Do we need another selective estrogen receptor modulator for the adjuvant treatment of breast cancer?

Editorials

Guest Editorial

Do we need another selective estrogen receptor modulator for the adjuvant treatment of breast cancer?


T. Shenkier , MDCM

doi: http://dx.doi.org/10.3747/co.20.1466

In this issue of Current Oncology, Qin and colleagues1 from the Sun Yat-sen University Cancer Centre in Guangzhou, China, report their experience using toremifene as adjuvant treatment for 396 premenopausal women with early endocrine-responsive breast cancer at a mean follow-up of 6.9 years. The reported outcomes for disease-free and overall survival are similar to those of the 1451 patients who received tamoxifen.

Why should we take note? After all, tamoxifen is the selective estrogen receptor modulator ( serm ) of choice in Canada, a practice supported by robust data. The latest meta-analysis of more than 10,000 women of all ages with early breast cancer who participated in randomized controlled trials of 5 years of adjuvant tamoxifen compared with placebo confirms a reduction of breast cancer recurrence rates by half and of breast cancer–specific mortality by one third at 5 years’ follow-up2. The meta-analysis also demonstrates a strong effect for the 2614 women younger than 45 at study entry: relative risk reductions of 42% for breast cancer recurrence and 25% for breast cancer mortality. Furthermore, a beneficial effect of tamoxifen persists at 10 and 15 years.

Toremifene, a nonsteroidal triphenylethylene serm differs from tamoxifen by the addition of a single chlorine side chain. A recent Cochrane review3 endorsed toremifene as an alternative to tamoxifen in the first-line treatment of endocrine-responsive advanced breast cancer in postmenopausal women. Marketed under the brand name Fareston (ProStrakan, Bridgewater, NJ, U.S.A.), toremifene is approved for this indication worldwide, except in Canada. Preclinical data suggested that toremifene had a more favourable efficacy-to-toxicity ratio, but clinical data have not borne out that promise; the side-effect profiles are very similar. All of the toremifene studies included in the Cochrane review pre-dated the era of widespread first-line use of aromatase inhibitors ( ai s) for metastatic breast cancer, and none of the patients involved would have received adjuvant ai s.

Toremifene has also been studied as adjuvant therapy for hormone receptor–positive breast cancer in postmenopausal women. In that setting, three large randomized trials comprising 3747 postmenopausal women demonstrated that toremifene and tamoxifen are equivalent in efficacy and safety46. However, despite those three trials, toremifene is not approved for that indication in any jurisdiction. Given the extensive clinical data supporting the use of ai s as adjuvant treatment in endocrine-responsive breast cancer in older women, toremifene is unlikely to gain widespread clinical traction in the adjuvant setting7. The use of serm s in the management of postmenopausal breast cancer has declined in the past decade because of the general adoption of ai s, but serm s continue to be clinically useful—especially for patients who cannot tolerate or who have a contraindication to ai s.

The options for premenopausal women are more limited. For those women, tamoxifen remains the only approved serm available for the treatment of hormone receptor–positive breast cancer, because ai s are not effective in women with functioning ovaries. The publication of the atlas trial demonstrating the benefit of extending the duration of adjuvant tamoxifen to 10 years, may lead to renewed interest in serm s in the adjuvant setting8. Seeing that no randomized trials are, at the present time, comparing toremifene with tamoxifen in premenopausal patients in the adjuvant setting, the data from the Qin series are of some interest. The authors report that toremifene could be used as adjuvant treatment in younger women, and within the limits of a retrospective study, the women appear to have derived clinical benefit comparable to that provided by tamoxifen.

The article does not provide level 1 evidence to support widespread use of toremifene in the adjuvant setting. Nevertheless, toremifene offers a viable option to patients and their physicians for situations in which, for some reason, neither tamoxifen nor an ai would be suitable. One such scenario might involve patients who require continued use of selective serotonin uptake inhibitors to control severe depression or hot flashes. Tamoxifen is converted to its active metabolites by the CYP2D6 gene, and because some selective serotonin uptake inhibitors are potent inhibitors of CYP2D6 activity, their concurrent use may substantially compromise the efficacy of tamoxifen9,10. In contrast, toremifene is primarily metabolized by CYP3A4, and CYP2D6 is thought to play a minor role11.

In summary, the retrospective Qin data are consistent with the conclusion that toremifene, like tamoxifen, is efficacious and safe to use in premenopausal patients with estrogen receptor–positive breast cancer. The data are consistent with randomized controlled trials in the published literature that demonstrate similar outcomes for the two agents in other clinical settings. Toremifene, while by no means the first-choice agent for adjuvant therapy of hormone receptor–positive breast cancer, might be a practical alternative in the real-world clinical setting, where patients requiring hormonal treatment for breast cancer cannot use either tamoxifen or ai s.

CONFLICT OF INTEREST DISCLOSURES

TS has acted as a consultant for Amgen.

REFERENCES

1. Qin T, Yuan ZY, Peng RJ, et al. Efficacy and tolerability of toremifene and tamoxifen therapy in premenopausal patients with operable breast cancer: a retrospective analysis. Curr Oncol 2013;20:196–204.

2. Davies C, Godwin J, Gray R, et al. on behalf of the Early Breast Cancer Trialists’ Collaborative Group (ebctcg). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378:771–84.
pubmed  pmc  

3. Mao C, Yang ZY, He BF, et al. Toremifene versus tamoxifen for advanced breast cancer. Cochrane Database Syst Rev 2012;7:CD008926.
pubmed  

4. Holli K, Valavaara R, Blanco G, et al. Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. Finnish Breast Cancer Group. J Clin Oncol 2000;18:3487–94.
pubmed  

5. Pagani O, Gelber S, Price K, et al. on behalf of the International Breast Cancer Study Group. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12–93 and 14–93. Ann Oncol 2004;15:1749–59.
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6. Lewis JD, Chagpar AB, Shaughnessy EA, Nurko J, Mc-Masters K, Edwards MJ. Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer. Cancer 2010;116:2307–15.
pubmed  

7. Burstein HJ, Prestrud AA, Seidenfeld J,et al. on behalf of the American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28:3784–96.
cross-ref  pubmed  

8. Davies C, Pan H, Godwin J, et al. on behalf of the Adjuvant Tamoxifen: Longer Against Shorter (atlas) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor–positive breast cancer: atlas, a randomised trial. Lancet 2012;:[Epub ahead of print].

9. Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of adjuvant tamoxifen in postmenopausal women: lessons learned. J Natl Cancer Inst 2012;104:427–8.
cross-ref  pubmed  

10. Brauch H, Schroth W, Goetz MP, et al. Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J Clin Oncol 2013;31:176–80.
cross-ref  

11. Kim J, Coss CC, Barrett CM, et al. Role and pharmacologic significance of cytochrome P-4502D6 in oxidative metabolism of toremifene and tamoxifen. Int J Cancer 2013;132:1475–85.
cross-ref  


Correspondence to: Tamara Shenkier, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6. E-mail: tshenkier@bccancer.bc.ca

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Current Oncology , VOLUME 20 , NUMBER 4 , AUGUST 2013








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ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)