Neoadjuvant erlotinib and surgical resection of a stage iiia papillary adenocarcinoma of the lung with an L861Q activating EGFR mutation

Case Report

Neoadjuvant erlotinib and surgical resection of a stage iiia papillary adenocarcinoma of the lung with an L861Q activating EGFR mutation


M. Ong , MD * , K. Kwan , MD , S. Kamel–Reid , PhD , M. Vincent , MD *

*Department of Oncology, London Health Sciences Centre, London, ON
Department of Pathology, London Health Sciences Centre, London, ON
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON

ABSTRACT

The use of epidermal growth factor receptor tyrosine kinase inhibitors ( egfr - tki s) is evolving, as is an understanding of predictive biomarkers for tumour response in non-small-cell lung cancer ( nsclc ). In this report, we describe a case of rapidly progressing, borderline-resectable, clinical stage iiia (micro) papillary adenocarcinoma in a 78-year-old woman who experienced a profound response to neoadjuvant erlotinib without short-term toxicity. On EGFR mutation testing, this patient had an uncommon activating point mutation at L861Q in exon 21. Her response permitted successful surgical resection with negative margins and avoidance of chemoradiation, which she was deemed too frail to tolerate. Our case addresses unique management issues such as preoperative testing for EGFR mutation, utility of histology in predicting EGFR mutations, and use of egfr - tki s pre- and postoperatively for potentially resectable nsclc .

KEYWORDS: Papillary adenocarcinoma , EGFR , erlotinib , neoadjuvant

1.  INTRODUCTION

Non-small-cell lung cancer ( nsclc ) is well known to comprise a collection of biologically heterogeneous disease entities that exhibit variable sensitivity to cytotoxic and novel targeted therapies. Although chemotherapy, radiation, and surgery are often used in various combinations for the treatment of locally advanced nsclc , tolerance of treatment remains a major concern, especially in frail elderly patients. The use and selection of targeted therapy in that setting remains poorly studied, but potentially better tolerated. Here, we report a case of locally advanced nsclc in an elderly, deteriorating patient who was treated with neoadjuvant erlotinib and subsequent surgical resection.

2.  CASE DESCRIPTION

A 78-year-old Caucasian woman presented in August 2009 with progressive nonproductive cough for 5 months and dyspnea and fatigue for 2 weeks. Her symptoms were unresponsive to clarithromycin, and chest radiography revealed a large, ill-defined right lower lung opacity. Past medical, family, and occupational history were not contributory; she had smoked 1 pack–year until age 22. Functionally, she was independent and had been swimming daily until 2 months earlier, but she was now dyspneic walking on level ground (Medical Research Council Dyspnea Index grade 3 1). Physical examination revealed diminished breath sounds at the right base. There was no digital clubbing. Blood count and chemistry were normal. Eastern Cooperative Oncology Group ( ecog ) performance status ( ps ) was 1.

Staging computed tomography ( ct ) demonstrated a 7.4×5.6-cm mass in the right middle lobe and a 12-mm pre-carinal lymph node. Bronchoscopy was normal, but transbronchial biopsies (Figure 1) revealed numerous large malignant cells with glandular papillary structures and micropapillae positive for cytokeratin 7 and thyroid transcription factor 1, and negative for cytokeratin 20, consistent with papillary adenocarcinoma of the lung.

 


 

FIGURE 1 Transbronchial biopsy of right-sided lung mass, revealing numerous large malignant cells with glandular structures and micropapillae, positive for cytokeratin 7 and thyroid transcription factor 1, but not for cytokeratin 20.

The patient was assessed by Thoracic Surgery, and positron-emission tomography ( pet )– ct showed enlargement of the mass to 10.5×8.2×6.7 cm in a 2-month interval, with extension to the lateral pleural surface [Figure 2(B)] and suspicion of a small right-sided malignant pleural effusion [standardized uptake value 2.7, Figure 2(A)]. The pre-carinal node was unchanged in size, and liver, adrenals, and brain were uninvolved. The mass was felt to be borderline resectable, and the predicted 1-second postoperative forced expiratory volume was 41% based on preoperative volume of 75%. A referral was made for concurrent chemoradiation.

 


 

FIGURE 2 (A) Fluorodeoxyglucose positron-emission tomography of the lungs demonstrates localized uptake in the right lower lobe. (B) Pre-erlotinib computed tomography for staging shows a 10.5×8.2×6.7-cm mass extending to the pleura. (C) Response after 3 months of erlotinib.

Further assessment by medical and radiation oncology revealed worsening functional status ( ecog ps 2). The patient now had significant dyspnea on exertion and weight loss of 10 pounds over 2 months. Blood work revealed anemia (hemoglobin: 106 g/dL), thrombocytosis (423×109/L), elevated alkaline phosphatase [158 U/L (upper limit of normal: <126 U/L)], and elevated lactate dehydrogenase [432 U/L (upper limit of normal: <214 U/L)]. The patient was offered chemoradiotherapy, but alternative treatment was sought because of the declining ps and her preference to avoid chemotherapy or chemoradiation for fear of toxicity and worsened quality of life. Although her EGFR mutation status was not initially available, her papillary/micropapillary adenocarcinoma features, female sex, and light smoking history suggested a higher likelihood of EGFR activating mutation. At our centre, EGFR mutation testing was not routinely available at the time. After extensive discussion of her treatment options and a multidisciplinary review, the patient was started on erlotinib 150 mg daily in October 2009.

The patient was re-evaluated weekly while on erlotinib, and a rapid clinical and radiographic response was observed. Blood work normalized, including decline of lactate dehydrogenase to 147 U/L. Repeat ct imaging in mid-November showed diminishment of the mass to 2.9×4.5×3.9 cm and resolution of the pleural effusion [Figure 2(C)]. Side effects were mild: grade 1 diarrhea and xerosis of the skin.

Re-evaluation by Thoracic Surgery resulted in an uncomplicated right middle lobe lobectomy January 2010. Pathology revealed a 2.0×5.0×3.0 cm primary tumour, with no pleural involvement and negative margins. Fibrosis constituted 30% of the tumour volume. Lymph nodes at locations 4R and 11 were anthracotic only. The microscopy description revealed a mixed-subtype adenocarcinoma with a prominent papillary pattern and bronchioalveolar features without lymphovascular invasion. EGFR testing at an outside laboratory revealed no amplification by fluorescence in-situ hybridization, a point mutation (L861Q) in exon 21 of EGFR (Figure 3), and no KRAS mutation.

 


 

FIGURE 3 EGFR mutational analysis on the resected lung mass (after neoadjuvant treatment with erlotinib) reveals an L861Q activating point mutation.

The patient continued erlotinib 150 mg in the postoperative period. By March 2010, she had returned to an active lifestyle, swimming daily, with an ecog ps of 0. Because of acneiform rash on the chest wall, two erlotinib dose reductions were instituted, and in May 2010, the patient was on erlotinib 50 mg daily. Unfortunately, in November 2010, she developed recurrent cough and fatigue. Imaging by ct revealed a locally recurrent right lower lobe mass and several right-sided pulmonary and pleural nodules. Erlotinib was discontinued. Thoracic Surgery felt that pneumonectomy was not indicated; the patient was treated with 3 cycles of doublet chemotherapy with carboplatin and vinorelbine.

Unfortunately, re-staging demonstrated further progression, and the patient’s therapy was changed to second-line single-agent pemetrexed in February 2011. Initially, her lung nodules stabilized, but after 6 cycles (interspersed with palliative radiotherapy to the left 11th rib in May 2011), ct imaging in early July 2011 showed further disease progression. She was then switched to oral afatinib 40 mg daily through a special access program, achieving subjective improvement (relief of pain, cough, and dyspnea) and an objective partial response on that regimen, although requiring a dose reduction to 30 mg on alternating days because of grade 2 diarrhea coupled with a mild grade 1 rash. She currently remains on afatinib, with the diarrhea now completely controlled and no further evidence of disease progression, as of her most recent follow-up in April 2012.

3.  DISCUSSION

This case represents a borderline resectable cT3N2M0 papillary adenocarcinoma of the lung, arising in an elderly woman with poor- ps who was a former light smoker. Her functional status did not favor concurrent chemoradiation, and chemotherapy alone was not preferred by the patient. Instead, 3 months of neoadjuvant erlotinib produced a promising response, that agent being justified based on the higher probability of EGFR mutation given her clinical and pathologic features 2,3, her baseline poor ps , and an approach of vigilantly monitoring her initial clinical response to treatment. Her tumour response allowed surgeons to perform a well-tolerated resection with negative margins. An eventual EGFR analysis was positive for a less-common L861Q activating point mutation in exon 21, and erlotinib was continued postoperatively for 10 months. Her recurrent tumour unfortunately highlights the limited understanding of the optimal management strategy for her situation.

Although not a preferred standard, neoadjuvant therapy of potentially resectable nsclc is well described for conventional chemotherapy 4,5 and chemoradiation 6. In some studies, age was an independent predictor of worse outcome 7. Neoadjuvant use of egfr - tki s has been reported only anecdotally so far. One case reported from the Netherlands involved a 67-year-old never-smoker with pet -staged iiia nsclc with an EGFR exon 19 deletion 8. That patient was treated with preoperative erlotinib, resulting in a rapid and complete pathologic response. Interestingly, pet - ct on treatment detected an early metabolic response. Two other cases were reported from Japan 9. One patient with a cT2N2M1 tumour (adjacent lobe metastasis) had a substantial response to second-line gefitinib, with pT1N0M1 after resection and confirmation of an exon 19 deletion. A second patient with cT1N2M0 was shown to have an exon 21 L858R point mutation, with subsequent resection and demonstration of complete pathologic response.

Response to egfr - tki therapy is generally predicated on EGFR copy number or mutational status 10,11. The use of egfr - tki without EGFR mutational testing in the first-line setting can be associated with harm, as demonstrated in ipass (Iressa Pan-Asia Study) 11. Patients in ipass were selected to be a cohort enriched for EGFR mutation: Asian, nonsmokers or former light smokers, and adenocarcinoma histology. Those who were EGFR mutation-negative experienced worse progression-free survival (hazard ratio: 2.85; 95% confidence interval: 2.05 to 3.98; p < 0.001) if they received gefitinib rather than chemotherapy. Those data argue against the blind use of egfr - tki s, even after selection for clinical characteristics. However, in our patient’s case, we judged her to be a poor candidate for chemotherapy because of age and frailty, and we monitored her closely for the possibility of harm on erlotinib.

The papillary adenocarcinoma histology in this patient favoured the possibility of EGFR mutation. Adenocarcinoma is most commonly of a mixed subtype (>90%), and papillary morphology represents a commonly dominant pattern. In one series of 100 patients with adenocarcinoma, the major histologic subtypes were papillary (33%), acinar (31%), solid with mucin (25%), bronchoalveolar (7%), and micropapillary (4%) 3. Patients with major papillary morphology had a higher rate of EGFR mutations (55%) than did those with nonpapillary morphology (5%, p < 0.001), and micropapillary pattern was also correlated with EGFR mutation 3. Micropapillary features are associated with aggressive disease and poor prognosis 1214. The lack of micropapillary features in the final resected pathology for our patient may reflect a change after neoadjuvant erlotinib treatment.

Although the exon 19 del and exon 21 L858R mutations represent the most common and well-described EGFR activating mutations, the exon 21 L861Q mutation occurs with relative frequency (5% in one series 15) and is generally thought to confer sensitivity to egfr - tki therapy 16; however, this mutation is infrequently reported in egfr - tki treated series 1719. Compared with exon 19 del or exon 21 L858R 20, L861Q may be less sensitive to egfr - tki . Dose escalation of egfr - tki may be one strategy to overcome resistance 21. Amplification or high polysomy of egfr was not found in this patient’s tumour. EGFR fluorescence in-situ hybridization positivity may occur independently of mutational status 22 and has been more associated with exon 19 del than with other mutations 23.

Erlotinib was continued post-resection in our patient, but the value of this approach is unknown. The ncic Clinical Trials Group br .19 study randomized 503 patients with resected stage ib iiia nsclc to oral gefitinib 250 mg daily for 2 years or to placebo 24. Overall survival trended in favor of placebo (hazard ratio: 1.23; p = 0.136), and patients with EGFR wild-type (hazard ratio: 1.21; p = 0.301) and EGFR mutation (hazard ratio: 1.58; p = 0.16) alike experienced nonsignificantly worse survival on gefitinib. That strongly counterintuitive result defies explanation, unless it relates to acceleration of drug-resistant forms of the disease. These data may or may not be applicable to situations in which the egfr - tki was started before surgery, but they do argue that egfr - tki may not have to be maintained postoperatively. On the other hand, if our patient’s tumour had not been resected, there would be no question of continuing the erlotinib until progression or intolerance.

4.  CONCLUSIONS

With this case, we have added to the meager world literature on neoadjuvant administration of the egfrtki s. Without short-term toxicity, erlotinib provided a rapid and profound response in a (micro)papillary adenocarcinoma of the lung, which permitted a safe and ostensibly complete surgical resection. In this frail and declining patient, we provided effective initial palliation rather than the more dubious option of chemoradiation. However, the duration of response was short, perhaps reflective of the aggressive micropapillary histology. Learning points include these:

  • Response to erlotinib can be rapid in an EGFR- mutated nsclc tumour, with improvement in surgical resectability.

  • EGFR mutations with (micro)papillary morphology are frequent, but not frequent enough to obviate the need for EGFR testing.

  • The effectiveness of neoadjuvant erlotinib is still unknown and the subject of ongoing clinical trials.

  • The role and effectiveness of egfr - tki s post resection remain controversial.

5. CONFLICT OF INTEREST DISCLOSURES

MO has no financial conflict of interest to disclose. MV has received honoraria for speaking engagements and advisory boards, and research funding from Hoffmann–La Roche Canada Inc.

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Correspondence to: Mark D. Vincent, London Health Sciences Centre, London, Ontario N6A 4L6. E-mail: Mark.Vincent@lhsc.on.ca

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Current Oncology , VOLUME 19 , NUMBER 3 , 2012








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