*, Nuria Romero-Laorden*, Rebeca Lozano*, Ana Medina, Javier Puente, Josep M. Piulats§, Lorena Magraner*, Ángela del Pozo, Ylenia Cendón*, Paz Nombela*, Pablo Lapunzina, David Olmos*


ABSTRACT

Background

Germline dna repair defects have been identified in up to 12% of patients with metastatic resistant prostate cancer (mcrpc) and retrospective studies have associated some of these variants with poor prostate cancer outcomes and progression to metastatic disease. However, no conclusive data are available regarding survival from mcrpc and response to currently approved therapies.

Methods

rorepair-b (NCT03075735) is a prospective observational cohort study. Patients diagnosed with mcrpc of unknown mutational status who were about to start a first-line treatment for mcrpc were eligible. Patients were screened for germline mutations in 107 dna damage and repair genes (ddr) and treated at physician’s choice with either abiraterone, enzalutamide, docetaxel, cabazitaxel, or Ra-223. Primary endpoints were to describe the prevalence of ddr germline mutations in our mcrpc population and to assess their impact in cause-specific survival (css) from diagnosis of mcrpc. Secondary endpoints included the impact of other ddr genes in css and the association between ddr defects and the response to therapies for mcrpc.

Results

The study included 419 mcrpc patients. BRCA2 (3.3%), ATM (1.9%) and BRCA1 (0.9%) were the genes more commonly mutated. Pathogenic variants in any of the 107 genes analyzed were identified in 15% of patients. Carriers and noncarriers presented similar characteristics at baseline, but carriers progressed earlier to mcrpc (18.6 vs. 28.2 months), particularly BRCA2 carriers (13.2, p = 0.039). The mcrpc css was shorter in carriers (23.3 vs. 33.2 months, p = 0.260), but the difference was significant only for BRCA2 (median 17.4 months, p = 0.025). Carriers responded (prostate-specific antigen and radiographically) to abiraterone/enzalutamide and taxane-based chemotherapy, but the duration of the responses was significantly shorter in carriers, particularly in BRCA2 carriers.

Conclusions

Not all ddr defects have the same impact on mcrpc outcomes. BRCA2 mutation carriers tend to shorter responses to currently approved therapies, which may contribute to the shorter survival observed.

AUTHOR AFFILIATIONS

*Spanish National Cancer Research Centre, Madrid,,
Centro Oncológico de Galicia, A Coruña,,
Hospital Clínico Universitario San Carlos, Madrid,,
§Institut Catalá d`Oncologia, Badalona, and,
Instituto de Genetica Medica y Molecular, Madrid, Spain..


Proffered Papers

S5-PP1: Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses from a BRCA1 and BRCA2 Mutation Carrier Cohort Study


Lieske H. Schrijver*, Håkan Olsson, Kelly-Anne Phillips,§, Mary Beth Terry, David E. Goldgar#, Karin Kast**, Christoph Engel††, Nadine Andrieu‡‡, Douglas F. Easton§§, Flora E. van Leeuwen*, John L. Hopper§, Roger L. Milne§, Antonis C. Antoniou§§, Matti A. Rookus*


ABSTRACT

Background

For BRCA1 and BRCA2 mutation carriers, the association between use of oral contraceptive preparation (ocp) and breast cancer (bca) risk is still unclear.

Methods

bca risk associations were estimated from ocp data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed.

Results

For BRCA1 mutation carriers, ocp use was not associated with bca risk from prospective analyses [hazard ratio (hr): 1.08; 95% confidence interval (ci): 0.75 to 1.56], but from the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% ci: 6% to 51%) and 39% (95% ci: 23% to −58%) respectively. For BRCA2 mutation carriers, ocp use was associated with bca risk from prospective analyses (hr: 1.75; 95% ci: 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated hr: 1.06; 95% ci: 0.85 to 1.33; full-cohort hr: 1.52; 95% ci: 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before first full-term pregnancy; for BRCA1 mutation carriers from both retrospective analyses (p < 0.001 and p = 0.001 respectively); and for BRCA2 mutation carriers from full-retrospective analysis (p = 0.002).

Conclusions

Prospective analyses did not show that past use of ocp causes an increased bca risk for BRCA1 mutation carriers in young middle-aged women (40–50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be attributable to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Use of ocp for indications other than contraception should therefore be avoided by BRCA1/2 mutation carriers.

AUTHOR AFFILIATIONS

*Netherlands Cancer Institute, Amsterdam, Netherlands;,
Lund University Hospital, Lund, Sweden;,
Peter MacCallum Cancer Centre and,
§The University of Melbourne, Melbourne, VIC, Australia;,
Columbia University, New York, NY, and,
#University of Utah School of Medicine, Salt Lake City, UT, U.S.A.;,
**Technische Universität, Dresden, and,
††University of Leipzig, Leipzig, Germany;,
‡‡National Institute for Health and Medical Research inserm U900, Paris, France;,
§§University of Cambridge, Cambridge, U.K..


Proffered Papers

S5-PP2: Population Genetic Testing for Breast and Ovarian Cancer Susceptibility—the Australian Experience


Alison H. Trainer*,,, Simone M. Rowley, Lyon Mascarenhas*,, Lisa Devereux, Kaushalya C. Amarasinghe, Magnus Zethoven, Jue Er Amanda Lee, Alexandra Lewis*,, Mary-Anne Young§, Lara Petelin*, Paul A. James*,,, Ian G. Campbell,


ABSTRACT

To date, population-based testing of hereditary breast and ovarian (hboc) genes has been restricted to specific BRCA founder mutations in high-risk populations, such as the Ashkenazi Jewish population, in whom the prevalence of such mutations ranges between 1.1% and 4.5%. In this context, a population-based testing approach saved more life-years and quality-adjusted life-years, and had potential to lower the incidence of breast and ovarian cancer compared with a family history-based testing approach.

Since 2014, population-based genetic testing of 11 hboc genes has been offered to 5910 cancer-free unselected women recruited into the LifePool cohort study through their attendance at a government-funded population breast surveillance program. The aim of this study is to determine the prevalence of pathogenic mutations in an unselected cancer-free Western population and to assess the rate of uptake of genetic counselling, risk-reduction surgery and cascade testing after notification of a potential clinically relevant finding. This study will also provide primary data for a health economic model of hboc genetic screening, specific to the Australian population.

To date, 38 of 5910 women (0.64%) carried a clinically actionable mutation [BRCA1, n = 6; BRCA2, n = 15; PALB2, n = 14; ATM (c.7271T>G), n = 3]. The 38 women ranged in age from 24 to 77 years, with an average age of 57 years. Of the mutation carriers, 42% did not have a 1st-degree relative with breast or ovarian cancer, and 91% accepted referral to a familial cancer clinic. Uptake of cascade testing and risk-reduction surgery was similar to that in families identified through standard clinical practice.

Within our cohort of healthy women attending population mammographic surveillance, hboc genetic testing was well accepted. It identified families with mutations who would not otherwise have presented to a familial cancer clinic. The findings indicate that the clinical utility of identifying a mutation in this setting is in keeping with the utility reported with the current model of clinical practice.

AUTHOR AFFILIATIONS

*Parkville Familial Cancer Center, Parkville, VIC,,
University of Melbourne, Melbourne, VIC,,
Peter MacCallum Cancer Centre, Parkville, VIC, and,
§Garvan Institute of Medical Research, Darlinghurst, NSW, Australia..


Proffered Papers

S5-PP3: The Screen Project: Population-Based Genetic Testing for BRCA1/2 : Genes in Canada


Mohammad R. Akbari*,, Nicole Gojska*, Steven Narod*,


ABSTRACT

The current model for delivering genetic testing for BRCA genes in North America was developed in the mid-1990s, at a time when genetic testing was expensive and the clinical benefits were largely unproven. In this model, women are referred by their physicians to a specialized cancer genetics clinic where a formal assessment is conducted. If women are qualified for genetic testing based on some restricted criteria, then the test for the BRCA genes ensues.

We believe the current model is outdated, and we propose an alternative model based on guided direct-to-consumer population-based testing. This approach uses genetic testing as a screening tool to identify high-risk patients, followed by genetic counselling in preventive options for those identified as high-risk. With these goals in mind, we launched the Screen Project in March 2017 for evaluating population-based genetic testing for BRCA mutations in Canada. We now offer testing to all Canadian women and men who are 18 years of age or older. We use a guided direct-to-consumer approach for enrolling individuals through the study Web site (http://www.thescreenproject.ca). We are testing for BRCA1 and BRCA2 only. All individuals with a pathogenic mutation in either gene will be contacted by our team of genetic counsellors in person or by telephone to discuss their options for cancer prevention. Our team will also facilitate referral to a local genetics clinic for long-term follow-up.

Among the first 330 individuals tested across the country, we have identified 8 carriers of pathogenic BRCA mutations. Of those 8 individuals, 4 did not meet the criteria for a provincially covered test. The other 4 carriers met the criteria, but they did not have access to a cancer genetics clinic or had not been referred by their physicians for genetic testing. We will have 1000 reported tests by May 2018.

AUTHOR AFFILIATIONS

*Women’s College Hospital and,
University of Toronto, Toronto, ON..


Proffered Papers

S6-PP2: Clinical Characteristics and Outcomes in Elderly Women with BRCA1 and BRCA2 Mutations


Christine Kobelka*, Chelsea Salyer*, Allison Barrie, Ramey D. Littell, C. Bethan Powell


ABSTRACT

This is a retrospective study of elderly women in a community-based health system with BRCA mutations identified from 1995 to 2015. There were a total of 69 women with BRCA mutations who lived to age 75 or greater. The median age of the cohort at time of genetic testing was 73.5 years (range: 57–92 years). Most women were white (81%), and 14% were Ashkenazi Jewish.

At the time of genetic testing, 47 (68%) had a personal history of breast cancer, and 27 (39%) had a personal history of ovarian cancer. Twenty-three (33%) were tested because a BRCA mutation had been identified in another family member. Of 19 women with no prior history of breast cancer, 3 (15.8%) elected risk-reducing mastectomies (rrms) after learning their BRCA-positive status (at ages 58, 66, and 68). Of the 3 women who elected a rrm, 2 had a prior personal history of ovarian cancer. Among 30 women who had ovaries in place at the time of genetic testing, 14 (47%) elected to have a risk-reducing salpingo-oophorectomy (rrso); 6 of these women were age 70 or older at time of rrso. After genetic testing, 3 women developed cancer: 1 woman developed breast cancer at age 67, and 2 women developed pancreatic cancer at age 76. Six women (8.7%) had no personal diagnosis of a BRCA-related cancer.

In conclusion, most women with BRCA mutations who survived beyond age 75 received their genetic test result at an older age, and most had a personal history of BRCA-related cancer. Almost half the women with ovaries in place underwent rrso after identification of their BRCA mutation. Older women are making medical decisions based on information from the BRCA genetic testing, and it is important that the health care needs of this cohort be acknowledged.

AUTHOR AFFILIATIONS

*Kaiser Permanente San Francisco, San Francisco,,
University of California, San Diego, and,
Kaiser Permanente Northern California Gynecologic Cancer Group, San Francisco, CA, U.S.A..


Proffered Papers

S6-PP3: Outcomes Associated with Rapid Genetic Testing for BRCA1 and BRCA2 at Time of Breast Cancer Diagnosis


Kelly Metcalfe*,, Aletta Poll*, Mohammad Akbari*, Jordan Lerner-Ellis, Andrea Eisen§


ABSTRACT

Objective

Most women are unaware of their BRCA status at the time of cancer diagnosis. However, there are survival advantages associated with both bilateral mastectomy and bilateral salpingo-oophorectomy (bso) in women with a BRCA mutation. Rapid genetic testing (rgt) allows for genetic test results before cancer surgery, but whether rgt has an impact on surgical decision-making or psychosocial functioning is unclear. The objective of the present study was to assess the impact of rgt at the time of breast cancer (bca) diagnosis on surgery choices and psychosocial functioning.

Methods

Eligible women were referred from surgeons at time of bca diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer-related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling. Genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year after genetic testing. Medical charts were reviewed to abstract data about pathology and treatments.

Results

894 women consented to participate, and 53 (6.0%) were identified with a BRCA mutation. 17.0% were not eligible for genetic testing based on provincial criteria. Mean levels of cancer-related distress, anxiety, and depression declined significantly from baseline to 1 year for all women (all p < 0.05), and no differences between those with and without a BRCA mutation were observed. 77.0% of BRCA carriers had a bilateral mastectomy, compared with 20.4% of noncarriers (p < 0.001), and 42.9% of BRCA carriers had a bso by 1 year. 80.4% of the participants were satisfied or very satisfied with rgt.

Conclusions

With the provision of rgt for BRCA1 and BRCA2 at the time of bca diagnosis, women identified with a BRCA mutation are significantly more likely than noncarriers to have a bilateral mastectomy and bso. Satisfaction with rgt is high, and there are no negative psychosocial consequences associated with rgt.

AUTHOR AFFILIATIONS

*Women’s College Research Institute,,
University of Toronto,,
Mount Sinai Hospital, and,
§Sunnybrook Odette Cancer Centre, Toronto, ON..


Proffered Papers

S7-PP1: Gen Y and Hereditary Breast/Ovarian Cancer: Understanding the Experiences and Information Gaps of Young Adults


Alison Luk Young*, Phyllis N. Butow*, Katherine M. Tuker, Rachel Williams, Claire E. Wakefield


ABSTRACT

A striking feature of hereditary breast cancer is the younger age of onset, occurring frequently in the 30s and 40s and even in the 20s. Despite growing up in an era prevalent with breast cancer awareness, the hereditary cancer information and resource needs of the young adult population (18–40 year old) with a known BRCA1/2 gene change in the family is largely unknown. The current findings are drawn from two large data sets: young adults and their families with a known BRCA1/2 gene change (21 families), and health professionals (for example, geneticists, genetic counsellors) working with the families recruited from familial clinics from five states of Australia (n = 75).

The unique information preferences of young adults (18–25 years old) were also explored. Discrepancies between the views of health professionals and those of young adults reveal possible reasons for unmet needs. Familial communication patterns, parental anxiety, and attitudes toward the health care system are poignant areas that have to be targeted to meet the information needs of young adults. Recommendations for health service delivery of information and novel interventions will also be presented.

AUTHOR AFFILIATIONS

*The University of Sydney and,
University of New South Wales, Sydney, NSW, Australia..


Proffered Papers

S7-PP2: Modified Panel-Based Genetic Counselling for Ovarian Cancer Susceptibility: A Randomized Noninferiority Trial


Jeanna McCuaig*, Alicia Tone*, Tina Romagnuolo*, Nicole Ricker*, Jennifer Shuldiner, Gary Rodin*, Manjula Maganti*, Marcus Bernardini*


ABSTRACT

Objective

An estimated 20%–30% of ovarian cancers are hereditary; however, despite available recommendations, fewer than 25% of these women are referred for genetic testing. Widespread use of poly-adp ribose polymerase inhibitors (parpis) has led to increased demands and urgency for genetic testing, which is not sustainable using traditional genetic counselling (gc) models. The objective of this study is to evaluate a new model to improve the efficiency of pre-test gc.

Methods

A parallel, two-arm, randomized noninferiority/equivalency study compared modified and traditional pre-test gc models (2:1) before gene panel testing. Participants were adult women, whose 1st-degree relative died of serous ovarian cancer. Participants were excluded if they, or their affected relative, had received comprehensive BRCA1/2 testing. In the modified group, participants were e-mailed a 20-minute presentation before a scheduled pre-test gc phone call. All results were disclosed during a scheduled phone appointment with the study genetic counsellor. Psychosocial and knowledge questionnaires were provided before (P1) and 1 week after (P2) pre-test gc.

Results

To date, 365 women have completed pre-test gc (243 modified, 122 traditional). Women randomized to modified compared with traditional pre-test gc had no differences in marital status, education level, or household income. Pre-test gc time was shorter for the modified compared with the traditional method (average 19 vs. 46 minutes, p < 0.0001), with no difference in post-test gc time (average 16 minutes each, p = 0.6). Based on 357 and 324 responses for P1 and P2 respectively, we observed no statistically significant differences in the following variables for modified compared with traditional gc: cancer-specific distress, depression, anxiety, decisional conflict, ovarian cancer knowledge, or satisfaction.

Conclusions

The use of a 20-minute presentation before pre-test phone counselling was found to be noninferior to traditional in-person gc in a low-risk population of women. This modified model improved gc efficiency without negatively affecting psychosocial outcomes.

AUTHOR AFFILIATIONS

*Princess Margaret Cancer Centre and,
University of Toronto, Toronto, ON..


Proffered Papers

S7-PP3: BRCA1/BRCA2 Population Screening in Ashkenazi Jews: Long-Term Impact and Health Behaviours


Sari Lieberman*,, Ariela Tomer*, Avraham Ben-Chetrit, Oded Olsha§, Rachel Beeri*, Aviad Raz, Amnon Lahad,#, Ephrat Levy-Lahad*,


ABSTRACT

Background

In Ashkenazi Jews, population screening for common (2.5%) BRCA1/BRCA2 mutations could identify all carriers, including many (about half) lacking suggestive family history. Toward implementation, we examined the psychosocial and health behaviour long-term impacts of BRCA screening.

Methods

Unaffected Ashkenazi Jews, age ≥ 25 years were either self-referred (sr) or recruiter-enrolled (re) irrespective of family history (fh). The pre-test process was streamlined, including written information and self-reported fh. After testing, noncarriers with significant fh and carriers received in-person genetic counselling. Psychosocial outcomes and health behaviours were assessed using questionnaires at 1 week, 6 months, and 2 years after testing

Results

We report the 2-year follow-up of 1771 participants, including 32 carriers (25 women, 7 men). Psychosocial outcomes: sr and re participants had similar rates of satisfaction (94%) and endorsement of population screening (91%), and similarly low stress [Impact of Event (ies) score: 4/75]. Knowledge scores were higher in sr that in re participants (7.4/10 vs. 6.9/10, p < 0.001). Among carriers, 92% expressed satisfaction, and 92% endorsed population screening. Stress was higher in carriers, but declined over time (ies score: 13.19 at 2 years vs. 19.9 at 6 months; nonsignificant). Knowledge was greater in carriers than in noncarriers (8.7/10 vs. 7.2/10, p < 0.001).

Health Behavior

All 25 women carriers had breast surveillance, 3 of 25 (12%) underwent risk-reducing bilateral mastectomy (similar to published rates in Israeli carriers). Of 16 carriers more than 40 years of age, 15 (94%) underwent risk-reducing salpingo-oophorectomy (rrso). Among noncarriers, mammography screening rates did not decline compared with pre-test rates; rates even increased in participants more than 50 years of age with nonsuggestive fh (p = 0.001) and in participants less than 50 years with significant fh (p = 0.009).

Conclusions

Long-term, BRCA screening with a nongenetic counselling pre-test process is highly acceptable, through both self-referral and recruitment. Noncarriers do not demonstrate false reassurance, and carriers universally adopted increased surveillance, with almost all undergoing age-appropriate rrso.

Funded by the Breast Cancer Research Foundation.

AUTHOR AFFILIATIONS

*Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem,,
Hebrew University of Jerusalem, Jerusalem,,
Women’s Health Center, Clalit Health Services, Jerusalem,,
§Shaare Zedek Medical Center, Jerusalem,,
Ben-Gurion University, and,
#Clalit Health Services, Jerusalem, Israel..


Proffered Papers

S9-PP1: Breast Cancer Prevalence and Clinical Characteristics in Carriers of ATM Missense Versus Loss-of-Function Variants


Katherine Skora, Jessica Mester, Hubert Kuete, Kevin Arvai, Sheila Solomon, Lauren Yackowski, Patricia Murphy, Rachel Klein, Kathleen Hruska


ABSTRACT

Background

Studies suggest that rare ATM missense variants within important functional domains increase the risk of breast cancer (bca), possibly above that conferred by loss-of-function (lof) variants. However, there is limited evidence supporting this assertion, except in the case of ATM Val2424Gly. Here, we compare the prevalence of bca and other clinical factors among carriers of ATM missense and lof variants.

Methods

We retrospectively reviewed personal and family cancer histories for female heterozygous ATM variant carriers identified through multigene inherited cancer panel testing. Women had testing for at least ATM, BRCA1/2, CHEK2, and PALB2, and carried a lof or single rare missense variant. Individuals were excluded if they were < 18 years or carried a pathogenic or likely pathogenic variant in another bca-associated gene. Variants were categorized as lof, missense in the fat, fatc, or kinase domains (mid), or missense outside these domains (mod). Benign/likely benign variants were excluded. Chi-square, unpaired t-tests, and anova were used in the analysis.

Results

We identified 4098 women, including 484 lof, 1335 mid, and 2259 mod carriers, 59% of whom (2405/4098) had a personal history of bca. There was a significant difference in the prevalence of bca among lof, mid, and mod carriers (68% vs. 59% vs. 56% respectively, p < 0.01). Carriers of lof or mid variants were each more likely than mod carriers to report a family history of bca (p < 0.01), but less likely to have triple-negative bca (p < 0.01). No difference in bilateral compared with unilateral bca prevalence (p = 0.69) or age at diagnosis (p = 0.09) was identified between groups. Excluding ATM Val2424Gly (mid) did not change these results.

Conclusions

ATMmid variants, compared with mod, but not lof variants, were associated with higher prevalences of personal history and family history of bca. Studies including evolutionary conservation and segregation data might elucidate differences in bca risk between lof and rare missense variants, within and outside crucial domains.

AUTHOR AFFILIATIONS

GeneDx, Gaithersburg, MD, U.S.A..


Proffered Papers

S9-PP2: Multigene Panel Testing in BRCA1/2 Mutation-Negative Male Breast Cancer Patients: Results from a Multicenter Study in Italy


Piera Rizzolo*, Veronica Zelli*, Valentina Silvestri*, Virginia Valentini*, Antonio Russo, Liliana Varesco, Giuseppe Giannini*, Daniele Calistri§, Laura Cortesi, Alessandra Viel#, Marco Montagna**, Paolo Peterlongo††, Paolo Radice‡‡, Domenico Palli§§, Laura Ottini*


ABSTRACT

Background

Male breast cancer (mbc) is rare, representing less than 1% of all breast cancers (bca). Inherited mutations in BRCA1/2 predispose to mbc and account for about 10% of all cases. To gain more insight into genetic susceptibility in mbc, we performed an extensive genomic screening of a large series of BRCA1/2 mutation-negative mbcs.

Methods

A well-characterized series of 502 Italian men with BRCA1/2 mutation–negative mbc was analyzed by a custom multigene panel of 50 cancer-related genes, using the MiniSeq platform (Illumina, San Diego, CA, U.S.A.). We also compared the main clinicopathologic characteristics of mbcs in mutation carriers and noncarriers.

Results

About 5% of BRCA1/2 mutation–negative MBCs were found to carry a pathogenic variant in the genes analyzed. PALB2 and ATM were the most frequently altered genes (1.1% and 0.6%, respectively). Mutations in known or proposed bca genes, such as BARD1, BLM, CASP8, CHEK2, FANCM, NF1, RAD50, RAD51C, and RAD51D, as well as in genes not closely related to bca predisposition, such as EPCAM and MUTYH, were also identified. Compared with noncarriers, mutation carriers were more likely to have a personal history of cancer (p = 0.0045) and a family history of cancer other than breast/ovarian cancer (p = 0.0004).

Conclusions

Our results support a central role of PALB2 in mbc susceptibility, point to a relevant role of ATM and confirm a low impact of CHEK2 in the Italian population. Our data also suggest that the multigene testing approach might benefit appropriately selected patients, especially those with personal or family history of cancer other than breast/ovarian cancer, and indicate that the selection of appropriate genes for the genomic screening of mbc cases might be essential to develop a comprehensive cancer susceptibility panel with implications for clinical management and counselling of patients and their families.

Study supported by airc (IG 16933) to LO.

AUTHOR AFFILIATIONS

*Sapienza University, Rome,,
University of Palermo, Palermo,,
irccs aou San Martino–ist, Genoa,,
§irst, Meldola (fc),,
University of Modena and Reggio Emilia, Modena,,
#cro Aviano, National Cancer Institute, Aviano (pn),,
**Veneto Institute of Oncology iovirccs, Padua,,
††ifom, firc Institute of Molecular Oncology, Milan,,
‡‡irccs–Istituto Nazionale Tumori (int), Milan, and,
§§Cancer Research and Prevention Institute, Florence, Italy..


Proffered Papers

S9-PP3: Utilization of Pathogenic Mutations Beyond BRCA1/2 in Breast Cancer Patients Up to 36 Months Post-Testing


Whitney Espinel*, Lindsay Kipnis, Scott T. Michalski, Shan Yang, Heather Hampel§, Joanne Jeter§, Kevin Sweet§, Robert Pilarski§, Rachel Pearlman§, Judith Westman§, Anu Chittenden, Jill Stopfer, Stephen Lincoln, Robert Nussbaum, Edward Esplin


ABSTRACT

Background

Management recommendations for pathogenic/likely pathogenic (p/lp) variants in genes beyond BRCA1/2 have only recently been included in clinical guidelines. Clinician recommendations for findings in these genes are not well studied. We report interim results from a multisite study of clinical actions taken in patients with p/lp variants in cancer risk genes beyond BRCA1/2.

Methods

We retrospectively examined 2184 patients referred for hereditary cancer multigene testing. Clinicians of patients with p/lp findings in a non-BRCA1/2 cancer risk gene were asked to complete a case report form describing genetic-test-result-based clinical actions. Some patients were lost to follow-up and answers of “unknown” were permitted. For this analysis, de-identified case report forms were available for 80 patients.

Results

In 85% of cases, clinicians reported that counselling and/or clinical management recommendations were changed for the patient and/or patient’s family members in response to the genetic test findings, with 61% of patients (49/80) receiving result-based recommendations. Pathogenic variants were identified most often in ATM, CHEK2, and PALB2 and changes in management were recommended for 55%, 63%, and 69% of patients respectively. Overall, 80% of patients (8/10) with variants causing known high-risk cancer syndromes (APC, CDH1, Lynch syndrome, and PTEN) received changes to clinical management, and 63% with variants in moderate-risk breast cancer genes (27/43) received changes to clinical management. Family member testing or screening was changed for 66% of cases.

Conclusions

This study provides evidence that p/lp variants in cancer genes beyond BRCA1/2 changed clinical management for most patients. Moderate cancer-risk genes, which might not be ordered or covered by insurance, are having a significant impact on patient care. More research is needed to understand the obstacles to clinician implementation of genetic testing based management recommendations.

AUTHOR AFFILIATIONS

*Huntsman Cancer Institute, Salt Lake City, UT,,
Dana Farber Cancer Institute, Boston, MA,,
Invitae, San Francisco, CA, and,
§Ohio State University, Columbus, OH, U.S.A..


Proffered Papers

S10-PP1: Polygenic Risk from Common Genomic Variants Modifies the Effect of Many Moderate-Risk Breast Cancer Predisposition Genes and Can Improve Clinical Interpretation


Paul A. James*,,, Li Na*,, Simone McInerny*, Simone Rowley*, David Goode*, Rodney Scott§, Lisa Devereux*, Norah Grewal*, VIP Study Investigators, LifePool Study*, Ian Campbell*,


ABSTRACT

Many “new” breast cancer risk genes fall into the moderate-risk category (typically an increased risk between 1.5- and 4-fold). Translation of these findings has been limited by inconsistent replication, the moderate level of risk, and frequent non-segregation in high-risk families. We used data from a large familial breast cancer case–control study to examine the influence of common genomic variants [single nucleotide polymorphisms (snps)] on these genes to determine whether combined effects could better identify women at actionable levels of breast cancer risk.

Methods

4139 women affected by breast cancer (BRCA1/BRCA2 excluded) and 4244 healthy controls were screened for variants in 160 genes with known or potential association with breast cancer, and a polygenic risk score (prs) made up of 74 snps reported in genome-wide association studies. Loss of function and pathogenic missense variants in established risk genes (for example, CHEK2, ATM) or reported candidates, such as MRE11A, RAD51C, BRIP1, and so on, were analysed together with the individual’s prs.

Results

Rare coding variants and the prs showed the expected association with breast cancer; the mean odds ratio (or) for loss-of-function variants in “panel” genes was 3.3 [95% confidence interval (ci): 2.7 to 3.9]. For a large number of genes, the measured risk from rare variants was significantly modified by the prs, with no risk observed associated with a low prs background and clinically significant risk for the same variants associated with high prs. For example, for 15 common panel genes: low prs (quartile) or: 0.8 (0.5 to 1.3); high prs or: 4.0 (2.7 to 5.9). The same strong modification was found for some candidate genes—for example, RAD51B: mean or: 1.0; high prs or: 4.7 (1.9 to 11.9).

Conclusions

There is evidence of significant snp-modifying effects for many suggested moderate-risk breast cancer genes, potentially contributing to the conflicting reports of risk for these genes. Combined interpretation of rare variants with prs data can significantly improve the accurate identification of high-risk individuals.

AUTHOR AFFILIATIONS

*Peter MacCallum Cancer Centre, Melbourne, VIC,,
Royal Melbourne Hospital, Melbourne, VIC,,
University of Melbourne, Melbourne, VIC, and,
§Hunter Area Pathology Service, NSW, Australia..


Proffered Papers

S10-PP2: Functional Analysis of the RAD51C Tumour Suppressor


Hermela Shimelis, Kun Lee, Fergus Couch


ABSTRACT

Inherited mutations in RAD51C are associated with a high risk [odds ratio (or): >5.0] for ovarian cancer and might also confer moderate risks (or: >2) for certain subtypes of breast cancer. Many germline nonsense, frameshift, and splice consensus site mutations have been identified in RAD51C through clinical multigene cancer panel testing. In addition, large numbers of missense variants in RAD51C have been reported in public databases such as ClinVar. However, the contribution of these variants of uncertain significance (vus) to ovarian or breast cancer has not been established.

Rad51c is directly involved in homologous recombination-based repair of dna double-strand breaks, and loss of this activity is thought to account for the tumorigenic potential of inherited mutations. Rad51c is recruited to Rad51 foci in response to dna damage and forms protein independent complexes with Rad51B, Rad51D, xrcc2, and xrcc3, which mediate strand exchange reactions during the homologous recombination repair process. In addition, Rad51c inactivation is associated with sensitivity to cisplatin and parp inhibitors.

We present results from functional characterization of the dna damage repair activity of Rad51c. In addition, we report on the application of functional assays for Rad51c activity to systematic characterization of RAD51Cvus. Using 70 vus described in ClinVar from all domains of Rad51c, we conducted Rad51 foci formation, homologous recombination repair, cisplatin response, and protein–protein interaction studies in Rad51c null cells reconstituted with full-length Rad51c-expressing lentivirus. We identified vus in all domains of the protein that disrupt homologous recombination and also established that homologous recombination defects were fully consistent with cisplatin response. Based on these results, we propose that functional assays for Rad51c are an effective method for establishing the pathogenicity of RAD51Cvus and for predicting response of breast and ovarian tumours with these variants to cisplatin therapy.

AUTHOR AFFILIATIONS

Mayo Clinic, Rochester, MN, U.S.A..


Proffered Papers

S10-PP3: A Microsimulation Model for Optimizing BRCA Mutation Carrier Cancer Risk Management: MiBRovaCAre


Lara Petelin*,, Lucinda Hossack*, Gillian Mitchell*, Danny Liew,, Alison Trainer*,, Paul James*,


ABSTRACT

BRCA mutation carriers are currently offered screening and risk-reducing surgery to mitigate cancer risk. The optimal clinical management for these patients is uncertain because of the lack of randomized trials and the expense and duration of longitudinal observational studies. An alternative approach is required for rapid initial assessment of changes in practice to improve clinical management and optimize the use of health care resources. To this end, we developed mibrovacare: a validated BRCA-specific microsimulation model built in Python.

This model incorporates real-world values and uncertainty for cancer incidence and pathology, mortality, risk management uptake and effectiveness, and resource use. The core module predicts the natural course of BRCA-related disease in the absence of screening or preventive surgery. This natural history module was externally validated and accurately predicted published outcomes for BRCA breast and ovarian cancer risk estimates and mortality rates (by stage and pathology).

Additional inputs were incorporated for risk management behaviour and clinical pathways, which were obtained from the experiences of 983 BRCA carriers managed through a familial cancer clinic (fcc) in Melbourne, Australia.

Applying the mibrovacare model to 100,000 women from age 25 demonstrated that standard fcc care led to an average of 4.68 and 3.49 life-years gained (lyg) per person for BRCA1 and BRCA2 respectively. The addition of a dedicated risk management clinic to standard care increased the clinical benefit estimates to 4.91 and 3.58 lyg, reflecting increased adherence to scheduled breast screens. The model further shows that this benefit could be increased to 5.13 for BRCA1 and 3.74 for BRCA2 by encouraging an additional 10% of women to undergo bilateral prophylactic mastectomy before age 45.

mibrovacare accurately models existing outcomes and can identify areas that would most benefit from interventions that optimize clinical management programs, maximizing the benefit to patients in a cost-effective manner.

AUTHOR AFFILIATIONS

*Peter MacCallum Cancer Centre,,
University of Melbourne, and,
Monash University, Melbourne, VIC, Australia..


Posters

Poster P001: p53 Is Required for Cisplatin-Induced Drp1 Dephosphorylation and Apoptosis in Ovarian Cancer


Mohammad Reza Abedini*,, Benamin K. Tsang,


ABSTRACT

Mitochondria are highly dynamic organelles, and mitochondrial fission is a crucial step of apoptosis. Although Drp1 is believed to be involve in mitochondrial fragmentation, whether and how its regulation is involved in the regulation of cisplatin (cddp) sensitivity is not known.

Chemosensitive ovarian cancer (ovca) cells were treated with cddp. Apoptosis, protein contents, and phosphorylation were assessed by nuclear Hoechst staining and Western blot respectively. The requirements of p53 for cddp-induced Drp1 processing and apoptosis were examined by sirna or cdna. Protein interaction was also detected by proximity ligand assay and Western co-immunoprecipitation.

We showed that

  • cddp decreased Drp1 content and induced apoptosis in a concentration-dependent manner in chemosensitive ovca;

  • ■ chemoresponsiveness is associated with Drp1 downregulation, decreased p-Drp1 (ser637), and increased ser616/637 ratio in response to cddp in ovca cells;

  • ■ p53 is required for cddp-induced Drp1 downregulation, ser637 dephosphorylation, and apoptosis;

  • ■ intact cellular gelsolin interacts with Drp1 and transport to mitochondria in response to cddp;

  • ■ chemoresponsiveness is associated with increased p-p53 (ser15)–Drp1 and decreased gelsolin–Drp1 interactions in response to cddp.

These findings demonstrate that cddp induces Drp1 dephosphorylation (ser637), mitochondrial fragmentation, and cddp-induced apoptosis in ovca cells, and that mitochondrial dynamics might in part be involved in cddp sensitivity in a p53-dependent manner.

AUTHOR AFFILIATIONS

*Birjand University of Medical Sciences, Birjand, Iran;,
The Ottawa Hospital Research Institute and,
University of Ottawa, Ottawa, ON..


Posters

Poster P002: Epigenetic Therapies to Target Ovarian Cancer


Tatiana Shorstova, Jake Johnston, Jie Su, Maud Marques, William D. Foulkes, Michael Witcher


ABSTRACT

Small-cell carcinoma of the ovary, hypercalcemic type (scco-ht) is a malignant tumour with a dismal prognosis observed in young women. scco-ht is hereditary and invariably characterized by inactivating mutations in the SMARCA4 gene. SMARCA4 plays an important role in gene transcription by shifting or evicting repressive nucleosomes, generally leading to transcriptional activation. SMARCA4 and the bromodomain protein brd4 independently co-regulate a transcriptional network of proliferation-related genes in a redundant manner. Thus, we propose that tumours with a loss of SMARCA4 will depend solely on brd4 for the expression of this gene network. We hypothesize that inactivating brd4 with bet inhibitors (beti) is a rational therapeutic approach to target SMARCA4-mutant cancers because that approach should critically repress brd4-dependent oncogene expression.

Using complementary in vitro techniques, we demonstrated that SMARCA4-deficient scco-ht cells are exquisitely sensitive to beti. We further established, for the first time, an orthotopic ovarian xenograft model of scco-ht. These tumours showed a very significant response to beti at doses of only 20 mg/kg daily. No response in SMARCA4-expressing tumours was observed at that dose. To identify target genes driving the sensitivity to beti, we carried out rna-seq on beti-exposed sensitive and resistant cells. Interestingly, beti induced changes in scco-ht cells in mrna levels for many genes from the oncogenic receptor tyrosine kinase pathway. Western blotting validated that beti repressed expression of her3 and downstream effectors. Mechanistically, our chromatin immunoprecipitation experiment revealed that beti directly represses the transcriptional elongation of the ERBB3 (HER3) gene. Importantly, we found that ectopic expression of SMARCA4 or HER3 lead to resistance to beti.

Our data demonstrates a potent antitumorigenic effect of beti in vitro and in vivo against SMARCA4-negative scco-ht having poor outcome. We suggest that the loss of SMARCA4 might act as a biomarker for therapeutic intervention with beti.

AUTHOR AFFILIATIONS

McGill University, Lady Davis Institute, Montreal, QC..


Posters

Poster P003: Circulating Osteoprotegerin and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers


Tasnim Zaman*,, Leonardo Salmena,, Shana J. Kim*, Ping Sun*, Jan Lubinski§, Steven A. Narod*,, Joanne Kotsopoulos*,


ABSTRACT

Background

Experimental and epidemiologic evidence points toward aberrant signalling in the receptor activator of nuclear factor κB (rank)/rank ligand (rankl) pathway in the pathogenesis of BRCA-associated breast cancer. Osteoprotegerin (opg) is the endogenous decoy receptor for rankl that antagonizes rank/rankl-mediated signalling. Lower circulating opg levels among BRCA mutation carriers compared with noncarriers has previously been reported. Furthermore, we observed an inverse relationship between plasma opg and BRCA breast cancer risk. This study aims to validate those findings in a larger group of BRCA mutation carriers with a longer follow-up period.

Methods

This prospective study included 606 BRCA mutation carriers with no previous history of cancer or prophylactic mastectomy who were under active follow-up. Serum opg concentrations (pg/mL) were quantified through enzyme-linked immunosorbent assay (elisa). Kaplan–Meier survival analysis was used to estimate the cumulative incidence of breast cancer by median opg level.

Results

Over a mean follow-up of 2.7 years (range: 0.003–7.5 years), 20 incident breast cancer cases were diagnosed. The mean serum opg level was 124.4 pg/mL (range: 32.1–368.6 pg/mL). We stratified women by median opg level [<116.7 pg/mL (n = 303) vs. ≥116.7 pg/mL (n = 303)]. There were 14 incident cases among women with opg levels below the median and 6 incident cases among women with opg levels above or equal to the median. The cumulative incidence of breast cancer for women with an opg level <116.71 pg/mL was 31% compared with 3% for women with an opg level ≥116.71 pg/mL (log rank p = 0.11). Quantification of opg and rankl from additional women and collection of follow-up information are underway.

Conclusions

These interim findings support the role of aberrant rank-signalling in BRCA breast cancer development and suggest that rankl-blockade is a likely candidate for non-surgical prevention. Pending completion of the study, circulating opg level might improve the identification of women who are ideal candidates for rankl-chemoprevention.

AUTHOR AFFILIATIONS

*Women’s College Hospital,,
University of Toronto, and,
Princess Margaret Cancer Centre, University Health Network, Toronto, ON;,
§International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland..


Posters

Poster P004: Heritable Methylation Marks Associated with Breast and Prostate Cancer Risk


Melissa C. Southey*,,, Jihoon E. Joo*,, James G. Dowty*, David E. Goldgar§, Ee Ming Wong*,, Pierre-Antoine Dugué*,, kConFab*, ABCFR*, Dallas English*,, John L. Hopper*, Roger L. Milne*,, Graham G. Giles*,


ABSTRACT

Although most epigenetic marks are reprogrammed during early embryogenesis, some studies have reported Mendelian-like inheritance of germline dna methylation—in particular, in cancer susceptibility genes. For instance, individuals with MLH1 silenced throughout the soma fit the clinical criteria for hereditary nonpolyposis colorectal cancer indistinguishably from the syndrome that results from germline mutations in MLH1. Research using multiple-case breast cancer families has shown that LINE-1 and SAT2dna methylation levels are lower in individuals with a strong family history. Family clustering of cancer could therefore be attributable to epigenetic as well as genetic and shared environmental factors.

We have identified heritable methylation marks associated with breast and/or prostate cancer susceptibility by conducting genome-wide studies involving Australian multigenerational families with multiple cases of breast and/or prostate cancer who are not known to carry genetic mutations in cancer susceptibility genes. We developed and applied a new statistical method to identify heritable methylation marks based on complex segregation analysis and identified methylation marks significantly associated with breast and/or prostate cancer risk. Several marks across VTRNA2-1, a gene located in a differentially methylated region that is involved in imprinting and shows allele-specific methylation, were associated with heritable risk of both cancer types. A proportion of all identified marks were found to be associated with cancer risk in independent nested case–control studies (that is, outside the multiple-case family setting). We found evidence that some of these are likely to be methylation quantitative trait loci, and some are likely to be involved in tumorigenesis.

We are expanding these successful studies to include additional families and to estimate hazard ratios and age-specific cumulative risks of cancer associated with these marks to enable the incorporation of this information into clinical tools for risk prediction.

AUTHOR AFFILIATIONS

*Monash University, Clayton,,
The University of Melbourne, Melbourne, and,
Cancer Council Victoria, Melbourne, VIC, Australia;,
§Huntsman Cancer Institute, Salt Lake City, UT, U.S.A..


Posters

Poster P005: Whole-Exome Sequencing of Brazilian Families at High Risk for Hereditary Breast/Ovarian Cancer, Negative for Mutations in BRCA1/BRCA2 Genes


Paula Silva Felicio*, Rebeca Silveira Grasel*, Bruna Durães de Figueiredo Barros, Natalia Campacci*, Henrique de Campos Reis Galvão*, Cristiano de Pádua Souza*, Rozany Mucha Dufloth*, Adriane Feijó Evangelista*, Dirce Maria Carraro, Edenir Inêz Palmero*


ABSTRACT

Background

BRCA1 and BRCA2 testing is uninformative in approximately 80% of families with clinical features of inherited susceptibility to breast and ovarian cancers. Early identification of high-risk individuals could lead to improvements in screening and prevention strategies and could potentially improve overall cancer survival.

Aim

To identify the missing heredity associated with cancer development in high-risk families, BRCA1/2 wild-type (BRCAx families) through whole-exome sequencing (wes) of constitutive dna.

Methods

We performed wes (Nextera Rapid Capture Exome and Expanded Exome Kit: Illumina, San Diego, CA, U.S.A.) in 45 BRCA1/2 wild-type individuals with high risk for breast/ovarian cancer. The criteria for data analysis were coverage ≥10x; variants present in less than 15% (≤7 samples); and missense, in-frame, and stop-loss variants classified as pathogenic by at least 3 of 6 in silico prediction programs selected.

Results

For each sample, an average of 122 genetic changes per sample (ranging from 5 to 196 variants) were identified. In addition, most of the identified variants were of the missense type, followed by the nonsense variants. Of the 20 most commonly altered genes, many have already been associated with hereditary predisposition syndromes to cancer, such as the ATM, MLH1, MSH6, MUTYH genes. Besides, pathogenic or probably pathogenic alterations in dna repair genes such as ATXN3, ERCC3, ERCC4, EXO1, and FAN1 were identified.

Conclusions

Our data show that significant genetic heterogeneity exists in BRCAx families. Large-scale collaborative efforts will be required to attain sufficient power to understand the missing heredity associated with breast/ovarian cancer development in high-risk families.

AUTHOR AFFILIATIONS

*Barretos Cancer Hospital, Barretos, and,
cipe–A.C. Camargo Cancer Center, São Paulo, Brazil..


Posters

Poster P006: Discovery of Novel Genetic Variants Predisposing to Ovarian Cancer in a Large, Affected Population of Familial and Sporadic Cases with No Known Hereditary Cause


Deepak Subramanian*, Magnus Zeethoven*, Simone Rowley*, Simone McInerny*, Amanda Lee*, Na Li*, Ed Dicks, Jonathan Tyrer, Honglin Sin, Simon Gayther, Susan Ramus§,, Paul Pharoah, Paul James*, Ian Campbell*


ABSTRACT

Many women referred for genetic testing with epithelial ovarian cancer and a family history of ovarian and/or breast cancer do not have an identifiable deleterious mutation in any of the known hereditary breast and ovarian cancer (hboc) genes. Progress toward the identification of novel genetic causes has been slow, partly because of the limited number of cases available for discovery studies considering the likely high genetic heterogeneity of these families. We have generated and collected germline whole-exome sequencing (wes) data for a cohort of more than 1400 patients diagnosed with epithelial ovarian cancer (including high-grade and low-grade serous, endometrioid, mucinous, and clear-cell types) who tested negative for known deleterious mutations in BRCA1/2 and other hboc genes. Approximately 900 of those cases are women with a family history of ovarian and/or breast cancer or with young-onset ovarian cancer. We have access to tumour blocks from our patient population to perform loss-of-heterozygosity analysis and have potential access to other affected and unaffected family members for segregation studies. The wes data were interrogated for rare deleterious germline genetic variants (population allele frequency < 0.005) that were more than 3-fold enriched compared with the frequency in the GnomAD database. Preliminary analysis of a subset of the familial cases found that < 5% are explained by mutations in currently known or suspected hboc genes (for example, RAD51C/D) and, at best, no single novel gene could explain more than 2% of cases.

These data demonstrate that the remaining families are likely to be extremely genetically heterogeneous, and emphasizes the need for large discovery and validation cohorts. Our poster will describe details of our methodology for identifying and validating novel genetic variants from this population, as well as early results and future work for further validation of the most promising candidate genes.

AUTHOR AFFILIATIONS

*Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;,
University of Cambridge, Cambridge, U.K.;,
Cedars–Sinai Medical Center, Los Angeles, CA, U.S.A.;,
§School of Women’s and Children’s Health, unsw, and,
Garvan Institute of Medical Research, Sydney, NSW, Australia..


Posters

Poster P007: Mapping Homologous Recombination Genes Using Multi-clade Phylogenetic Profiling of 600 Species


Dana Sherill-Rofe*, Dolev Rahat*, Supriya Behl, Anna Malul*, Alexandre Orthwein, Aviad Zick, Yuval Tabach*


ABSTRACT

Mutations in homologous recombination repair (hrr) genes trigger numerous genetic disorders. In hereditary breast and ovarian cancer (hboc), these mutations are the drivers underlying approximately 30% of cases. The genetic cause of the remaining 70% is unknown, but molecular evidence suggests the involvement of uncharacterized hrr genes.

To systematically map novel hrr genes, we introduce a computational algorithm that screens 578 eukaryote genomes on different evolutionary scales. To further prove the validity of our method, functionally characterize our predicted genes, and generate a complete cohort of genes that are functionally related to the hrr, we integrate 24 different genetic screens and databases into a database (hrrbase) that maps the interaction of every gene with the hrr pathway and yields 435 genes predicted to be highly involved in hrr. These genes mght play a significant role in hrr-related genetic disorders and hboc, potentially yielding new targets for therapeutics.

AUTHOR AFFILIATIONS

*The Institute for Medical Research–Israel–Canada, Hebrew University of Jerusalem, Jerusalem, Israel;,
McGill University, Montreal, QC;,
Sharett Institute of Oncology, Hadassah Medical Center, Ein-Kerem, Jerusalem, Israel..


Posters

Poster P008: ATM Whole-Gene Deletion in an Italian Family with Familial Pancreatic Cancer


Lorrie Lynch*, Daria Grafodatskaya,, Heleen Arts,, Kathleen Bell*,, Kevin Zbuk*,, Elizabeth McCready,


ABSTRACT

Background

Biallelic mutations in ATM are a known cause of ataxia–telangiectasia, while heterozygous pathogenic mutations in the ATM gene are known to increase risks for development of various cancers, including breast and pancreatic cancer. ATM whole-gene deletions have not been reported in families with either ataxia–telangiectasia or familial cancer. We report a whole-gene deletion of ATM in an Italian family with a history of pancreatic cancer.

Methods

Next-generation sequencing of a 16-gene cancer panel identified a heterozygous deletion of ATM in an individual with pancreatic cancer. The presence and size of the deletion were validated and assessed by quantitative polymerase chain reaction and CytoScan HD microarray (Thermo Fisher Scientific, Waltham, MA, U.S.A.) respectively. Family studies were performed to identify at-risk individuals.

Results

A heterozygous whole-gene deletion of ATM was identified in a 56-year-old male with adenocarcinoma of the pancreas who presented with a strong family history of pancreatic cancer. Microarray analysis suggests that the deletion spans 960 Kb and ablates ATM, putative tumour suppressor genes CUL5 and NPAT, and various other genes. The proband’s mother was diagnosed with breast cancer at the age of 75, and brother was diagnosed with non-Hodgkin lymphoma at the age of 35. Pancreatic cancer was diagnosed in a maternal aunt, maternal uncle, and maternal first cousin. Genetic testing indicates that patient’s brother and daughter are carriers of the whole-gene ATM deletion; the genotypes of other family members remain unknown.

Conclusions

This report is the first of an inherited microdeletion that fully ablates ATM. Given that ATM haploinsufficiency is a proven cause of increased cancer risk, it is reasonable to deem this copy number loss to be a cause of hereditary susceptibility to cancer in this family. The lack of breast cancer in the family makes it particularly challenging in assessing the breast cancer risk in female ATM deletion carriers.

AUTHOR AFFILIATIONS

*Juravinski Cancer Centre,,
McMaster University, and,
Hamilton Regional Laboratory Medicine Program, Hamilton, ON..


Posters

Poster P009: Genetic and Molecular Analyses of a Rare FANCI Missense Variant Found in a BRCA1 and BRCA2 Mutation–Negative Ovarian Cancer Family


Caitlin Fierheller*, Laure Guitton, The Montreal Hereditary Ovarian Cancer Study Group, Celia Greenwood*, Jiannis Ragoussis*, Jean-Yves Masson, Patricia Tonin*


ABSTRACT

Heterozygous carriers of pathogenic germline mutations in the Fanconi anemia (fa) complementation group genes, such as BRCA2 (FANCD1), BRIP1 (FANCJ), and PALB2 (FANCN), have been associated with increased risk of breast and/or ovarian cancer. Recently, rare heterozygous carriers of potentially pathogenic mutations in other fa genes have been reported in BRCA1/BRCA2 mutation–negative breast/ovarian cancer families, suggesting that other members of this pathway might also play a role in cancer risk.

We identified heterozygous carriers of a potentially damaging missense variant in FANCI (FANCI p.L605F), a fa pathway gene, using whole-exome sequencing (wes) of a BRCA1/BRCA2 mutation–negative French Canadian (fc) ovarian cancer (oc) family. FANCI p.L605F allele frequency is unknown in fcs, but varies from 0% to 1.8% in ethnically defined populations (Exome Aggregation Consortium). Thorough wes analysis of 10 other BRCA1/BRCA2 mutation–negative fc oc families found no other FANCI p.L605F carriers, mutation screening found heterozygous carriers in 7 of 439 (1.6%) largely fc oc cases not selected for family history of cancer. Most carriers (6 of 7) had high-grade serous oc and did not carry any of the BRCA1/BRCA2 mutations found to recur in fcs. Targeted mutation screening of FANCI p.L605F in cancer cohorts identified heterozygous carriers in another multi-case BRCA1/BRCA2 mutation–negative fc oc family.

Molecular analysis of FANCI p.L605F protein revealed that it is destabilized in vitro upon treatment with endogenous or exogenous dna-damaging agents. Immunofluorescence shows that, compared with the wild-type protein, FANCI p.L605F protein, although expressed, severely impedes localization of FANCD2 (known heterodimeric binding partner of FANCI) to sites of dna damage.

FANCI is an essential member of the fa dna repair pathway that functions upstream of the homologous recombination dna repair pathway that involves BRCA1/BRCA2 function. Taken together, our data suggest the involvement of FANCI p.L605F in risk or progression to oc.

AUTHOR AFFILIATIONS

*McGill University, Montreal, and,
Laval University, Quebec City, QC..


Posters

Poster P010: Development and Validation of a Combined Residual Risk Score to Predict Breast Cancer Risk in Unaffected Women Negative for Mutations on a Multigene Hereditary Cancer Panel


Elisha Hughes, Thaddeus Judkins, Susanne Wagner, Eric Rosenthal, Johnathan Lancaster, Jerry Lanchbury, Alexander Gutin


ABSTRACT

Background

Large-scale genotyping studies have identified common variants that individually confer modest breast cancer (bca) risk, but together partially explain bca genetic susceptibility in many women without monogenic mutations in bca risk genes. Here, we describe the development and validation of a combined polygenic residual risk score (crrs) that takes into account both genetic and nongenetic factors in a large consecutive cohort of women who tested negative for mutations in known bca susceptibility genes.

Methods

This irb-approved study included women of European ancestry who had multigene hereditary cancer testing and were negative for mutations in 11 bca risk genes (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Previously published variants (n = 94) were genotyped using next-generation sequencing. Multivariable logistic regression models were then used to develop a residual risk score (rrs) as a predictor of personal bca history in the training cohort (n = 24,259) and to assess the performance of the rrs in the independent validation cohort (n = 10,575). Independent variables included age, personal/family cancer history, and ancestry. The rrs was combined with the Tyrer–Cuzick model to generate a crrs and was validated in an additional independent cohort (n = 1617).

Results

The rrs was strongly associated with personal history of bca in the validation cohort (p < 10−31) with the odds ratio (or) per unit standard deviation of the rrs being 1.41 (95% ci: 1.33 to 1.49). The remaining lifetime and 5-year risk estimates were highly significant for the crrs (or: 2.10; 95% ci: 1.85 to 2.38; p = 4.1×10−35), adding significant risk discrimination independent of that captured by Tyrer–Cuzick for both remaining lifetime risk (p = 8.3×10−13) and 5-year risk (p = 1.0×10−12).

Conclusions

The validation and clinical implementation of a crrs for women at risk for hereditary bca might offer significant potential for the management of high-risk unaffected women who test negative for monogenic bca mutations.

AUTHOR AFFILIATIONS

Myriad Genetics Inc., Salt Lake City, UT, U.S.A..


Posters

Poster P011: Familial Breast Cancer and DNA Repair Genes: Insights into Known and Novel Susceptibility Genes from the GENESIS Study


Fabienne Lesueur*, Elodie Girard*, Séverine Eon-Marchais*, Robert Olaso, Anne-Laure Renault*, Francesca Damiola, Marie-Gabrielle Dondon*, Laure Barjhoux, Didier Goidin§, Vincent Meyer, Dorothée Le Gal*, Juana Beauvallet*, Noura Mebirouk*, Christine Lonjou*, Juliette Coignard*, Morgane Marcou*, Eve Cavaciuti*, Odile Cohen-Haguenauer*, Dominique Leroux, Clotilde Penet#, Sandra Fert-Ferrer**, Chrystelle Colas*, Thierry Frebourg††, François Eisinger‡‡, Annie Chevrier††, Claude Adenis§§, Anne Fajac*, Laurence Gladieff‖‖, Julie Tinat††, Anne Floquet##, Jean Chiesa***, Sophie Giraud†††, Isabelle Mortemousque‡‡‡, Florent Soubrier*, Séverine Audebert-Bellanger§§§, Jean-Marc Limacher‖‖‖, Christine Lasset, Sophie Lejeune-Dumoulin§§, Hélène Dreyfus,###, Yves-Jean Bignon****, Michel Longy##, Pascal Pujol††††, Laurence Venat-Bouvet‡‡‡‡, Valérie Bonadona, Pascaline Berthet§§§§, Elisabeth Luporsi‖‖‖‖, Christine M. Maugard####, Catherine Noguès‡‡, Capucine Delnatte*****, Jean-Pierre Fricker####, Paul Gesta†††††, Laurence Faivre‡‡‡‡‡, Alain Lortholary§§§§§, Bruno Buecher*, Olivier Caron‖‖‖‖‖, Marion Gauthier-Villars*, Isabelle Coupier††††, Nicolas Servant*, Anne Boland, Sylvie Mazoyer, Jean-François Deleuze, Dominique Stoppa-Lyonnet*, Nadine Andrieu*


ABSTRACT

Pathogenic variants in BRCA1 and BRCA2 explain about 10% of hereditary breast and ovarian cancer families. Because of cost-effectiveness, multigene panel testing is now often performed in such families, but whether the identification of an alteration in some of the genes screened in parallel with BRCA1 and BRCA2 is useful for clinical management of the patient and her/his relatives remains questionable. We assessed the contribution of rare, damaging predicted variants in dna repair genes in a case–control study involving a representative set of French familial breast cancer (bca) cases and controls from the general population (the genesis study).

A total of 113 dna repair genes were screened, 77 of which were candidates selected from exome sequencing data, in 1207 cases with no BRCA1/2 mutation and a sister affected with bca, and in 1199 controls. Sequencing data were filtered for rare loss-of-function (lof) variants and likely deleterious missense variants (mvs).

lof variants in ATM, CHEK2, and PALB2 were associated with an increased bca risk (orATM: 17.1; 95% ci: 2.3 to 129; orCHEK2: 5.9; 95% ci: 2.0 to 17; orPALB2: 3.8; 95% ci: 1.0 to 14). Likely deleterious mvs in the 3 genes were also associated with bca risk (orATM: 1.6; 95% ci: 1.0 to 2.4; orCHEK2: 2.5; 95% ci: 1.4 to 4.1; orPALB2: 3.5; 95% ci: 1.4 to 8.6). In addition, likely deleterious mvs in MAST1 were associated with an increased bca risk (or: 2.5; 95% ci: 1.0 to 6.0), while such variants in POLH, RTEL1, and FANCI were associated with a decreased bca risk (orPOLH: 0.3; 95% ci: 0.1 to 0.9; orRETL1: 0.4; 95% ci: 0.2 to 0.9; orFANCI: 0.4; 95% ci: 0.2 to 1.0).

Hence, our approach identified more dna repair genes (MAST1, POLH, RTEL1, and FANCI) involved in familial bca and showed that, depending on the gene, lof and mv might contribute differently to the susceptibility to the disease.

AUTHOR AFFILIATIONS

*France, Paris – inserm, Institut Curie, Mines ParisTech, psl University (Andrieu, Beauvallet, Cavaciuti, Coignard, Dondon, Eon-Marchais, Girard, Le Gal, Lesueur, Lonjou, Marcou, Mebirouk, Renault, Servant); Hôpital Saint-Louis (Cohen-Haguenauer); Groupe Hospitalier Pitié-Salpêtrière, aphp (Colas); Institut Curie (Buecher, Colas, Gauthier-Villars); Hôpital Tenon (Fajac, Soubrier); Institut Curie, inserm, Université Paris Descartes (Stoppa-Lyonnet);,
Evry – Institut de biologie François Jacob, cea;,
Lyon – Centre Léon Bérard (Barjhoux, Bonadona, Damiola, Lasset); Université Claude Bernard Lyon 1, Villeurbanne, and cnrs (Bonadona, Lasset); inserm, cnrs, Centre de Recherche en Neurosciences de Lyon (Mazoyer);,
§Les Ulis – Agilent Technologies France;,
Grenoble – chu de Grenoble;,
#Reims – Institut Jean-Godinot and icc Courlancy;,
**Chambéry – Centre Hospitalier de Chambéry;,
††Rouen, Hôpital Universitaire de Rouen;,
‡‡Marseille – Institut Paoli-Calmettes and Aix Marseille University;,
§§Lille – Centre Oscar-Lambret (Adenis); Hôpital Jeanne de Flandre (Lejeune-Dumoulin);,
‖‖Toulouse – Institut Claudius Regaud, iuct-Oncopole;,
##Bordeaux – Institut Bergonié;,
***Nîmes – chru Hôpital Caremeau;,
†††Bron – hcl, Groupement Hospitalier Est;,
‡‡‡Tours – Hôpital Bretonneau;,
§§§Brest – chu Brest, Hôpital Morvan;,
‖‖‖Colmar – Hôpital Pasteur;,
###Avignon – Clinique Sainte Catherine;,
****Clermont-Ferrand – Centre Jean-Perrin;,
††††Montpellier – Hôpital Arnaud de Villeneuve, chu Montpellier, and inserm, crcm Val d’Aurelle;,
‡‡‡‡Limoges – Hôpital Universitaire Dupuytren;,
§§§§Caen – Centre François Baclesse;,
‖‖‖‖Vandoeuvre-lès-Nancy – icl Alexis Vautrin;,
####Strasbourg – Hôpitaux Universitaires de Strasbourg (Maugard); Centre Paul Strauss (Coupier, Fricker);,
*****Nantes Saint Herblain – Centre René Gauducheau;,
†††††Niort – Service d’Oncogénétique Régional Poitou-Charentes;,
‡‡‡‡‡Dijon – Institut gimi, chu de Dijon, Centre Georges François Leclerc;,
§§§§§Nantes – Centre Catherine de Sienne;,
‖‖‖‖‖Villejuif –Gustave Roussy..


Posters

Poster P012: Cellular Gelsolin Modulates Cisplatin-Induced p53-Mediated Drp1 Dephosphorylation and Apoptosis in Ovarian Cancer


Mohammad Reza Abedini*,, Benamin K. Tsang,


ABSTRACT

Mitochondria are highly dynamic organelles, and mitochondrial fission is a crucial step of apoptosis. Although Drp1 is believed to be involved in mitochondrial fragmentation, whether and how its dysregulation is involved in the modulation of cisplatin (cddp) resistance and the involvement of intact cellular gelsolin (i-cgsn) is unknown.

Chemosensitive and chemoresistant ovarian cancer (ovca) cells were treated with cddp. Apoptosis, protein content, and phosphorylation were assessed by nuclear Hoechst staining and Western blot respectively. The requirements of p53 for cddp-induced Drp1 processing and apoptosis were examined by sirna or cdna.

Protein interaction was also detected by proximity ligand assay and Western co-immunoprecipitation.

  • cddp-induced Drp1 and p-Drp1 (ser637) downregulation, ser616/637 ratio enhancement is not observed in chemoresistant ovca cells.

  • cddp increased p-p53 (ser15)-Drp1 and decreased gsn-Drp1 interaction in chemosensitive, but not resistant, cells—a response that depends on p53.

  • i-cgsn inhibits cddp-induced Drp1 and p-Drp1 (ser637) downregulation and apoptosis in ovca cells

These findings demonstrate that p53 mediates Drp-1 dephosphorylation (ser637) and mitochondrial fragmentation and is involved in cddp-induced apoptosis in ovca cells, and that dysregulated mitochondrial dynamics by i-cgsn could in part be involved in the pathophysiology of cddp resistance.

AUTHOR AFFILIATIONS

*Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran;,
Ottawa Hospital Research Institute and,
University of Ottawa, Ottawa, ON..


Posters

Poster P013: Pathogenic Variant Detection in a 19-Gene Core Panel and Yield of Opportunistic Screening in BRCA1/2 and Mismatch Repair Genes in a Cohort of 1121 Hereditary Cancer Patients


Joan Brunet*,,,§, Judith Balmaña§,,#, Lídia Feliubadaló*,,§, Natalia Teixeira, Agostina Stradella*,,§, Jesús del Valle*,,§, Marta Pineda*,,§, Orland Díez§,,#, Gabriel Capella*,,§, Sara Gutiérrez§,,#, Conxi Lázaro*,,§


ABSTRACT

Background

Multigene panels provide a powerful tool for analyzing several genes simultaneously and identifying cancer susceptibility beyond the suspected clinical phenotype. We evaluated the pathogenic variant (pv) frequency in customized predefined panels according to phenotype, and we extended the analysis to our 19-gene research panel. We also investigated the yield of opportunistic screening in the BRCA1/2 and mismatch repair (mmr) genes in all patients.

Methods

Overall, from Sep 2014 to Jul 2017, 1121 unrelated probands underwent multigene testing with customized predefined panels according to their phenotype and a 19-gene research panel, in addition to the BRCA1/2 and mmr genes.

Results

Overall, 1015 women and 106 men were studied, mean age at cancer diagnosis was 47 years (14), 579 had breast cancer (bca), 258 ovarian cancer (oc), 124 colorectal cancer, and 27 were unaffected. A bca, oc, or bca/oc panel was requested in 66% and a hereditary nonpolyposis colorectal cancer (hnpcc) panel, in 12%. The customized diagnostic panel found 151 (13%) probands who carried at least 1 pv. All BRCA1/2 carriers fulfilled bca, oc, or bca/oc criteria. Among the mmr carriers, 50 pvs (89%) were identified with the hnpcc panel, and 6 (11%) were opportunistic, all in MSH6. The 19-gene research panel provided 22 additional pvs (2%) beyond the customized panel according to clinical phenotype: 5 BARD1, 4 NBN, 3 BRIP1, 3 ATM, 2 CHEK2, 2 RAD51C, 2 RAD51D, and 1 CDH1. Of these pvs, 13 were in actionable genes (BRIP1, ATM, CHEK2, RAD51C, RAD51D, CDH1).

Conclusions

The yield of pv detection in various actionable genes identified by multiplex testing is clinically relevant. Of mmr mutation carriers (all carrying MSH6pvs), 11% were identified through opportunistic screening. Identification of pvs in BARD1 and NBN genes by the research panel deserve further investigation.

AUTHOR AFFILIATIONS

*Catalan Institute of Oncology, Barcelona;,
Girona Biomedical Research Institute (idibgi), Catalonia;,
Bellvitge Biomedical Research Institute (idibell), Barcelona;,
§Catalan Cancer Network, Barcelona;,
Vall d’Hebron Institute of Oncology, Barcelona; and,
#Vall d’Hebron University Hospital, Barcelona, Spain..


Posters

Poster P014: Comprehensive Analysis of Fanconi Anemia Genes in Hereditary Cancer


Jesús del Valle*,,, Agostina Stradella*,,, Lídia Feliubadaló*,,, Marta Pineda*,,, Paula Rofes*,,, Sara González*,,, Eva Tornero*,,, Mireia Menéndez*,,, Xavier Muñoz*,,, Mónica Salinas*,,, Judith Balmaña,,#, Gabriel Capellá*,,, Joan Brunet*,,,§, Conxi Lázaro*,,


ABSTRACT

Introduction

Fanconi anemia (fa) is caused by biallelic mutations in the fa pathway genes. Heterozygous mutations in 4 of those genes (BRCA2, PALB2, BRIP1, and RAD51C) increase the susceptibility to breast and/or ovarian cancer and as such are used in clinical diagnostics. There is increasing evidence suggesting that other fa genes could predispose in heterozygosity to develop other tumours, especially breast cancer. To gain insights into this field, we performed an extensive analysis of 12 fa-associated genes (FAN1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, and SLX4) in addition to BRCA2, PALB2, BRIP1, and RAD51C in a cohort of hereditary cancer patients.

Methods

The mutation analysis was performed using a next-generation sequencing custom panel (Castellanos et al., 2017). In total, 1021 patients were analyzed: 632 (61.9%) with clinical suspicion of hereditary breast and/or ovarian cancer, 210 (20.6%) with clinical suspicion of hereditary nonpolyposis colorectal cancer, and 179 (17.5%) with other clinical suspicions of hereditary cancer.

Results

We identified 45 pathogenic mutations in the well-established breast/ovarian cancer genes: 29 BRCA2, 6 PALB2, 5 BRIP1, and 5 RAD51C. Moreover, 40 pathogenic mutations were found in the 12 remaining genes: 11 FANCL, 8 FANCA, 7 FANCM, 7 FAN1, 2 FANCI, 2 FANCE, 2 FANCC, and 1 FANCF. In this second group, 80% of mutation-positive patients have criteria of hereditary breast/ovarian cancer suspicion. In addition, 533 variants of unknown significance were detected in the studied genes, 20 of them predicted, by several in silico tools, to affect normal splicing. Analysis of copy number alterations and co-segregation analysis of the pathogenic variants is currently under way.

Conclusions

These results support the role of fa-associated genes in cancer susceptibility, being mainly associated with predisposition to breast or ovarian cancer.

AUTHOR AFFILIATIONS

*Catalan Institute of Oncology, Barcelona;,
Bellvitge Biomedical Research Institute (idibell), Barcelona;,
Catalan Cancer Network, Barcelona;,
§Girona Biomedical Research Institute (idibgi), Catalonia;,
Vall d’Hebron Institute of Oncology, Barcelona; and,
#Vall d’Hebron University Hospital, Barcelona, Spain..


Posters

Poster P015: Association of Non-BRCA Homologous Recombination Genes with Breast and Ovarian Cancers


Lauren Yackowski, Kevin J. Arvai, Rebecca I. Torene, Erin Sutcliffe, Lisa R. Susswein, Megan L. Marshall, Maegan E. Roberts, Patricia Murphy, Rachel T. Klein, Kathleen S. Hruska


ABSTRACT

Introduction

The association with breast and ovarian cancer is well established for BRCA1 and BRCA2, but evidence for other genes involved in homologous recombination (hr) continues to evolve. We sought to determine the association of pathogenic and likely pathogenic variants (pvs) in 9 hr-related genes in a cohort of women with breast and ovarian cancers undergoing multigene hereditary cancer panel testing.

Methods

We performed a retrospective case–control study to assess breast and ovarian cancer association with ATM, BARD1, BRIP1, CHEK2, FANCC, NBN, PALB2, RAD51C, and RAD51D. Cases were women with breast (n > 31,000) and/or ovarian (n > 4500) cancer referred for testing of up to 62 genes. Controls included 8749 reportedly cancer-free mothers of individuals referred for whole-exome sequencing. We reviewed genetic testing results and reported history of cancer for both groups. Adjusted odds ratios (ors) were generated by multivariate logistic regression analysis, controlling for age, with a Bonferroni-corrected significance threshold of 0.005 to determine significance.

Results

In this large, independent case–control cohort, a statistically significant breast cancer association was observed for ATM (or: 2.44), BARD1 (or: 8.00), CHEK2 (or: 3.01), and PALB2 (or: 6.69) and with ovarian cancer for RAD51C (or: 10.21) and RAD51D (or: 16.85). Although the associations of ovarian cancer with PALB2 and breast cancer with RAD51D are not significant using the defined p value threshold, the 95% confidence intervals suggest that the most probable effect sizes lie above 1.0. No significant breast or ovarian cancer associations were observed for BRIP1, FANCC, and NBN.

Conclusions

Using a large control population of phenotypically well-described women, we observed significant breast or ovarian cancer associations for ATM, BARD1, CHEK2, PALB2, RAD51C, and RAD51D. This novel approach addresses limitations of previous case–control studies performed with general population database cohorts while substantiating the results of previous reports in the literature.

AUTHOR AFFILIATIONS

GeneDx, Gaithersburg, MD, U.S.A..


Posters

Poster P016: Characterization of the Clinical Phenotype of Homozygous/Compound Heterozygous CHEK2 Mutation Carriers


Brittany DeGreef*, Theresa Sciaraffa*, Carmen Williams*, Lee Shulman*, Erin O’Leary, Terri Lefler*


ABSTRACT

Pathogenic heterozygous mutations in the CHEK2 gene are associated with an approximate 2-fold increased risk of female breast cancer, estimated to be 20% −25% lifetime risk. Given that data about the magnitude of the cancer risk attributable to CHEK2 mutations are limited, testing negative for a familial CHEK2 mutation does not eliminate familial risk factors, and a discussion of potentially increased screening might be appropriate based on the family history of cancer. Additionally, limited data are available about breast cancer risk in the setting of homozygous CHEK2 mutations.

Our case series identified 23 CHEK2 patients carrying two CHEK2 mutations, including 6 CHEK2*1100delC homozygotes and 17 CHEK2 compound heterozygotes, including truncating mutations and many low-penetrant pathogenic mutations. A subset of CHEK2 compound heterozygotes showed a profound younger age of onset and appeared to have a greater than 2-fold increased risk of breast cancer. Given that further data are needed to extrapolate the lifetime risk of female breast cancer for CHEK2 homozygotes or CHEK2 compound heterozygotes, our results suggest that increased earlier breast screening might be indicated for females who are identified to have two CHEK2 mutations.

AUTHOR AFFILIATIONS

*Northwestern Medicine, Chicago, IL, and,
Invitae Laboratories, San Francisco, CA, U.S.A..


Posters

Poster P017: Comparing Cancer Prevalence in Individuals with Biallelic Versus Single CHEK2 Pathogenic Variants


Erin Sutcliffe, Stacey Miller, Lauren Yackowski, Kevin Arvai, Kathleen Hruska, Rachel Klein


ABSTRACT

Background

CHEK2 pathogenic variants increase the risk for breast and other cancers. Published reports suggest that female CHEK2 c.1100delC homozygotes could have a breast cancer risk more than twice that of heterozygous females, and biallelic CHEK2 carriers have been reported to present with other cancer types; however, data are limited. We aimed to describe cancer prevalence among patients with biallelic CHEK2 pathogenic or likely pathogenic variants (pvs) and to compare it with that among CHEK2 heterozygotes.

Methods

We retrospectively reviewed results and self-reported histories of individuals with CHEK2pvs undergoing hereditary cancer testing, excluding those with pvs in other genes. The Fisher exact test was used to assess differences in cancer prevalence between biallelic and heterozygote carriers. A two-tailed t-test showed no significant difference in age at testing between the two groups.

Results

The evaluation considered 25 individuals (22 women, 3 men) with two, presumably biallelic, CHEK2pvs and 2087 CHEK2 heterozygotes (1919 women, 168 men). Female breast cancer (14/22 vs. 1039/1919, p = 0.4), male breast cancer (2/3 vs. 12/168, p = 0.018), colorectal cancer (4/25 vs. 64/2087, p = 0.007), and stomach cancer (2/25 vs. 5/2087, p = 0.003) were more prevalent in our biallelic cohort; however, the results were underpowered (0.05–0.06) to detect a significant effect. Although underpowered, no difference was observed for breast cancer prevalence in women with two truncating pvs (5/7) versus those with two missense pvs (6/8, p = 1.0).

Conclusions

Although we did not observe significantly increased odds (p = 0.4) for female breast cancer in women with biallelic versus single CHEK2pvs, colorectal cancer, male breast cancer, and stomach cancer occurred significantly more often in biallelic carriers. Those findings cannot be attributed to age differences between the two groups. However, our sample sizes might not have been large enough to detect significance. Further studies with larger cohorts are needed to assess cancer risks for individuals harbouring biallelic CHEK2pvs.

AUTHOR AFFILIATIONS

GeneDx, Gaithersburg, MD, U.S.A..


Posters

Poster P018: A Likely Pathogenic Founder Mutation in RAD51C Causing Ovarian Cancer in Newfoundland


Lesa Dawson*, Darren O’Rielly*, Tammy Benteau*, Werdyani Salem*, Andree MacMillan, Sheila Drover*, Terry Lynn Young*

Eastern Health Authority, St. John’s, NL.

ABSTRACT

Background

RAD51C is involved in the homologous recombination and repair of dna. If dysfunctional, the result is defective homologous recombination and increased ovarian cancer risk. Variants of uncertain significance (vus) remain a significant challenge in the study of high risk breast/ovarian families. High-risk large pedigrees from a founder population, such as that in Newfoundland and Labrador (NL), can assist with effective characterization of those variants. Multigene panels performed on 5 women from 4 families identified the RAD51C c.571+4A>G (rs587780257) variant reported as a vus.

Objective

To determine if the RAD51C c.571+4A>G variant represents a pathogenic founder variant in NL.

Methods

The 4 families, plus a series of unselected ovarian cancer cases and unaffected NL controls, were evaluated to determine if the vus segregated with cancer diagnosis and to evaluate the variant frequency in affected and unaffected populations. The evaluation used a combination of mined existing whole-exome sequencing data and targeted Taqman analysis. Additional analyses were performed to determine if the variant affects splicing and structure.

Results

RAD51C c.571+4A>G was detected in 5 women with breast or ovarian cancer in 4 large families from NL. The variant causes aberrant splicing and skipping of exon 3 and/or 4 and a frameshift and/or early-stop codon predicted to result in a truncated Rad51c protein (Phyre and JSmol). Of 7 additional relatives with available dna, 2 of 3 unaffected males carried the variant. There were no unaffected carrier females (0/4). In 30 unselected NL ovarian cancer cases, no additional women with RAD51C+4A>G were identified. In a series of NL controls, the allele frequency in NL (0/358) was similar to that reported in the Single Nucleotide Polymorphism Database (∼1/33,333).

Conclusions

The RAD51C c.571+4A>G variant causes exon skipping and represents a rare likely pathogenic variant in the NL founder population. Additional work including haplotype analysis and further functional investigation (gene/protein expression) is ongoing.

AUTHOR AFFILIATIONS

*Memorial University and,
Eastern Health Authority, St. John’s, NL..


Posters

Poster P019: BRA-STRAP: Personalized Medicine to Precision Public Health


Tu Nguyen-Dumont*,, Katherine Tucker, Judy Kirk§, Paul James, Alison Trainer, Ingrid Winship#, Nicholas Pachter**, Nicola Poplawski††, Scott Grist‡‡, Daniel J Park*, Fleur Hammet*, Maryam Mahmoodi*, Helen Tsimiklis*, Jared J Burke*, Ella Thompson, Ian Campbell, Jeffrey Weitzel§§, Fergus Couch‖‖, Jenny Leary##, John L. Hopper*, David E. Goldgar***, April Morrow, Melissa C Southey*,


ABSTRACT

In 30,000 Australian women of all ages across the cancer risk spectrum, affected and unaffected with breast cancer, and their families, bra-strap is performing targeted sequencing of 24 genes commonly included on panel tests for breast cancer predisposition. Contributing to bra-strap are large research cohorts (of aging populations and of women above population risk) and the clinical genetics community and women found negative for BRCA1 and BRCA2 mutations after testing in a Familial Cancer Centre over the last 2 decades. bra-strap is also engaged with the broader translational research community and other similarly designed studies set outside of Australia (for example, bridges and carriers).

Data on this scale represent the spectrum of genetic variation observed in these genes and exemplify the opportunities and challenges for realizing precision medicine and precision public health for breast cancer. All women identified to carry genetic variants supported by Australian best practice guidelines have the opportunity to receive this information free of charge (should they wish to receive it) to inform risk management and treatment options and to enable predictive testing in family members.

A large number of genetic variants will require further study to determine their clinical utility, including variants of uncertain clinical significance in known breast cancer susceptibility genes, variants in genes that are not well characterized outside a specific cancer syndrome, and variants in genes for which the evidence is currently insufficient for them to be called bona fide breast cancer susceptibility genes.

We discuss these challenges, as well as those arising for precision medicine when trying to estimate breast cancer risk for women who carry a number of different rare genetic variants in these genes or when actionable mutations are identified in the healthy aging population (or both). Addressing those challenges is allowing for the shift from personalized medicine to precision public health for breast cancer.

AUTHOR AFFILIATIONS

*The University of Melbourne, VIC;,
Monash University Clayton, VIC;,
Prince of Wales Hospital, Sydney, NSW;,
§Westmead Institute for Cancer Research, University of Sydney, NSW;,
Peter MacCallum Cancer Centre, VIC;,
#Royal Melbourne Hospital, VIC;,
**King Edward Memorial Hospital, WA;,
††South Australian Clinical Genetics Service, SA; and,
‡‡South Australia Pathology, Flinders Medical Centre, SA, Australia;,
§§City of Hope, Duarte, CA, and,
‖‖Mayo Clinic Cancer Center, Rochester, MN, U.S.A.;,
##Westmead Institute for Medical Research, NSW, Australia;,
***Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, U.S.A..


Posters

Poster P020: Prognosis of BRCA1/2–Negative Breast Cancer Patients with Hereditary Breast and/or Ovarian Cancer (HBOC) Risk Factors Compared with Sporadic Breast Cancer Patients Without HBOC Risk Factors


Jai Min Ryu, Jeong Eon Lee, Jonghan Yu, Seok Won Kim, Seok Jin Nam, Se Kyung Lee


ABSTRACT

Background

Demands for genetic counselling with BRC A1/2 examination have markedly increased. Accordingly, the incidence of uninformative results on BRCA1/2 mutation status has also increased. We compared oncologic outcomes between BRCA1/2–negative breast cancer with high risk of hboc and sporadic breast cancer without risk of hboc.

Methods

The criteria for high risk for hboc were defined as family history of breast and/or ovarian cancer in 1st- or 2nd-degree relative, early-onset breast cancer at less than 35 years of age, and bilateral breast cancer. Patients were matched maximally 1:3 into those who identified as negative for BRCA1/2 mutation with risk of hboc (study group) and those who were not examined for BRCA1/2 mutation without risk for hboc (control group). Matched variables were pathologic stage and receptor status (estrogen, progesterone, and human epidermal growth factor receptor 2).

Results

All matching variables were successfully matched. Median follow-up was 57.8 months. There was no significant difference between the groups in disease-free survival (dfs, log-rank p = 0.197); however, the study group showed significantly better overall survival (os) and breast cancer–specific survival (bcss) (both p < 0.0001). We conducted a subgroup analysis in the middle-aged group (36–54 years) and showed no significant difference for dfs (p = 0.072), but significantly better os and bcss in the study group (p = 0.002 and p < 0.0001).

Conclusions

Compared with patients having sporadic breast cancer without hboc risk factors, those having BRCA1/2–negative breast cancer with hboc risk factors showed a similar dfs and better os and bcss.

AUTHOR AFFILIATIONS

Sungkyunkwan University School of Medicine, Samsung Comprehensive Cancer Center, Samsung Medical Center, Seoul, R.O.K..


Posters

Poster P021: Spectrum of Benign Tumours in Families with a Germline TP53 : Gene Mutation: Clinical Experience at the Children’s Hospital of Eastern Ontario


Erika Smith, Eva Tomiak, Alison Rusnak, Sarah Sawyer, Kelly Anderson, Kara Bellai Dussault, Emilie Creede, Cathy Gilpin, Valerie Hastings


ABSTRACT

Introduction

Li–Fraumeni syndrome (lfs) is a hereditary cancer predisposition syndrome causing a range of cancers across the lifespan. Germline mutations in the TP53 gene are typically associated with lfs, but the phenotype continues to emerge. Classical cancers seen in lfs include soft-tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumours, adrenocortical carcinoma, and leukemias. Cancers often occur in childhood or young adulthood. Survivors have an increased risk for multiple primary cancers. Benign tumours are not typically described, but could be an uncommon manifestation.

Methods

We performed a retrospective chart review of families with a germline TP53 mutation at the Children’s Hospital of Eastern Ontario covering a 5-year period (Jan 2013–Dec 2017). We recorded types of benign tumours, cancer history, and ages at onset. We also documented whether the mutation was de novo, ancestry, ascertainment because of premenopausal breast cancer, and whether the family met the classical lfs criteria.

Results

We identified 12 families (23 patients) with a germline TP53 pathogenic or likely pathogenic mutation. Among the 12 probands, 33% had benign tumours, including dermatofibromas, bilateral ovarian teratomas, schwannoma, ovarian serous tubal intraepithelial carcinoma lesion, clear-cell hidradenoma, cutaneous fibroxanthoma, ovarian atypical follicular cell proliferation, subungual glomus tumour, and cutaneous fibrous histiocytoma. None occurred in areas of previous radiation. Mean age of benign tumour onset was 18 years (range: 6–29 years). Mean age of malignant tumour onset was 25 years. Analysis revealed that 8% of probands had a confirmed de novo TP53 gene mutation, 67% of families were of Caucasian ancestry, 67% of families were ascertained because the proband had a diagnosis of premenopausal breast cancer, and 25% of families met the classical lfs criteria.

Conclusions

Benign tumours and ovarian lesions could be an uncommon manifestation in lfs. Additional studies are required to fully describe the range of benign lesions.

AUTHOR AFFILIATIONS

Children’s Hospital of Eastern Ontario, Ottawa, ON..


Posters

Poster P022: Biallelic CHEK2 Pathogenic Variants Identified in Two Generations of an Ashkenazi Jewish Family


Megan Priston, Wendy Meschino


ABSTRACT

Introduction

Variants in the checkpoint kinase 2 (CHEK2) gene have been shown to confer a moderate breast cancer risk in the heterozygous state. Women with biallelic CHEK2 variants have an increased breast cancer risk above those with heterozygous variants, based on studies of the CHEK2 founder mutation 1100delC. Additionally, the CHEK2 variant I157T, which is associated with a more modest breast cancer risk than some other CHEK2 variants, is suspected to increase breast cancer risk when found in biallelic form with another CHEK2 variant. Current data are insufficient to well-define breast and other cancer risks in such cases of biallelic inheritance, and screening recommendations rely heavily on family and personal history.

Case Description

We present a 42-year-old woman of Ashkenazi Jewish ancestry diagnosed with an invasive mucinous carcinoma of the left breast. Family history includes papillary serous ovarian cancer in her mother at age 71 and breast cancer in her maternal grandmother and in two of the maternal grandmother’s sisters. Our patient was offered an 18-gene breast/ovarian cancer panel which revealed the following two variants in CHEK2: c.1283C>T (pSer428Phe) and c.470T>C (I157T). Testing for her parents was recommended to determine zygosity. Subsequent parental testing showed that her father was heterozygous for the I157T variant, and her mother was homozygous for the S428P variant. Before genetic testing, the patient had a left lumpectomy and chemotherapy. Given her strong family history and the finding of biallelic CHEK2 variants, the patient chose bilateral prophylactic mastectomy after chemotherapy.

Conclusions

The finding of biallelic variants in CHEK2 presents a challenge for genetic counselling. Further study into the frequency of such cases and the relative cancer risks will be essential in elucidating management recommendations for such individuals.

AUTHOR AFFILIATIONS

North York General Hospital, Toronto, ON..


Posters

Poster P023: Re-contacting 20 Years of BRCA1/2-Negative Cancer Genetics Patients: A Pilot Study


Stacy Lenarcic*, Aly Athens*, Laurie Demmer, Sara Elrefai*, Stephanie Nix*, Megan Pollard*, Kelly Warsinske*, Lisa Amacker-North*


ABSTRACT

In recent years, the landscape of testing for hereditary cancer predisposition has drastically changed from single-syndrome analysis to much larger multigene panels. As management guidelines evolve with advancing technology, we begin to explore the need for offering updated analysis using these expanded panels to patients who previously tested negative for single-gene syndromes. Genetics professionals have the unique opportunity to directly improve patient care by taking the initiative to proactively contact patients to educate them about the availability of additional genetic analysis and updated medical recommendations.

The Cancer Genetics department at Carolinas Healthcare System Levine Cancer Institute reviewed more than 20 years of patients tested for BRCA1 and/or BRCA2. In our pilot initiative, we used a mailed letter to contact patients with a negative BRCA1/BRCA2 analysis seen between 1996 and 2005, stating that they might be eligible for additional cancer predisposition testing. Since the 250 letters were sent, 37 patients (14.8%) have so far contacted our department and scheduled a follow-up visit with a genetic counsellor. Of the 28 patients who elected to proceed with panel testing, 7 (25.0%) were found to carry a pathogenic variant in a cancer predisposition gene that altered medical management recommendations. Outside of patients re-contacted by letter, 19 individuals returned for update testing either through physician or self-referral, and 2 (10.5%) were identified as having a clinically actionable variant. As knowledge about hereditary cancer predisposition expands, patients previously tested should not be overlooked, because medical management for both the patients and the family members could be affected.

AUTHOR AFFILIATIONS

*Carolinas Healthcare System, Levine Cancer Institute, and,
Carolinas Healthcare System, Levine Children’s Hospital, Charlotte, NC, U.S.A..


Posters

Poster P025: Hereditary Cancer Testing in Hispanic Population


Heidi Owen, Jeana DaRe, Kevin Jacobs, Stephanie Woods, Lindsay Dohany


ABSTRACT

Background

The clinical utility of hereditary cancer multigene panel testing is well-established. However, most testing has been performed in the Caucasian population, with a relative shortage of data in other ethnic groups. Evaluation of hereditary cancer variants within ethnic populations is important to drive accurate variant interpretation. This study aims to describe the outcomes of hereditary cancer testing in a Hispanic population in the United States.

Methods

We conducted a retrospective review of patients evaluated with the 31-gene Riscover hereditary cancer panel (Progenity, San Diego, CA, U.S.A.) from Oct 2016 to Nov 2017. We evaluated results in the Hispanic population and compared that population with the total tested population.

Results

Of 219 tested individuals who self-identified as Hispanic only, 114 (52%) were negative, 13 (6%) were positive, and 92 (42%) had a variant of uncertain significance (vus). In contrast, in the entire patient population, 58% were negative, 8% were positive, and 35% had a vus. The difference is nominally statistically significant with p value of 0.03 based on a multinomial 2 goodness-of-fit test with 2 degrees of freedom. Within the positive and vus results, there were certain variants whose prevalence was higher in the Hispanic population than in the general population.

Discussion

Our results suggest that the vus rate might be higher, and that certain variants might occur more frequently, in the Hispanic population than in the general population. The vus rate might be attributable in part to a relative underrepresentation of well-characterized variant classifications in this ethnic group in the medical literature and available databases. Data-sharing practices support an increased understanding of ethnic variation in hereditary cancer and help to eliminate heath disparities.

AUTHOR AFFILIATIONS

Progenity, Inc., Ann Arbor, MI, U.S.A..


Posters

Poster P026: Novel Pathways Underlying the Role of RAD51 Paralogs in the Maintenance of Genome Stability and Tumorigenesis


Estelle R. Simo-Cheyou*, Damien Grapton*, Halil Bagci, Jean-Francois Coté, Barbara Rivera*, William D. Foulkes*, Alexandre Orthwein*


ABSTRACT

dna double-strand breaks (dsbs) are the most cytotoxic dna lesions. They can lead to major genomic rearrangements, promoting the development of cancer if left unrepaired. Variants in genes that play a major role in dsb repair by homologous recombination (hr) are currently good predictors for the development of both hereditary and sporadic breast and/or ovarian cancers. The relevant genes include BRCA1, BRCA2, and RAD51 paralogs. The latter group—which includes RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3—has been described to cooperate with the recombinase RAD51 in promoting strand invasion and sister-chromatid exchange. Still, it remains largely unclear how these paralogs promote hr and whether they might have additional function(s) in the maintenance of genome integrity. We therefore sought to provide more insight into their contribution to dna repair.

Using a variety of dna repair reporter assays, including the dr-gfp and sa-gfp assays, we confirmed the role of these paralogs for dsb repair by hr. To decipher their full interactome, we performed a proximity biotin-based labelling approach, called bioid, which allows for the identification of both proximal/interacting partners of these factors. Using this approach, we identified previously uncharacterized interactors of the RAD51 paralogs that we are currently investigating for their contribution to dna repair. Our study confirms the central role of RAD51 paralogs in dna repair by hr and suggests novel signalling partners that participate in their function.

AUTHOR AFFILIATIONS

*Lady Davis Institute, McGill University, and,
Institut de recherches cliniques de Montréal (ircm), Montreal, QC..


Posters

Poster P027: Truncating and Deleterious Missense Hereditary CHEK2 Mutations Confer a Risk for Development of Luminal Breast Cancer Subtypes


Petra Kleiblova*,, Lenka Stolarova*, Libor Macurek, Katerina Krizova, Marta Cerna*, Petra Zemankova*, Klara Lhotova*, Marianna Borecka*, Michal Vocka§, Kamila Vesela, Ales Panczak, Jaroslav Kotlas, Marketa Janatova*, Jana Soukupova*, Zdenek Kleibl*


ABSTRACT

Hereditary CHEK2 mutations predispose to various cancer types, including breast cancer (bca), but most studies have considered only recurrent CHEK2 variants. Those studies revealed that the bca risk is considerably greater for c.1100delC carriers than for p.I157T carriers. Recent inclusion of CHEK2 into cancer predisposition gene testing panels has increased the spectrum of identified variants. Although variants truncating the CHK2 kinase domain are considered to be deleterious, the significance of rare missense variants is largely unknown and hampers the estimation of cancer risk attributed to hereditary CHEK2 variants.

We analyzed the entire CHEK2 coding sequence in 1928 high-risk bca and/or ovarian cancer (oc) patients (previously tested for mutations in bca/oc susceptibility genes using gene-by-gene analysis or simultaneously by multigene panel testing) and in 2184 geographically-matched controls. The analysis in bca/oc patients revealed 39 carriers of 8 deleterious truncating mutations and 92 carriers of 22 in-frame deletions or missense variants. The functional assessment of 22 non-frame-shift variants in a crispr/Cas9 CHEK2 knockout cell line model identified 12 of those variants as deleterious. Compared with controls, the carriers of deleterious variants were strongly enriched in the female bca subgroup [51/1526 (3.34%) vs. 8/2184 (0.37%), p = 5.25−13] and in 48 male bca patients [4/48 (8.3%), p = 8.22−5). The prevalence of deleterious CHEK2 variants was lower in oc-only patients [6/354 (1.69%), p = 0.008] and statistically nonsignificant when compared with European non-Finish controls (Exome Aggregation Consortium). The analysis of histopathologic data showed that, compared with noncarriers, female carriers of deleterious CHEK2 variants more frequently develop the luminal A bca subtype [19/37 (51%) vs. 269/898 (30%), p = 0.006] and low-grade tumours; G3 was detected in 8/40 CHEK2 carriers (20%) compared with 366/927 noncarriers (39.5%, p = 0.008).

Our analysis demonstrates that deleterious CHEK2 variants also include rare missense mutations and collectively increase female bca risk (or: 3.87; 95% ci: 2.80 to 5.25).

Supported by grant AZV NV15-28830A and NV-16-29959A.

AUTHOR AFFILIATIONS

*Charles University, Institute of Biochemistry and Experimental Oncology;,
Charles University, General University Hospital, Institute of Biology and Human Genetics;,
Czech Academy of Sciences, Institute of Molecular Genetics; and,
§Charles University, General University Hospital, Prague, Czech Republic..


Posters

Poster P028: NTHL1 Mutation Carriers Found in BRCA1 and BRCA2 Mutation-Negative Ovarian Cancer Families


Wejdan M. Alenezi*, Timothee Revil*,, Suzanna L. Arcand, Anne-Marie Mes-Masson§,, Ioannis Ragoussis*,, Patricia N. Tonin*,


ABSTRACT

It has been proposed that germline mutations in other homologous recombination (hr) and Fanconi anemia (fa) dna repair genes RAD51C, RAD51D, and BRIP1, together with BRCA1 and BRCA2, confer increased risk for ovarian cancer (oc). Our group has shown that, because of common ancestors, recurrent BRCA1, BRCA2, and most recently, RAD51D germline mutations account for a significant proportion of hereditary oc cases in the French Canadian (fc) population of Quebec. However, we observed that 20%–30% of fc multi-case oc families are BRCA1 and BRCA2 mutation–negative, which prompted our investigation for new candidate oc-predisposing genes. Whole-exome sequencing (wes) analysis was performed on germline dna extracted from 11 such families.

A candidate gene approach was applied, focusing on potentially damaging rare alleles found in 200 dna repair pathway genes. Using various public databases, a total of 44 variants were identified in 38 dna repair genes with minor allele frequency less than 0.1% in the general population. Heterozygous germline NTHL1p.Q90* reported as pathogenic in ClinVar was identified in 2 oc cases from the same family. By targeted mutation screening of NTHL1p.Q90* in 439 oc cases not selected for family history of cancer (∼80% of fc descent), 2 NTHL1p.Q90* heterozygous carriers with oc were identified (0.46%). Although no significant difference between familial and sporadic oc cohorts was observed (because of the small sample size), no other potential pathogenic mutation was found by global wes analysis of all NTHL1p.Q90* heterozygous carriers. The Cancer Genome Atlas cohort of oc cases showed a significant association of low NTHL1 mrna expression with poor clinical outcome and reported significant deletion of the 16p arm where NTHL1 is located.

Our preliminary results suggest that NTHL1 is a potential candidate oc-predisposing gene warranting further investigation of its inactivation mechanism and overall role in ovarian carcinogenesis.

AUTHOR AFFILIATIONS

*McGill University,,
McGill University and Génome Québec Innovation Centre,,
The Research Institute of the McGill University Health Centre,,
§Université de Montréal, and,
Centre de Recherché chum et Institut du Cancer de Montréal, Montreal, QC..


Posters

Poster P029: Large Case–Control Study and Functional Analyses Indicate That FANCM Truncating Mutations Are Moderate or Low-Risk Factors for Breast Cancer Depending on Their Location


Gisella Figlioli*, Massimo Bogliolo, Laura Caleca, BCAC collaborators§, Paolo Radice, Jordi Surralles, Paolo Peterlongo*


ABSTRACT

Breast cancer is the most common female oncologic disease, and up to 15%–20% of all cases are familial. About 50% of familial cases are explained by rare mutations in BRCA1 and BRCA2 and other high-risk genes; by mutations in moderate-risk genes, including PALB2, ATM, and CHEK2; and by several dozens of common low-risk alleles. Truncating mutations in FANCM recently emerged as novel breast cancer predisposition factors. In a large case–control study, we showed that the p.Arg1931* mutation is associated with breast cancer risk. In Finland, another C-terminal mutation, p.Gln1701*, was associated specifically with estrogen receptor (er)–negative breast cancer. This particular association was confirmed in a mutational burden analyses in cases and controls from Germany.

In the present study, the 3 most common FANCM truncating mutations p.Arg658*, p.Gln1701*, and p.Arg1931* were genotyped in 67,112 breast cancer cases and 53,766 controls, collected within the Breast Cancer Association Consortium and representing the largest sample size tested to date. Logistic regression analyses in populations with mutation carriers suggested that the p.Arg658* is a moderate risk factor for er-negative and for triple-negative breast cancer (tnbc)—odds ratios (ors) 2.44 (1.12 to 5.34) and 3.79 (1.56 to 9.18) respectively. Similar analyses showed that p.Gln1701* and p.Arg1931* could be low-risk factors for tnbc [or: 2.15 (1.05 to 4.38)] and for er-negative breast cancer [or: 1.98 (1.26 to 3.13)].

These genetic data, together with our published clinical observations on individuals homozygous for FANCM mutations, suggest that upstream FANCM protein truncation is associated with a higher breast cancer risk and more severe clinical phenotypes. We are testing this hypothesis by performing functional analyses in immortalized FANCM-deficient fibroblasts. Cells are transduced with vectors carrying 5 patient-derived truncating mutations to test dna repair activity and hypomorphism of the mutant forms in an isogenic background. Our results will provide information allowing for better breast cancer risk estimation in FANCM mutation carriers.

AUTHOR AFFILIATIONS

*ifom–The firc Institute of Molecular Oncology, Milan, Italy;,
Universitat Autònoma de Barcelona, Barcelona, Spain;,
Fondazione irccs Istituto Nazionale dei Tumori, Milan, Italy;,
§bcac–Breast Cancer Association Consortium..


Posters

Poster P030: Emerging Genes: What Clinical Implications?


Zaki El Haffaf, Nadine Dumas, Bouchra Labraki, Alexandra Lemyre, Laura Dempsey-Nunez, Marie-Claire Binet, Maude Lefebvre, Diane Provencher, Pavel Hamet


ABSTRACT

Introduction

Since next-generation sequencing (ngs) technologies have become more clinically accessible, the genetic counselling in high-aggregation families of breast (wbc) and ovarian cancers (ovc) tested negative for BRCA1 and BRCA2 has recently changed significantly. We present the clinical and molecular profile of 55 women extracted from our families negative for BRCA1/2, but positive for PALB2, CHEK2, RAD51C, RAD51D, RAD50, and BRIP1.

Results

Of 55 families, 43 wbc and 12 ovc are predominantly French Canadian. Of 43 wbc, 24 had PALB2 mutation, with 21 being French Canadian, 12 having c.2323C>T (p.Gln775*), and 7 having exon 11 deletion, and 14 having bilateral and/or triple-negative bca. A new mutation was identified in 14 women on a clinical basis on RAD51D c.620C>T (p.Ser207Leu), with 8 having high-grade serous ovc and 5 having breast cancer (middle age: 52 years), of which 3 were triple-negative or multifocal tumours. CHEK2 mutation was found in 10 wbc and 2 ovc. Only 4 of those 12 had c.1100delC mutation. On the other hand, 4 had deletion or duplication in the CHEK2 gene or other types of mutations. Strangely, in the other cases (BRIP1, RAD50, RAD51C), breast cancer predominates (5 of 6).

Commentary

We observed a significant augmentation in the identification of hereditary predispositions to cancer through a nonselective multigene approach. Full sequencing and deletion/duplication research has identified non-targeted mutations in older approaches and recognition of frequent and recurrent mutation in the French Canadian population. In addition, recommendations were more complete and more appropriate to the reality of the context of family predisposition. The identification of mutations in RAD51D, RAD51C, and RAD50 as well as in CHEK2, in proportions that seem less related to mere chance, show a greater increase in the risk of breast and ovarian cancer than we can imagine. The phenotype/genotype correlation leads us to redefine our thinking about the criteria of testing.

Conclusions

This approach is essential and constitutes an important advance for personalized medicine. Screening could have an efficient impact. The expansion of genetic investigations is fundamental and must also be based on good observation of the family tumour spectrum and reassessment of the certainty of the past.

AUTHOR AFFILIATIONS

Centre hospitalier universitaire de Montréal, Montreal, QC..


Posters

Poster P032: The Use of Software Can Address Workforce Shortage and Access Barriers to Genetic Counselling


Lauren Ryan, Lily Servais, Anjali Zimmer, Will Stedden, Alicia Y. Zhou


ABSTRACT

Since the discovery of BRCA1 in 1994, the prevalence and uptake of germline genetic testing for hereditary cancer has increased dramatically. As a result, clinical genetics providers have struggled to keep up with the increase in demand. Previous analyses of time-based effort have determined that clinical genetic services are time-consuming and labour-intensive, with as little as 25%–41% of a genetic counsellor’s time spent on direct client care and up to 3.5–7 total hours spent per client. As demand for germline testing continues to increase, the traditional delivery model for clinical genetics services has proven to be a bottleneck and a barrier to testing.

Here, we present a novel service model that uses software and technology to deliver genetic services in a more streamlined and efficient way. Using this model, genetic counsellors spend much less time than industry averages conducting non-direct client care activities, thus increasing the proportion of time spent on direct care and availability for more clients. To achieve those results, we implemented custom software tools, including online health history collection, automated pedigree creation and risk-model calculation, online scheduling and rescheduling, and templated summary notes.

Genetic counsellors tracked time spent conducting direct and non-direct care activities to provide more than 1800 post-test telephone genetic counselling sessions for clients who received a multigene panel for hereditary cancer risk. The average total time spent per client was 37 minutes, and more than 50% of the time spent on a client invovled providing direct care. Post-counselling surveys revealed high levels of comprehension and client satisfaction with their genetic counselling. Broader implementation of similar software tools for all genetic counselors providing clinical care might improve access to and efficiency of genetic counselling services to help meet rising demand.

AUTHOR AFFILIATIONS

Color Genomics, Inc., Burlingame, CA, U.S.A..


Posters

Poster P033: Should We Reform Our Practice in Oncogenetics?


Zaki El Haffaf*,, Pavel Hamet*,


ABSTRACT

Numerous challenges are on the horizon in oncogenetics. They are set in a context of extraordinary technological development that makes diagnostic investigations linked to hereditary predispositions to cancer more accessible. The personalization of care is more and more necessary. In fact, it depends on the speed of the teams to respond effectively to requests for investigations from oncologists, surgeons, gynecologist–oncologists, radio-oncologists, and patients themselves.

In Quebec, there is a mismatch between high demand for genetic evaluation on the one hand and the natural ability of ontogenetic teams to meet that demand on the other hand. To achieve that objective at the chum, we have proceeded to two levels of intervention. The first intervention was the complete overhaul of the form-based application prioritization system and a triage that takes into account the patient’s therapeutic planning. The second intervention, which is much more ambitious, is the realization of an integrated evaluation activity in the cancer centre cicc (integrated oncology centre).

The response rate to “urgent” requests was very good: 98% of responses were given within the therapeutic times; but nonetheless, dissatisfaction persists. We found several factors of dysfunction.

Integration of therapeutic planning by an expert team of geneticists and genetic counsellors is a possibility. It seems that this solution is ideal for overhauling the dysfunctional elements and providing patients and their physicians with the appropriate guidelines and recommendations in a time-useful clinic. The realization of good oncogenetic evaluative integration will provide a pedagogic dimension as well as efficiency in the transversal exchange of skills. It will also contribute to the exchange of knowledge between the teams.

AUTHOR AFFILIATIONS

*Centre hospitalier universitaire de Montréal and,
Centre de recherche du chum, Université de Montréal, Montreal, QC..


Posters

Poster P034: Is It Really BRCA1 or BRCA2? The Importance of Confirming the Familial Mutation in a “BRCA”-Focused World


Sara V. Brown, Samantha S. Wiley


ABSTRACT

As genetic testing becomes more prevalent, performing laboratories could experience a higher rate of order errors. At arup Laboratories, complex genetic test orders undergo pre-test review by arup’s genetic counsellors to ensure that the most appropriate test is ordered based on the clinical information provided. This pre-test review identified a recurring scenario in which testing is ordered for a family history of “BRCA mutation,” but the familial variant is actually not in the BRCA1 or BRCA2 genes.

We present three cases encountered by arup in which BRCA1/2 full gene analysis was ordered on unrelated individuals with reported “BRCA positive” family history. Further investigation, including obtaining genetic lab reports from affected relatives, determined that there was no family history of a BRCA1/2 mutation. Rather, patient 1 had a family history of a CHEK2 mutation, patient 2 had a family history of an ATM variant of uncertain significance, and patient 3 had a family history of Lynch syndrome caused by a PMS2 mutation. For those 3 patients, documentation of the familial variants allowed for the inappropriate BRCA1/2 tests to be cancelled, and targeted testing for the appropriate gene was offered. Without the correction in test orders, the BRCA1/2 test results would likely have been clinically irrelevant and falsely reassuring, because the true familial variant would not have been analyzed.

These cases demonstrate the need for clinicians to confirm reported family history whenever possible by obtaining documentation of familial genetic variants, thereby ensuring that a clinically relevant result is issued for the patient. As genetic testing for hereditary cancer predisposition and BRCA1/2 continues to receive attention in the media, it is crucial to raise awareness of the growing list of clinically actionable hereditary cancer genes so that patients, health care providers, and laboratories understand that a family history of a “breast cancer mutation” doesn’t always mean BRCA1/2.

AUTHOR AFFILIATIONS

arup Laboratories, Salt Lake City, UT, U.S.A..


Posters

Poster P035: Learning About Breast Cancer Risks, Stratification, and Prevention: An Innovative Web Site


Samar Attieh*, Jacqueline Vachon*, Emmanuelle Lévesque, Michel Dorval, Jacques Simard§, Bartha Knoppers, Carmen G. Loiselle*,


ABSTRACT

Canadian women are more likely to develop breast cancer (bca) than any other cancer, with 1 in 8 women expected to be diagnosed in her lifetime1. Breast cancer accounts for 13% of female cancer deaths, making it the second leading cause of cancer deaths in women1. Accordingly, strategic and timely activities in early detection and actionable domains are crucial. Currently, screening practices are based mainly on age rather than on personalized risk assessment, resulting in some women not being appropriately screened according to their actual bca risk.

A bilingual website called perspective was recently developed in Quebec to inform women about a novel stratification approach for bca, including risk assessment, risk factors (for example, lifestyle, genetic), and prevention. This resource is part of a broader initiative that aims to develop this approach, specifically by providing women with the tools they need to plan, act, and follow up on their personalized risk results. The perspective Web site was piloted, modified, and then tested for knowledge improvement in a community sample of 156 women 30–60 years of age with no previous cancer history. Paired-sample t-tests showed significant changes in general knowledge of bca risk factors, prevention, and genetics pre–post Web site exposure, with improvements ranging from 14% to 58% (p < 0.001). Knowledge improvement examples include a 48% knowledge increase for the influence of alcohol consumption on bca risk, 31% on the nature of BRCA1/2, and 49% on breast density as a risk factor.

These initial findings indicate that perspective is a promising means to disseminate information on bca risk factors, screening, and follow-up. Ongoing perspective work will provide further evidence about the extent to which e-health solutions such as this one can be used to support cancer-related decisions pertaining to personalized risk assessments. Future work will also test interactive features embedded into a perspective platform.

AUTHOR AFFILIATIONS

*McGill University, Montreal;,
Centre of Genomics and Policy, McGill University, Montreal;,
L’Université Laval, Montreal;,
§Genomics Centre, chu Quebec–Université Laval Research Centre, Quebec City; and,
Segal Cancer Centre, Jewish General Hospital, Montreal, QC..

1 Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2017. Toronto, ON: Canadian Cancer Society; 2017.

1 McGee et al., Gynecol Oncol 2017;145:346–51.
cross-ref  pubmed  

2 Gangi et al., JAMA Surg 2014;149:1306–13. [Erratum in: JAMA Surg 2015;150:183]
cross-ref  pubmed  

3 Vencken et al., Cancer 2013;119:955–62
cross-ref  

4 Domchek et al,. Cancer 2013;119:1344–8.
cross-ref  


Posters

Poster P036: Impact of Genetic Counselling and Genetic Testing on High-Risk Hereditary Breast and Ovarian Cancer


Natalia Campacci*, Henrique Campos Galvão, Paula Carvalho, Lucas França Garcia, Rebeca Silveira Grasel*, Patricia Ashton-Prolla§, Edenir Inêz Palmero*,,


ABSTRACT

The aim of this study from the Oncogenetics Department of Barretos Cancer Hospital (Brazil) is to evaluate the effects of genetic counselling (gc) and genetic testing (gc) in families at risk for hereditary breast and ovarian cancer. The study uses four time points: M1, before gc; M2, after a gc session and blood draw for gc; M3, after the gc result; and M4, 12 months after the gc result. At points M1 and M4, questionnaires about cancer worr y, risk perception, strategies for coping with problems, anxiety, and depression were administered, and the pedigree, genogram, and ecomap were constructed. In addition, at points M2 and M3, questionnaires about cancer worry, risk perception, anxiety, and depression were administered.

Qualitative analysis was performed based on content thematic analysis. Currently, 83 women have been enrolled, with 14 having pathogenic mutations, 47 being wild-type, and 3 having a variant of unknown significance (64 completed M3, and 20, M4). Mean age of the participants was 41 ± 9.77 years, and 73 participants (88%) had a diagnosis of breast cancer. The perception for risk of cancer development is lower in participants than the general population, but there is a greater concern about developing cancer at all time points. Anxiety and depression at all times were not significantly different. The coping strategy for problems is religiosity. The main topics raised by genograms and ecomaps analysis were positive or negative relationship with relatives, religiosity as a social support network, and concern about future generations. In conclusion, most patients, even in the presence of mutation, have a cancer risk perception lower than that in the general population. Few changes in family dynamics (changes of relationship) were observed. It is important to understand gc and gc processes so that the individual can adequately follow prevention and control strategies.

AUTHOR AFFILIATIONS

*Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos;,
Barretos Cancer Hospital, Barretos;,
Program on Health Promotion, UniCesumar;,
§Federal University of Rio Grande do Sul, Porto Alegre; and,
Barretos School of Health Sciences, Dr. Paulo Prata–facisb, Barretos, Brazil..


Posters

Poster P037: What Do Women Want? Genetic Information Preferences Among Women Undergoing Panel-Based Genetic Testing


Jennifer Shuldiner*, Julia Knight*, Gary Rodin, Yvonne Bombard, Sarah Ferguson, Joanne Kotsopoulos§, Kelley Metcalfe§, Alicia Tone, Jeanna McCuaig, Carl Virtanen, Taymaa May, Stephane Laframboise, Raymond Kim, Terri Stuart-McEwan, Marcus Bernardini


ABSTRACT

Background

Panel-based genetic testing (pbgt) is becoming increasingly prevalent in clinical practice, but little is understood about information preferences. In pbgt, similar genes are grouped, and results of varying significance are produced, including only a small proportion of medically actionable results. A greater understanding is essential to the development of genetic testing guidelines specific to pbgt, together with educational materials and decision-support tools for patients and providers.

Methods

This mixed-methods study explored the pbgt preferences of participants with a 1st-degree relative who has died from ovarian cancer. We conducted a cross-sectional survey of self-referred unaffected women in Ontario who are undergoing pbgt through a clinical research study. Participants had the option to receive results from 4 different panels. Quantitative data were collected using a Web-based survey platform. Using logistic regression, we determined the relationship of sociodemographic and psychological factors (anxiety, depression, decisional conflict) with genetic information preferences. We also conducted semistructured telephone interviews with 20 participants who were purposively sampled based on their diverse panel selection. Transcripts were analyzed using conventional content analysis.

Results

350 women participated in pre-genetic counselling and consented to the results that they would like to receive. Most women chose to receive information from all panels (84%). Those with more decisional conflict did not want to receive genetic information from all panels. Interviews revealed that participants appreciated all forms of genetic “knowledge” and expected to use this information to reduce their cancer risk. Many contemplated participation in the program, but once committed did not truly consider which information they preferred to receive.

Conclusions

In our sample, most women opted to select all panels for pbgt, including panels without actionable results. This preference was associated with a lower level of decisional conflict. Our findings have important implications for the advancement of pbgt in screening for breast and ovarian cancer.

AUTHOR AFFILIATIONS

*University of Toronto,,
Princess Margaret Cancer Centre,,
St. Michael’s Hospital, and,
§Women’s College Research Institute, Toronto, ON..


Posters

Poster P038: Performance of Current Hereditary Breast and Ovarian Cancer Testing Criteria for the Detection of Carriers of Pathogenic Variants in Clinically Significant Breast Cancer Risk Genes Other Than BRCA1/2


Eric Rosenthal, Ryan Bernhisel, Susan Manley, Karla Bowles


ABSTRACT

Background

Although genetic testing for hereditary breast cancer risk is no longer limited to BRCA1 and BRCA2, it is not clear that current testing criteria adequately target individuals with pathogenic variants (pvs) in other clinically important genes. We evaluated the performance of testing criteria designed for BRCA1 and BRCA2 for the detection of pvs in 3 moderate-penetrance breast cancer genes: ATM, CHEK2, and PALB2.

Methods

We analyzed multigene panel test results (Myriad Genetic Laboratories) for 294,234 women ascertained for suspicion of hereditary breast and ovarian cancer (hboc) to evaluate how various personal and family history factors affect the likelihood of detecting a pv in BRCA1, BRCA2, ATM, CHEK2, or PALB2. All clinical data were collected from provider-completed test request forms.

Results

The likelihood of finding a BRCA1pv was strongly affected by age of breast cancer diagnosis, with a striking inflection point between ages 41 and 45 years. In contrast, the likelihood of finding a BRCA2pv declined gradually from age 21 to 80 years. The likelihood of finding a pv in ATM, CHEK2, or PALB2 declined slightly after age 30, and then remained almost constant from age 31 to 70 years. As expected, a personal or family history of ovarian cancer was strongly predictive of a pv in BRCA1 or BRCA2, but was not consistently associated with pvs in ATM, CHEK2, or PALB2. For all probands, a family history of breast cancer increased the probability of finding a pv in all 5 genes, but that finding was largely independent of the reported age at which relatives were diagnosed.

Conclusions

Current testing criteria based on the clinical features of BRCA1 and BRCA2 might perform poorly in distinguishing women at risk for mutations in other clinically significant breast cancer risk genes. Revision of the criteria might be appropriate if these genes are routinely included in hereditary breast cancer risk assessment.

AUTHOR AFFILIATIONS

Myriad Genetic Laboratories Inc., Salt Lake City, UT, U.S.A..


Posters

Poster P039: Families with a Known Mutation in a Cancer Predisposition Gene: Is Single-Site Testing Always the Best Option for Relatives?


Jamie Willmott, Merideth Sanders, Hannah Cox, Heidi Gorringe, Michelle Landon, Susan Manley


ABSTRACT

Background

The current paradigm prescribes site-specific testing for family members when there is a known familial mutation (kfm) in a cancer-risk gene, with tested individuals typically managed as true positives or negatives. However, panel testing has revealed that some families carry more than one mutation in cancer-risk genes. Our aim was therefore to assess whether panel testing could be appropriate even in the setting of a kfm.

Methods

We assessed patients who had clinical genetic testing with a multigene panel (Myriad Genetic Laboratories) after testing negative for a kfm between March 2005 and August 2017 (n = 902).

Results

Overall, 37 individuals who tested negative for a kfm (4.1%) were found to carry ≥1 pathogenic variant (pv) upon panel testing. That group included 16 individuals whose panel test was performed ≥1 year after kfm testing, 2 of whom developed interim cancers. One woman with bilateral breast cancer tested negative for a kfm in BRCA2 and was found to carry pvs in both CHEK2 and CDH1. Several additional cases were also observed in which individuals tested positive for pvs in genes with cancer risks different from those for the kfm. Included was an unaffected woman who tested negative for a kfm in BRCA2 and later developed colon cancer. Panel testing revealed a pv in APC.

Conclusions

In this cohort, approximately 4% of individuals who tested negative for a kfm were found to carry a different pv in a cancer-risk gene. That finding suggests that an “informative negative” test result for a kfm might give a false sense of security when more than one mutation could be contributing to the family history of cancer. Collectively, our results suggest that there might be added value to panel testing for individuals with a kfm.

AUTHOR AFFILIATIONS

Myriad Genetic Laboratories Inc., Salt Lake City, UT, U.S.A..


Posters

Poster P040: Painting a Portrait: Analysis of National Health Survey Data for Cancer Genetic Counselling


Monica Helm Stamp*, Ora Karp Gordon*,, Christopher P. Childers,§, Miles Picus‖, Kimberly K. Childers*


ABSTRACT

Data about the geographic and sociodemographic distribution of cancer genetic counselling (gc) at the national level are limited. However, prior studies focused on cancer genetic testing have suggested disparities in awareness and access by race, sex, education, and insurance (Wideroff et al., Public Health Genomics, 2003).

Using the 2015 National Health Interview Survey—a cross-sectional in-person interview survey collecting self-reported health data for the U.S. population—geographic and sociodemographic factors were compared between individuals receiving gc and the national sample. Bivariate analysis and subsequent multivariable logistic regression were performed with stratification by cancer status (affected or unaffected). The reason for gc was also assessed. To generate nationally representative estimates, all analyses were adjusted for survey weights.

An estimated 5 million individuals in the United States had undergonecancer gc by 2015. On bivariate analysis, there were significant differences in the proportions undergoing gc by sex, race or ethnicity, insurance, citizenship, education, age, and cancer status (p < 0.001). After adjustment, however, only female sex [odds ratio (or): 1.78 (1.18 to 2.67)] remained a significant predictor of gc among the affected. Among the unaffected, female sex [or: 1.70 (1.30 to 2.21)], non-Hispanic black race [or: 1.44 (1.02 to 2.05)], and graduate education [or: 1.76 (1.03 to 2.98)] predicted higher rates of gc. Rates of gc for those with a history of cancer were 17.8% breast, 18.7% ovarian, 10.2% uterine, 8.1% colon, and 4.4% prostate. Most individuals receiving gc reported that they did so because their doctor recommended it (65%), with smaller proportions describing self (12%), family (10%), or media (5%) influences.

This study is the first to provide a national portrait of cancer gc. Despite perceived disparities in access, with the exception of male sex, genetic counselling appears to reach across most geographic, social, and educational contexts, as well as cancer types or status. With physician recommendation as the predominant driver for counselling, targeting physician education or awareness is crucial to utilization.

AUTHOR AFFILIATIONS

*Providence Health and Services Southern CA, Los Angeles,,
Providence John Wayne Cancer Institute, Santa Monica,,
David Geffen School of Medicine at ucla, Los Angeles,,
§Fielding School of Public Health at ucla, Los Angeles, and University of California, Los Angeles, CA, U.S.A..


Posters

Poster P043: The Gynecology–Oncology BRCA Pilot Project: Oncologist-Mediated Genetic Testing of the BRCA1/2 Genes for Women with Ovarian Cancer


Stephanie Desmarais*, Ruth Kohut*, Renee Perrier*, Sarah Glaze, Pam Sweeney


ABSTRACT

Objective

Ensure that ovarian cancer patients in Southern Alberta have timely, seamless access to BRCA1/2 testing, while preserving informed choice and genetic counselling support. Timely results disclosure is vital, because results might direct treatments. Gynecology–Oncology BRCA (go-brca) was driven by a need to challenge existing models because of increased referrals to the Hereditary Cancer Clinic (hcc).

Methods

BRCA1/2 testing was historically offered after pre-test genetic counselling in the hcc. During go-brca, pre-test genetic counselling was facilitated by the Gynecology–Oncology (go) team, in parallel with referral to the hcc. The hcc provided results and post-test genetic counselling. go-brca was a proof-of-concept pilot, modelled after the U.K. Mainstreaming Cancer Genetics program.

The go team was oriented to pre-test genetic counselling by the hcc’s geneticist and was provided with information support materials. To facilitate informed consent, the go team provided patients with a brochure and video. To evaluate go-brca, qualitative surveys were issued to the go team at the outset and close of the pilot, and to patients when offered testing and after results disclosure.

Results

121 women opted for BRCA1/2 testing; 109 results were disclosed. Elimination of pre-test meetings with the hcc resulted in results disclosure 1.9 times faster than before go-brca (159 days vs. 306 days). Capacity of the hcc was increased by 121 hours. From the surveys returned, 97% of women felt that they had made an informed decision, 100% reported that expectations were met, and 100% were happy that testing was offered by the go team compared with a separate hcc appointment. Clinicians felt that the model was feasible.

Conclusions

go-brca provided BRCA1/2 genetic test results to ovarian cancer patients 1.9 times faster than previously, and the model is acceptable to patients and clinicians. Elimination of pre-test meetings for this cohort increased the hcc’s capacity by 121 hours. This is now a provincial model, and expansion to other tumour groups is anticipated.

AUTHOR AFFILIATIONS

*Alberta Children’s Hospital and,
Tom Baker Cancer Centre, Calgary, AB..


Posters

Poster P044: Genetic Risk Assessment Guides Young Women Opting for Contralateral Prophylactic Mastectomy


Thorkild Terkelsen, Hanne Rønning, Anne-Bine Skytte


ABSTRACT

Purpose

Genetic counselling has been introduced in the primary diagnostic workup for young women with breast cancer in Denmark. We investigated the influence of genetic risk assessment on the uptake of contralateral prophylactic mastectomy (cpm) in a prospective study.

Methods

The cohort consists of 154 women with breast cancer diagnosed at a median age of 36 years (range: 21–44 years). The women were seen at the Genetics department (2013–). Risk evaluation was made using family history and the results of BRCA1/2 screening. Women were counselled according to four categories: carriers of a pathogenic variant in BRCA1/2, high risk of breast cancer, moderate risk, and non-increased risk. Using electronic medical records, we examined the cumulative uptake of cpm after a maximal follow-up period of 4.2 years.

Results

A pathogenic variant in BRCA1/2 was identified in 17 of 154 women (11%). Uptake of cpm in the entire group was 38% (95% ci: 29% to 49%). Carriers of a pathogenic variant in BRCA1/2 had the highest uptake at 80% (95% ci: 46% to 99%), followed by high-risk women at 72% (95% ci: 42% to 95%) and moderate-risk women at 28% (95% ci: 19% to 41%). The uptake increased with decreasing age up to 59% (95% ci: 36% to 83%) in those less than 30 years of age.

Conclusions

The genetic risk assessment guided young women with breast cancer opting for cpm; however, a re-evaluation of the risk assessment scheme suggested that the breast cancer risk was sometimes overestimated. We are in a process of optimizing national guidelines and now attempting to implement the boadicea model as support for individualized risk assessment in clinical practice, because both molecular screening and family history have a major effect on the cpm rate.

AUTHOR AFFILIATIONS

Aarhus University Hospital, Aarhus, Denmark..


Posters

Poster P045: Predictors of Next-Generation Sequencing Panel Selection Using a Shared Decision-Making Approach: Data from Singapore


Joanne Ngeow*


ABSTRACT

Purpose

Next-generation sequencing (ngs) has transformed the way clinical cancer genetics services approach testing, particularly for cancers. The Cancer Genetics Service at the National Cancer Centre Singapore was established in 2014 using a shared decision-making approach in which patients play an active role in ngs panel selection.

Methods

Demographic and clinical data were gathered for female breast or ovarian cancer patients 21 years of age and older who underwent ngs panel testing. Panel type was classified as “breast cancer panel” (bcp) or “multi-cancer panel” (mcp). Univariate, multiple, and stepwise multiple logistic regression analyses were used to identify clinical factors predictive of ngs panel selection.

Results

Overall, 265 subjects were included in the study: 49 (18.5%) selected a bcp and 216 (81.5%) selected mcps. Subjects who chose mcps were significantly more likely to be 50 years of age or older (49% vs. 31%, p < 0.05), to be Chinese (76% vs. 47%, p < 0.001), and to have have a personal history of ovarian cancer (41% vs. 8%, p < 0.001); the latter two characteristics were identified as being the best predictors of ngs panel selection. Family history of cancer was not significantly associated with ngs panel selection. There were no statistically significant differences in clinical outcome between the bcp and mcp groups.

Conclusions

Our results indicate that personal factors, rather than family history, are more likely to predict ngs panel selection. Further research is needed to evaluate patient outcomes, empowerment, and perception in assessing the success of this approach for ngs panel selection. We will also present our 3-year experience establishing the Cancer Genetics Service and share data abot the mutation spectrum seen in Singapore hboc cases and how subsidies affect genetic testing uptake in Singapore.

AUTHOR AFFILIATIONS

*National Cancer Centre and Lee Kong Chian School of Medicine, Singapore..


Posters

Poster P046: DNA-Direct: Increasing Efficiency for Pre-test Genetic Counselling in Multigene Panel Testing


Angela Bedard*, Jennifer Nuk*, Chalaine Lawrence*, Sophie Sun*,, Kasmintan Schrader*,


ABSTRACT

Introduction

With demand for cancer genetics services increasing, alternative modes of service delivery are being considered. One alternative is termed dna-Direct, which was studied and successfully implemented with BRCA1 and BRCA2 testing in the Netherlands. dna-Direct delivers an abbreviated pre-test telephone appointment to expedite the testing process. In April 2017, the Hereditary Cancer Program of BC Cancer began trialling dna-Direct for patients undergoing multigene panel testing.

Methods

The process included

  • ■ triage of eligible patients (geographic location, fluency in English, eligibility for index testing);

  • ■ brief telephone appointment to review the reason for referral, an abbreviated psychosocial assessment, and review of the testing process; and

  • ■ mailing a package containing test forms and written educational materials.

Once results were received, patients were scheduled for a typical results disclosure appointment. Patients consenting to further contact were sent the Multidimensional Impact of Cancer Risk Assessment (micra) questionnaire, assessing for coping and adaptation to genetic test results, and scores were compared with patients seen with a traditional pre-test appointment.

Results

Over a 7-month period, 112 patients had a dna-Direct appointment. A greater than 95% acceptance rate for the appointment type was observed. The average time spent for the pre-test telephone appointment was 15 minutes. Most patients were referred for query hereditary breast and ovarian cancer syndrome (82%). Among the 62 results returned to date, 8 pathogenic mutations were detected. The results of the micra have shown no statistically significant differences between patients who had a dna-Direct or a longer traditional pre-test appointment (n = 117).

Conclusions

The dna-Direct approach demonstrates significant efficiencies in pre-test genetic testing appointments. Patient satisfaction and distress levels are comparable to those seen with longer pre-test appointments. dna-Direct is efficacious in the setting of multigene panel testing and helps to address increasing demands for service.

AUTHOR AFFILIATIONS

*BC Cancer and,
University of British Columbia, BC..


Posters

Poster P047: Oral Contraceptive Use and Ovarian Cancer Risk: A Pooled Cohort Study of BRCA1/2 Mutation Carriers


Lieske H. Schrijver*, Håkan Olsson, Kelly-Anne Phillips,§, Mary Beth Terry, David E. Goldgar#, Karin Kast**, Christoph Engel††, Nadine Andrieu‡‡, Douglas F. Easton§§, Flora E. van Leeuwen*, John L. Hopper§, Roger L. Milne§, Antonis C. Antoniou§§, Matti A. Rookus*

††University of Leipzig, Leipzig, Germany; inserm U900 Paris, Paris, France; and University of Cambridge, Cambridge, U.K.

ABSTRACT

Background

Use of oral contraceptive preparations (ocps) might reduce ovarian cancer risk. Only a few previous studies stratified analyses for BRCA mutation, and possible survival bias was not well examined.

Methods

Using age-dependent Cox regression, ovarian cancer risk associations were estimated from data for 4767 BRCA1 and 3038 BRCA2 mutation carriers, stratified by study and birth cohort. To minimize survival bias, analyses were left-truncated at 5 years before the baseline questionnaire.

Results

An inverse association with ever ocp use was comparable for both BRCA1 and BRCA2 mutation carriers, but was significant only for BRCA1 mutation carriers (BRCA1hr: 0.58; 95% ci: 0.43 to 0.78; BRCA2hr: 0.71; 95% ci: 0.42 to 1.19). From multivariate BRCA1-analyses, including various ocp characteristics, only duration of use was associated with a reduced ovarian cancer risk (p = 0.005). Stratified analyses of duration of use by recency showed an attenuation of the risk over time (duration of 10 years: <15 years since last use hr: 0.27; 95% ci: 0.15 to 0.49; 15+ years since last use hr: 0.61; 95% ci: 0.37 to 0.98). Multivariate and stratified BRCA2-analyses were underpowered; however, univariate analyses suggested an inverse association with longer duration of use (<5 years hr: 1.01; 95% ci: 0.49 to 2.10; 5–9.9 years hr: 0.46; 95% ci: 0.22 to 0.96; 10+ years hr: 0.61; 95% ci: 0.29 to 1.27).

Conclusions

For BRCA1 mutation carriers, ocp use is inversely associated with ovarian cancer risk, which is stronger with a longer duration. This reduced risk is attenuated over time, but still significantly reduced 15 years after use. For BRCA2 mutation carriers, findings are consistent, but lack power.

In clinical management, associations of ocp use with both breast and ovarian cancer have to be considered. We will calculate the sum of the absolute excess incidence and mortality of breast cancer and the absolute reduced incidence and mortality of ovarian cancer, varying relative risks, ocp duration, and the uptake of prophylactic surgeries. Results of those calculations will be presented at brca 2018.

AUTHOR AFFILIATIONS

*Netherlands Cancer Institute, Amsterdam, Netherlands;,
Lund University Hospital, Lund, Sweden;,
Peter MacCallum Cancer Centre and,
§The University of Melbourne, Melbourne, VIC, Australia;,
Columbia University, New York, NY, and,
#University of Utah School of Medicine, Salt Lake City, UT, U.S.A.;,
**Technische Universität Dresden, Dresden, and,
††University of Leipzig, Leipzig, Germany; inserm U900 Paris, Paris, France; and University of Cambridge, Cambridge, U.K..


Posters

Poster P048: Nurses’ Roles and Contribution in Breast Cancer Genetic Services in Hong Kong


Ling-Fun Lo*, Annie Tsz-Wai Chu*, Winner Cheng, Ava Kwong*,


ABSTRACT

Background

The Hong Kong Hereditary Breast Cancer Registry has established a program to support Hong Kong patients and families in need of genetic counselling and testing services at Tung Wah Hospital since 2007. Advances in dna sequencing technology, reduction in cost, and increasing availability have resulted in increasing demands for genetic counselling. In Asia, there is a lack of genetic counsellors and hence a pragmatic need to increase the roles of nurses in cancer genetic services to meet the demand.

Methods

Since 2013, the team has adopted a new model that involves trained specialty nurses to assist in the multidisciplinary cancer genetic services under supervision. Nurse roles include initial screening of referrals, taking family history, pedigree drawing, and consolidating medical records for eligible cases. Clinical decisions will be made by the supervisory genetics team, and individuals with a true negative genetic test result will be assigned to see trained nurses to receive their results and be discharged.

Results

During 2013–2016, 1030 patients attended our nurse-led genetics counselling service to receive their genetic reports. Average genetic counselling time was approximately 30 minutes. The nurses-led genetics counselling service achieved a 30% reduction in patient waiting time to obtain results.

Conclusions

Nurses can be trained to contribute more in cancer genetics services to enhance the efficiency of running a high-risk clinic and shorten patient waiting time, particularly in Asia where genetic counsellors are a rarity. With multigene panel testing and the concept of population-based genetic testing being introduced, different methods of genetic counselling rather than the traditional method will likely have to be designed based on the resources available in various countries. In our locality, the assistance of nurse-led genetic services is likely to aid in the expansion of genetic services in Hong Kong.

AUTHOR AFFILIATIONS

*The University of Hong Kong,,
Hung Chao Hong Integrated Centre for Breast Diseases, Tung Wah Hospital, and,
Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, P.R.C..


Posters

Poster P049: Acting on BRCA: Breaking Down Barriers to Save Lives. Recommendations to the U.K. Government on BRCA Testing and Patient Management from Ovarian Cancer Action


Marie-Claire Platt, Joanne Stanford, Georgina Tharp


ABSTRACT

BRCA testing could prevent up to 1000 cases of ovarian cancer in the United Kingdom each year. Ovarian Cancer Action is committed to maximizing and fulfilling the potential of BRCA testing as an effective cancer prevention tool.

To assess current rates of testing in the United Kingdom, the charity carried out research that included commissioning surveys, interviews with case studies, Freedom of Information Requests, and literature reviews.

Quantitative data from the survey revealed that, despite current guidelines, 29% of women diagnosed with ovarian cancer after 2015 were not offered testing, and 68% of women diagnosed before 2015 had not been offered testing. Of individuals found to have a mutation, 42% received no counselling after their test results. Only 34% were given support about choosing the right risk-reducing method for them.

Qualitative data yielded insight into patient experiences and the challenges faced, particularly in terms of psychological counselling after testing and lack of support concerning risk-reducing surgery, family planning, and hormone replacement therapy.

Combining the collected data, the charity makes detailed recommendations for the U.K. Government. Those recommendations include to embed BRCA testing in National Institute for Health and Care Excellence guidelines, specifically at the point of an ovarian cancer diagnosis; to contact women diagnosed with ovarian cancer before 2015 to inform them of their eligibility for BRCA testing; to lower the testing eligibility threshold from 10% to 5% carrier probability; and to ensure that patients have access to high-quality standardized information.

With 24 recommendations in total, Ovarian Cancer Action is calling on the government to improve genetic testing services in the United Kingdom to save lives.

AUTHOR AFFILIATIONS

Ovarian Cancer Action, London, U.K..


Posters

Poster P050: Diagnostic Yield and Genetic Counselling Challenges of a 19-Gene Hereditary Breast and Ovarian Cancer Panel: The Trillium Health Partners Experience


Elaine Suk-Ying Goh*,, Shamini Selvarajah*,, Cynthia Forster-Gibson*,, Linda Kim*,, Donna Cushing*, Nicole Forster*, Marsha Speevak*,, Andrea Vaags*,


ABSTRACT

The rapid adoption of next-generation sequencing (ngs) and identification of additional non-BRCA1/2 genetic factors in hereditary breast and ovarian cancer (hboc) has led to a paradigm shift in genetic testing. However, multigene panels pose several challenges: interpretation of sequence variants in less-well-characterized genes, balancing diagnostic yield with the identification of more variants of unknown significance (vus), and genetic counselling dilemmas in complex cases.

As an academic community hospital providing a regional Genetics program, Trillium Health Partners has been offering a 19-gene hboc ngs panel since April 2017 based on Ontario’s testing criteria. To compare the diagnostic yield and vus rate of the ngs panel compared with Sanger sequencing for BRCA1/2 only, hboc cases tested through the panel (n = 334) were compared with cases tested by Sanger-only from the preceding 2 years (n = 723). Based on this retrospective analysis, the diagnostic yield was 14.1% (n = 47/334) for pathogenic and likely pathogenic variants in the group tested by the panel compared with 11.2% (n = 81/723) in the group tested for BRCA1/2 alone. The corresponding vus rates were 19.5% (n = 65/334) and 6.9% (n = 50/723).

Genetic counselling challenges specific to panel test interpretation included relaying the clinical relevance of variants in medium- and low- penetrance genes, particularly if the associated cancer risks did not match the reported family history. With panel testing, the diagnostic yield has increased and is comparable to that described in recent literature, while the clinical complexity of results interpretation highlights several challenges. We propose some strategies for pre- and post-test genetic counselling in this context.

AUTHOR AFFILIATIONS

*Trillium Health Partners, Mississauga, and,
University of Toronto, Toronto, ON..


Posters

Poster P051: Is It Really Worth It? An Experience with Contacting Past Patients for Updated Testing


Kathryn Zarnawski, Janice Christiansen, Julie Handy, Priya Gor, Noah Lindenberg


ABSTRACT

Purpose

With constant advances in genetics knowledge and testing technology, genetic counsellors are often tasked with determining whether they have a duty to inform previous patients of such updates. Many factors have to be considered, including the motivation of patients, contact methods, response rates, and overall clinical utility; however, the process is not well documented in the literature.

Methods

Here, we present our experience at Virtua, a community-based hospital in New Jersey, in which we contacted patients seen through our Cancer Genetics program from 2003 to July 2015 who had previously undergone BRCA1/2 analysis and were offered additional genetic testing. In June 2016, 1764 patients were contacted by e-mailed newsletter, which included a leading article about the option of additional genetic testing. Afterward, from August 2016 through July 2017, 1898 personal letters were mailed.

Results

After distribution of the newsletter, 13 patients (0.74%) contacted us, and after receiving the mailed letter, an additional 107 patients contacted us (120 patients total, 6.3% response rate). Of those 120 patients, 87 (72.5%) were seen by 1 of 3 genetic counsellors, and 82 (94.2%) elected to pursue additional testing. Only 1 patient (1.2%) received a result that altered clinical management (pathogenic CHEK2 alteration). In 16 patients (19.5%), at least 1 variant of uncertain significance (vus) was found; the remaining patients were negative.

Conclusions

Our experience indicates that mail contact is a more effective method than e-mail contact and suggests that we may have to consider the feasibility, design, and benefits of such a project in the future, given the low overall response rates and clinical utility.

AUTHOR AFFILIATIONS

Penn Medicine Virtua Cancer Program, NJ, U.S.A..


Posters

Poster P052: Next-Generation Counselling: A Model for Hereditary Cancer Genetic Test Results Disclosure and Counselling


Kristin Price, Rotem Ben-Shachar, Beth Denne, Kaylene Ready, Gabriel Lazarin


ABSTRACT

Objective

Because of changing guidelines and increased patient demand, hereditary cancer screening (hcs), including testing and counselling, is increasingly being performed by non-genetics specialists in the United States. Genetic counselling is an important aspect of hcs, but many patients cannot access counselling services. Our laboratory provides genetic testing, as well as a proprietary service called Counsyl Complete that includes automated results delivery, Web-based education, and telegenetic counselling. We report how this service is used for patients undergoing hcs.

Methods

The results delivery service is an opt-in program for ordering providers and allows patients to receive results through a secure patient portal in tandem with provider receipt of results. Negative results and variants of uncertain significance (vus) results can be viewed immediately, accompanied by written and video resources. Additionally, patients have the option to speak with a genetic counsellor on-demand or schedule an appointment. Patients with positive results can be informed only during a genetic counselling appointment or by the ordering provider. All patient interactions are tracked and consult notes are sent to the ordering provider.

Results

Between April 2015 and December 2017, 21,247 hcs results were issued through the system. Genetic consults were conducted for 4109 results. 57% of positive results, 14% of negative results, and 30% of vus results were accompanied by telegenetic counselling. 53% of consults were completed on-demand. Median consultation time was 15 minutes (iqr: 10–22) for positive, 11 minutes (iqr: 8–16) for negative, and 15 minutes (iqr: 10–20) for vus results. The mean patient satisfaction rating for consultations was 4.9/5.

Conclusions

Using Web education, automated notifications, and telegenetic counselling, we implemented a service that manages hcs results disclosure as a companion to results discussion and management by a health care provider. This method could help overcome barriers to access to hcs for a broader population.

AUTHOR AFFILIATIONS

Counsyl, Inc., San Francisco, CA, U.S.A..


Posters

Poster P053: Addressing Barriers for Rapid Cancer Genetic Counselling: Triage System for Treatment-Focused Genetic Testing


Amanda Morgan*, Nora Wong


ABSTRACT

Objective

The objective of this study is to determine the effectiveness of the new hereditary breast and ovarian cancer (hboc) referral triage system implemented since December 2014 at the Jewish General Hospital in Montreal, Quebec. The new system aims to prioritize affected patients by decreasing the turnaround time from referral to result-giving, so that genetic results can be used to inform treatment options and management of affected patients. Analysis of the mutation yield is expected to provide insights for improvement of the triage process and resource allocation.

Methods

A retrospective chart review is in progress to assess the performance of the new hboc referral triage system at the Jewish General Hospital. Eligibility for the study included all referrals sent for a breast and ovarian cancer assessment between January 2015 and August 2017. Patient demographics, referral information, wait times, clinical characteristics, and results of genetic testing will be extracted and summarized. Yield of genetic testing will be analyzed by referral criteria using the chi-square and Fisher exact tests.

Expected Results

We focused on determining whether the current hboc referral criteria used by the triage team are performing at the expected 10% detection rate. Initial analysis shows that most of the referral criteria are performing as expected and target wait-times are being met. In the group that did not fulfill the established criteria, but were granted special consideration by the triage group, initial findings suggest a lower mutation yield.

Conclusions

As the demand for treatment-focused genetic testing becomes more prevalent, so does the need for genetics departments to prioritize patients by both utility of genetic testing and by the likelihood of identifying a mutation. This study provides the first evidence of the effectiveness of the new triage system at the Jewish General Hospital for meeting wait-time targets and highlights points for future improvement.

AUTHOR AFFILIATIONS

*McGill University and,
Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC..


Posters

Poster P054: BRCA1/2 Genetic Testing Ordering Practices: A Snapshot from a Large Commercial Laboratory


Dagny Noeth, Eric Bowyer, Christine Riordan, Mary Hricik, Elizabeth Lyon, Melissa Hayden, Alecia Willis


ABSTRACT

BRCA1/2 genetic testing orders received at LabCorp for a period of 4 weeks in 2017 were analyzed for their clinical appropriateness and tracked through reporting to ascertain trends in the hereditary breast and ovarian cancer ordering practices of providers. All test orders are reviewed by genetic counsellors and, during this period, 94 (approximately 15% of total orders) were identified that required a discussion of alternative testing with the ordering provider.

Of the tests that were able to be updated, more than half (61.73%) were updated to BRCA1/2 sequencing and deletion/duplication testing (BRCA1/2 comprehensive) from either an order of BRCA1 or BRCA2 targeted testing or a deletion/duplication–only order. Without genetic counsellor clarification of those test orders, only 3 (6%) total would have had BRCA1/2 comprehensive testing performed, and only 1 of 5 medically actionable results would have been reported. Orders that were not updated to BRCA1/2 comprehensive testing were either cancelled because of a lack of response from the ordering physician (13.83%) or were updated to a more comprehensive cancer genetic testing panel (38.27%). More comprehensive genetic testing panels include expanded breast cancer panels (9.68%), breast and gynecologic cancer panels (41.94%), general cancer panels (35.48%), or other testing. Of these samples, 18 (58.06%) received results, with 1 being a medically actionable result in a gene other than BRCA1/2. Most of the test orders were received from primary care physicians and general internists (59.57%) and from obstetricians and gynecologists (29.79%). Other specialists placed test orders, but none involved a clinical genetic counsellor.

These data represent the larger testing trends of BRCA1/2 ordering at LabCorp. It suggests that laboratory genetic counsellor review of complicated testing improves the clinical appropriateness of genetic testing ordered by non-genetic specialists.

AUTHOR AFFILIATIONS

LabCorp Center for Molecular Biology and Pathology, Durham, NC, U.S.A..


Posters

Poster P055: Portrait de l’oncogénétique au Québec en 2017


Jocelyne Chiquette


ABSTRACT

Objectifs

Évaluer les différents aspects de la pratique en oncogénétique au Québec.

Méthodes

Un sondage effectué auprès des 7 cliniques de génétique du Québec, de 2 ch membres du Réseau rose et de 5 centres privés effectuant des consultations et des tests en oncogénétique.

Un courriel envoyé à la présidente de l’Association des conseillères et conseillers en génétique du Québec qui a répondu. Consultation du site Web de l’Association des médecins généticiens du Québec.

Résultats

9 des 9 centres publics sondés ont répondu : 7 des 7 cliniques de génétique et les 2 ch du Réseau rose. 1 seul des 5 centres privés a répondu pour un total de 10 réponses.

Les effectifs sont peu nombreux : 10 généticiens, 4 omnipraticiens, 4 médecins spécialistes, 2 infirmières, 16 conseillères en génétique répartis comme suit : 29 personnes pour le conseil génétique et 7 pour le suivi des porteuses.

Les consultations en oncogénétique se répartissent ainsi dans les centres : 30 %–100 % seins-ovaires; 0 %–40 % côlon; 0 %–40 % autres tumeurs.

Parmi les 10 centres répondants : 7 ont un registre des tests effectués; 9 effectuent des panels multigènes; 3 ont eu des patients ayant fait des tests en ligne; 8 font des tests en urgence; 7 font le suivi de porteuses; 8 offrent du soutien psychologique; 7 utilisent le Réseau rose.

Les liste d’attente varient de 0 à 1453 personnes et le délai d’attente varie selon la priorité de 2 semaines (ou moins) à plus de 1 an.

Conclusions

Face à l’augmentation prévue des demandes a-t-on des effectifs suffisants au Québec avec les 30 généticiens et les 50 conseillères dont un faible pourcentage seulement fait de l’oncogénétique. Un réseau clinique multidisciplinaire est une solution possible.

AUTHOR AFFILIATIONS

chu de Québec-Université Laval, Québec and Réseau rose, QC..


Posters

Poster P056: Prevalence and Oncologic Outcomes of BRCA1 and BRCA2 Germline Mutations in Unselected Patients with Triple-Negative Breast Cancer


Jai Min Ryu, Seok Won Kim, Seok Jin Nam, Jonghan Yu, Se Kyung Lee, Jeong Eon Lee


ABSTRACT

Introduction

Triple-negative breast cancer (tnbc) accounts for 15%–20% of all breast cancers, and tnbc is enriched for germline mutation of BRCA. U.S. National Comprehensive Cancer Network guidelines suggest that a BRCA1/2 test is needed for patients less than 60 years of age with tnbc, but many Asian countries do not suggest testing because of a lack of evidence in Asian ethnic populations. We examined BRCA1/2 mutation in patients with unselected tnbc and analyzed prognosis.

Methods

For 1051 women with tnbc operated on at Samsung Medical Center (smc) between 2008 to 2016, 999 samples were available from the smc biobank for testing germline BRCA1/2 mutation by next-generation sequencing. All patients were Korean.

Results

The mean follow-up duration was 60.0 months. Overall, 125 patients (12.5%) had BRCA mutations: 92 (9.2%) in BRCA1, and 33 (3.3%) in BRCA2. Median age was 49.7 years. Mean age of diagnosis was significantly younger in BRCA1/2 mutation carriers than in noncarriers (45.4 years vs. 50.3 years, p < 0.0001). In patients less than 50 years of age with tnbc, the prevalence of BRCA mutation was 16.0%. No significant difference in os and dfs was observed between patients with BRCA1/2 and sporadic breast cancers (log-rank p = 0.138 and 0.993 respectively). Significantly more contralateral breast cancer is observed in patient with BRCA1/2 mutation (p = 0.000).

Conclusions

We found a 12.5% incidence of BRCA mutations in unselected tnbc. Patients less than 50 years of age with tnbc should be added as criteria to genetic screening guidelines in Korea.

AUTHOR AFFILIATIONS

Samsung Medical Center and KOHBRA study investigators, Seoul, R.O.K..


Posters

Poster P058: Group Counselling for Breast Cancer Genetics: Perspectives of Women at Risk for HBOC


Jacklyn Hynes*, Andrée MacMillan, Sara Fernandez, Karen Jacob, Shannon Carter, Sara Predham, Holly Etchegary*, Lesa Dawson*


ABSTRACT

Background

Genetic counselling is a standard of care before BRCA mutation testing. Access to timely counselling and testing is limited by time constraints and a shortage of trained health care professionals. The purpose of this quality improvement initiative was to explore whether pre-test group counselling for breast cancer genetics, followed by a “mini” individual session, would be acceptable to women at risk for BRCA in Newfoundland and Labrador.

Methods

60 women on the wait list for BRCA genetic testing through the Provincial Medical Genetics Program in St. John’s, NL, were included. Between July 2016 and October 2017, women were called and offered the option of a group counselling session, followed by a mini (∼20 minutes) individual session of genetic counselling, versus waiting for their individual appointments. All women agreed to the group and mini session. A 12-item Likert survey was distributed after the conclusion of the mini session; it measured the women’s perceptions of the group clinic and satisfaction with the counselling model.

Results

Responses to all 12 items were overwhelmingly positive. Large proportions strongly agreed that they were comfortable with the group session: the explanation of cancer genetics was clear, they understood their cancer risks, and they would recommend such a session to others. Women strongly disagreed they would prefer to wait for an individual appointment. Genetic counsellors were also very satisfied with the new model, and the waitlist for BRCA counselling and testing was reduced by a year.

Conclusions

Results of this quality improvement initiative revealed very positive evaluations from all participants and counsellors. Data suggest that group counselling combined with an immediate individual “mini” session is strongly supported by women on the wait list for BRCA mutation counselling. Further, a reduction in wait time was observed. Additional investigation of this approach in larger numbers of patients is warranted.

AUTHOR AFFILIATIONS

*Memorial University and,
Provincial Medical Genetics Program, St. John’s, NL..


Posters

Poster P059: Assessing Cascade Carrier Testing for Hereditary Cancer Across a Publicly-Funded Provincial Program


Vivienne K. Beard*, Angela C. Bedard, Jennifer Nuk, Sean Young, Stephen Yip, James E.J. Bedard*, Sophie Sun, Kasmintan A. Schrader


ABSTRACT

Introduction

Cascade carrier testing for hereditary cancer enables the identification of at-risk individuals most likely to benefit from increased screening and preventive measures. Despite predicted positive health outcomes, there is a paucity of recent literature on the uptake and health impact of program-wide carrier testing for hereditary cancer.

Methods

We assessed carrier testing uptake and demographic factors between 1 January 1997 and 31 December 2016 for families in which the index patient received testing through the Hereditary Cancer Program (hcp) in British Columbia. We began with BRCA1 and BRCA2, and will be conducting additional analyses on other high- and moderate-penetrance genes tested by the hcp. Future analyses will elucidate the health effects of carrier testing for hereditary breast and ovarian cancer syndromes.

Results

A total of 424 and 398 positive BRCA1 and BRCA2 index cases have, respectively, been identified through our provincial program; carrier testing for at-risk family members has been performed for 723 and 664 individuals for BRCA1 and BRCA2 respectively. 45% (323/723) tested positive for a BRCA1 mutation, and 45% tested positive for a mutation in BRCA2 (298/664). The average age of individuals receiving carrier testing for BRCA1 was 46.0 ± 15.9 years; it was 47.7 ± 16.3 years for BRCA2. A significantly higher number of women (n = 1051) than men (n = 336) received carrier testing for BRCA1 and BRCA2 (p < 0.01). In families with pathogenic or likely pathogenic mutations in BRCA1 and BRCA2, 1.7 carrier tests (mean) per index test were performed. Carrier testing uptake corresponded with the geographic population distribution of the province.

Conclusions

This analysis highlights the carrier testing uptake for BRCA1 and BRCA2 mutations in the population served by the hcp. Future analyses could inform decisions about how resources might be allocated to better serve this high-risk population.

AUTHOR AFFILIATIONS

*University of the Fraser Valley, Abbotsford,,
Hereditary Cancer Program, BC Cancer, Vancouver, and,
The University of British Columbia, Vancouver, BC..


Posters

Poster P060: Polygenic Risk Score Refines Clinical Risk Model Estimates : in a Population-Based Trial


Irene Acerbi*, Yiwey Shieh*, Allison Stover Fiscalini*, Lisa Madlensky, Jeffrey A. Tice*, Elad Ziv*, Martin Eklund, Amie Blanco*, Hoda Anton-Culver§, Alexander Borowsky, Andrea LaCroix, Arash Naeim#, Laura Esserman*, Laura van ‘t Veer*, Wisdom Study and Athena Breast Health Network Investigators and Advocate Partners*


ABSTRACT

Background

Genetic variants known as single nucleotide polymorphisms (snps) are promising markers of breast cancer risk. wisdom (Women Informed to Screen Depending on Measures of Risk) is the first prospective trial comparing personalized with annual breast cancer screening. Personalized screening recommendations are based on sequencing of hereditary breast cancer genes and a 5-year risk estimate from the Breast Cancer Surveillance Consortium (bcsc) risk model modified by a polygenic risk score (prs) comprised of 75 snps. wisdom allows risk model performance to be compared in a population setting.

Methods

The wisdom study (NCT02620852) opened in 2016 and is enrolling women 40–74 years of age. Self-reported demographic and risk factor information was collected through an online portal. snp genotyping was done using a panel from Color Genomics. Here we used paired statistical tests (McNemar) to compare the distributions of bcsc and bcsc-prs risk estimates around a low-risk threshold (<1%), a moderately high-risk threshold (=3%, corresponding to a 5-year risk above which some guidelines suggest chemoprevention), and a very high-risk threshold (>6%, corresponding to the 5-year risk of a BRCA mutation carrier).

Results

We analyzed 2060 participants in the personalized arm of wisdom who have completed risk assessment. The median age was 56 years, with 83% being Caucasian, 1% African American, and 7% Asian. 10% self- reported as Hispanic. The median 5-year risk was 1.5% (iqr: 1.0%–2.1%) using the bcsc model and 1.4% (iqr: 0.8%–2.5%) using the bcsc-prs model. Compared with the bcsc model, the bcsc-prs model classified more women into the low-risk (<1%) and the moderately high-risk or very high-risk (=3% or >6%) risk categories (p < 0.001).

Conclusions

Our findings suggest that incorporating genetic variants into a validated clinical model is feasible and could enhance risk prediction.

AUTHOR AFFILIATIONS

*University of California–San Francisco, San Francisco, CA, and,
University of California–San Diego, San Diego, CA, U.S.A.;,
Karolinska Institutet, Stockholm, Sweden;,
§University of California–Irvine, Irvine, CA,,
University of California–Davis, Sacramento, CA, and,
#University of California–Los Angeles, Los Angeles, CA, U.S.A..


Posters

Poster P061: Genetic Counselling and Testing for Hereditary Breast and Ovarian Cancer: 22 Years’ Experience in a Single Swiss Institution


Aurélie Ayme*, Valeria Viassolo*, Anne Murphy*, Isabelle Gauchat-Bouchardy*, Thomas von Känel, Thomas A. McKee*, Pierre O. Chappuis*


ABSTRACT

Objective

Genetic counselling and testing for cancer predisposition syndromes have been available in a clinical setting for many years. In this study, we assessed genetic consultation and testing, particularly for hereditary breast and ovarian cancer (hboc) syndromes, performed for more than 20 years in a single Swiss university hospital.

Methods

All pedigrees of probands managed in the Unit of Oncogenetics and Cancer Prevention in the Geneva University Hospitals between 1996 and 2017 were reviewed. Types of consultation were classified according to personal or family history. For pedigrees suggestive of hboc syndrome or familial breast or ovarian cancer, we collected brcapro scores and, if performed, genetic testing results. Over time, we evaluated the medical history of probands referred to counselling, the clinical criteria and brcapro scores used to propose genetic testing, and the rate of pathogenic variants identified.

Results

Between 1996 and 2017, 3489 consecutive probands from distinct families had genetic counselling. New families managed per year increased over time, and thus half the families have been seen since May 2013. Altogether, 66% of all consultations concerned familial or hereditary breast or ovarian cancer; 12%, familial or hereditary colorectal cancer; and 22%, other situations. Overall, 1253 genetic analyses for hboc were performed, with a spectacular increase over time. 149 (11.9%) pathogenic variants (81 BRCA1, 67 BRCA2, 1 ATM) were identified. The mutation detection rate was 15% during 1996–2002, 18.5% during 2003–2009, and 10% during 2010–2017. Mean brcapro scores decreased to about 1% in 2017 from 10% before 2010. The number of asymptomatic index cases increased to 15% after 2010 from 9% before 2010.

Conclusions

Genetic counselling and testing for hboc drastically increased over time. The rate of pathogenic variants detection decreased, concurrently with a decrease in brcapro scores and the proportion of index cases affected by cancer. Swiss guidelines for counselling and testing for genetic predisposition to hboc were set up in 2017.

AUTHOR AFFILIATIONS

*Geneva University Hospitals, Geneva, and,
Institut Central des Hôpitaux, Hôpital du Valais, Sion, Switzerland..


Posters

Poster P062: Age-Specific Ovarian Cancer Risks Among Young Women : with a BRCA1 or BRCA2 Mutation


Joanne Kotsopoulos*,, Jacek Gronwald, Beth Karlan§, Barry Rosen, Tomasz Huzarski, Pal Moller#, Henry T. Lynch**, Christian F. Singer††, Leigha Senter‡‡, Susan L. Neuhausen§§, Nadine Tung‖‖, Andrea Eisen##, William D. Foulkes***, Peter Ainsworth†††, Ping Sun*

†††London Health Sciences, London, ON.

ABSTRACT

For women at high risk of developing ovarian cancer, it is important to provide an accurate recommendation for the optimal age for preventive surgery to maximize cancer prevention while delaying symptoms associated with early surgical menopause. The goal of the current study was to estimate age-specific incidence rates of ovarian cancer among young women with a BRCA1 or BRCA2 mutation.

From our international registry, we identified 5689 women with no previous diagnosis of ovarian or fallopian tube cancer or preventive oophorectomy. Women were followed from the date of completion of the baseline questionnaire until either a diagnosis of ovarian or fallopian tube cancer, prophylactic oophorectomy, death, or last follow-up. The annual and cumulative incidence rates of ovarian cancer were estimated. Over a mean follow-up period of 4.7 years (range: 0–22.6 years), 195 incident ovarian or fallopian tube cancers were diagnosed [169 ovarian cancers (86%), 22 fallopian tube cancers (11%), and 4 cancers that involved both the ovaries and fallopian tubes (2%)]. Of those cancers, 45 (23%) were diagnosed at preventive surgery (occult cancers). The cumulative risk of ovarian cancer to age 80 was 49% for BRCA1 and 21% for BRCA2 mutation carriers. Mean age at diagnosis was 51.3 years (range: 33–84 years) among women with a BRCA1 mutation and 61.4 years (range: 44–80 years) among women with a BRCA2 mutation. Based on a cumulative risk of 0.55% to age 35 for BRCA1 mutation carriers and 0.56% to age 45 for BRCA2 mutation carriers, we recommend bilateral salpingo-oophorectomy at age 35 for women with a BRCA1 mutation and age 45 for those with a BRCA2 mutation to maximize prevention.

AUTHOR AFFILIATIONS

*Women’s College Hospital and,
University of Toronto, Toronto, ON;,
Pomeranian Medical University, Poland;,
§Cedars Sinai Medical Center, Los Angeles, CA, U.S.A.;,
University of Toronto, Toronto, ON;,
#The Norwegian Radium Hospital, Oslo, Norway;,
**Creighton University School of Medicine, Omaha, NE, U.S.A.;,
††Medical University of Vienna, Vienna, Austria;,
‡‡The Ohio State University Medical Center, Comprehensive Cancer Center, Columbus, OH,
§§Division of Biomarkers of Early Detection and Prevention, City of Hope, CA and,
‖‖Beth Israel Deaconess Medical Center, Boston, MA, U.S.A.;,
##Toronto–Sunnybrook Regional Cancer Centre, Toronto, ON;,
***McGill University, Montreal, QC;,
†††London Health Sciences, London, ON..


Posters

Poster P063: Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: First Year of a Low-Cost, Accessible Family Testing Program


Elaine Chen*, Jennifer L. Caswell-Jin, Anjali Zimmer*, Will McFadden*, Kerry E. Kingham, James M. Ford, Alicia Zhou*, Allison W. Kurian


ABSTRACT

To achieve the goal of genetically-targeted primary disease prevention, testing for an identified familial mutation must extend to unaffected relatives in a process known as “cascade testing.” However, there are major barriers to effective cascade testing of relatives, including cost, insurance constraints, and confidentiality laws.

We report on the first year of a low-cost, accessible cascade testing initiative offered by a testing laboratory and supported by a genetics-focused foundation. The family testing program allowed 1st-degree relatives (fdrs) of individuals (“carriers”) with a pathogenic variant in any of 30 cancer-associated genes, including BRCA1 and BRCA2, to be invited to undergo testing at an out-of-pocket cost of US$50. The fdrs were invited by e-mails directly from the testing laboratory.

From 27 September 2016 to 26 September 2017, 1118 applicants (748 carriers, 370 fdrs) invited 2645 fdrs. Of the carriers, 44.0% had a BRCA1 (n = 221) or BRCA2 (n = 271) mutation. More than half (56.0%) of all invited fdrs underwent genetic testing. Uptake specifically by fdrs of BRCA carriers was similar to that by all carriers: 56.8% for BRCA1 and 57.2% for BRCA2. Of the 1480 invited fdrs who underwent genetic testing, 46% tested positive for the known familial pathogenic variant (kfpv) only; 1.6% tested positive for the kfpv and for a pathogenic variant in a different gene; 3.4% tested positive for a pathogenic variant in a different gene only; 7.6% had a variant of uncertain significance, but no pathogenic variant; and the remaining 41% had normal results. Among all invited fdrs who tested positive, 11% continued the cascade by inviting other fdrs.

Future research should explore relatives’ motivations and barriers to testing and strategies to integrate clinician expertise with low-cost, direct-contact approaches to cascade testing.

AUTHOR AFFILIATIONS

*Color Genomics, Burlingame, and,
Stanford University School of Medicine, Stanford, CA, U.S.A..


Posters

Poster P064: Portrait of a Divorce: When Variants of Unknown Significance and Cancer History Are Not Meant to Be


Corinne Serruya*, Wejdan M. Alenezi*,, The Montreal Hereditary Breast and Ovarian Cancer Study Group, Patricia N. Tonin*,


ABSTRACT

When patients come to a hereditary cancer clinic, their expectation is that genetic testing will provide a more precise estimate of their cancer risk, which may in turn affect their clinical management. The ultimate goal is to decrease the morbidity and mortality associated with a potential cancer diagnosis by methods that include increased surveillance or prophylactic surgery. The identification of mutations in the highly-penetrant hereditary breast and ovarian cancer (hboc) susceptibility genes BRCA1 and BRCA2 provides a well-established example of this. With the advent of next-generation sequencing (ngs), the classification of some variants in known or proposed cancer predisposing genes as variants of unknown clinical significance (vus) has led to the complicated issue of untangling rare but non-pathogenic variants from those that might confer an increased risk of disease.

An example from our lab to illustrate this potential conundrum follows whole-exome sequencing (wes) performed on 14 families of French Canadian descent with at least 2 cases of ovarian cancer (oc) in 1st-degree relatives, where a pathogenic BRCA1 or BRCA2 mutation had previously been identified by panel testing. Of those families, 6/14 (42.9%) were found to carry a rare vus (minor allele frequency < 0.1%), including 1 in MSH2, which reportedly has a role in oc. In 2 families, 1 or more vuss in other genes were detected. Interestingly, vuss in PALB2 and CHEK2 were identified in women who also had a personal and family history of breast cancer. If these multi-case oc families had not harboured known BRCA1 and BRCA2 mutations, one could argue whether it would have been tempting to assign disease causality to the vus, especially when identified in a gene already suggested to have a role in susceptibility to the diagnosed cancer. Cautionary interpretation of vuss remains essential in research and clinical settings.

AUTHOR AFFILIATIONS

*The Research Institute of the McGill University Health Centre and,
McGill University, Montreal, QC..


Posters

Poster P065: Case Presentation: Unexpected Findings from a Hereditary Breast/Ovarian Cancer Panel


Ingrid Ambus, Lea Velsher, Sonya Grewal, Peter Sabatini, Hong Wang


ABSTRACT

A 68-year-old woman was referred for genetic counselling to discuss her personal history of bilateral breast cancer diagnosed at ages 50 and 68, squamous cell skin cancer, and a keratoacanthoma diagnosed at age 66. Her family history included esophageal, bladder, and colon cancer. She was given a moderate risk for a hereditary cancer syndrome and initially declined testing.

Two years later, the patient was re-referred. Immunohistochemistry on the keratoacanthoma was intact, making Lynch syndrome less likely. A breast/ovarian 18-gene next-generation sequencing (ngs) cancer panel return a result of uninterpretable because of “a mixed genetic profile.” A skewed allele frequency was seen for some common sequence variants in BRCA1, but not BRCA2. Quantitative fluorescence polymerase chain reaction showed 2 female profiles, with some shared alleles on chromosomes 13, 21, and X. A bone marrow transplant was ruled out, leaving the possibility of sample mix-up or contamination. Results from a second blood sample were consistent with the original, showing skewed allele frequencies in BRCA1 and several other genes. The normal cut-off for heterozygous state allele frequency is 0.3–0.7. For this patient, the skewed ratios were ∼0.22. The variants with normal allele frequencies likely shared the same haplotype.

Two female profiles were seen consistently on both testing attempts. This patient is likely a chimera (one individual with two distinct genotypes). In follow-up, we discussed the unknown frequency of this rare event, how chimerism can occur (that is, vanishing twin), and the implications for the patient overall. Ultimately, ngs technology was unable to provide a result, and no other affected relatives are available for gene panel testing. This is the first time our lab has come across this situation in the context of ngs cancer gene panel testing, and the first time our clinical staff have counselled on this complex issue.

AUTHOR AFFILIATIONS

North York General Hospital, Toronto, ON..


Posters

Poster P066: Implementation of Oncology Clinic–Based Genetic Testing in the Population-Based Health Care System of British Columbia


Matthew Richardson*, Hae Jung Min, Katie Compton, Sze Wing Mung, Zoe Lohn, Jennifer Nuk, Mary McCullum, Cheryl Portigal-Todd, Aly Karsan*,, Dean Regier*,§, Lori Brotto*, Sophie Sun*,, Kasmintan A. Schrader*,


ABSTRACT

Patients of BC Cancer’s Hereditary Cancer Program are experiencing extended wait times for genetic counselling appointments and genetic testing results because of increasing demand for services. To reduce patient wait times, we implemented a modified strategy that was pioneered in the United Kingdom by George et al. (2016), where oncologists are given a more substantial role in the genetic testing and counselling process.

After completing a brief orientation, participating oncologists were able to initiate genetic testing for selected patients, who then received genetic test results from a genetic counsellor. Over an 18-month period, patients were offered either the standard genetic counselling clinical pathway or the oncologist-initiated (genonc) clinical pathway. Patients in both clinical pathways (n = 155) received a mailed survey package after their genetic test results disclosure appointment.

Key study findings were that patient satisfaction (n = 155) was similar for each clinical pathway and that the timeline to receive genetic test results (n = 1539) was reduced by half (to 170 from 407 days) for the genonc group. In addition, participating oncologists and genetic counsellors confirmed the acceptability and feasibility of the genonc process.

Next steps will focus on increasing the number of participating oncologists and expanding genonc eligibility criteria beyond hereditary breast and ovarian cancer with the goal of significantly reducing wait times for all British Columbia patients seeking hereditary cancer risk assessment.

AUTHOR AFFILIATIONS

*University of British Columbia,,
BC Cancer,,
Michael Smith Genome Sciences Centre, BC Cancer, and,
§Canadian Centre for Applied Research in Cancer Control, BC Cancer, Vancouver, BC..


Posters

Poster P067: Racial and Ethnic Differences in Hereditary Cancer Multigene Panel Testing Results Among Breast Cancer Patients


Hermela Shimelis*, Eric C. Polley*, Jenna Lilyquist*, Jie Na*, Chunling Hu*, Kun Y. Lee*, Steven Hart*, Raymond Moore*, David E. Goldgar, Amal Yussuf, Brigette Tippin-Davis, Tina Pesaran, Jill S. Dolinsky, Fergus J. Couch*, Holly LaDuca


ABSTRACT

Recently, the use of next-generation sequencing panels to aid in the diagnosis of hereditary cancer predisposition has increased. The discovery of pathogenic variants (pvs) in known susceptibility genes leads to focused screening and prevention strategies for individuals at increased risk of cancer. However, studies supporting the utility of multigene panel testing have focused on Caucasian individuals.

To understand the influence of results from panel testing on breast cancer (bca) risk in non-Caucasian individuals, we studied bca cases who underwent hereditary cancer panel testing at Ambry Genetics between 2012 and 2016. The frequency of pvs and variants of unknown significance (vus) in African American, Asian, Caucasian, and Hispanic populations was assessed, and gene-specific bca risk associations were estimated for each population by comparing pv frequencies between bca cases and Genome Aggregation Database African/African American, East Asian, non-Finnish European, and Latino reference controls. African American, Hispanic, and Asian (non-white) bca cases were significantly younger at testing relative to Caucasians (p < 0.05), suggesting population-specific differences in panel testing referral. Across 21 known and candidate bca predisposition genes, similar overall frequencies of pvs were identified in African American, Hispanic, and Caucasian bca cases (∼11%). The pv frequency was relatively lower in Asian cases (∼8%). vus frequency was significantly higher in non-Caucasian bca cases, with the vus frequency being highest among Asian cases. In an exploratory analysis of population- specific bca risk associations, pvs in BRCA1, BRCA2, and PALB2 were associated with high risk of bca across all ethnic groups. However, pvs in the ATM, CHEK2, MSH6, BARD1, and RAD51D moderate-risk genes showed population-specific associations with bca.

These studies provide important insights into the risks of bca associated with predisposition gene mutations in non-Caucasian populations and demonstrate the need for continued investigation of population-specific factors contributing to inherited bca risk.

AUTHOR AFFILIATIONS

*Mayo Clinic, Rochester, MN,,
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, and,
Ambry Genetics, Aliso Viejo, CA, U.S.A..


Posters

Poster P068: Barriers and Opportunities for Genetic Testing of BRCA Mutations in Breast Cancer Across Europe


Saara Akhtar*, Suzanne Wait*, Matthew Cotter, Maia Thrift-Perry


ABSTRACT

Background

This research aims to provide an overview of possible barriers to genetic screening, information, and support for individuals with BRCA+ breast cancer in Europe.

Methods

A pragmatic review of the published and grey literature was conducted. Focusing on 6 countries, we looked for epidemiologic data and assessed which systems, policies, and services are in place for testing, genetic counselling, and care. We also conducted qualitative, semi-structured telephone interviews with thought leaders from across Europe to supplement secondary data findings and identify opportunities for improvement relevant to policymakers and patients.

Results

Current guidelines for BRCA gene testing are insufficient to detect all carriers of BRCA mutations. Testing is restricted to high-risk patients, despite evidence that more than half of those diagnosed with BRCA+ breast cancer do not have a family history of breast cancer. Structural barriers to access to information and services vary greatly between countries. Such barriers include low referrals by physicians, limited knowledge of genetics in a general practitioner setting, and unequal access to genetic screening and counselling based on region, race, and age. Fear of discrimination prevents many people from undergoing screening, particularly in relation to employment or insurance coverage. Additionally, up-to-date prevalence data are rare, making it difficult to estimate the full impact of this condition in the general population.

Conclusions

This research aimed to identify areas in which policy change are needed in genetic testing and care pathways for women with BRCA+ breast cancer. Those areas include greater public awareness, investment in professional training and capacity-building, and reduced inequalities in access to genetic testing. Protection against discrimination for diagnosed patients is also critical in all social policies. Genetic testing should be built into comprehensive care pathways that offer individuals and their families appropriate information, support, and care through every stage of their journey.

AUTHOR AFFILIATIONS

*The Health Policy Partnership, London, U.K.;,
Pfizer Inc., New York, NY, U.S.A..


Posters

Poster P069: Evolving Testing Strategies and Outcomes in the Ashkenazi Jewish Population


Becky Milewski, Lisa Susswein, Katherine Skora, Susan Hiraki, Anna McGill, Rachel T. Klein, Kathleen S. Hruska, Patricia D. Murphy


ABSTRACT

Background

1 in 40 (2.5%) individuals of Ashkenazi Jewish (aj) ancestry will have at least 1 of the 3 ajBRCA1/2 founder variants (ajfvs). Testing for the ajfvs is recommended as a first-line test for aj individuals with histories suggestive of hereditary breast and ovarian cancer syndrome (hboc). We aim to compare testing strategies and outcomes in the aj population to determine if there is a benefit to more comprehensive testing.

Methods

We retrospectively reviewed genetic testing strategies for individuals with self-reported aj ancestry. We then analyzed results to calculate yield for all aj individuals who underwent testing using a select panel of genes related to hboc and who had no previous BRCA1/2 testing.

Results

As of November 2017, 8347 individuals reporting aj ancestry underwent testing. The rate of ajfv testing as a proportion of all testing for aj individuals has remained constant since 2013 (30.0% in 2013 vs. 34.0% in 2017), but the use of panel testing as a first-line approach has increased at an average rate of 27% per year (22% in 2013 to 52% in 2017).

The positive yield among aj individuals tested with the genes of interest was 10.1% (89/885). Of the 93 pvs identified in 89 individuals, 43% (40/93) were ajfvs. The 53 non-ajfvs (57% of all pvs) were identified in CHEK2 (n = 31), FANCC (n = 6), NBN (n = 3), ATM (n = 3), BRCA1 (n = 3), BRCA2 (n = 3), and 1 each in MSH2, MSH6, RAD51C, and XRCC2.

Conclusions

Testing for ajfvs and even BRCA1/2 alone could potentially miss more than 50.0% of pvs in breast/ovarian genes in the aj population. A broader approach to genetic testing among aj individuals has been observed in recent years, often because of mixed ancestry, bilineal risk, and history of non-BRCA1/2–associated cancers, and should continue to be considered.

AUTHOR AFFILIATIONS

GeneDx, Gaithersburg, MD, U.S.A..


Group 2 – Thursday, 10 May 2018

Poster P070: Facteurs psychosociologiques et cliniques impactant la communication familiale et la réalisation des tests dans les familles porteuses d’une mutation des gènes BRCA1/2


Pascal Pujol*, Nathalie Alegre*, Jean Chiesa, Héléna Berthet*, Marie-Christine Picot*, Solange Carton, Aude Michel§, Virginie Galibert*, Ornellia Mophawé*, Isabelle Coupier*, Carole Corsini*, Laura Mathieu, Lydie Bernhard, Yves-Jean Bignon


ABSTRACT

Contexte

Nous avons précédemment montré que seulement un tiers des apparentés potentiellement testables réalise le test ciblé dans une famille où une prédisposition BRCA1/2 a été identifiée (Pujol et al., BCRT, 2013). Le cas-index a un rôle déterminant dans la diffusion de l’information aux apparentés.

Objectifs et méthodes

Cette étude prospective multicentrique vise à identifier les facteurs psychosociologiques et médicaux du cas-index impactant l’information familiale et la réalisation de tests ciblés dans les familles prédisposées. Des questionnaires psychologiques validés ont été recueillis pour mesurer: le trait anxiété (stai), les traits dépressifs (bdi), l’alexithymie (tas-20), les niveaux de conscience émotionnelle (leas), l’optimisme dispositionnel (lot-r), les stratégies de coping (wcc), le vécu de la tâche de messager (échelles eva), et la qualité des relations familiales (fri).

Résultats

103 cas-index porteurs d’une mutation des gènes BRCA1/2 (n = 81) ou mmr (n = 22) ont été inclus. 68% des apparentés qui pouvaient bénéficier d’un test ciblé en avaient été informés. 37% des apparentés informés avaient réalisé un test ciblé. Le taux d’information était inversement corrélé à l’éloignement générationnel (p < 0.0001). En analyse multivariée, les facteurs corrélés à l’information familiale étaient l’ancienneté du diagnostic génétique (p < 0.01) et la cohésion au sein de la famille (fri, p = 0.01). La présence de traits dépressifs chez le cas index était positivement associée à la réalisation de tests ciblés (p = 0.02) et une tendance à un coping centré sur l’émotion était observée (p = 0.09). La réalisation de tests ciblés était négativement associée à une forte perception du risque de cancer chez le cas index (p = 0.03) et un vécu difficile de sa tâche de messager (p = 0.07).

Conclusions

Cette étude permet de mieux comprendre les déterminants psychologiques et relationnels impactant la qualité de l’information et la réalisation des tests au sein de familles prédisposées. Une information et un accompagnement personnalisés du cas-index pourraient améliorer l’accès aux tests dans les familles.

AUTHOR AFFILIATIONS

*chu Montpellier, Montpellier,,
chu de Nîmes, Nîmes,,
Laboratoire Onco, CLCC Jean Perrin, Clermont-Ferrand, and,
§Université Montpellier III Paul Valéry, Montpellier, France..


Posters

Poster P071: An Evaluation of Memory and Attention in BRCA Mutation Carriers Using an Online Cognitive Assessment Tool


Shana J. Kim*, Cindy X.W. Zhang, Angela K. Troyer,§, Steven A. Narod*,§, Joanne Kotsopoulos*,§


ABSTRACT

Background

BRCA mutation carriers might be at risk for cognitive impairment given their uptake of preventive surgery, exposure to chemotherapy, and increased psychosocial distress. In this preliminary evaluation, we used an online assessment tool designed to screen for cognitive deficits (http://www.cogniciti.com) to investigate the effect of potential risk factors on memory and attention in BRCA mutation carriers.

Methods

BRCA mutation carriers from a longitudinal study were invited to complete a validated online brain health assessment that evaluates 4 measures of memory and executive attention. Normative Z-scores were adjusted for age and education level for each task, and an overall cognitive score, approximately equal to a percentile, was calculated from the mean of the Z-scores. Participants reported if they had a past history of any conditions (for example, anxiety, depression, chemotherapy-treated cancer). The Student t-test was used to determine differences between various factors and the mean overall score.

Results

The online cognitive assessment was completed by 302 women with a BRCA mutation. The average age of the participants was 57.6 ± 9.2 years, of which 50% had a history of chemotherapy treatment, 25% had memory concerns, 16% had anxiety, and 9% had depression. The mean overall test score was 56 ± 22 (range: 0–93). Scores were significantly lower for women with self-reported anxiety than for women without anxiety (50 vs. 57; p = 0.05). Scores were also significantly lower for current smokers than for those who had never smoked (42 vs. 59; p = 0.02). The overall cognitive test score was not different for women who had memory concerns, a history of depression, or chemotherapy-treated cancer.

Conclusions

Preliminary findings suggest that a history of anxiety and smoking might impair memory and attention, while depression and chemotherapy treatment might not affect cognitive ability in BRCA mutation carriers. Participant enrolment is ongoing and additional analyses will focus on the role of prophylactic surgery and exogenous hormone use on cognitive deficits.

AUTHOR AFFILIATIONS

*Women’s College Research Institute, Women’s College Hospital, Toronto,,
University of Western Ontario, London,,
Baycrest Centre for Geriatric Care, Toronto, and,
§University of Toronto, Toronto, ON..


Posters

Poster P072: Implications of Multigene Panel Testing on Psychosocial Outcomes: A Comparison of Pancreatic and Breast or : Ovarian Patients


Whitney Espinel, Cathryn Koptiuch, Wendy Kohlmann, Jingsong Zhao, Sara Johnson, Kimberly Kaphingst


ABSTRACT

Pancreatic adenocarcinoma (pac), like breast and ovarian (brov) cancers, is associated with many hereditary cancer syndromes, making multigene panel testing ideal for identifying high-risk families. However, unlike brov patients, pac patients are not, in routine clinical practice, referred to genetic counselling. Research is needed to examine similarities and differences in the responses of these patients to complex test results.

This study examined cognitive and affective responses to genetic counselling and multigene panel testing among pac and brov patients. Questionnaires were completed by 32 pac and 51 brov patients before genetic counselling and 4 weeks after return of results (n = 13, n = 20). Testing was ordered (range: 15–28 genes) through clia-certified labs. At baseline, pac and brov patients reported similar interest in learning more about the role of genetics in cancer (somewhat or very important: pac, 90%; brov, 96%) and a similar number thought that genetic factors explained their cancer (somewhat or very likely: pac 72%; brov 78%). At follow-up, patients in both groups reported low levels of worry (pac, 15%; brov, 10%), sadness (23%; 5%), anxiety (8%; 5%), and loss of control (15%; 5%) about their test results. Conversely, a feeling of little to no relief about genetic test results was reported more often by pac patients than by brov patients (pac, 60%; brov, 30%; p < 0.03). Although interest in and response to testing was similar for brov and pac patients, pac patients were in poorer health, and 29% passed away after counselling.

Although multigene panel testing is not used as often for pac patients, this study shows that interest in and reaction to testing is similar for pac and brov patients. Novel strategies that incorporate health status and prognosis might be needed to effectively incorporate multigene panel testing into routine care, but overall genetic results are perceived to be as valuable in pac patient as in other populations.

AUTHOR AFFILIATIONS

University of Utah, Salt Lake City, UT, U.S.A..


Posters

Poster P073: Building a Patient-Oriented Research Program in Inherited Cancer: Early Experiences from Newfoundland and Labrador


Holly Etchegary*, Angelina Hayes, Doris Clarke, Lenora Walsh, Andrée MacMillan, Melanie Seal, Jane Green*, Nancy Wadden, Sharon Smith, Jacklyn Hynes*, Lesa Dawson*


ABSTRACT

Background

Women with mutations in BRCA1/2 face very elevated risks of breast and ovarian cancer. Despite clear recommendations to guide optimal cancer prevention and screening, many women in Newfoundland and Labrador (NL) do not receive care in accordance with published guidelines. A recent project evaluating compliance with breast and ovarian cancer screening and prevention showed that 30% of women chose mastectomy despite the associated 98% reduction in breast cancer risk. Of women not choosing mastectomy, 108 of 145 were eligible for breast mri screening, and yet only 37% received that test within recommended timeframes according to guidelines.

Methods

The BRCA research team at Memorial aims to improve the care of BRCA-positive women in NL through the development of an evidence-based and patient-oriented research program. Patient-oriented research aims to improve patient outcomes by focusing on patient-identified priorities and outcomes. We held two workshops with carriers of inherited cancer mutations (n = 7) to determine their priorities for care, ongoing management, and research.

Results

Mutation-positive carriers endorsed the need for a patient-oriented research program in inherited cancer and, specifically, the value of a cancer registry. Carriers confirmed the ongoing burden of screening and difficulties in coordinating appointments and tests. Family communication and understanding of the family risk were also identified as challenges. Workshop participants contributed as partners to two patient-oriented grant applications, one of which was successful.

Conclusions

Partnering with mutation carriers identified their priorities and outcomes, resulting in a successful patient-oriented grant application. This work will explore deficiencies in the current care model in NL and engage with patients to explore solutions. Ongoing work with patient partners ultimately aims to improve the care of high-risk individuals, but also to build a successful patient-oriented research program from which lessons learned can be distilled and shared.

AUTHOR AFFILIATIONS

*Memorial University,,
patient partner, and,
Eastern Health, St. John’s, NL..


Posters

Poster P074: Hereditary Breast Cancer Risk: Depression, Anxiety, and Impact of Cognitive Behavioral Therapy


Kathleen Ashton, Holly Pederson, Karen Hurley, Steven Grobmyer


ABSTRACT

Patients with hereditary risk for breast cancer (hbcr) face psychosocial challenges such as anxiety about cancer risk, decision-making about risk-reducing surgery, and coping with family issues, including cancer-related grief. Although mood and cognitive behavioral therapy (cbt) have been widely studied within the breast cancer population, there is less information about how patients with hbcr experience distress or benefit from psychological treatment. cbt might help hbcr patients by targeting cognitions associated with cancer-related anxiety, developing decision-making skills, and providing training in stress management.

Methods

Retrospective chart review of 43 consecutive patients with hbcr (mean age: 43.88 years; 93% Caucasian; 32.6% breast cancer survivors) referred to a psychologist embedded into an academic medical centre breast clinic completed diagnostic evaluation, the 7-item Generalized Anxiety Disorder (gad-7), and the 9-item Patient Health Questionnaire (phq-9). A subsample of 17 patients completed at least 3 cbt sessions.

Results

The phq-9 and gad-7 showed high reliability in the hbcr population (Cronbach alpha 0.90 and 0.93) and construct validity, with the phq-9 being more highly associated with depression diagnosis (F = 3.88, p < 0.01) and the gad-7, with anxiety diagnosis (F = 2.72, p < 0.05). hbcr patients showed clinically elevated anxiety (34.9%, gad-7) and depression (30.1%, phq-9). Levels of depression, but not anxiety, were significantly higher in patients with a history of breast cancer than in those with no history of breast cancer (t = 2.31, p < 0.05). Brief cbt was effective in reducing depressive symptoms (t = 4.84, p < 0.001) and anxiety symptoms (t = 3.76, p < 0.01) for hbcr patients. Preliminary results suggest that cbt was effective for hbcr patients with no history of breast cancer in reducing depressive symptoms (t = 2.65, p < 0.05, n = 6).

Conclusions

The phq-9 and gad-7 show promising reliability and validity for use with the hbcr population. This study represents a significant impact in showing brief cbt as effective for patients with hbcr.

AUTHOR AFFILIATIONS

Cleveland Clinic, Cleveland, OH, U.S.A..


Posters

Poster P075: Functional Mapping of Secondary Structures in the BRCA1 Tandem BRCT Domains Can Improve Cancer Risk Assessment


Vanessa C. Fernandes*, Volha A. Golubeva, Giuliano Di Pietro,, Cara Shields, Kwabena Amankwah, Carly Harro,§, Thales C. Nepomuceno*, Giuliana de Gregoriis*, Renata B.V. Abreu*, Thiago T. Gomes, Ricceli F. da Silva, Fergus Couch#, Edwin S. Iversen**, Marcelo A. Carvalho*,**, Alvaro N.A. Monteiro


ABSTRACT

Approximately one third of more than 1700 BRCA1 variants in the Breast Cancer Information Core database are missense variants of uncertain significance (vus). They lack evidence for an association with disease risk and present a challenge in making clinical decisions. Functional assays combined with bioinformatics prediction tools can be used to aid in the clinical annotation of vus. Importantly, higher prior probabilities of pathogenicity are assigned to variants in domains and motifs essential for BRCA1 function than to variants outside of those regions. However, the exact borders of the domains and the functional importance of their secondary structures remain uncertain.

In this study, we interrogated three underexplored features of tandem BRCA1 C-terminus (tbrct) domains based on their sensitivity to missense variants: the tbrct borders, the linker region, and both a1 helices. A total of 92 naturally occurring missense variants were subjected to transcriptional assay based on a fusion of the gal4 dna-binding domain to BRCA1 C-terminus (aa 1396–1863) in 293FT cells.

Analysis of the 20 variants at the border between the disordered region and the tbrct (residues K1648, R1649, M1650, and S1651) revealed the tbrct border to lie between residues M1650 and S1651. Of the 65 variants within the 23-aa linker region, 43 displayed less than 80% transcriptional activity, and 6 demonstrated inconsistent activity, suggesting a severe effect on BRCA1 function. Of 7 novel mutations in the tbrct a1 helices, 5 also performed with impaired function, despite the lack of functional impact of 16 of the 17 variants previously analyzed.

In summary, our study provides a refined understanding of BRCA1 regions less tolerant to changes and therefore more likely to contain pathogenic variants. That understanding will be critical for the assignment of different prior probabilities of pathogenicity given the variant location, improving risk assessment and clinical management for carriers of BRCA1 missense alleles.

AUTHOR AFFILIATIONS

*Instituto Nacional de Câncer, Rio de Janeiro, Brazil;,
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.;,
Universidade Federal de Sergipe, São Cristóvão, Brazil;,
§University of South Florida Cancer Biology PhD Program, Tampa, FL, U.S.A.;,
Instituto Federal do Rio de Janeiro, Rio de Janeiro, Brazil;,
#Mayo Clinic, Rochester, MN, and,
**Duke University, Durham, NC, U.S.A..


Posters

Poster P076: Intra-laboratory BRCA1 and BRCA2 Variant Reclassification Over a Five-Year Period


Chloe Mighton*,, Salma Shickh*,, Marina Wang*,, Nicholas Watkins*,, Kathleen-Rose Zakoor, Andrew Wong, Yvonne Bombard*,, Jordan Lerner-Ellis*,


ABSTRACT

Background

Genetic testing can identify individuals at risk for hereditary breast and ovarian cancer (hboc) and inform risk management. Although the BRCA1 and BRCA2 genes are well-characterized, variants are susceptible to inter-laboratory discordance and might be reclassified over time as new evidence is generated. The Advanced Molecular Diagnostics Laboratory (amdl) at Mount Sinai Hospital in Toronto provides BRCA1/2 testing for patients who are eligible based on Ministry of Health and Long-Term Care guidelines. Here, we report BRCA1/2 variant reassessment and reclassification at the amdl between 2012 and 2017.

Methods

Patients received complete sequencing of BRCA1/2; analysis of Ashkenazi Jewish founder mutations; or analysis for a known familial variant. Variants were assessed using a standardized variant assessment tool aligned with guidelines published by the American College of Medical Genetics and Genomics. Variant reassessment was tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar.

Results

Between 1 January 2012 and 18 August 2017, 1213 BRCA1/2 variants were reported. In total, 33.1% (402/1213) were reassessed, and 37.8% (152/402) of those that were reassessed were reclassified. 453 variants were originally classified as vus and 34.0% (154/453) of them were reassessed. Of the vus that were reassessed, 43.5% (67/154) were reclassified: 41 to benign, 23 to likely benign, 2 to likely pathogenic, and 1 to pathogenic.

Conclusions

The foregoing results demonstrate that BRCA1/2 variants, particularly vus, can undergo reclassification over time, highlighting the importance of periodic intra-laboratory reassessment. Reclassification presents ethical and practical challenges and suggests a need for research and guidance on the ethical, legal, and social implications, especially when reclassification could affect patient management. Data sharing within and between laboratories is essential for self-improvement and for accurate variant interpretation to ensure that patients receive the most appropriate care based on their genetic results.

AUTHOR AFFILIATIONS

*University of Toronto,,
St. Michael’s Hospital, and,
Mount Sinai Hospital, Toronto, ON..


Posters

Poster P078: Prevalence of Mutations in a Diverse Cohort of 3407 Subjects Tested Via the Same Multigene Cancer Panel in a Managed Care Health Plan


Mónica Alvarado, Xiaoquing Xu, George E. Tiller, Syed A. Ahmed, Joanie Chung, Reina Haque


ABSTRACT

Objective

Report on the prevalence and distribution of pathogenic or likely pathogenic variants (pv/lpv) by cancer history in an ethnically diverse cohort tested using the same cancer gene panel.

Methods

We conducted a cross-sectional analysis of 3407 subjects (>18 years, 3162 women, 245 men) referred for genetic counselling and tested for hereditary cancer using the same multigene cancer panel in a large nonprofit health plan in southern California. We examined the pv/lpv prevalence for all genes by clinical and demographic factors and stratified by sex and personal or family cancer history (or both). We calculated adjusted odds ratios for the association between race/ethnicity and mutation result using logistic regression.

Results

Median age at testing was 51 years in women and 54 years in men, with 11.7%/20.4% pv/lpv prevalence. Among women, the most common anatomic cancer sites were breast (75.1%), ovary (8.5%), and colon/rectum (4.3%). In men, the most common cancers were colorectal (41.3%), breast (16.8%), and prostate (13.2%). In women, 5.4% had BRCA1/2 mutations, and 6.3% had at least 1 mutation in other genes. In men, pv/lpv prevalence was higher for non-BRCA genes implicated with breast cancer (6.5%) and Lynch syndrome genes (6.1%) than for BRCA1/2 (3.3%). Overall, 53.8% of the total mutations (pv/lpv results) in women were in non-BRCA genes. The distribution of mutations was similar in women with and without a personal history of cancer. Latina/Hispanic subjects were half as likely as those from other ethnicities to have mutations in non-BRCA genes implicated with breast cancer (odds ratio: 0.55; 95% confidence interval: 0.36 to 0.87).

Conclusions

Given that more than half the pv/lpv results in women and 85% in men were in genes other than BRCA1/2, our results suggest that multigene cancer panel testing is appropriate for detecting germline mutations in a high-risk cohort in a managed care setting.

AUTHOR AFFILIATIONS

Kaiser Permanente Southern California, Pasadena, CA, U.S.A..


Posters

Poster P079: Broader Testing Identifies BRCA Mutation Carriers Missed : by Testing Guidelines


Jack Ji, Anjali Zimmer, Will Stedden, Robert O’Connor, Ray Chan, Zheng Tan, Elaine Chen, Dianne Keen-Kim, Alicia Y. Zhou, Annette Leon, Scott Topper


ABSTRACT

Screening for BRCA mutations was initially proposed for high-risk groups (Gabai-Kapara et al., 2014; Grindedal et al., 2017) and has more recently expanded to a call for universal population screening (King et al., 2014; Hughes 2017; Akbari et al., 2017). One barrier to expanding testing from high-risk groups to universal screening has been cost. However, a recent study demonstrated that there is a price point at which universal screening becomes cost-effective from a quality-adjusted life year perspective (Long and Ganz, 2015).

Here, we present our experiences with a more accessible genetic testing and delivery model, analyzing a cohort of 23,179 individuals who took a 30-gene panel for hereditary cancer risk. In this cohort, 846 individuals carried a pathogenic or likely pathogenic mutation in BRCA1 or BRCA2, for a BRCA mutation carrier rate of 3.6% (846/23,197). Because the test had an affordable cash-pay option, it was taken by individuals who both met and did not meet traditional criteria for genetic testing from the U.S. National Comprehensive Cancer Network (nccn). Only 33.6% of these BRCA carriers reported a personal history of breast or ovarian cancer. In the entire cohort, just under half (48.5%) the individuals would have met nccn testing criteria, 30.1% would not have met the criteria, and 21.4% did not provide sufficient information to determine eligibility. Importantly, among BRCA mutation carriers, 72.8% would have met the criteria, 12.6% would not have met the criteria, and 14.5% did not provide sufficient information to determine eligibility, demonstrating that current testing guidelines can miss BRCA mutation carriers. Additionally, 37.2% of BRCA carriers in the cohort were less than 40 years of age, and 73.0% of those individuals reported no history of cancer, indicating the importance of screening in younger populations, at an age when more preventive actions can be taken.

AUTHOR AFFILIATIONS

Color Genomics, Burlingame, CA, U.S.A..


Posters

Poster P080: Reconsideration of Risk-Reducing Surgery for BRCA VUS Patients


Kumiko Oseto*,, Naoto Kondo*, Yumi Wanifuchi-Endo*, Ryutaro Nishikawa*, Tatsuya Toyama*


ABSTRACT

Background

Risk-reducing surgery has come to be performed in Japan for patients with pathologic BRCA variants, but interventions for BRCA variants of uncertain significance (vus) have some obstacles to overcome. We report a patient that was confirmed BRCA1vus in a juvenile breast cancer.

Case Description

The patient was 30-year-old woman with triple-negative breast cancer (T2N1M0, stage 2b). The patient received preoperative chemotherapy (epirubicin–cyclophosphamide followed by weekly paclitaxel) and surgery (mastectomy and axillary lymph node dissection). The patient wanted genetic testing because of her age at diagnosis and family history of breast cancer in her mother, although other relatives were estranged. Genetic testing revealed a BRCA1vus (Y1853N(5676T>A).

The patient would like to undergo risk-reduction contralateral mastectomy, but obtaining approval from the ethics committee is difficult. Furthermore, risk-reducing surgery for vus cases is supposed to be considered in the same condition as before genetic testing, which leads to agonize over in such a case that is not pathologic.

Discussion

BRCA1c.5676 is in brct domain (BRCA1 C-terminal). The influence of this mutation for this domain function has yet to be determined. Although the mutation has not been reported in ClinVar, it has continues in some families with high penetrance. With respect to this family, surveillance as an hboc family and risk-reducing surgery might be required.

Conclusions

It is important to make an effort to reduce vus by examining cellular functions as well as databases. Establishing systems to determine procedures for surveillance and indications for risk-reducing surgery is now required for vus cases, considering family history. Furthermore, it is also important to establish the standards for surveillance and indications for risk-reducing surgery for vus according to individual vus family.

AUTHOR AFFILIATIONS

*Nagoya City University Hospital, Nagoya City, and,
Tazuke Kofukai Foundation, Medical Research Institute, Kitano Hospital, Osaka, Japan..


Posters

Poster P081: The Influence of BRCA Variants of Unknown Significance on Cancer Risk Decision-Making


Jing-Yi Chern*, Sarah S. Lee, Melissa K. Frey, Jessica Lee*, Stephanie V. Blank§


ABSTRACT

Objective

To compare gynecologic cancer risk management between women with BRCAvus to women with negative genetic testing.

Methods

At a single institution, 99 patients whose BRCA genetic testing yielded vus were matched with 99 control patients with definitive negative BRCA results. Demographics and risk management decisions were obtained through chart review. The primary outcome was the rate of risk-reducing bilateral salpingo-oophorectomy (rrbso). Chi-square tests, t-tests, and logistic regression were performed, with significance considered at p < 0.05.

Results

vus patients were more likely to be non-Caucasian (p = 0.000) and of Ashkenazi Jewish descent (p = 0.000). No differences in gynecologic oncology referrals or recommendations to screen or undergo risk-reducing surgery were observed for vus and for negative patients. Ultimately, 44 patients (22%) underwent rrbso, with no significant difference in the surgical rate based on the presence of vus. Ashkenazi Jewish descent was associated with a 4.5 times increased risk of rrbso (or: 4.489; 95% ci: 1.484 to 13.579) and family history of ovarian cancer was associated with a 2.6 times increased risk of rrbso (or: 2.641; 95% ci: 1.107 to 6.299).

Conclusions

In our institution, patients with vus were surgically managed similarly to those with negative BRCA testing. The numbers of patients with vus are likely to increase with the implementation of multigene panel testing. Our findings underscore the importance of genetic counselling and individualized screening and prevention strategies in the management of genetic testing results.

AUTHOR AFFILIATIONS

*Moffit Cancer Center and Research Institute, Tampa, FL,,
New York University School of Medicine, New York, NY,,
Weill Cornell Medicine, New York, NY, and,
§Icahn School of Medicine at Mount Sinai, New York, NY, U.S.A..


Posters

Poster P082: A Breast Cancer Case with BRCA2 Variant of Uncertain Significance Suffering from the Concurrence of Pancreatic Cancer


Yukiko Yoshimoto, Kumiko Oseto, Aiko Obayashi, Ryohei Katsuragi, Yurina Maeshima, Sachiko Takahara, Shujiro Yazumi, Akira Yamauchi


ABSTRACT

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (hboc) is characterized by an increased risk for breast cancer, ovarian cancer, and to a lesser extent, other cancers such as pancreatic cancer. Medical management for variants of uncertain significance (vus) is recommended based on the strength of personal and family cancer history. Most vus are unlikely to be pathogenic, although some have been found to be.

A 49-year-old woman had an operation for left breast cancer followed by adjuvant chemotherapy and hormonal therapy. Her family history of cancer raised suspicions of hboc. Her older sister was diagnosed with breast cancer at age 47, and her father was diagnosed with prostate cancer in his 80s. She took a genetic test, analysis for germline BRCA mutations, which revealed BRCA2vus. At 19 months after her operation, stage iv pancreatic cancer was detected. Although chemotherapy was administered, the disease progressed. She died of her disease 10 months after the diagnosis of pancreatic cancer.

Surveillance for early detection of pancreatic cancer developing in hboc has not been established. We are planning a clinical trial for early detection of pancreatic cancer in cooperation with the gastroenterology department in our hospital. We will also discuss the reasonableness of risk-reducing surgery for BRCAvus instead of BRCA pathologic variants.

AUTHOR AFFILIATIONS

Kitano Hospital, Osaka, Japan..


Posters

Poster P083: Mutations in Unexpected Genes of Hereditary Cancer Panels: Incidental Findings or a Path for Reviewing Gene-Testing Criteria?


Damien Feret, Aude Lombard, Pascale Hilbert, Karin Dahan


ABSTRACT

The use of multigene panels in the diagnosis of hereditary cancers has become common in cancer genetics. However, with the use of these panels, we observed the emergence of variants in unexpected genes with respect to the clinical picture.

Between March 2016 and December 2017, we tested 2162 patients for hereditary predisposition to cancer using the Hereditary Cancer Solution panel (Sophia Genetics, Montpellier, France). 65 patients were found to carry a pathogenic variant in a clinically relevant gene that has, a priori, no link with the presenting disease (no or insufficient evidence for recommendations). Most of the variants (n = 33) were heterozygous mutations in the recessive MUTYH gene; 32 pathogenic variants were identified in autosomal dominant genes (APC I1307K, 6; ATM, 5; BRIP1, 4; CHEK2, 3; MLH1, 1; MSH2, 2; MSH6, 3; NBN, 3; PALB2, 1; PMS2, 2; RAD51C, 2).

Available clinical data and family histories were then analyzed with respect to the identified mutation. We found that 18 patients had at least 1 relative affected by a cancer associated with the mutated gene. However, for those patients, the criteria to undergo specific gene testing were insufficient. We also found 47 patients who had no relatives affected by the gene-related disease.

These variants were reported as incidental findings. Genetic counselling and patient management were done regarding their clinical relevance and the family histories. However, this study suggests that, in some cases, the use of restrictive criteria alone might exclude relevant patients from specific gene testing, particularly in small families or in carriers of moderate-penetrance gene variants. It also questions some established recommendations in genes for which the evidence for specific cancer-site risk is insufficient. For patients with unexpected discoveries, genetic counselling remains complex, especially with respect to the risk assessment for cancer sites not part of the diagnosed cancer syndrome spectrum.

AUTHOR AFFILIATIONS

Institut de Pathologie et de Génétique ipg Gosselies, Belgique..


Posters

Poster P084: Assessment of Genetic Variation at Splicing Junctions Using an In-Cell Fluorescence Reporter System


Nikko Torres, Christina Yeh, Leo Wan


ABSTRACT

Sequencing technologies have facilitated comprehensive cataloguing of disease-associated single nucleotide polymorphisms at intron–exon junctions. However, the bottleneck of determining the effect of those variants on alternative splicing or protein function remains. Minigene assays have proven to be the “gold standard” of measuring splicing efficiency, but they are tedious to implement because of the rna isolation steps, and they offer only a qualitative assessment of splicing.

To make the assessment of genetic variation at exon–intron junctions quantifiable and easy to implement, we developed a simple fluorescence- based reporter to quantify splicing efficiency in mammalian cells. Splicing efficiency can be measured quantitatively and on a per-cell basis by fluorescence microscopy or through cell sorting. Additionally, our fluorescence reporter affords scalability and flexibility, as well as an intrinsic fluorescence control for reporter plasmid intake efficiency. To demonstrate the clinical and biological relevance of our reporter system, we have performed proof-of-concept experiments with BRCA1 junctions that involve pathogenic mutations known to disrupt splicing.

AUTHOR AFFILIATIONS

Ranomics, Toronto, ON..


Posters

Poster P086: Simultaneous Defect in BRCA1 and BRCA2 in a Male Subject with Late-Onset Breast Cancer and Family History of Breast : and Lung Cancers


Christopher Ede*, Jeannine Oldzej*, Candice Jackel-Cram, Kellie Davis, Samuel Strom*


ABSTRACT

A male subject, presenting with late-onset breast cancer (64 years of age at Dx), was referred to our laboratory for molecular genetic testing. Significant family history includes a sister with breast cancer (Dx: 82 years) and a maternal aunt with ovarian cancer (Dx: 87 years). Further family history includes at least 7 cases of lung or oral cancers, and other unspecified cancers, all within the maternal family, strongly suggesting a genetic predisposition. Sequencing of 14 hereditary breast cancer–associated genes revealed 2 pathogenic frameshift variants, one in the BRCA2 gene (c.2808_2811del) and another in the BRCA1 gene (c.3481_3491del), consistent with a significantly increased risk for both male and female breast cancers. Although statistics about the effect of concomitant BRCA1 and BRCA2 mutations are not well established, available evidence suggests an earlier age of onset in individuals with 2 mutations (PubMed ID: 20924075).

Contrary to those findings, the proband, as well as his sister and maternal aunt (genotype not available), were diagnosed at an atypically late age. More interestingly, the family history provided, including several cases of lung and oral cancers, does not match the cancer spectrum commonly associated with BRCA1/2 defects. However, this individual also harboured a variant of unknown significance in the CHEK2 gene (c.1420C>T, p.Arg474Cys), which has previously been reported to potentially be causative in an unrelated family presenting with multiple members diagnosed with lung cancer, including 2 individuals with multiple primary lung cancers who were homozygous for the variant (PubMed ID: 27900359).

The atypical clinical presentation within the proband’s family, together with the concomitant appearance of two pathogenic variants and a possibly causative CHEK2 mutant, potentially implies a modifying effect on age of onset, severity, and cancer spectrum resulting from genetic interactions between the observed mutations, and might provide new perspectives for the evaluation of concomitantly occurring mutations in cancer susceptibility genes.

AUTHOR AFFILIATIONS

*Fulgent Genetics, Temple City, CA, U.S.A.;,
Royal University Hospital, Saskatoon, SK..


Posters

Poster P087: Mosaic BRCA1 Pathogenic Variant in a Male with Breast Cancer


Andrea Vaags, Cynthia Forster-Gibson, Kaitlyn Higgins, Andrea Newell, Shamini Selvarajah, Marsha Speevak, Loren Mackay-Loder


ABSTRACT

Heterozygous germline mutations in the BRCA1 and BRCA2 genes are routinely screened in individuals at increased risk of hereditary breast and ovarian cancer (hboc). Detection of low-level mosaic germline mutations is very rare (Freidman et al., 2015). The adoption of next-generation sequencing (ngs) at high read depth allows for a limit of detection of <20% variant allele frequency (vaf) and, as such, will likely increase the detection of additional mosaic variants in hboc.

Here, we present a case of low-level mosaic BRCA1 mutation in a male breast cancer patient. This case was initially detected by manual inspection of Sanger sequencing trace, later confirmed by ngs. The BRCA1 mutation (c.685delT) was present at 14% vaf in peripheral blood. Testing of additional tissues showed low-level mosaicism in saliva and histologically normal breast tissue. However, the variant was not detected in the buccal or breast tumour tissue.

These results suggest the possibility of tissue-specific constitutional germline mosaicism or acquired somatic mosaicism. From a clinical perspective, this case highlights the unique challenges that mosaic results can present, both in providing genetic counselling and in providing the appropriate cancer screening recommendations to the proband and his family members. Although genetic counsellors face challenges in the transmission of complex genetic information in many scenarios, this case underlines the need for comprehensive pretest genetic counselling and also the difficulty, when providing results, of selecting the pertinent information to relay to the proband and the family.

AUTHOR AFFILIATIONS

Trillium Health Partners–Credit Valley Hospital Site, Mississauga, ON..


Posters

Poster P088: Expanded Panel Testing in Patients with Breast Cancer in a Rural Familial Cancer Program


Kara K. Landry, David Hermel, Melissa Cuke, Wendy C. McKinnon, Laura Colello, Marc S. Greenblatt, Marie E. Wood


ABSTRACT

Objective

To assess indicators of pathogenic variants for expanded genetic testing, we examined results from multigene panel testing in patients with a history of breast cancer, dcis or invasive, from a largely rural patient population.

Methods

We conducted a retrospective review of breast cancer patients who underwent panel testing between May 2011 and August 2017. A variety of commercial gene panels were used, with variant classification determined by the individual laboratory. The chi-square test of independence or one-way ANOVA was used to analyze differences in patient demographics for the pathogenic variant–positive, −negative, and vus patient subsets. The chi-square or Fisher exact test was used to analyzehormone and her2 status, histology, and differentiation by pathogenic panel test result.

Results

We identified 422 patients with breast cancer who underwent panel testing, and 104 (24.5%) of those patients had a reportable finding of either “pathogenic variant–positive” (n = 38, 9.0%) or “vus” (n = 66, 15.6%). Median age at the time of genetic testing was 54 years (range: 24–89 years), and median age of first cancer onset was 47 years (range: 6–89 years). Panel test results were significantly associated with median age of first cancer diagnosis (F2,416 = 5.61, p = 0.004); individuals with pathogenic variants tended to be younger at the time of diagnosis. Panel test results were not associated with age at genetic testing, the number of primary cancers (single vs. multiple), or the number of genes tested. Panel test results were associated with breast tumour histology (Fisher exact test p =< 0.001), with most patients having invasive ductal carcinoma (73.0%), but were not associated with hormone receptor or her2 status, or tumour differentiation.

Conclusions

Expanded panel testing should be considered in breast cancer patients, because about 9% will have a pathogenic mutation. Tumour characteristics do not seem to be important in identifying who should undergo expanded panel testing.

AUTHOR AFFILIATIONS

University of Vermont Medical Center, VT, U.S.A..


Posters

Poster P089: Clinicopathologic Features of Patients with BRCA1 c.5339T>C : (p.leu1780pro) Variant Based on Multicentre Data in Korea


Jai Min Ryu*, Jeong Eon Lee*, Seok Won Kim*, Seok Jin Nam*, Jonghan Yu*, Se Kyung Lee, Sung-Won Kim, Hyung Seok Park, Ji Soo Park§


ABSTRACT

Purpose

BRCA1 c.5339T>C, p.Leu1780Pro mutation (L1780P) has been considered to be a variant of unknown significance. The recent evidence with respect to the function of L1780P suggests that L1780P is pathogenic or likely pathogenic. The aim of the present study is to use retrospective multicentre data to evaluate the clinicopathologic features of patients with L1780P in Korea.

Methods

Data of 51 cases from 8 institutions were collected. Their clinicopathologic data and genetic variants of BRCA1/2 other than L1780P were reviewed and analyzed. Survival curves were assessed according to onset of ovarian and breast cancer.

Results

Median age of patients with L1780P was 37.6 years (range: 25–58 years). The proportions of patients with a family history of breast and ovarian cancer were 64.1% and 28.1% respectively. Bilateral breast cancer was shown in 7 of 51 cases. More than one third of germline L1780P tumours (39.7%) were grade 3 and had a high Ki-67 proliferation index. More than two thirds of patients showed estrogen and progesterone receptor negativity. her2 overexpression was shown in only 3.9% of all patients with L1780P (2/51). In cases with immunohistology data available, triple-negative breast cancer was the most common subtype (32/50). Risk-reducing oophorectomy was performed in 4 patients. Recurrence was observed in 13 patients with L1780P. The 5- and 10-year recurrence-free survival rates of patients with L1780P were 68.4% and 42.8% respectively.

Conclusions

Most breast cancers in patients with L1780P showed aggressive clinicopathologic features, including younger age, poor histologic grade, triple-negative status, and high Ki-67 index. Patients with L1780P showed clinicopathologic features that were similar to those in patients with BRCA1 pathogenic mutations.

AUTHOR AFFILIATIONS

*Samsung Medical Center,,
Daerim St. Mary’s Hospital,,
Yonsei University College of Medicine, and,
§Yonsei Cancer Center, Seoul, R.O.K..


Posters

Poster P090: Qualitative and Quantitative Splicing Analysis by Targeted RNA-Seq for Hereditary Breast/Ovarian Cancer Genetic Diagnosis


Rita D. Brandão*, Klaas Mensaert, Irene López-Perolio, Demis Tserpelis*, Markos Xenakis*,§, Vanessa Lattimore, Logan Walker, Anders Kvist#, Ana Vega**, Sara Gutiérrez-Enríquez††, Orlando Díez††,‡‡, KConFaB Investigators§§, Miguel de la Hoya, Amanda B. Spurdle‖‖, Tim De Meyer, Marinus J. Blok*


ABSTRACT

A subset of genetic variants found during genetic screening of patients with hereditary breast and ovarian cancer (hboc) syndrome have an effect on rna splicing. A targeted rna-seq approach was used to analyze the naturally-occurring splicing events for a panel of tumour suppressor genes that are important for genetic screening of individuals with hboc and hereditary nonpolyposis colorectal cancer (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53, MLH1, MSH2, and MSH6). For BRCA1, BRCA2, RAD51C, and RAD51D, the results were validated by capillary electrophoresis and were compared with a non-targeted rna-seq approach. We also compared splicing events from our lymphoblastoid cell lines with those from breast and ovarian fimbriae tissues. The potential of targeted rna-seq to detect pathogenic changes in rna-splicing was validated by inclusion of samples with previously characterized BRCA1/2 spliceogenic variants.

The first step was to validate the approach. We detected 94% and 96% of the previously described naturally-occurring splicing events in BRCA1 and BRCA2 respectively. Additional splicing events were also detected and further confirmed with pcr-based techniques. For RAD51C and RAD51D, we detected 44 and 34 alternative splicing events respectively. In most samples, a RAD51D isoform lacking exon 3 was more abundant than the full-length transcript or the isoform containing a downstream alternative exon 3. Additionally, the aberrant BRCA1 and BRCA2 events caused by variants were also identified, and we could distinguish between complete and partial exon-skipping events. Comprehensive lists of alternative splice events for the other tumour suppressor genes were also obtained.

Our results indicate that targeted rna-seq provides sufficient sensitivity/specificity to be used in clinical testing. This approach is an improvement of the current rt-pcr–based rna-splicing screening protocols. In addition, this approach has the potential to identify mutations in deep-intronic regions that affect rna splicing, but that are missed with current dna genetic, exon-focused, screening methods

AUTHOR AFFILIATIONS

*Maastricht University Medical Centre, Maastricht, Netherlands;,
Ghent University, Ghent, Belgium;,
Instituto Investigación Sanitaria San Carlos (idissc), Madrid, Spain;,
§Maastricht University, Maastricht, Netherlands;,
University of Otago, Christchurch, New Zealand;,
#Lund University, Lund, Sweden;,
**Universidade de Santiago de Compostela, Santiago de Compostela,,
††Vall d’Hebron Institute of Oncology (vhio), Barcelona, and,
‡‡University Hospital of Vall d’Hebron, Barcelona, Spain;,
§§Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia;,
‖‖qimr Berghofer Medical Research Institute, Brisbane, QLD, Australia..


Posters

Poster P091: Pathogenic Mutations Other Than the BRCA1/2 Founder Mutations in Ashkenazi Jewish Patients Undergoing Genetic Testing


Melissa K. Frey, Bailey Jordan, Ama Buskwofie, Sudeshna Chatterjee-Paer, Zhenni Zhou, Jessica Fields, Dimitrios Nasioudis, Rohini Kopparam, Thomas Caputo, Kevin Holcomb, Eloise Chapman-Davis


ABSTRACT

Background

People of Ashkenazi Jewish (aj) descent have a 2.5% risk of carrying 1 of the 3 BRCA1/2 founder mutations. Because of this risk, aj patients often undergo founder mutation evaluation as the first step in genetic assessment, and based on the results, make a decision with their physician about reflex evaluation of the complete BRCA1/2 genes or a larger panel that includes BRCA1/2 and other cancer-associated genes. We sought to evaluate the prevalence of pathogenic mutations other than founder BRCA1/2 mutations in aj patients.

Methods

Genetic results for all aj patients presenting for counselling and testing at a single institution between Jan 2013 and Dec 2016 were reviewed.

Results

730 aj patients underwent genetic testing. Of those patients, 53% (390) had a personal cancer history, and 87% (637) had a family cancer history. In 97 patients (13%), a pathogenic mutation was detected; in 40 (6%), a vus; and in 2 (0.2%), mutation and vus. In 2 patients, 2 mutations were detected. Among the 101 identified mutations, 80 (79%) were in BRCA1/2, and 21 (21%) were in non-BRCA1/2 genes. Among the 47 BRCA1 mutations, 1 (2%) was a non-founder mutation, and among the 33 BRCA2 mutations, 3 (9%) were non-founder mutations.

Conclusions

Genetic testing in the aj patients in our population identified 25 pathogenic mutations (25% of all identified mutations) that would be missed with BRCA founder mutation testing alone. That result emphasizes the utility of multigene panel testing in aj patients and the need to re-evaluate our current practice of genetic testing in this population.

AUTHOR AFFILIATIONS

Weill Cornell Medicine, New York, NY, U.S.A..


Posters

Poster P092: Bridging the Gap: A Priorities Assessment Tool to Support Shared Decision-Making, Maximize Limited Appointment Time, and Increase Patient Satisfaction in Women with BRCA1/2 Mutations


Melissa Frey*, Annie Ellis, Savannah Shyne, Ryan Kahn*, Stephanie Blank


ABSTRACT

Objective

Our previous qualitative and quantitative work has shown that women with ovarian cancer identify patient–physician communication as an essential element in determining treatment course and believe that a discussion about goals and values should precede all treatment decisions. We sought to develop a patient-centreed priorities assessment tool (pat) that could be completed quickly and easily in the waiting room immediately before appointments to streamline communication, enhance treatment discussions, and increase patient satisfaction. This is especially pertinent for women with BRCA1/2 mutations who demonstrate improved progression-free and overall survival and increased sensitivity to anticancer agents, and who, as a result, often undergo multiple lines of treatment.

Methods

We designed a 1-page pat using the validated ovarian cancer symptom index (nccn-fact fosi-18) combined with an index to assess daily quality of life priorities that could be affected by treatment side effects. The pat was distributed to women with ovarian cancer in small focus group settings and online.

Results

Between September 2015 and May 2016, 36 women completed the pat. All participants reported that the pat was easy to understand and comprehensive in scope. Of those participants, 34 (94%) completed the pat in under 15 minutes, with most (29, 81%) completing it in 5–10 minutes. Most participants (31, 86%) were able to stratify their priorities and identify 5 top treatment-related priorities. Participants who indicated that their goals and priorities had changed since diagnosis (26, 72%) reported that the pat helped them to identify current goals and priorities (22 of 26, 85%) and that the pat would help them feel more comfortable participating in shared decision-making with their medical team (21 of 26, 81%).

Conclusions

A pat that combines a current symptom index with daily quality-of-life priorities was easy to complete and viewed as comprehensive and useful in a pilot cohort of women with ovarian cancer. Use of a pat has the potential to enhance communication, promote shared decision-making, and improve patient satisfaction, especially in women with BRCA1/2 mutations who have a long disease course and undergo multiple treatment regimens. A pilot of this pat in gynecologic oncologists’ offices, including post-activity assessments from survivors and physicians, is ongoing.

AUTHOR AFFILIATIONS

*Weill Cornell Medicine,,
share, and,
Icahn School of Medicine at Mount Sinai, New York, NY, U.S.A..


Posters

Poster P093: Seeking Molecular Mechanisms of Diminished Ovarian Reserve in BRCA1/2 Mutation Carriers


Rita D. Brandao*, Koen Van de Vijver, Brigitte Slangen*, Steffen Hauptmann*, Vivianne Tjan-Heinen*, Ron Van Golde*, Christine de Die*, Marinus J. Blok*


ABSTRACT

Several studies have suggested that female BRCA1 mutation carriers have diminished ovarian reserve (loss of oocytes). This would imply that these women could have a decreased chance of a successful pregnancy (spontaneous or in vitro fertilization/preimplantation genetic diagnosis). Decrease in ovarian reserve is a normal phenomenon seen with increasing age, but is associated with chemotherapy and with mutations in genes such as FMR1 and ATM. Because BRCA1 and BRCA2 are both involved in dna damage repair and spindle checkpoint, we hypothesize that decreased ovarian reserve in BRCA1/2 carriers is the result of increased dna damage in oocytes, leading to apoptosis.

Normal paraffin-embedded ovarian tissue from 16 BRCA1 and 17 BRCA2 mutation carriers and 11 age-matched (29–45 years) non-carrier controls who underwent preventive surgery was collected in two Dutch centres. γ-H2AX and cleaved caspase-3 (Asp175) immunohistochemistry analysis to test for dna damage and apoptosis respectively was performed in triplicate. Our preliminary results show significantly increased dna damage in follicles from BRCA2 carriers than in follicles from controls (17.6% vs. 11.2%, p = 0.023), but not in follicles from BRCA1 carriers (15.5% vs. 13.2%, p = 0.235). Despite this, apoptosis doesn’t seem to be increased (p = 0.324). Analysis of replicates is ongoing, but our preliminary results do not seem to support that an increased loss of oocytes is present among BRCA1/2 carriers. Interestingly, a recent study reported that levels of anti-Müllerian hormone are not significantly different in Dutch BRCA1/2 carriers than in controls. And yet, BRCA1/2 carriers required 40% higher doses of follicle-stimulating hormone and had a lower number of mature oocytes collected upon in vitro fertilization.

Diminished ovarian reserve and oocyte/embryo quality in BRCA1/2 carriers are important factors to take into account during counselling because of the effect they could have in the reproductive choices of BRCA1/2 couples. An extension of our studies will help to clarify whether BRCA1/2 mutations lead to diminished ovarian reserve and reduced oocyte/embryo quality.

AUTHOR AFFILIATIONS

*Maastricht University Medical Centre, Maastricht, and,
Antoni van Leeuwenhoek, nki (Dutch Cancer Institute), Amsterdam, Netherlands..


Posters

Poster P094: Comparing Surveillance Strategies Among Women with BRCA1/2 : Mutations at High Risk of Developing Ovarian Cancer


Reina Haque*, Steven Skates, Scott Lentz*, Maryanne Armstrong, Mónica Alvarado*, Giulia Chillemi, Xiaoqing Xu*, Sally Shaw*, Bethan Powell


ABSTRACT

Objective

Current surveillance recommendations for ovarian cancer are limited because tests for cancer antigen 125 (CA125) are poor predictors, and biannual compliance with ultrasound and blood tests is low. The primary objective of this pilot is to test the acceptability of two surveillance strategies for ovarian cancer in women with BRCA1/2 mutations. Here we present patient recruitment and baseline characteristics.

Methods

We recruited participants with BRCA1/2 mutations from Kaiser Permanente Northern and Southern California, the state’s two largest managed care organizations, for a nonrandomized prospective study. Eligible women were offered enrolment in the standard of care (soc) arm, which included ultrasonography and CA125 testing every 6 months, or the roca (risk of ovarian cancer algorithm) arm, which included CA125 testing and human epididymis protein 4 (HE4) testing performed every 4 months. Patients will be enrolled from 4 Aug 2016 to 30 Jun 2018.

Results

From among 547 eligible women, we recruited 204 (38%) BRCA carriers. Of those carriers, 160 (78%) elected the roca arm, and 44 (22%), the soc arm. The retention rate has been high (75%). Withdrawal has been similar in the two groups (25% roca; 23% soc). Compared with the soc arm participants, the roca-arm participants tended to be younger (13% vs. 23%, 40–49 years), less likely to be Ashkenazi Jewish (17% vs. 23%), and postmenopausal (18% vs. 9%). Most who underwent prior gynecologic surgeries or mastectomy (for breast cancer) elected the roca arm. To date, 355 combined HE4 and CA125 tests have been performed in the roca arm, and 84 ultrasound and CA125 tests in the soc arm.

Discussion and Next Steps

This pilot study demonstrates that high-risk women are interested in participating in biomarker surveillance, with a roca score combining longitudinal CA125 and HE4 tests 3–4 times annually. Our next steps include calculating each participant’s longitudinal roca scores and determining if the scores affect the surveillance behaviour of the participants.

AUTHOR AFFILIATIONS

*Kaiser Permanente Southern California, Pasadena, CA,,
Massachusetts General Hospital, Boston, MA, and,
Kaiser Permanente Northern California, Pasadena, CA, U.S.A..


Posters

Poster P096: A Review of Current Breast Reconstruction Options for Women with BRCA1 and BRCA2 Mutations Choosing Risk-Reduction or Prophylactic Mastectomy to Prevent Breast Cancer


John L. Semple, Kelly A. Metcalfe, Ali Candib, Tulin Cil


ABSTRACT

Introduction

Breast reconstruction is an option for women with BRCA1 or BRCA2 mutations who elect to undergo risk-reduction or prophylactic mastectomy to prevent breast cancer. Here, we report on advances in reconstruction after mastectomy, specifically examining the differences and outcomes of the available options and the outcomes of immediate reconstruction in an ambulatory setting.

Methods

Women with BRCA1 and BRCA2 mutations choosing risk-reduction or prophylactic mastectomy to prevent breast cancer who had surgery at Women’s College Hospital during the period 2014–2017 in an ambulatory setting were retrospectively reviewed. Current trends and selection preferences in available reconstructive options, including the use of acellular dermal matrix, and outcomes of immediate reconstruction in an ambulatory setting will be discussed. eras (“enhanced recovery after surgery”) in relation to international protocols will be reviewed.

Results

The long-term follow-up time post-mastectomy a nd reconstruction was 60 months (5 years). For the entire cohort, younger women tended to choose less-invasive procedures without donor-site morbidity such alloplasty (implant and expander). Nipple-sparing and less conspicuous scars were most common in selection. Complication rates were low and reconstruction failure was minimal.

Conclusions

Most women elect for breast reconstruction after risk-reduction or prophylactic mastectomy. However, younger women tend to choose less-invasive procedures (implant and expander). Current updated reconstructive options, trends in ambulatory surgery or same-day surgery, and selection preferences will be discussed.

AUTHOR AFFILIATIONS

University of Toronto, Toronto, ON..


Posters

Poster P097: Comparison of Cancer Risks in Truncating Compared with Missense CHEK2 Pathogenic Variants


Erin Mundt, Jean Paul De La O, Ryan Bernhisel, Irene Rainville, Susan Manley


ABSTRACT

Background

Estimated CHEK2-associated cancer risks are based mainly on studies of the common truncating variant, c.1100del, leaving uncertainty about cancer risks associated with other types of pathogenic variants. Here, we compare personal and family cancer histories of individuals with pathogenic CHEK2 truncating variants and missense variants.

Methods

Patients who had pan-cancer panel genetic testing (Myriad Genetic Laboratories) and were found to carry 1 truncating or missense pathogenic variant in CHEK2 were included in this analysis (n = 3368). Personal and family histories (1st- and 2nd-degree relatives) of breast cancer, colorectal cancer, prostate cancer, gastric cancer, and melanoma were evaluated based on variant type (truncating vs. missense). All clinical information was obtained from the provider-completed test request form.

Results

In total, truncating CHEK2 pathogenic variants were identified in 2650 individuals, and missense CHEK2 pathogenic variants were identified in 718 individuals. No significant differences were observed in the proportions of patients reporting a personal history of breast cancer (43.8% truncating, 46.4% missense; p = 0.23) or colon cancer (2.5% truncating, 1.7% missense; p = 0.20). Comparisons of personal histories of other assessed cancers were similar, with no differences between the two variant types. Some differences were observed in reported family history of breast cancer (74.4% truncating, 69.1% missense; p < 0.01), gastric cancer (4.9% truncating, 7.2% missense; p = 0.02), and prostate cancer (16.5% truncating, 13.0% missense; p = 0.02). No significant difference was observed in family history of colorectal cancer (25.6% truncating, 23.4% missense; p = 0.23).

Conclusions

In this cohort, no significant differences in personal cancer history and only slight differences in reported family history were observed between CHEK2 pathogenic truncating and missense variants. These data demonstrate that missense and truncating variants in CHEK2 are associated with similar cancer risks, which can inform management recommendations for individuals with missense pathogenic CHEK2 variants.

AUTHOR AFFILIATIONS

Myriad Genetic Laboratories Inc., Salt Lake City, UT, U.S.A..


Posters

Poster P098: First Results of the Prospective Multicentre TUBA Study in BRCA1/2 Mutation Carriers


Miranda P. Steenbeek*, Marline G. Harmsen*, Nicoline Hoogerbrugge*, Jurgen M. Piek, Helena C. van Doorn, Marc van Beurden§, Marian J.E. Mourits, Ronald P. Zweemer#, Katja N. Gaarenstroom**, Birgitte F.M. Slangen††, M. Caroline Vos‡‡, Luc R.C.W. van Lonkhuijzen§§, Leon F.A.G. Massuger*, Rosella P.M.G. Hermens*, Joanne A. de Hullu*


ABSTRACT

Background

Risk-reducing salpingo-oophorectomy (rrso) around the age of 40 is currently recommended to BRCA1/2 mutation carriers, resulting in premature menopause. Approximately 70% of the epithelial ovarian cancers are high-grade serous ovarian carcinomas (hgscs). Recent data indicate that the Fallopian tube and not the ovary is the origin of hgsc, and so more research into the role of risk-reducing salpingectomy (rrs) is necessary. The tuba study (NCT02321228) investigates quality of life for standard rrso and for rrs with delayed oophorectomy (rro).

Methods

In a multicentre nonrandomized trial in 13 oncology centres in the Netherlands, premenopausal BRCA1/2 mutation carriers choose between rrso at age 35–40 (BRCA1) or 40–45 (BRCA2) and the innovative strategy (rrs after completion of childbearing and rro) at age 40–45 (BRCA1) or 45–50 (BRCA2). This abstract focuses on decisive elements at the patient level.

Results

Of the first 200 participants, 95 (47.5%) chose rro at the recommended age, and 105 (52.5%) chose to delay rro. Women choosing delayed rro were more likely to be conjoined in a relationship and to have known their BRCA mutation diagnosis for longer. Most important reasons to delay rro were the opportunity to delay premature menopause, trust in the hypothesis, and a willingness to participate in research for the next generation. Defining factors for choosing rrso were the known safety of rrso and fear of ovarian cancer.

Conclusions

More understanding of the key factors in the process of decision-making between rro at the recommended age and delayed rro can enhance patient satisfaction. We invite more countries to take an initiative such as the tuba study; pooled data will inform us not only about quality of life for and decision-making by BRCA1/2 mutation carriers, but also about the safety of salpingectomy with delayed rro in cancer prevention. We expect to present data from more than 300 BRCA mutation carriers at the symposium in Montreal.

AUTHOR AFFILIATIONS

*Radboud University Medical Center, Nijmegen,,
Catharina Hospital, Eindhoven,,
Erasmus MC Cancer Clinic, Rotterdam,,
§Netherlands Cancer Institute, Amsterdam,,
University Medical Center Groningen, Groningen,,
#UMC Utrecht Cancer Centre, Utrecht,,
**Leiden University Medical Centre, Leiden,,
††Maastricht University Medical Centre, Maastricht,,
‡‡Elisabeth-TweeSteden Hospital, Tilburg, and,
§§amc, Amsterdam, Netherlands..


Posters

Poster P099: EMBRACA: Quality of Life in Patients with HER2-Negative Advanced Breast Cancer and a Germline BRCA1/2 Mutation Receiving Talazoparib Compared with Physician’s Choice Chemotherapy Treatment


Johannes Ettl*, Ruben G.W. Quek, Kyung-Hun Lee, Hope S. Rugo§, Sara Hurvitz, Anthony Gonçalves#, Louis Fehrenbacher**, Rinat Yerushalmi††, Lida A. Mina‡‡, Miguel Martin§§, Henri Roché‖‖, Young-Hyuck Im##, Denka Markova, Helen Bhattacharyya, Alison L. Hannah, Wolfgang Eiermann***, Joanne L. Blum†††, Jennifer K. Litton‡‡‡


ABSTRACT

Background

embraca, a randomized 2:1 open-label phase 3 study (NCT01945775), showed a statistically significant improvement in progression-free survival with talazoparib (n = 287) compared with physician’s choice chemotherapy [pct (n=144)] in patients with her2-negative advanced breast cancer and a germline BRCA1/2 mutation (hr: 0.54; 95% ci: 0.41 to 0.71; p < 0.0001). This study evaluated exploratory quality-of-life (qol) endpoints.

Methods

qol was assessed at day 1 (baseline), at the start of each treatment cycle (every 3 weeks), and at the end of treatment, using eortc qlq-C30 and its breast cancer module, qlq-BR23. Higher scores indicate better functioning or global health status (ghs)/qol or worse symptom severity. Pre-specified qol analyses of both ghs/qol and breast symptom scales include overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to clinically meaningful deterioration (ttd) (per survival analysis methods). Between-arm comparisons of ttd were made using a stratified log-rank test and a Cox proportional hazards model.

Results

Baseline scores were similar in the treatment arms. A statistically significant estimated overall mean improvement from baseline in ghs/qol was seen for talazoparib compared with a statistically significant deterioration for pct [3.0 (95% ci: 1.2 to 4.8) vs. −5.4 (−8.8 to −2.0); between-arms p < 0.0001]. A statistically significant greater delay in ttd in ghs/qol favouring talazoparib was observed (hr: 0.38; 95% ci: 0.26 to 0.55; median: 24.3 months vs. 6.3 months; p < 0.0001). A statistically significant estimated overall mean improvement from baseline in breast symptoms with talazoparib was observed compared with a non-statistically significant improvement with pct [–5.1 (95% ci: −6.7 to −3.5) vs. −0.1 (−2.9 to 2.6), between arms p = 0.002]. A statistically significant delay in ttd in breast symptoms favouring talazoparib was observed (hr: 0.39; 95% ci: 0.20 to 0.78; because of censoring, median times not reached for both arms; p = 0.005).

Conclusions

Talazoparib resulted in significant overall improvements and delayed ttd in both ghs/qol and breast symptoms.

AUTHOR AFFILIATIONS

*Klinikum rechts der Isar, Technische Universität München, Munich, Germany;,
Pfizer Inc., San Francisco, CA, U.S.A.;,
Seoul National University Hospital, Seoul, R.O.K.;,
§UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, and,
University of California–Los Angeles, Los Angeles, CA, U.S.A.;,
#Institut Paoli-Calmettes, Marseille, France;,
**Kaiser Permanente, Northern California, Velljo, CA, U.S.A.;,
††Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel;,
‡‡Banner Health, Phoenix, AZ, U.S.A.;,
§§Instituto de Investigación Sanitaria Gregorio Marañón, ciberonc, geicam, Universidad Complutense, Madrid;,
‖‖Institut Universitaire du Cancer Toulouse, Toulouse, France;,
##Samsung Medical Center, Seoul, R.O.K.;,
***Interdisziplinäres Onkologisches Zentrum München, München, Germany;,
†††Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, and,
‡‡‡MD Anderson Cancer Center, Houston, TX, U.S.A..


Posters

Poster P100: TRACEBACK: Finding BRCA1 and BRCA2 Mutations in Women with Ovarian Cancer Diagnosed Prior to Changes to Genetic Testing Guidelines


Rachel Delahunty*, Penny Webb, Georgia Chenevix-Trench, Angela Rutherford,§, Paul Cohen,#, Mary-Anne Young**, Michael Friedlander††, Laura Forrest*, Paul James*, David Bowtell*

††Prince of Wales Hospital, Sydney, Australia.

ABSTRACT

Background

Women with deleterious germline BRCA1/2 mutations are at increased lifetime risk of breast and ovarian cancer (oc)1. Population-based studies indicate an incidence of pathogenic germline mutations of 14%–17%2. Testing provides a cost-effective and efficient mechanism to detect mutations in unaffected relatives for whom effective risk-reducing strategies are available3.

Australian guidelines were revised in 2013 recommending BRCA1/2 testing for patients diagnosed with non-mucinous epithelial oc. Historically fewer than 50% of eligible patients were referred for testing4. We estimate that, over the last 15 years, more than 11,000 oc patients in Australia were not tested. Many of those patients will since have died of their disease, and their family members could unknowingly be at risk, with no current systematic process for them to be found or tested.

traceback aims to reduce the number of BRCA1/2-related cancers in Australia by identifying undiagnosed germline BRCA1/2 and other pathway-related pathogenic mutations in oc patients that have been missed, and then returning findings to family members to facilitate cascade testing.

Methods

Participants are recruited by 3 methods: cancer cohort studies, self-referral, and clinic-based outreach. Living women are referred to a familial cancer centre (fcc). For deceased women, targeted sequencing is performed on dna from blood or formalin-fixed paraffin-embedded tissue, assessing 9 genes of interest, including BRCA1/2. We are now piloting all aspects in conjunction with patient advocacy groups, researchers with large patient cohort collections, and fccs.

Conclusions

Although conceptually simple, the study is logistically and ethically challenging. traceback will allow unaffected carriers of germline BRCA1/2 mutations and additional oc susceptibility genes the opportunity to adopt risk-reducing strategies. The study will establish methodology and experience returning unanticipated genetic information to individuals, which is likely to be relevant to other cancers and inherited disorders.

AUTHOR AFFILIATIONS

*Peter MacCallum Cancer Centre, Melbourne,,
qimr Berghofer Medical Research Institute, Brisbane,,
East Brunswick Medical Centre, Melbourne,,
§Royal Australian College of General Practitioners,,
St John of God Subiaco Hospital, Perth,,
#University of Western Australia, Perth,,
**Garvan Institute of Medical Research, Sydney, and,
††Prince of Wales Hospital, Sydney, Australia..

1Kuchenbaecker, 2017.

2Alsop, 2012.

3Eccleston, 2017.

4Cohen, 2016.


Posters

Poster P101: BRCA2 Mosaicism As a Cause of Young-Onset Breast Cancer


Lesley Andrews*, Susan Dooley, Rodney Scott


ABSTRACT

A 29-year-old, previously well, nulliparous woman was diagnosed with a 16 mm invasive ductal breast cancer, estrogen and progesterone receptor–positive and her2-negative. She underwent wide local excision and sentinel node biopsy, and had egg harvesting and embryo freezing before chemotherapy. She is undecided about bilateral mastectomy or radiotherapy.

Both of her parents are unaffected by cancer, but her father reported 2 sisters being diagnosed with breast cancer in their 60s, one of whom has a granddaughter who was diagnosed with breast cancer at 35.

The patient underwent next-generation sequencing to a depth greater than 200× of BRCA1, BRCA2 (using reference sequence NM_000059.3), TP53, PALB2, and PTEN. A pathogenic mutation of BRCA2 [c.2152G>T; p.(Glu718*)] was identified at a low level of approximately 16% in 2 independent white blood cell samples and was confirmed by Sanger sequencing, using reference sequence NM_000059.3. The same mutation was identified in approximately 13% of normal breast tissue and 50% of breast tumour cells. As expected, the mutation was not identified in the white blood cells of either parent.

This case represents a rare example of BRCA2 mosaicism resulting in young-onset breast cancer. With the increasing use of ngs, mosaicism is more frequently being identified. BRCA1 or BRCA2 mosaicism poses a number of management and counselling challenges. The risks of contralateral breast cancer and ovarian cancer cannot be accurately quantified without knowing the mutation level in each tissue. Additionally, the risk of an offspring carrying the mutation cannot be quantified, complicating decisions about preimplantation genetic diagnosis.

AUTHOR AFFILIATIONS

*Prince of Wales Hospital, Randwick, and,
New South Wales Health Pathology North, Newcastle, Australia..


Posters

Poster P102: Molecular and Genetic Characterization of Contralateral Breast Cancer (CBC) and the Identification of Markers of CBC Risk: Opportunities for Personalized Surgery


Colin McIlmunn*, David Gonzalez de Castro*,, Jacqueline James*,, Deirdre Fitzpatrick, Kienan Savage*, Stuart McIntosh*,§


ABSTRACT

The incidence of contralateral breast cancer (cbc) is 0.4%–0.7% per year after initial diagnosis. Young age at primary tumour diagnosis and family history are known risk factors for cbc development, in common with hereditary breast and ovarian cancer syndromes. Although the cbc incidence is low, requests for contralateral prophylactic mastectomy (cpm) for treatment of unilateral breast cancer are rising, despite the absence of a survival advantage. This study aims to guide cpm decision-making by improving our understanding of cbc risk in individuals.

403 women with cbc in Northern Ireland were identified. Detailed clinicopathologic and survival data were curated on each patient. Archival formalin-fixed paraffin-embedded primary and contralateral tumours were obtained for each patient for targeted sequencing of a panel of genes, including those commonly mutated in breast cancers and all known breast cancer risk predisposition genes. This study had two principal aims:

  • ■ To determine the clonal relatedness of primary and contralateral tumours

  • ■ To investigate the rate of underlying predisposition gene mutations in this cohort by sequencing germline dna from normal tissue

This study is ongoing. Preliminary data suggest limited clonal relatedness between primary and contralateral tumours, but have revealed a higher-than-expected rate of both known pathogenic mutations and variants of unknown significance (vus) in known predisposition genes in the germline of these women. Further sequencing and analysis is currently ongoing.

Our data suggest that a significant proportion of women who develop cbc might do so because of the presence of a predisposing mutation in a known breast cancer risk gene, although the completed sequencing of this cohort will refine these data. Nonetheless, if these findings bear out, our data might suggest that the use of routine panel testing in women requesting cpm could be a strategy to help tailor surgical treatment to the individual.

AUTHOR AFFILIATIONS

*Centre for Cancer Research and Cell Biology,,
Institute for Health Sciences,,
Northern Ireland Cancer Registry, and,
§Belfast Health and Social Care Trust, Belfast, U.K..


Posters

Poster P103: Do Women After Risk-Reducing Salpingo-oophorectomy Have Increased Risk of Cardiovascular Disease?


Nora Johansen*, Astrid Helene Liavaag*, Lars Mørkrid, Randi Selmer, Serena Tonstad§, Trond Melbye Michelsen


ABSTRACT

Objective

Premenopausal bilateral oophorectomy increases the risk of cardiovascular disease (cvd); however, hormone replacement therapy (hrt) might attenuate this risk. Our primary aim was to examine cvd risk in women after risk-reducing salpingo-oophorectomy (rrso) compared with premenopausal women from the general population. Secondarily, we aimed to study the effect of hrt on cvd risk after rrso.

Methods

Participants were 138 women after rrso and 1352 premenopausal women from the general population (control group), all 52 years of age or younger. Both groups underwent physical examination and blood sampling. The 10-year cvd risk was estimated by the norrisk 2 score, based on age, systolic blood pressure, cholesterol, daily smoking, antihypertensive medication, high density lipoprotein, and cvd in the family. cvd risks were compared by the independent samples t-test.

Results

The cvd risk was significantly higher in the rrso group than in the control group (1.27% vs. 0.89%, p = 0.001), but not after age adjustment (p = 0.37). Further, compared with the controls and adjusted for age, the women after rrso had higher systolic blood pressure (123 vs. 117, p = 0.036), total cholesterol (5.49 vs. 5.13, p = 0.021), and high-sensitivity C-reactive protein (2.34 vs. 1.82, p = 0.035), and lower body mass index (25.0 vs. 25.9, p = 0.015) and waist circumference (86.3 vs. 88.4, p = 0.016). Within the rrso group, total cholesterol and waist circumference were significantly lower for the hrt users than for the hrt nonusers, but the norrisk 2 scores in the hrt users and nonusers were similar.

Conclusions

The 10-year cvd risk was similar in the rrso and control groups. Major cvd risk factors were increased in the rrso group even though the women were slimmer and had a lower body mass index. We found no effect of hrt on cvd risk. We speculate that a detrimental effect of rrso on cvd risk is outweighed by a healthy lifestyle.

AUTHOR AFFILIATIONS

*Sørlandet Hospital Arendal, Arendal,,
Oslo University Hospital Rikshospitalet, Oslo,,
Norwegian Institute of Public Health, and,
§Oslo University Hospital Ullevål, Oslo, Norway..


Posters

Poster P104: Uptake of Pre-implantation Genetic Diagnosis in Female BRCA1 and BRCA2 Mutation Carriers


Pnina Mor*, Kelly Metcalfe, Sarah Brennenstuhl


ABSTRACT

Background

Women with a germline mutation in the breast cancer genes (gBRCA) have an increased risk of breast and ovarian cancer. Healthy gBRCA carriers of childbearing age can choose to preclude mutation transmission to the next generation with preimplantation genetic diagnosis (pgd). We report on pgd practices in gBRCA-positive Israeli women who were offered pgd at no cost.

Methods

The sample consisted of healthy gBRCA carriers 25–36 years of age seen in the genetics clinic from January through August 2015 who were offered pgd (at no cost) and who agreed to complete 3 questionnaires. Age, education level, occupation, years married, parity, religious affiliation, history of infertility, age at time gBRCA testing, prior risk-reducing mastectomy (rrm), receipt of prior information about prenatal genetic testing, decision regret scale (drs), and satisfaction with decision (swd) scale were obtained from participants. Univariate and multivariate analyses were performed for predictors of pgd uptake and were tested for multicollinearity. Differences in the outcomes of the drs and swd scales were tested using independent t-tests.

Results

The final sample (n = 70) had a median age of 31.95 years; 84.3% had more than 1 child; and 8.6% had undergone rrm. pgd uptake was 25.7% (18/70) for the entire sample. pgd uptake differed significantly (p < 0.001) for the subsets with and without a history of infertility: 70% (7/10) and 18% (11/60) respectively. Prior infertility was the only significant predictor of pgd uptake (p < 0.001) on multivariate analyses. Uptake of pgd was not predicted by age or religious affiliation. swd scores were significantly higher for those who had pgd (p < 0.04).

Conclusions

Compared with gBRCA status, a history of infertility has a greater effect in the decision-making process for pgd in women with a gBRCA mutation.

AUTHOR AFFILIATIONS

*Shaare Zedek Medical Center, Jerusalem, Israel;,
University of Toronto, Toronto, ON..


Posters

Poster P105: Impact of gBRCA Identification on Subsequent Breast Cancer Stage and Therapy—Implications for Routine Screening


Pnina Mor*, Tal Hadar*, Geffen Amit*, Sari Lieberman*, Esty Tahover*, Ora Rosengarten*, Oded Olsha*, Moshe Carmon*, Rachel Rabinovitch, Ephrat Levy-Lahad*


ABSTRACT

Background

Screening healthy Ashkenazi Jews (ajs) for germline BRCA1/BRCA2 mutations (gBRCA) is not standard policy, despite a high carrier rate (2.5%). Most carriers are identified only after breast cancer (bca) diagnosis. We hypothesized that pre-symptomatic knowledge of carrier status would favourably affect bca stage and management.

Methods

We reviewed records of gBRCA carriers who did not undergo risk-reduction mastectomy and who were diagnosed with bca between April 1996 and April 2016. Patient age, parity, family history, genotype, screening compliance, method of bca detection, disease characteristics (grade, receptor status, stage), and treatment [breast and axillary surgery, chemotherapy (ctx)] were compared between carriers whose gBRCA was identified before and after bca.

Results

165 women with gBRCA and bca were identified, in whom carrier status was determined pre-bca in 45 (27%) and post-bca in 120 (73%); mean age at bca diagnosis was similar in both groups (50.6 years and 50.5 years; range: 27–86 years), as was the BRCA1:BRCA2 distribution (64%:36% and 65%:35%). Pre-bca carriers were significantly (p < 0.001) more likely to have a suggestive family history (90% vs. 62%), prior bca screening (78% vs. 60%), and bca diagnosed by imaging (78% vs. 25%) rather than by clinical symptoms (19% vs. 73%). Pre-bca carriers had a higher dcis:invasive bca presentation (40%:60% vs. 2%:98% in post-bca) and lower T, N, and combined staging (p < 0.005). No differences in tumour grade or estrogen receptor or her2 status were identified. Compared with post-bca carriers, pre-bca carriers were more likely to undergo sentinel lymph node biopsy (91% vs. 45%), less likely to receive ctx, and more likely to elect bilateral mastectomy (62% vs. 10%, p < 0.001 for all comparisons). Overall, pre-bca gBRCA identification and routine screening predicted for early-stage (0–i) bca diagnosis (p < 0.001).

Conclusions

Pre-symptomatic identification of gBRCA status is significantly associated with bca screening and earlier-stage bca diagnosis, requiring less axillary surgery and ctx. These significant health effects support routine gBRCA testing in all healthy aj women.

AUTHOR AFFILIATIONS

*Shaare Zedek Medical Center, Jerusalem, Israel;,
University of Colorado Comprehensive Cancer Center, Denver, CO, U.S.A..


Posters

Poster P106: BRCA Testing in Ovarian Tumours Initiated by a Pathologist: A Pre-screen for Genetic Testing and Therapy Choice


Ingrid E. Fakkert*, Arjen R. Mensenkamp*, Edward M. Leter, Joanne A. de Hullu*, Carolien M. Kets*, Gwendolyn H. Woldringh*, Michiel Simons*, Johan Bulten*, Riki W. Willems*, Marjolijn C. Jongmans*, Marjolijn J.L. Ligtenberg*, Nicoline Hoogerbrugge*


ABSTRACT

Background

Germline BRCA mutation testing is advised to all ovarian cancer (oc) patients. According to the literature, approximately 20% will have BRCA mutations in their tumour dna, of which about 75% are germline and 25% somatic mutations. Both may benefit from parp inhibitor therapy. We evaluated the yield of tumour dnaBRCA testing initiated by the pathologist in all newly diagnosed oc patients (opa) as pre-screen for germline dnaBRCA testing and therapy choice.

Methods

Pathologists were invited to submit formalin-fixed paraffin-embedded samples of all newly diagnosed epithelial ocs. Tumour dnaBRCA testing was performed using single-molecule molecular inversion probe–based, targeted, next-generation sequencing and BRCA1 multiplex ligation-dependent probe amplification. The gynecologist was to communicate outcomes and refer patients with tumour dnaBRCA mutations for genetic counselling. Patients experiences were evaluated by semi-structured interviews.

Results

From October 2015 to June 2017, opa was initiated in 312 oc patients. In 9 women (3%), opa was not feasible. In 303 women with a median age of 66 years at oc diagnosis, opa revealed 53 tumour dnaBRCA mutations (17%). Germline testing was performed in 42 women and revealed 24 BRCA mutations (57%). The experiences of the first patients were positive; however, waiting times for germline testing after tumour testing were considered inconvenient.

Conclusions

opa provides a feasible pre-screen for genetic testing and parp inhibitor therapy shortly after oc diagnosis. If evaluation by patients and physicians is positive, national implementation can be considered.

AUTHOR AFFILIATIONS

*Radboud University Medical Center, Nijmegen, and,
Maastricht University Medical Center, Maastricht, Netherlands..


Posters

Poster P107: Pilot Study of Denosumab in BRCA1/2 Mutation Carriers Scheduled for Risk-Reducing Salpingo-oophorectomy


Goli Samimi*a, Meghna S. Trivedia, Jason D. Wright, Kevin Holcomb, Judy E. Garber§, Neil S. Horowitz§, Nadir Arber, Eitan Friedman#, Robert M. Wenham**, Margaret House*, Howard Parnes*, J. Jack Lee††, Saba Abutaseh††, Lana A. Vornik††, Brandy Heckman-Stoddard*, Powel H. Brown††, Katherine D. Crew

††University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.

ABSTRACT

Denosumab is a monoclonal antibody that inhibits rankl. It is approved for prevention of fractures in patients with osteoporosis or bone metastases. Adverse effects of denosumab include hypocalcemia and osteonecrosis of the jaw. The rankl signalling pathway has been shown to be involved in BRCA-associated mammary tumorigenesis via a progesterone-induced paracrine effect of rankl on luminal progenitor cells. Preclinical studies have demonstrated that rankl inhibition results in reduced progression of mammary tumours.

Early findings from an ongoing presurgical study demonstrate that denosumab treatment results in decreased Ki-67 expression in breast tissue. Based on those data, denosumab is being pursued as a potential preventive agent for breast cancer in BRCA1/2 mutation carriers. Although promising, the effect of rankl inhibition on gynecologic tissues such as the ovaries and fallopian tubes, in which progesterone has a protective effect, is unknown.

We will conduct a multicentre, open-label randomized pilot of presurgical administration of denosumab compared with no treatment in premenopausal women with BRCA1/2 mutations undergoing risk-reducing salpingo-oophorectomy. A total of 60 women will be randomized 1:1 to arm 1 (3–4 doses denosumab 120 mg subcutaneously every 4 weeks) or arm 2 (no treatment). Participants will be stratified by mutation status (BRCA1 or BRCA2) and use of hormonal contraceptives within the past 3 months (yes or no). Assuming a 10% unevaluable rate, we expect to have 54 evaluable participants (27 per arm).

Our primary objective is to compare denosumab with no treatment with respect to the effect on Ki-67 expression in the fimbrial end of the fallopian tube. Secondary objectives are to assess Ki-67 in ovary and endometrium; to investigate apoptosis, rank/rankl, estrogen/progesterone receptor, CD44, and stat3 expression in fallopian tube, ovary, and endometrium; to analyze gene expression profiling in the fallopian tube and ovary; to investigate serum markers and drug levels; and to evaluate toxicity.

AUTHOR AFFILIATIONS

*National Cancer Institute, nih, Bethesda, MD,,
Columbia University Medical Center, New York, NY,,
Weill Cornell Medical Center, New York, NY, and,
§Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA, U.S.A.;,
Tel Aviv Sourasky Medical Center, and,
#Sheba Medical Center, Tel Aviv, Israel;,
**Moffitt Cancer Center, Tampa, FL, and,
††University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A..

aJoint first authors.


Posters

Poster P108: Screening Accuracy and Breast Cancer Characteristics in BRCA Mutation Carriers in the High-Risk Ontario Breast Screening Program


Kristina M. Blackmore*, Anna M. Chiarelli*,, Derek Muradali*, Vicky Majpruz*, Ashini Weerasinghe*, Lucia Mirea, Susan J. Done§, Linda Rabeneck*,


ABSTRACT

Background

The Ontario Breast Screening Program (obsp) expanded in July 2011 to screen women 30–69 years at high risk for breast cancer with annual magnetic resonance imaging (mri) and digital mammography (dm). This study examined the accuracy of mri and dm in mutation carriers by BRCA status, age, and breast cancer characteristics.

Methods

Information was collected for eligible women referred to the high-risk obsp from July 2011 to June 2015, screened until 30 June 2016, and followed until 31 December 2016 (n = 9003). Among BRCA1/2 mutation carriers, cancer detection rates (cdrs), sensitivity, and specificity were compared stratified for BRCA mutation status and age (30–49, 50–69). Prognostic features of cancers by BRCA mutation status were also examined.

Results

In 1771 BRCA1/2 mutation carriers (BRCA1, 870; BRCA2, 901) having 4499 screening episodes, 114 breast cancers were detected (BRCA1, 61; BRCA2, 53; cdr: 25.3/1000; 95% ci: 20.9 to 30.4). The cdr was nonsignificantly higher in women with BRCA1 compared with BRCA2 mutation [cdr: 27.9/1000 (95% ci: 21.4 to 35.6) vs. 23.0/1000 (95% ci: 17.2 to 29.9)], especially among those 50–69 years of age [cdr: 30.2/1000 (95% ci: 20.9 to 42.2) vs. 22.6/1000 (95% ci: 15.3 to 32.1)]. Among the women overall, screening sensitivity and specificity were 90.6% (95% ci: 83.0 to 96.0) and 83.5% (95% ci: 82.2 to 84.8) respectively. Among women 50–69 years of age, sensitivity was nonsignificantly higher by 14% in women with BRCA1 compared with BRCA2 mutation [95.8% (95% ci: 78.9 to 99.9) vs. 81.8% (95% ci: 59.7 to 94.8%)], while specificity was significantly higher in women with BRCA2 mutation [89.5% (95% ci: 87.4 to 91.3) vs. 85.8% (95% ci: 83.2 to 88.2)]. In BRCA2 compared with BRCA1 mutation carriers, the risk of ductal carcinoma in situ was significantly higher (or: 3.63; 95% ci: 1.04 to 12.61) and the risk of triple-negative cancers was significantly lower (or: 0.17; 95% ci: 0.05 to 0.67).

Conclusions

Screening with annual mri combined with dm has been effectively implemented into an organized breast screening program and could be considered an important management option for known BRCA gene mutation carriers.

AUTHOR AFFILIATIONS

*Cancer Care Ontario, and,
University of Toronto, Toronto, ON;,
Phoenix Children’s Hospital, Phoenix, AZ, U.S.A.;,
§University Health Network, Toronto, ON..


Posters

Poster P109: Preventive Care Patterns in Utah Women with BRCA from 1995 to 2017


Lindsay Hunter*, Whitney Espinel, Lisa Pappas, Ken Smith, Wendy Kohlmann, Sarah Colonna*,


ABSTRACT

Background

Women who have BRCA1/2 pathogenic variants are advised to obtain intensive screening and/or risk-reducing surgeries to prevent breast and ovarian cancer. Inappropriate use of risk-reduction measures could result in unnecessary morbidity or preventable cancers. This study characterizes preventive care patterns from 1995 to 2017.

Methods

Data for 3442 women 18 years of age and older with BRCA1/2 testing were identified using clinical genetic testing records at the University of Utah Huntsman Cancer Institute. Women were included if they were BRCA1/2-positive with at least 1 visit after the genetic test date. Demographics, breast screening tests, risk-reducing surgeries, and hormonal medication data from 1995 to 2017 were gathered using icd and cpt codes pulled from the Utah Population Database and the University of Utah electronic data warehouse. These variables were described using means, medians, ranges, and proportions.

Results

592 women from 1995 to 2017 who met the inclusion criteria were identified. Most women were non-Hispanic white (72%) and less than 50 years of age at genetic testing (72%). Median follow-up time was 56.4 months. 235 women had at least 1 breast mri, 60% of whom had annual testing. 310 women had at least 1 mammogram, 42.9% of whom had annual testing. Of those without breast cancer at the time of genetic testing, only 67 individuals (14.9%) underwent risk-reducing mastectomy (rrm). For women without a diagnosis of ovarian cancer, only 71 (12%) underwent risk-reducing bilateral salpingo-oophorectomy (rrbso).

Conclusions

This is a large cohort of women with BRCA1/2 followed over several decades. For women who had ever had breast imaging, the proportion undergoing yearly breast imaging was high at 60%; however, the number of women who underwent rrm or rrbso was lower than expected. That observation might be attributable to incomplete data sources, or it could represent a change in women’s risk management choices over time. Further analysis is needed to clarify.

AUTHOR AFFILIATIONS

*University of Utah and,
Huntsman Cancer Institute, Salt Lake City, UT, U.S.A..


Posters

Poster P111: The Incidence of Occult Ovarian Neoplasia and Cancer in BRCA1/2 Mutation Carriers After Bilateral Prophylactic Salpingo-oophorectomy: A Single-Centre Prospective Study


Ramunas Janavicius*,, Gediminas Januska, Vilius Rudaitis


ABSTRACT

Background

Because of ineffective ovarian cancer (oc) screening programs, prophylactic bilateral salpingo-oophorectomy (pbso) is suggested for BRCA1/2 mutation carriers. The reported incidence of clinically occult neoplasia and oc detected during pbso varies widely (2%–17%), reflecting differences in study designs.

Objective

We aimed to prospectively evaluate the incidence of occult neoplasia in specimens collected during pbso performed in a single tertiary centre and to determine the effectiveness of this procedure in BRCA1/2 mutation carriers.

Methods

Between January 2010 and October 2016, 564 new germline BRCA1/2 mutation–positive women were identified, and 71 carriers underwent laparoscopic pbso. The date and time of operation, the woman’s age, complications, histologic reports of adnexa and BRCA1/2 gene mutation types were reported.

Results

Serous tubal intraepithelial carcinoma (stic) was diagnosed in 7 women (9.85%), and oc, in 4 women [5.6%; 1 advanced (figo iiic) and 3 early (figo ia/c)], for a total incidence of 15.5%. Mean age at the time of surgery was 46.5 years. The mean age of women diagnosed with stic and oc was 45.9 years, the youngest women being 42 and the oldest, 64. Median time to perform pbso was 43 minutes (range: 25–65 minutes). No surgical complications occurred during the operations. Interestingly, we found a statistically significant enrichment of stic lesions in the BRCA1 c.4035delA (an established Baltic founder mutation) carrier group (6 of 7 stic patients, p = 0.0105).

Conclusions

The incidence of pathologic findings in BRCA1/2 mutation carriers after pbso is sufficiently high, and our prospective data support pbso as the most effective measure for reducing the risk of oc in BRCA1/2 mutation carriers. A novel finding of the enrichment of stic lesions in BRCA1 c.4035delA carriers might show important biologic differences in oc tumorigenesis between different BRCA1 mutations, warranting further investigation.

AUTHOR AFFILIATIONS

*Vilnius University Hospital Santaros Klinikos,,
State Research Institute Innovative Medicine Center, and,
Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania..

Funding: This study was supported by Lithuanian Research Council grant SEN18/2015.


Posters

Poster P112: Fertility and Risk-Reduction Surgery


Sachiko Takahara, Kumiko Oseto, Aiko Obayashi, Yurina Maeshima, Ryohei Katsuragi, Yukiko Yoshimoto, Akira Yamauchi


ABSTRACT

Both risk-reducing mastectomy (rrm) and risk-reducing salpingo-oophorectomy (rrso) for the patient with BRCA pathologic variants have come to be recommended even in guidelines in Japan in 2017. We have carried out heredity counselling for 224 hboc high-risks individuals since January 2013, and 102 (46%) have undergone genetic testing, revealing 23 cases (23%) of BRCA pathologic variants. Afterward, 5 cases of rrm and 6 of rrso were carried out by the end of 2017. Furthermore, a genetic counsellor has been consulted about the desire for childbearing and has offered information about fertility preservation before start of breast cancer treatment since 2013.

We now report the distinctive case of a 38-year-old female patient. She noticed induration on the right breast soon after nursing was finished. Needle biopsy revealed triple-negative breast cancer. Family hstory revealed breast cancer and cervical cancer in the mother, stomach cancer in the maternal grandmother, and prostate cancer in a maternal uncle. Genetic testing revealed a deleterious variant in BRCA1 [L1086X (3376T>G)].

The patient required neoadjuvant chemotherapy, but she wanted to maintain her fertility. After breast surgery, she still wanted the second child, and so we could not discuss contralateral rrm and rrso. She has received gynecologic examinations every 6 months. One year after breast surgery, she consulted our gynecology department complaining of the left lower abdominal pain. Because diagnostic imaging showed swelling of the left ovary, she underwent laparotomy, and an intraoperative pathology examination demonstrated bilateral ovarian cancer with lymph node metastases.

In conclusion, specific consideration is required to resolve a dilemma between fertility and risk-reducing surgery in juvenile hboc patients because of associated cancer development. A consideration of the patient’s marriage status and social situation is also required. rrso/rrm should be carried out based on sufficient informed consent and the patient’s wishes with respect to childbearing.

AUTHOR AFFILIATIONS

Kitano Hospital, Osaka, Japan..


Posters

Poster P113: Impact of Breast Cancer Hereditary High-Risk Medical Home


Lauren Bolden*, Courtney Yanda, Caitlin McCarthy, Brandie Heald, Kathleen Ashton, Stephen R. Grobmyer, Charis Eng, Holly J. Pederson


ABSTRACT

Background

Women carrying certain germline genetic mutations have markedly elevated risks for cancer. Surgical interventions and surveillance outlined in U.S. National Comprehensive Cancer Network guidelines reduce the risk in such patients; however, guideline adherence is required for optimal outcomes. We analyzed the effect of a central interdisciplinary “Medical Home” on guideline adherence and long-term follow-up.

Methods

Patients carrying germline mutations at a single institution (2000–2017) were retrospectively reviewed. Rates of risk-reducing salpingo-oophorectomy (rrso), risk-reducing mastectomy (rrm), and adherence to recommended breast cancer screening (mammography and mri) were evaluated for patients with BRCA mutations.

Results

313 patients with mutations conferring increased cancer risk were identified and followed for an average of 10.5 years. The average age at genetic testing was 43.7 years. 298 carried mutations in highly penetrant genes, 287 in BRCA1 and BRCA2. 93% (226/242) had rrso (if >41 years of age), and 43% overall (105/242) had rrso while less than 41 years of age (61 BRCA1, 44 BRCA2). Of 210 BRCA patients without a previous breast cancer diagnosis, 91 (43.3%) chose rrm at an average age of 43. Younger age at genetic testing correlated with rrm (p = 0.003). Of patients who were being followed, 75% (77/103) remained current with mammographic guidelines, and 77.3% (75/97) with mri guidelines. Overall, 81 patients (28.2%) were diagnosed with breast cancer, 16 after genetic diagnosis (3 stage 0, 12 stage i, and 1 stage iii). 29 (10.1%) had an ovarian malignancy, 5 after the genetic diagnosis.

Conclusions

Early identification of genetic mutation carriers, coupled with adherence to national guidelines for risk management, improves early cancer detection through surveillance and provides the opportunity for chemoprevention and discussions concerning rrso and rrm. Creation of a “Medical Home” at our institution has resulted in reasonable adherence to guidelines, but challenges remain.

AUTHOR AFFILIATIONS

*Wright State University, Dayton, OH,,
Cleveland Clinic, Cleveland, OH, and,
Michigan State University, Lansing, MI, U.S.A..


Posters

Poster P114: Synchronous Breast and Ovarian Cancers in BRCA Mutation Carriers: An Emerging Issue


Pooja Murthy*, Leslie Boyd*, Tamar Safra, Franco Muggia*


ABSTRACT

Background

Although the lifetime risk of both ovarian cancer (oc) and breast cancer (bca) is a high in BRCA mutation carriers (61%–79% bca risk, and 11%–53% oc risk), synchronous cancers, defined as the diagnosis of both cancers in the same patient within 6 months of each other, are rare, with only a few cases being reported in the literature. In 2008, we reported a case series of 8 BRCA-mutated patients who had both bca and oc, and we highlighted the unusual features and variable management of both synchronous and metachronous cancers. We now focus on synchronous presentations.

Methods

6 patients with BRCA germline mutations and synchronous diagnoses of bca and oc were identified at New York University Langone Medical Center and Tel Aviv Sourasky Medical Center. Their clinical presentations and outcomes to date were analyzed.

Results

In 3 of 6 patients, the diagnoses of synchronous bca and oc were a result of risk-reducing surgeries or initial staging imaging. The bcas were all early-stage disease (i and ii); the ocs were high-grade, primarily serous, and advanced even if detected incidentally during the bca work-up. All 6 patients received chemotherapy with platinum and a taxane initially, a regimen that doubled as adjuvant or neoadjuvant treatment for bca. All 6 patients had excellent local and systemic control of bca, but the eventual progression in their oc or the occurrence of another primary cancer resulted in unfavourable outcomes.

Conclusions

Synchronous bca and oc diagnoses in BRCA-mutated women might become more common because of widespread genetic testing, use of staging imaging, and prophylactic surgeries. Platinum-and taxane-based chemotherapy directed at oc, coupled with local and systemic treatments, appears to adequately deal with bca, but long-term outlook is driven primarily by risk of oc recurrence or unrelated cancers. Dual primaries might provide a further rationale for consolidation with parp inhibitors.

AUTHOR AFFILIATIONS

*New York University Langone Medical Center, New York, NY, U.S.A.;,
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel..


Posters

Poster P115: Mosaic or Not? Additional Investigations to Explore the Validity of Mosaic Results Identified Using NGS


Jennifer Diraimo*, Karen Panabaker*, Bekim Sadikovic*,, Peter Ainsworth*,, Han-Xin Lin*,


ABSTRACT

Introduction

Since February 2016, patients who met eligibility criteria were offered a hereditary cancer panel at London Health Sciences Centre (lhsc). Our targeted deep-sequencing approach has enabled effective detection of mosaicism. Low-level mosaicism creates challenges in management and genetic counselling. Here, we report on our centre’s experience with 4 local patients who elected to pursue additional investigations after a positive mosaic result.

Methods

A positive mosaic result was identified in 4 local patients. Repeat analysis using a new blood sample, in addition to a skin biopsy or tumour analysis, was performed. Sequence variants were detected either by deep-sequencing approaches, including the lhsc custom targeted hereditary cancer next-generation sequencing (ngs) panel (pmid 27376475, 28818680), or the AmpliSeq Cancer Hotspot Panel [for TP53 only (Thermo Fisher Scientific, Waltham, MA, U.S.A.).

Results

Mutant allele frequencies ranged from 12% to 15% on initial testing. On repeat testing, the levels of mosaicism either decreased or remained unchanged in 3 of the 4 cases. Tumour testing in 1 case failed to confirm the presence of the mosaic mutation identified in peripheral blood. On repeat analysis after chemotherapy, a reduction in the mutation frequency was observed. All 4 cases were 55 years of age or older, with 3 being in their mid-60s to late 70s, suggesting the possibility of age-related clonal hematopoiesis (Jaiwal et al., 2015). Germline mosaicism could not be excluded.

Conclusions

This case review is one of the first to report on additional testing after detection of a low-frequency pathogenic germline mosaic result. These findings emphasize the power of custom targeted ngs sequencing to uncover mosaicism as an important, but not yet well understood, molecular mechanism of disease.

AUTHOR AFFILIATIONS

*London Health Sciences Centre and,
Western University, London, ON..


Posters

Poster P116: Prospective Results of Breast Cancer Screening in 2049 Norwegian Women with BRCA Mutation


Kjersti Jørgensen, Anita Vabø, Eli Kvaal, Nora Marinussen Tandstad, Eldbjørg Hanslien, Tone Bøe Aaman Vamre, Trine Levin, Astrid Stormorken, Lovise Mæhle, Teresia Wangensteen, Yngvild Storlykken, Eli Marie Grindedal


ABSTRACT

Background

The Section of Inherited Cancer at Oslo University Hospital (ouh) has referred BRCA1/2 mutation carriers not choosing prophylactic mastectomy to annual breast screening with, first, only mammography and then, since 2002, also mri. In this study, we describe prospective breast cancers (bcas) detected in these women, and therefore avoid the selection bias associated with retrospective studies.

Methods

We identified 1385 BRCA1 carriers and 664 BRCA2 carriers who had been followed prospectively for 8186 and 3421 years respectively. Information was collected on all bcas detected during follow-up. Cancers detected on the first round were excluded. All first bcas occurring after the first round were included. The study was defined as a quality-of-care study by the Data Protection Officer at ouh.

Results

bca was detected in 164 of 1385 BRCA1 carriers (11.8%) and 55 of 664 BRCA2 carriers (8.3%). The annual incidence rate was 2.0% for BRCA1 and 1.6% for BRCA2. For BRCA1 carriers, mean age of onset was 49.5 (26–90), and 93 cancers (56.7%) occurred before 50 years of age. Of those cancers, 120 (73.2%) were node-negative, 28 (17.1%) were node-positive, and 16 (9.8%) were dcis. her2 was analyzed in 103 tumours. Of those tumours, 67 (65.0%) were triple-negative. For BRCA2 carriers, mean age of onset was 54.1 (30–78), and 21 cancers (38.2%) occurred before 50 years of age. Of those tumours, 33 (60%) were node-negative, 8 (14.5%) were node-positive, and 14 (25.4%) were dcis. her2 was analyzed in 30 tumours. Of those tumours, 7 (23.3%) were triple-negative.

Conclusions

Most prospective BRCA1bcas occurred before the age of 50 years and were triple-negative. However, overall, about 50% of BRCA1/2bcas occurred after 50 years of age, and 44% were not triple-negative. dcis constituted 10% of BRCA1bcas and as many as 25% of BRCA2bcas. These observations could be of importance when selecting patients for BRCA testing.

AUTHOR AFFILIATIONS

Oslo University Hospital, Oslo, Norway..


Posters

Poster P117: Preventive Ovarian Cancer Clinic: A Model for Care of Women at Risk for Hereditary Ovarian Cancer


Michelle Jacobson*, Gabrielle Ene*,, Melissa Walker*, Mara Sobel*,, Lisa Allen*,, Marcus Bernardini*,


ABSTRACT

Objective

Gynecologic care for women with hereditary breast and ovarian cancer syndrome is complex. These women have unique challenges throughout their reproductive lives. The Preventive Ovarian Cancer and Aftercare Clinic (pocc) was established to address those needs through expert and evidence-based care. The aim of this study was to examine the outcomes of our clinic 2 years after its inception.

Methods

A retrospective chart review of women with confirmed BRCA1/2 mutations referred to the pocc at Women’s College Hospital, Toronto, was performed. Patient demographics, diagnostic codes, preoperative investigations, and intraoperative and pathology findings were recorded.

Results

After referrals from genetic counsellors in Toronto, our clinic expanded in 2017 to 175 new patients visits, 75–85 outpatient procedures [that is, bilateral salpingo-oophorectomy (bso), bilateral salpingectomy], 20 inpatient procedures (total laparoscopic hysterectomy or medically complex bso), and 130 aftercare visits. Our cohort included 183 women, of whom 132 (72.1%) underwent risk-reducing salpingectomy (rrs) and 51 (27.9%) deferred or declined surgery. In women who underwent rrs (mean age: 46 years; range: 30–72 years), 115 (87.1%) underwent rrso, and 17 (12.9%) chose initial risk-reducing bilateral salpingectomy with delayed oophorectomy. Three occult malignancies (2.3%) were detected (2 serous tubal intraepithelial carcinoma, 1 invasive ovarian cancer). Preoperative investigations were normal in all women with abnormal pathology. Visit codes included contraception counselling, liaison with fertility specialists, counselling in risk reduction, risk-reducing surgery, and menopause management.

Conclusions

The pocc is providing comprehensive clinical care to women at risk of hereditary ovarian cancer. This unique model encourages comprehensive management and continued research collaboration and advancement. Ongoing goals include collection of patient satisfaction data and integrative care with the breast centre.

AUTHOR AFFILIATIONS

*Women’s College Hospital,,
University Health Network, and,
Sinai Health System, Toronto, ON..


Posters

Poster P118: Collection of Fallopian Tube Cytology with a Novel Hysteroscopic Tubal Catheter


C. Bethan Powell*, Ramey D. Littell*, Charles Landen, Sharmila Pramanik, Isabella Hamilton*, Betty Suh Burgmann*


ABSTRACT

Objective

To demonstrate the ability of a hysteroscopic tubal catheter to collect samples from the fallopian tube for identification of cytologic abnormalities and correlation with histopathology.

Methods

Study subjects were recruited prospectively to an institutional review board–approved trial in 3 gynecologic oncology centres of women undergoing salpingo-oophorectomy. Eligibility criteria included women undergoing risk-reducing surgery for BRCA mutations or for pelvic masses suspicious for malignancy. A novel hysteroscopic catheter (nVision Medical, San Bruno, CA, U.S.A.) was used to collect cells from the fallopian tube. Cytology from the collection was compared with pathology findings.

Results

50 patients were enrolled, of whom 8 were BRCA mutation carriers undergoing surgery for risk reduction; the other 42 had a pelvic mass. In 42 evaluable cases, hysteroscopy was performed in 40 women with 78 fallopian tubes, of which 63 ostia were identified, with 58 catheterizations. There were 44 adequate samples (44/58, 76%), with 34 being benign; 5, reactive atypical; and 5, neoplastic. There were 11 cases of ovarian cancer. In 9 of those cases, cell collection was attempted, with adequate specimens collected in 7 cases on the side of the carcinoma. When a specimen was successfully collected and the tube was involved with carcinoma on histology, cytology was positive in all 3 tubes. In 2 stage i ovarian cancers, tubal cytology was positive on the side of the cancer. There were 3 ovarian cancers with negative tubal cytology and tubal histology: stage i cystic teratoma containing invasive squamous carcinoma, stage ic endometrioid ovarian cancer, and stage ii high-grade serous ovarian cancer. The 32 benign and 5 reactive atypical cytology results corresponded with the histology.

Conclusions

Malignancy can be identified in the hysteroscopic collection of cytology from the fallopian tube in cases of ovarian cancer. This device could be used for high-risk surveillance in the outpatient setting.

AUTHOR AFFILIATIONS

*Kaiser Permanente Northern California, CA,,
University of Virginia, Charlottesville, VA, and,
Santa Clara Valley Medical Center, CA, U.S.A..


Posters

Poster P119: The Incidence of Peritoneal Cancer After Oophorectomy and Among BRCA1 and BRCA2 Mutation Carriers


Steven A. Narod*,, Joanne Kotsopoulos*,, Ping Sun*, Jan Lubinski


ABSTRACT

We followed 5475 BRCA1 and BRCA2 carriers from date of oophorectomy to June 2017 to estimate the 20-year cumulative incidence of primary peritoneal cancer. After a mean of 7.8 years of follow-up, 40 incident peritoneal cancers were diagnosed in the cohort. The annual risk was 0.13% for BRCA1 carriers and 0.06% for BRCA2 carriers. The annual risk of peritoneal cancer was constant throughout the 20-year follow-up period. The risk of peritoneal cancer varied substantially by current age: among BRCA1 carriers, the annual risk of peritoneal cancer was higher for women between 45 and 60 years of age (0.16% per year) than for women between 35 and 44 years of age (0.06% per year). The actuarial risk of peritoneal cancer to age 60 was 2.1% for those who underwent their oophorectomy before or at age 45 and 1.9% for those who had the operation after age 45. The 10-year cumulative risk of peritoneal cancer in BRCA1 carriers was 1.4% for women who had the oophorectomy before 2000 and 1.4% for women who had the oophorectomy after 2000.

AUTHOR AFFILIATIONS

*Women’s College Hospital and,
University of Toronto, Toronto, ON;,
Pomeranian Medical University, Szczecin, Poland..


Posters

Poster P120: Is Prophylactic Breast Surgery Essential in BRCA Mutation Carriers After Diagnosis of Ovarian Cancer?


Tamar Safra*,, Dianna Gerber, Melissa Frey, Annie Yang, Jessica Taff, Jeanne Chern, Bhavana Pothuri, Franco Muggia


ABSTRACT

Background

Prophylactic salpingo-oophorectomy significantly reduces ovarian cancer risk in BRCA mutation carriers diagnosed with breast cancer. Conversely, after a diagnosis of ovarian cancer, patients can be followed annually with mri or can undergo prophylactic breast surgery (pbs) to mitigate potential breast cancer risk.

Objective

To define actuarial risks of breast cancer and overall mortality in a multi-ethnic cohort of BRCA1 and BRCA2 mutation carriers after a diagnosis of ovarian cancer.

Methods

BRCA mutation carriers were diagnosed with ovarian cancer from 2000 to 2017 at New York University (n = 140) and the Tel Aviv Sourasky Medical Center (n = 124). Clinical data about pbs, diagnosis of subsequent breast cancers, and type of deleterious BRCA mutation (1 or 2) were analyzed.

Results

During this period, 6 women underwent pbs. The cumulative risk of breast cancer after oc in BRCA carriers was lower than projected. Of the 124 Israeli BRCA-carrier oc patients with annual mri (automatically reimbursed for BRCA carriers in Israel), none went through pbs and only 3 (2.4%) developed sequential breast cancer. Issues to be studied further include risk according to the specific BRCA mutation, instances of synchronous presentations, pre-existing breast pathology, and the emerging role of parp inhibitors.

Conclusions

We presume that the observed lower-than-expected rates of breast cancer are partially attributable to mortality from ovarian cancer, which occurs before the affected patients develop any breast cancer. Our data are consistent with 4 prior series of BRCA mutation carriers diagnosed with ovarian cancer14; pbs or mri breast surveillance are unlikely to affect outcomes until ovarian cancer survivors have been disease-free for 10 years.

AUTHOR AFFILIATIONS

*Tel Aviv Sourasky Medical Center and,
Tel Aviv University, Tel Aviv, Israel;,
New York University, NY, U.S.A..

1 McGee et al., Gynecol Oncol 2017;145:346–51.

2 Gangi et al., JAMA Surg 2014;149:1306–13. [Erratum in: JAMA Surg 2015;150:183]

3 Vencken et al., Cancer 2013;119:955–62

4 Domchek et al,. Cancer 2013;119:1344–8.


Posters

Poster P121: Mortality After Ovarian Cancer by Method of Detection Among Women with a BRCA Mutation


Vasily Giannakeas*,, Jacek Gronwald, Beth Karlan§, Joanne Kotsopoulos*,, Steven A. Narod*,


ABSTRACT

Women with a BRCA mutation have a 20%–40% lifetime risk of developing ovarian cancer. Most BRCA-associated ovarian cancers are of an aggressive subtype and are diagnosed at a late stage, resulting in a poor prognosis. We sought to determine ovarian cancer–specific survival rates by method of detection in BRCA mutation carriers enrolled in a longitudinal study and diagnosed with incident ovarian cancer.

Women diagnosed with an incident ovarian cancer (or fallopian tube cancer) were categorized into 3 subgroups defined by method of detection: screen-detected (cancer antigen 125 test, ultrasonography), clinically detected (physician, self-report), and occult (at the time of preventive oophorectomy). A cohort of 195 incident ovarian cancer cases was followed for an average of 4.7 years from their date of diagnosis until death or end of follow-up. Kaplan–Meier survival estimates were generated to estimate 10-year ovarian cancer–specific survival by method of detection. Survival was 18% among women with clinically detected cancers, 40% among those with screen-detected cancers, and 76% among those with occult cancers. A statistically significant difference across subgroups was observed (log-rank p < 0.0001). Better survival for women with screen-detected cancers might merit the implementation of ovarian cancer screening programs in high-risk women. Improved survival for woment with occult cancers suggests the need for detection of ovarian cancer in the earliest stages.

AUTHOR AFFILIATIONS

*Women’s College Research Institute, Women’s College Hospital, and,
Dalla Lana School of Public Health, University of Toronto, Toronto, ON;,
International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland;,
§Cedars Sinai Medical Center, Los Angeles, CA, U.S.A..


Posters

Poster P122: Reducing Disparities in Referral to Breast Cancer Genetic Counselling: Development and Evaluation of a Blended Learning Program for Health Care Professionals


Margreet Ausems*, Jeanine van der Giessen*, Maria van den Muijsenbergh,, Mary Velthuizen*, Cora Aalfs§,, Klaartje van Engelen, Margriet Collée#, Thijs van Dalen**, Maartje Hooning††, Mirjam Fransen§


ABSTRACT

Patients with less education or a non-Western migrant background have poorer access to (breast) cancer genetic counselling. Because of limited health literacy or language barriers, referral is not always adequately discussed with these vulnerable groups of patients. Erfo4all is a multicentre project designed to address the problem of disparity in referral to breast cancer genetic counselling.

In co-creation with health care professionals and patients, a blended learning program was developed for surgeons and specialized nurses involved in the referral process. Awareness, knowledge, attitude, and (perceived) skills to communicate with patients having a low education background, low health literacy skills, or migrant status will be assessed before (T0) and 6 months after the training. Effectiveness on referral will be assessed prospectively by clinical geneticists and genetic counsellors for all new counselees referred for breast cancer genetic counselling in 4 academic centres. The relative number of referred patients with a low education background and migrant status will be compared in a one-group pre-test/post-test design, taking into account differences between trained and untrained hospitals. We expect to include more than 2500 completed checklists (900 before the training and 1600 after the training). Baseline data from the 4 academic centres will be presented at the conference, as will preliminary data from the T0 questionnaire completed by participants attending the first-trained hospitals (n = 30).

First results at T0 indicate that professionals had poor knowledge about (recognizing) low health literacy and had lower perceived skills to communicate effectively with vulnerable groups of patients. Although they recognized the importance of considering the background and literacy skills of patients, it seems that they experienced problems in adapting their communication to the needs of patients.

AUTHOR AFFILIATIONS

*University Medical Center Utrecht,,
Pharos, Nijmegen,,
Radboud University Center, Nijmegen,,
§Academic Medical Center, Amsterdam,,
VU University Medical Center, Amsterdam,,
#Erasmus University Medical Center, Rotterdam,,
**Diakonessenhuis, Utrecht, and,
††Erasmus Medical Center, Cancer Institute, Rotterdam, Netherlands..


Posters

Poster P123: The High-Risk Ontario Breast Screening Program: Organized Screening of BRCA Mutation Carriers


Lauren Chun*, Ayesha Salleh*, Chamila Adhihetty*, Derek Muradali*, Joan Glazier*, Anna Chiarelli*,


ABSTRACT

Established in 2011, the High-Risk Ontario Breast Screening Program (obsp) is an organized breast screening program for women 30 to 69 years of age identified as “high risk,” including known carriers of a deleterious gene mutation (for example, BRCA1, BRCA2). Gene mutation carriers can be eligible for screening in the program through one of two pathways, depending on whether they are known or suspected carriers. Known mutation carriers referred into the High-Risk obsp are considered immediately eligible to begin high-risk screening. Suspected mutation carriers (based on personal or family history) referred into the High-Risk obsp are required to undergo genetic assessment. Genetic testing might be performed as part of genetic assessment, and women found to be BRCA1/2 mutation carriers are eligible for high-risk screening. In the High-Risk obsp, women are screened with annual mammography and breast magnetic resonance imaging (mri)—or, if mri is not medically appropriate, screening breast ultrasonography.

The objectives of this poster are to describe the High-Risk obsp and clinical pathway, and the experience of the High-Risk obsp in identifying and screening BRCA1/2 mutation carriers. Since its inception, the High-Risk obsp has evolved in response to operational and clinical needs. The program is continually monitored and adopts best practices to provide optimal breast screening services to high-risk women.

AUTHOR AFFILIATIONS

*Cancer Care Ontario and,
University of Toronto, Toronto, ON..


Posters

Poster P124: Salpingectomy for Ovarian Cancer Prevention at the Time of Cesarean Delivery: Comparison of Outcomes of Surgical Technique


Nancy Nguyen*, Amy Alabaster, Sarah Simmons, Bethan Powell


ABSTRACT

Objective

To evaluate the surgical outcomes of prophylactic salpingectomy during sterilization at time of cesarean delivery by surgical technique (bipolar electrocautery vs. suture ligation).

Methods

This retrospective cohort study uses electronic medical records at Kaiser Permanente Northern California of women 18 years of age and older undergoing sterilization by salpingectomy at the time of cesarean delivery. The study includes all eligible women from 2011 to 2016 at time of elective surgical sterilization. The primary objective is to compare surgical outcomes by electrosurgical bipolar (LigaSure: Medtronic, Minneapolis, MN, U.S.A.) or suture ligation, including estimated blood loss, major or minor intraoperative complications, blood transfusions, operative time, length of hospital stay, and postoperative readmission and emergency department visits.

Results

There were 190 patients with salpingectomies for sterilization at time of cesarean delivery identified. There were 96 salpingectomies by bipolar electrocautery device and 94 by suture ligation. The primary indication for a caesarean procedure was repeat cesarean delivery. In Cesarean deliveries with salpingectomies estimated blood loss was lower in procedures performed by bipolar electrocautery than by suture ligation (average: 600 mL vs. 762 mL, p = 0.03). Surgery time and operating room time were longer for suture ligation than for electrocautery (66 vs. 60 minutes, p = 0.03, and 104 vs. 100 minutes, p = 0.04, respectively) During cesarean delivery with salpingectomy, 2 major and 8 minor intraoperative complications occurred, but only 2 minor complications were specifically related to salpingectomy. There was 1 postoperative blood transfusion. No emergency room visits occurred within 7 days of discharge in either group, and no difference in the readmission rate was observed. The postoperative length of stay did not differ.

Conclusions

Salpingectomy instead of tubal ligation at the time of cesarean delivery for sterilization is faster and associated with less blood loss when performed with a bipolar device than with suture ligation. However, there are no differences in postoperative care complication rates. The balance of the cost of the instrument and the time saved could vary in different health care systems.

AUTHOR AFFILIATIONS

*Kaiser Permanente Oakland California, Oakland,,
Kaiser Permante Northern California, and,
Kaiser Permanente, San Francisco, CA, U.S.A..


Posters

Poster P125: Ensuring Equity of Access to BRCA Testing


Alison Trainer*,, Helen Widdowson, Helen Farrugia


ABSTRACT

Because BRCA mutations affect both cancer treatment and familial risk assessments, equitable access to testing is of increasing social importance. The association between BRCA mutations and the development of triple-negative (tn) breast cancer diagnosed at the age of less than 50 years, or high-grade serous ovarian (hgso) cancer diagnosed at the age of less than 70 years defines a cohort of women who warrant BRCA testing based on tumour-pathology alone. Comparing the characteristics of women referred and not referred to familial cancer clinics (fccs) can identify and quantify drivers underlying inequitable access to testing at a population level.

We performed a retrospective data cross-match of all women with BRCA-related cancers (defined by icd-o and icd-10 codes and immunohistochemistry) reported to the Victorian cancer registry from 1 Jan 2008 to 31 Dec 2014, with the subset of women referred to the Victorian fccs. All Victorian women with an incident tn breast cancer or hgso cancer were categorized as either “referred” or “not referred.” Individual-level parameters relating to year and age of diagnosis, survival, socioeconomic indexes, geographic location, and region of birth were available.

Logistic regression analysis was undertaken using “not referred” as the outcome variable. The results indicate that, compared with 2008 (55%), tn breast cancer referrals significantly increased from 2011 to 2014 (80%); hgso cancer referrals remained constant at 65%. Evidence of an inequitable referral process was demonstrated, because the multivariate analysis demonstrated that increased age at diagnosis, tumour grade, decreased length of survival, and increased socioeconomic disadvantage were significantly associated with decreased referral of hgso cancers, and that increased age at diagnosis, increased grade, survival, and non-native English speaker status were associated with decreased referral for tn breast cancers.

Those findings have led to development of the embed study. embed circumvents current barriers to fcc referral by integrating the cancer registry directly into the fcc referral process. The logistic regression results and the description of embed will both be discussed in more detail.

AUTHOR AFFILIATIONS

*Parkville Familial Cancer Center, Parkville,,
University of Melbourne, Melbourne, and,
Victorian Cancer Registry, Cancer Council Victoria, Melbourne, VIC, Australia..


Posters

Poster P126: Counselling in the Population Genomics Context: Participant Experiences in the WISDOM Breast Cancer Screening Trial


Jennifer James, Barbara A. Koenig, Leslie Riddle, Galen Joseph


ABSTRACT

Population-based genomic screening is at the forefront of a new approach to disease prevention and raises many elsis (ethical, legal, and social issues). Our “embedded” elsi study of the wisdom trial, an innovative randomized controlled trial comparing annual mammography with risk-stratified breast cancer screening based on genetic testing (9 genes plus a polygenic risk score), uses mixed methods to assess the effect of genomic screening on a healthy population of women. In this presentation, we offer insight into several key ethical and social questions concerning population-based genetic testing for breast cancer–associated gene mutations.

First, we describe the return of results procedure in the wisdom trial, which is preceded by an online consent process without traditional pre-test counselling. Women categorized at high or moderate breast cancer risk, including but not limited to those with a gene mutation, receive a “breast health specialist” (bhs) consultation by telephone. That session, conducted by a nurse or a genetic counsellor, involves disclosure of the genetic mutation, basic information about the mutation, and recommendations for follow-up care—often including referral to formal genetic counselling. Second, we describe the process of giving and receiving positive genetic testing results in this population screening context based on audio-recordings of sessions with bhss. Third, we present results of qualitative interviews with women conducted after the bhs consultation, focusing specifically on issues such as how women without a personal or family history of breast cancer and who might not even remember the possibility of receiving such a result (because of the remote consent process) make sense of the news that they have a mutation and/or are at high risk.

Our examination of the implementation of the wisdom trial will provide practical ethical and policy guidance on the translation of genomic findings into precision medicine and population health.

AUTHOR AFFILIATIONS

University of California, San Francisco, CA, U.S.A..


Posters

Poster P127: Guidelines for Reporting Secondary Findings of Genome Sequencing in Cancer Predisposition Genes: French Society of Predictive and Personalized Medicine Recommendations


Pierre Vande Perre*, David Geneviève*, Laurence Faivre, Damien Sanlaville, Carole Corsini*, Bernard Baertschi§, Michèle Anahory, Dominique Vaur#, Nadem Soufir**, Anne-Sophie Lapointe††, Sarah Amar, Michèle Vintraud‡‡, Noëlle Bastide*, Arash Rafii§§, Pascal Pujol*


ABSTRACT

The use of multigene panel analysis to explore familial cancer syndromes or to identify somatic mutations in tumours has led to increased discovery of inherited variants that are not directly related to the initial yield of the search. The American College of Medical Genetics and Genomics published a clear policy statement about secondary findings management for a list of genes, including 23 cancer-related genes. Europe currently has no equivalent recommendations. The French Society of Predictive and Personalized Medicine undertook an in-depth multidisciplinary reflection on the restitution of secondary findings to the patient.

We present guidelines concerning the management of secondary findings in cancer-predisposing genes in adults. From June 2016 to May 2017, 47 experts were divided into two working subgroups: one dedicated to medical expertise (consisting of oncologists, clinical geneticists, and molecular geneticists), and the other specialized in ethical and legal expertise (psychologists, ethicists, lawyers, and representatives of patient associations). 61 genes were evaluated by a mean of 3 different experts (228 evaluation forms collected). The main criteria for the recommendations were their “actionability” (access to validate screening or prevention strategies), risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into 3 subgroups according to the score.

Of 28 genes in class 1 (for which return of the result is recommended), the breast cancer predisposition genes BRCA1, BRCA2, TP53, STK11, PTEN, CDH1, and PALB2 were retained. Classes 2 and 3 included the genes BAP1, ATM, CHEK2, RAD51C, RAD51D, and BRIP1, BARD1, and NBN respectively. The ethics group provides information recommendations and information materials in various forms (written consent and video). These first European recommendations for secondary findings could help clinician to standardize and guide practices for genetic predispositions to cancer.

AUTHOR AFFILIATIONS

*University Center Hospital Montpellier, Montpellier,,
University Center Hospital Dijon, Dijon, and,
Lyon University Hospitals, Lyon, France;,
§University of Geneva, Geneva, Switzerland;,
Pech de Laclause, Bathmanabane and Associés Law Firm, Paris,,
#clcc François Baclesse, Normandie,
**Bichat Hospital, Paris,
††Université Paris Descartes, Sorbonne Paris Cité, Paris, and,
‡‡American Hospital of Paris, Neuilly, France;,
§§Weill-Cornell Medical College in Qatar, Doha, Qatar..


Posters

Poster P129: Distinct Molecular Pathways Expression Profiles After Neoadjuvant Chemotherapy Associated with Survival in Patients with High-Grade Serous Ovarian Cancer


David Octeau*,,, Roy Kessous*,, Liron Kogan*,, Ido Laskov*,, Kathleen Klein,§, Manuela Pelmus, Shannon Salvador*, Susie Lau*, Patricia Tonin§, Walter Gotlieb*,, Amber Yasmeen*,


ABSTRACT

Background

Tumour biomarkers, such as germline and somatic mutations in BRCA1 and BRCA2, and aberrant expression profiles have been linked to improved response in patients with high-grade serous ovarian cancers (hgscs) undergoing primary debulking surgery. Recently, the use of neoadjuvant chemotherapy (nact) has become more widespread. Although large-scale genomic studies have detailed the molecular landscape of tumours from patients who underwent primary debulking surgery and correlated the identified subgroups with survival, none have done the same for patients who received nact.

Objective

Describe the underlying genomics of nact-treated hgsc and correlate them with patient progression-free survival (pfs) and overall survival (os).

Methods

Tumour samples were collected from patients with hgsc after neoadjuvant chemotherapy (nact cohort, n = 39). Tumour content was validated by histologic examination and by biostatistical analysis. Gene expression analysis was performed using a tailored NanoString-based assay, and next-generation sequencing was performed on the MiSeq platform. Unsupervised pathway-based clustering and the appropriate survival models were used to assess the associations between genetic alterations and survival.

Results

Mutations in BRCA1 and BRCA2 (n = 6 and n = 7 of 39 respectively) did not correlate with better os (log rank p = 0.24). Unsupervised pathway-based clustering of the gene-expression data revealed a better outcome in patients characterized by lower expression of dna damage and cell-cycle genes (pfsp = 0.02; osp < 0.05).

Conclusions

A partial genomic profiling of the intratumoural molecular pathway signatures observed after nact revealed prognostic significance that was different from that for chemonaïve tumours.

AUTHOR AFFILIATIONS

*Segal Cancer Centre, Jewish General Hospital, McGill University,,
Lady Davis Institute, Jewish General Hospital, McGill University,,
McGill University,,
§The Research Institute of the McGill University Health Centre, and,
Jewish General Hospital, Montreal, QC..


Posters

Poster P130: lncRNA HOTAIRM1 Might Be a Novel Tumour Suppressor in the Basal-Like Subtype of Breast Cancer


Xiaoping Su*, Gabriel Malouf


ABSTRACT

Breast cancer is a heterogeneous disease that can be classified in 4 subgroups using transcriptional profiling. The role of long non-coding rna (lncrna) expression in human breast cancer biology, prognosis, and molecular classification remains unknown. Using an integrative comprehensive analysis of lncrna, mrna, and dna methylation in 900 breast cancer patients from the Cancer Genome Atlas project, we unraveled the molecular portraits of 1700 expressed lncrna. Some of those lncrna (for example, hotair) are previously reported; others are novel (that is, hotairm1, mapt-as1).

The lncrna classification correlated well with the pam50 classification for the basal-like, her2-enriched, and luminal B subgroups; in contrast, the luminal A subgroup behaved differently. Importantly, estrogen receptor expression was associated with distinct lncrna networks in lncrna clusters iii and iv. Gene-set enrichment analysis for cis- and trans-acting lncrna showed enrichment for breast cancer signatures driven by breast cancer master regulators. Almost two thirds of those lncrna were marked by enhancer chromatin modifications (that is, H3K27ac), suggesting that lncrna expression might result in increased activity in neighbouring genes. Differential analysis of gene expression profiling data showed that lncrna hotairm1 was significantly downregulated in the basal-like subtype, and dna methylation profiling data showed that lncrna hotairm1 was highly methylated in the basal-like subtype. Thus, our integrative analysis of gene expression and dna methylation strongly suggested that lncrna hotairm1 should be a tumour suppressor in the basal-like subtype.

Our study provides the first lncrna molecular portrait of breast cancer and shows that lncrna hotairm1 might be a novel tumour suppressor.

AUTHOR AFFILIATIONS

*MD Anderson Cancer Center, Houston, TX, U.S.A.;,
University of Strasbourg, Strasbourg, France..


Posters

Poster P131: Association Between BRCA Mutations and Survival in the Epithelial Ovarian Cancer COEUR Cohort


Cecile Le Page*, Kurosh Rahimi*, Martin Kobel, Patricia N. Tonin, Brad H. Nelson§, Marcus Q. Bernardini, John M.S. Bartlett#, Walter H. Gotlieb, Blake Gilks**, Jessica N. McAlpine**, Mark W. Nachtigal††, Alain Pich采, Peter H. Watson§, Dimcho Bachvarov§§, Barbara Vanderhyden‖‖, David G. Huntsman**, Diane Provencher*, Anne-Marie Mes-Masson*


ABSTRACT

Background

The Canadian Ovarian Experimental Unified Resource (coeur) is a Canadian repository of epithelial ovarian cancer that provides researchers with biologic material and associated clinical data to conduct biomarker validation studies. Here, we describe the presence and prognostic value of germline BRCA mutations in the coeur cohort.

Methods

With participation from 12 Canadian biobanks in Canada, we created a central retrospective cohort comprising more than 2000 patient tissue samples with associated clinical data. Cases tested at collection sites for germline BRCA mutation included 488 high-grade serous (hgsc), 35 low-grade serous, 44 endometrioid, 25 clear cell, and 6 mucinous carcinoma histotypes. A 2-step reclassification process, blinded of genomic BRCA sequencing, was applied to ensure contemporary histologic classification. We used Kaplan–Meier, Cox proportional hazards, and logistic regression analyses to evaluate the association between the BRCA mutation and disease-specific survival in hgsc platinum-treated patients only.

Results

After histotype reclassification, BRCA mutations (n = 112) were observed only in serous cases. Compared with hgsc noncarriers patients, patients with hgsc harbouring a BRCA mutation (n = 108) were younger (53 years vs. 60 years) and presented more often with advanced-stage disease (n = 370). When restricting the analysis to advanced-stage disease, the BRCA mutation carriers (n = 45 BRCA1, n = 26 BRCA2) demonstrated increased survival (hr: 0.57; 95% ci: 0.41 to 0.80; p < 0.001). There was no statistical evidence of improved outcome in women with early-stage hgsc (p = 0.82, n = 28). Compared with their BRCA1 counterparts, patients with BRCA2 mutations had a slightly better prognosis (BRCA2hr: 0.41; 95% ci: 0.22 to 0.76; BRCA1hr: 0.65; 95% ci: 0.44 to 0.95) We also observed increased long-term survival (>10 years) in BRCA mutation carriers (21% vs. 11%; or: 0.432; 95% ci: 0.21 to 0.90; p = 0.024).

Conclusions

Our results suggest that, in ovarian cancer, germline BRCA mutations are largely restricted to hgsc. In the setting of platinum-based standard treatment, BRCA mutations (particularly BRCA2 mutations) are associated with increased long-term survival.

AUTHOR AFFILIATIONS

*crchum and Institut du cancer de Montréal, Université de Montréal, Montreal, QC;,
University of Calgary, Calgary, AB;,
McGill University, Montreal, QC;,
§BC Cancer, Victoria, BC;,
University of Toronto and,
#Ontario Institute for Cancer Research, Toronto, ON;,
**Vancouver General Hospital and University of BC, Vancouver, BC;,
††University of Manitoba, Winnipeg, MB;,
‡‡Université de Sherbrooke and Centre de Recherche du chus, Sherbrooke, and,
§§Hôtel-Dieu de Québec, Université Laval, Quebec City, QC;,
‖‖The Ottawa Hospital Research Institute and University of Ottawa, Ottawa, ON..


Posters

Poster P132: Sequential Therapeutic Targeting of Ovarian Cancer Harbouring Dysfunctional BRCA1


Tahira Baloch*,, David Octeau*, Roy Kessous*,, Liron Kogan*,, Ido Laskov*,, Michael Witcher*, Amber Yasmeen*, Walter H. Gotlieb*,


ABSTRACT

Background

BRCA1 is mutated or epigenetically silenced in up to 23% of high-grade serous ovarian cancers (hgscs). parp inhibitors (parpi) are the first approved personalized treatments for BRCA1-mutated patients and have shown promising clinical results. Recently, in collaboration with Dr. Witcher’s lab, we described a significant reduction in parp1 protein levels in patients after standard carboplatin–paclitaxel chemotherapy. parpi are currently administered after standard chemotherapy, when parp levels are the lowest. Changing the sequence of administration—giving parpi first, followed by standard chemotherapy—might improve response rates. This study aims to evaluate that strategy in in vitro preclinical models.

Methods

BRCA1-mutated (UWB1.287, SNU-251), epigenetically silenced (OVCAR8), and wild-type BRCA1 (OVCAR3, SKOV3, A2780P, and A2780R) cell lines were exposed either to clinically relevant doses of parpi followed by standard chemotherapy, or to the inverse sequence of agents. Therapeutic efficacy was assessed by colony-formation assay, cell-cycle analysis, and apoptotic assays using flow cytometry. Western blotting was used to detect the levels of relevant apoptotic and cell-cycle proteins.

Results

Exposure to parpi before standard chemotherapy sensitized BRCA1-mutated or epigenetically silenced BRCA1 cell lines to lower doses of cisplatin or paclitaxel. Similarly, pre-treatment with parpi before chemotherapy induced apoptosis more effectively in the same cell lines. Similar results were observed in BRCA1 wild-type cell lines and cell lines in which BRCA1 functionality was restored.

Conclusions

Pre-treatment of cell lines with parpi, followed by standard chemotherapy, is more efficient (in vitro) in inhibiting growth and inducing apoptosis than is the present sequence of chemotherapy followed by parpi.

AUTHOR AFFILIATIONS

*Segal Cancer Centre, Lady Davis Institute of Medical Research,,
McGill University, and,
Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC..


Posters

Poster P133: One in Three Greek Patients with Early-Onset or Strong Family History of Breast Cancer Carries a Loss-of-Function Cancer-Predisposing Allele


Florentia Fostira, Irene Konstantopoulou, Myrto-Sotiria Papamantzelopoulou, Paraskevi Apostolou, Despoina Kalfakakou, Irene Konstanta, Aggeliki Delimitsou, Andromachi Vagena, Ioannis Vlachos, Drakoulis Yannoukakos


ABSTRACT

Introduction

The evolution of dna sequencing has revolutionized the clinical approach to genetic testing. Multiple genes can now be analyzed simultaneously at relatively low cost, providing important information for patient management. Although BRCA1 and BRCA2 mutations dominate the spectrum among breast cancer patients, additional genes are associated with susceptibility. We therefore sought to investigate the contribution of predisposing alleles in a highly selected cohort of Greek breast cancer patients.

Methods

To identify loss-of-function (lof) mutations, the sequences of 94 cancer genes were targeted by implementing the Trusight cancer panel (Illumina, San Diego, CA, U.S.A.) in 1382 breast cancer patients of Greek descent with diagnosis at very young age (<35 years) and/or a strong family history (at least 3 breast, ovarian, or pancreatic cancer cases).

Results

Approximately one third of the patients tested (437/1382, 31.6%) carried at least 1 lof mutation in 26 different genes, namely: BRCA1, BRCA2, ATM, BLM, BRIP1, CDKN2A, CHEK2, DICER1, ERCC3, FANCC, FANCI, FANCL, FANCM, MLH1, MSH6, NBN, NF1, PALB2, PTEN, RAD51C, RAD51D, PMS2, SLX4, TP53, SDHB, and SDHC. Of those patients, 6.7% (93/1382) carried lof alleles in genes involved in dna repair (other than BRCA1 and BRCA2 genes), with mutations in CHEK2, ATM, and PALB2 genes being the most frequent (4.5%). Of note are the remaining 2.2% of lof alleles, which to date have unclear associations with breast cancer susceptibility, which can be regarded as incidental findings, cannot be excluded as having putative causality for breast or ovarian cancer.

Conclusions

In a high-risk group of breast cancer patients of Greek descent, where there are strong founder effects, the mutational spectrum is heterogeneous with respect to both loci and alleles. This approach can shed light on associations with mutations in the post-BRCA genes and will provide connections of phenotypes with mutations in additional dna repair genes.

AUTHOR AFFILIATIONS

National Centre for Scientific Research, Athens, Greece..


Posters

Poster P134: Implementation of Universal BRCA Screening for Germline and Somatic Variants in Patients with Epithelial Ovarian Cancer


Charlotte Kvist Lautrup*,,, Bente Lund*, Christian Liebst Toft Andersen*, Anja Ernst*, Erik Soegaard-Andersen*, Bence Gabor Szilvasy, Inge Soekilde Pedersen*,


ABSTRACT

Introduction

With introduction of parp inhibitors as therapy for BRCA-positive high-grade serous ovarian cancer (hgsoc), BRCA screening has become part of standard diagnostics for hgsoc patients. Approximately 10% of hgsoc patients are expected to carry a germline pathogenic variant. The frequency of somatic variants is poorly described. Various mutation screening strategies have been used: either screening restricted to germline variants, screening of tumour tissue for somatic variants with subsequent germline screening of patients with a BRCA-positive tumour, or parallel screening of both types.

Methods

In the North Denmark region, treatment of ovarian cancer is centralized at Aalborg University Hospital. Since March 2016, all newly diagnosed patients with hgsoc and other epithelial ovarian cancers have been offered BRCA screening for both germline and somatic variants. Parallel screening for germline and somatic variants is requested after multidisciplinary conference and referral to genetic counselling. Patients diagnosed before March 2016 were identified at the Department of Oncology. From March 2016 to December 2017, 153 patients were screened.

Results

Pathogenic variants were identified in 40 patients (26%). Of those variants, 11 were germline variants (7%), and 24 were somatic variants (16%); 5 patients had screening conducted only on tumour tissue (3%). All germline variants were identified in the tumour. More than half of all somatic variants were whole-gene deletions (14/24). In 14 patients, variants of unknown significance were reported as the only finding (9%).

Conclusions

Most variants were of somatic origin, emphasizing the importance of screening tumour tissue. In addition, the high proportion of large structural variants substantiates the need for the use of analysis methods capable of detecting this group of variants. No germline variants were missed in analyzing tumour tissue. These findings have to be confirmed in larger studies, before tumour tissue screening is used as primary screening.

AUTHOR AFFILIATIONS

*Aalborg University Hospital,,
Clinical Cancer Research Center, Aalborg University Hospital, and,
Aalborg University, Aalborg, Denmark..


Posters

Poster P135: Evaluation of Cancer Stem Cells in Epithelial Cells from Different Regions of the Fallopian Tubes in Healthy BRCA1 and BRCA2 Carriers at Time of Risk-Reducing Salpingo-oophorectomy


Yael Naaman, Monica Huszar, Rakefet Chen-Shtoyerman, Offry Zelnik, Ayelet Harari, Noa Ephrat Ben-Baruch, Alon Ben-Arie


ABSTRACT

Introduction

Evidence suggests that early serous ovarian carcinomas originate in the distal part of the fallopian tube. Protocols examining the fimbriated end of the fallopian tube in carcinoma patients revealed a noninvasive, but potentially lethal form of serous tubal intraepithelial carcinoma. At least 10% of all epithelial ovarian cancers are hereditary, with mutations in BRCA1 and BRCA2 accounting for most cases. Ovarian cancers associated with germline BRCA mutations are diagnosed at a younger age, and are high-grade and advanced-stage serous carcinomas. For affected patients, risk-reducing bilateral salpingo-oophorectomy (rrbso) remains the mainstay for preventing malignancy. In recent years, the cancer stem cells model has suggested that a small proportion of cells are capable of initiating tumour growth.

Objective

This study aimed to combine the two models by testing the fallopian tubes of unaffected BRCA1/2 carriers for presence of the ovarian cancer stem-cell marker CD44 in various areas of the fallopian tube at the time of rrbso.

Methods

Fallopian tubes removed from 49 BRCA1/2 carriers were tested for the presence of the CD44 cancer stem cell marker by immunohistochemical staining in 3 areas: the fimbria, the ampulla, and the isthmus. Each slide received a score based on the percentage of CD44-positive cells and the intensity of staining, ranging from 0 (no cells stained) to 8 (all cells strongly stained).

Results

CD44 staining was positive from the fimbria in 98% of samples from normal-appearing fallopian tubes of healthy carriers at the time of rrbso. The population of CD44-positive cells was most dense in the fimbria (score: 3.2), then their presence gradually decreased toward the ampulla (score: 1.9), declining to very few in the isthmus (score: 0.5).

Conclusions

The distribution patterns of CD44-positive cells resembles that of serous tubal intraepithelial carcinomas, suggesting that the stem cells play a role in the formation of tumours.

AUTHOR AFFILIATIONS

Kaplan Medical Center, Rehovot, Israel..


Posters

Poster P136: Exome Characterization of High-Grade Serous Epithelial Ovarian Cancer Cell Lines with Varying Sensitivity to the PARP Inhibitor Olaparib


Setor Amuzu*,, Suzanna Arcand, Anne-Marie Mes-Masson§,,#, Patricia Tonin*,, Jiannis Ragoussis*,,**


ABSTRACT

Olaparib (Lynparza) is an oral inhibitor of poly (adp-ribose) polymerase (parp), currently developed by AstraZeneca (Cambridge, U.K.). It is indicated for use as monotherapy for maintenance treatment of platinum-sensitive relapsed BRCA-mutated (germline or somatic) high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Olaparib induces death in BRCA-mutated, homologous recombination repair (hrr)–defective tumour cells by blocking parp-mediated dna repair. Few biomarkers of olaparib sensitivity are available to help identify suitable cases for treatment. Apart from defective hrr, additional dna repair pathways have been implicated in olaparib sensitivity.

This study involved 18 high-grade serous ovarian carcinoma cell lines classified as sensitive (n = 5), intermediate (n = 9), and resistant (n = 4) based on their response to olaparib. Two of the cell lines are BRCA germline-mutated: a BRCA1-mutated cell line classified as intermediate, and a BRCA2-mutated cell line classified as sensitive. Because only about 40% of BRCA-mutated cases respond to olaparib, our objective is to identify additional genetic markers of olaparib response by first analyzing the exomes of these cell lines.

We found that the frequency of nonsense, frameshift, splice, and missense variants (moderate-and high-impact variants) in genes of 6 dna repair pathways does not separate cell lines into olaparib-response groups. Similarly, hierarchical clustering of cell lines based on copy number variants does not separate them, but reveals a unique cluster of germline BRCA-mutated cell lines. Cell lines harbour variants potentially relevant for olaparib response. Notably, one resistant cell line has a potentially damaging missense variant in ATM despite the association of ATM loss-of-function with increased olaparib sensitivity. Interestingly, the BRCA2-mutated cell line is enriched in moderate-and high-impact variants in genes of the Fanconi anemia pathway, in addition to harbouring BRCA1 missense variants. Further characterization of these exomes will inform our ongoing investigations into biomarkers of olaparib sensitivity.

AUTHOR AFFILIATIONS

*McGill University,,
McGill University and Génome Québec Innovation Centre,,
The Research Institute of the McGill University Health Centre,,
§Centre de recherche du Centre hospitalier de l’Université de Montréal (crchum),,
Institut du cancer de Montréal, and,
#Université de Montréal, Montreal, QC;,
**Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia..


Posters

Poster P138: Characteristics and Outcomes of Individuals Referred to Genetic Counselling on the Basis of a Personal History of Breast/Ovarian Cancer Without Family History


Valeria Viassolo, Joana Dias, Aurélie Ayme, Anne E. Murphy, Isabelle Gauchat-Bouchardy, Pierre O. Chappuis


ABSTRACT

Objective

Criteria to refer individuals to cancer genetic counselling and testing for hereditary conditions are based on personal and/or family cancer history. We aimed to retrospectively assess the proportions, characteristics, and outcomes of individuals referred to counselling on the basis of their personal medical history without family history, with a particular focus on breast and ovarian cancer.

Methods

Pedigrees of probands managed in the Unit of Oncogenetics and Cancer Prevention in the Geneva University Hospitals during 1994–2016 (n = 3000) were extensively reviewed. Probands with features (cancer or benign lesions) suggesting cancer predisposition syndromes and having no 1st- or 2nd-degree relative with such a phenotype, were included in the study. Clinical characteristics, indication to perform genetic analyses, and testing results were evaluated.

Results

438/3000 probands (14.6%) were eligible for the study. The proportion increased over time, to 16.2% (391/2411) during 2006–2016 from 8.0% (47/589) during 1994–2005. Overall, 285 (65.1%) probands (272 women, 13 men) had a breast cancer diagnosis (median age: 40 years), and among those, 63 showed a triple-negative phenotype; 40 (9.1%) probands were diagnosed with ovarian cancer (median age: 51 years). Genetic testing was proposed to 336 probands (76.7%) and performed in 275/336 cases (81.8%). In 203 BRCA1/BRCA2 analyses, 20 (9.8%) pathogenic variants were identified. The mutation detection rate remained stable over time and was 9.4%, 12.5%, and 13.8% in probands with breast cancer, triple-negative breast cancer, and ovarian cancer respectively.

Conclusions

Despite the fact that cancer family history is key information in recognizing hereditary cancer predisposition syndromes, personal history should also be considered as a predictor of hereditary conditions, even in the absence of other familial cancer cases. Several factors such as lack of or incorrect knowledge about family history, incomplete penetrance, de novo pathogenic variants, or non-paternity can contribute to this observation.

AUTHOR AFFILIATIONS

Geneva University Hospitals, Geneva, Switzerland..


Posters

Poster P139: The Global HeritX Initiative to Prevent Inherited BRCA Cancer


Thomas A. Bock, Douglas F. Hager


ABSTRACT

Background

An estimated 20 million people face an up to 87% risk of 5 aggressive cancers because of defective BRCA genes: breast, ovarian, prostate, and pancreatic cancers, and melanoma. These cancers strike at an early age, in women and in men, and their risk is passed from one generation to the next.

Goal

In 2015, we launched the global HeritX Initiative through an internationa l Banbur y Conference. Academic researchers, biopharmaceutical drug developers, U.S. Food and Drug Administration experts, and affected families created an r&d roadmap to BRCA prevention that includes all required parts, aspects, and anticipated roadblocks to an approved preventive (non-surgical) therapy.

Methods

To implement the roadmap faster than is traditional for r&d timelines, we redesigned the traditional r&d model into an Accelerated Roadmap to Prevention:

  1. Open-Source Approach To identify the best ideas from all fields, sectors, and geographies, we pursue an open-source approach through 1:1 scientific exchange, think tanks, and global rfps.

  2. Faster R&D Model Rather than pursuing a traditional sequential, phase-after-phase r&d process, we work on all drug development phases simultaneously from the start. This enables us to anticipate hurdles, and provides the time to set up accelerating solutions. As of today, we have initiated 6 acceleration projects.

Results

In less than 2 years, we connected with more than 200 scientific teams worldwide, selected their best ideas for HeritX support, and initiated 8 BRCA cancer prevention programs. Each program pursues a different scientific strategy. This portfolio includes pre-cancer vaccines to eliminate pre-cancer cells before they develop into cancer, and dna-repair-enhancing therapies to preclude cancer development before it starts. Across the portfolio, we collaborate with more than 15 scientific teams at recognized institutions in 5 countries and with 2 biopharmaceutical companies.

Priorities Forward

In 2018, we will focus on advancing current and adding new programs to maximize speed and success. We continue to seek partners to further accelerate momentum.

AUTHOR AFFILIATIONS

HeritX, Chester, NJ, U.S.A..


Posters

Poster P140: An Unexpected BRCA2 Mutation in a Never-Smoker Woman Diagnosed with Lung Cancer at 30—A Case Report


Astrid Tenden Stormorken, Yngvild Voldhaug Storlykken, Lovise Maehle


ABSTRACT

Introduction

Molecular tumour profiling can lead to the detection of somatic and germline mutations. Certain mutations can predict who might respond to targeted therapy and what the cancer risk is for family members. Numerous gene panels are available for testing solid tumours, and the results can yield unexpected opportunities.

Case Description

A 30-year-old woman, a never-smoker, was diagnosed with a pulmonary adenocarcinoma and bone metastasis. The tumour progressed in spite of treatment. Tumour tissue was selected for molecular profiling. A somatic mutation in the BRCA2 gene was detected and implicated a possible effect of a parp inhibitor. The patient was also referred for genetic assessment.

The family is small, with no cancer cases in the last three generations. Germline testing confirmed a founder mutation in the BRCA2 gene, passed down from the paternal family, most likely through several generations of male carriers.

She has recently started experimental treatment with a parp inhibitor.

Discussion

Lung cancer has been reported in Li–Fraumeni syndrome, but is not considered important in other hereditary cancer syndromes. Most cases are related to smokers. In the Western world about 15% of cases are found in nonsmokers.

In our registries, 10 BRCA2 mutation carriers from among 1354 individuals tested, have been diagnosed with a primary lung cancer at a mean age of 63 years (30–76 years). We lack information about smoking habits in most of these patients. We have confirmed that a never-smoker male BRCA2 mutation carrier was diagnosed with a pulmonary adenocarcinoma at 52 years of age.

Conclusions

More extensive use of molecular tumour profiling will lead to increased detection of somatic and germline mutations. It will also yield important knowledge about the associations between tumour-spectrum and mutated genes. Those advances will have implications for the patient’s treatment and the family’s risk.

AUTHOR AFFILIATIONS

Oslo University Hospital, Olso, Norway..


Posters

Poster P141: miRNA Expression Profiles in BRCA1-Associated Breast Cancers Reveal Upregulation of Specific miRNAs in Tumours Lacking a Clear Second Hit in a Large Proportion of the Tumour Cells


Mattias Van Heetvelde*,,, Mieke Van Bockstal,§, Jo Van Dorpe,§, Kim De Leeneer*,, Anne Vral,, Kathleen Claes*,


ABSTRACT

Background

mirnas are small, non-coding regulators of gene/protein expression. Several were found to be associated with specific molecular characteristics in breast cancers. Specific mirna signatures have been published in BRCA1-associated breast cancers. However, no studies have correlated mirna expression with the presence or absence of second hits at the BRCA1 locus. We found that a considerable proportion of BRCA1-associated breast cancers do not display a clear second hit in more than 50% of tumour cells (loss of heterozygosity, methylation, inactivating mutation). We hypothesize that, in these tumours, overexpression of oncogenic mirnas might downregulate expression of the retained wild-type BRCA1 allele.

Methods

Using small rna sequencing, we investigated the expression of 1232 mirnas in a well-characterized cohort of 51 BRCA1-associated breast cancers. We evaluated the association with molecular subtype and histopathologic features, and with loss of a functional BRCA1 wild-type allele.

Results

Our study confirmed previous associations between mirna expression and specific morphologic and molecular features of breast tumours. Differential expression analysis yielded fourteen mirnas that were upregulated in tumours not displaying loss of the BRCA1 wild-type allele in more than 50% of the tumour cells. According to http://www.mirdb.org/, none had any seed complementary to BRCA1, but for 5 mirnas complementarity was predicted to the 3′-untranslated region of BAP1 or BRIP1, both interaction partners of BRCA1.Those mirnas might therefore affect BRCA1 functionality in an indirect manner.

Conclusions

Our study revealed several candidate mirnas that could play a role in BRCA1-associated breast tumorigenesis. Those findings warrant further functional analyses and validation in other datasets to evaluate their potential to act as a non-coding second hit, deactivating BRCA1 functionality in breast cancer cells retaining a wild-type BRCA1 copy. OncomiRs could be an interesting target for future therapies.

AUTHOR AFFILIATIONS

*Center for Medical Genetics Ghent, Ghent University Hospital,,
Cancer Research Institute Ghent (crig),,
Ghent University, and,
§ Ghent University Hospital, Ghent, Belgium..


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Current Oncology, VOLUME 25, NUMBER 3, June 2018








Copyright © 2018 Multimed Inc.
ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)