- © 2010 by American Society of Clinical Oncology
Favorable Response to Gefitinib Treatment of Lung Adenocarcinoma With Coexisting Germline and Somatic Epidermal Growth Factor Receptor Mutations
In May 2007, a 76-year-old nonsmoking woman was admitted to the National Taiwan University Hospital for acute cholecystitis. On admission, right upper lobe tumor was an incidental finding by chest radiograph. Chest computed tomography (CT) confirmed a 3.3-cm solitary tumor at the right upper lobe with nonspecific mediastinal lymphadenopathies, and CT-guided tumor biopsy revealed adenocarcinoma with thyroid transcription factor-1 expression. Lung adenocarcinoma was diagnosed. Contrast-enhanced brain CT and positron emission tomography scans showed no metastases. Right upper lobectomy with lymph node dissection was performed in July 2007. Pathologic stage was IIIA (pT2pN2). Postoperatively, the patient received four cycles of adjuvant cisplatin and vinorelbine (cisplatin 80 mg/m2 on day 15 and vinorelbine 25 mg/m2 on days 1, 8, and 15, with cycles repeated every 4 weeks) from July to October 2007. In June 2009, follow-up chest CT scan showed right middle lobe nodule, right pleural effusion, and liver metastases (Figs 1A to 1C). Cytology of the right pleural effusion showed adenocarcinoma, and she was administered gefitinib 250 mg daily beginning in July 2009. After 5 months of gefitinib treatment, follow-up chest CT scan showed partial response (Figs 1D to 1F) in accordance with RECIST (Response Evaluation Criteria in Solid Tumors).1 At present, the patient is maintaining gefitinib use for disease control. Mutation analyses of EGFR in the frozen tissue specimen obtained intraoperatively (including the tumor and normal parts of the right upper lobe) and peripheral blood mononuclear cells were performed.2 Briefly, RNA was extracted from the frozen tissue specimen, and DNA was extracted from peripheral blood mononuclear cells. Reverse transcription–polymerase chain reaction (RT-PCR) or PCR amplified the tyrosine kinase domain of the EGFR gene (exons 18-21), and the resulting amplicons were sequenced. Two EGFR point mutations in exon 21—L861R (2582 T > G) and R831C (2491 C > T)—were identified in the patient's cancer cells (Fig 2). In the normal lung part and peripheral blood mononuclear cells, only one EGFR point mutation in exon 21—R831C—was identified (Fig 2). The results indicated the coexistence of germline and somatic EGFR mutations in the cancer cells. In reviewing the patient's family history, two family members were found to have died as a result of malignancies. Her sister died as a result of lung cancer at age 67 years, and her son died as a result of gastric cancer at age 36 years. Both were diagnosed and treated in other hospitals, so their cancer specimens could not be obtained for additional analysis.
Overexpression of the epidermal growth factor receptor in non–small-cell lung cancer that results in cancer cell proliferation, antiapoptosis, activating invasion and metastases, and angiogenesis has been reported in many studies.3,4 EGFR mutation may be an early event in lung cancer development.5,6 Specific somatic mutations in the EGFR gene, such as deletion in exon 19 and point mutation L858R in exon 21, are related to treatment response to epidermal growth factor receptor tyrosine kinase inhibitors.7–10 Some EGFR mutations, like T790M, may cause drug resistance.11,12 Although most reports in the literature involve a single EGFR mutation in lung cancer, a previous study has reported a high frequency of double somatic EGFR mutations (complex EGFR mutations) in lung cancer.13 Six amino acids are commonly affected in double EGFR mutations: E709, G719, S768, T790, L858, and L861.13 On the other hand, few germline EGFR mutations in lung cancer have been reported. To our knowledge, three patient cases involving germline T790M mutation have been reported in literature.5,14 Two of these occurred in a family in which multiple members developed bronchoalveolar carcinoma.14 EGFR mutation analyses of tumor specimens showed coexisting germline T790M mutation and somatic EGFR mutations, including L858R, deletion in exon 19 (delL747-T751), and G719A. In addition, a 70-year-old woman was also reported to have had multiple pulmonary adenocarcinomas with coexisting germline and somatic EGFR mutations.15 EGFR mutation analyses of the resected tumors showed germline V843I mutation combined with either L858R or L861Q mutations. Some of her family members also had germline V834I mutation. This patient had lung cancer with coexisting germline and somatic EGFR mutations (R831C and L861R, respectively). The report15 posits that some complex EGFR mutations in lung cancer may be responsible for the coexistence of somatic and germline mutations. Without EGFR mutation analysis of peripheral blood mononuclear cells, the true frequency of such complex mutation remains undetermined. As previously reported, response to gefitinib or erlotinib is similar in tumors with either double or single EGFR mutations.13 In patients with complex EGFR mutations, those with L858R or deletion in exon 19 have response, progression-free survival, and overall survival rates similar to patients with only L858R mutation or deletion of exon 19.2 The tumor of the 70-year-old woman, with R831C and L861R EGFR mutations, showed partial response to gefitinib. Lung cancer with a single L861R EGFR mutation showing stable disease under gefitinib treatment has been previously identified.10 In the database16 of EGFR mutations, only two patients with lung cancer have had somatic R831C EGFR mutation in cancer cells.17 To our knowledge, no reports exist in the literature on the response of lung cancer with R831C EGFR mutation. Despite instances of family histories involving epithelium-originating malignancies (ie, lung and gastric cancers), the clinical significance of this novel germline mutation in cancer development remains unknown.
In conclusion, lung cancer with coexisting somatic L861R and germline R831C EGFR mutations shows favorable response to gefitinib treatment. Future studies are needed to evaluate the frequency of coexisting germline and somatic EGFR mutations in lung cancer as well as the clinical significance of germline mutations in lung cancer development and treatment. Also, the possible association between germline EGFR mutations and hereditary lung cancers would be of interest.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position:None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Jin-Yuan Shih, AstraZeneca; Chong-Jen Yu, AstraZeneca Research Funding: None Expert Testimony: None Other Remuneration: None
