HHS Public Access Author manuscript Author Manuscript

Lung Cancer. Author manuscript; available in PMC 2017 July 24. Published in final edited form as: Lung Cancer. 2016 May ; 95: 65–72. doi:10.1016/j.lungcan.2016.02.012.

Epidermal Growth Factor Receptor (EGFR) Mutations in Small Cell Lung Cancers: Two Cases and a Review of the Literature Bradford J. Siegele, M.D.1, Konstantin Shilo, M.D.2, Bo H. Chao, M.D.2, David Carbone, M.D., Ph.D2, Weiqiang Zhao, M.D., Ph.D2, Olga Ioffe, M.D.3, Wilbur A. Franklin, M.D.1, Martin J. Edelman, M.D.3, and Dara L. Aisner, M.D., Ph.D1 1University

Author Manuscript

2The

of Colorado

Ohio State University

3University

of Maryland Greenebaum Cancer Center

Abstract Activating mutations in the epidermal growth factor receptor (EGFR) gene are exceedingly rare in small cell lung cancer (SCLC). We present two cases of SCLC harboring EGFR mutations, one in an 82 year-old male smoker with a combined SCLC and adenocarcinoma with a novel D855H point mutation in exon 21, and the second in a 68 year-old female never smoker with the L858R point mutation in exon 21. The cases, accompanied by a review of the literature, highlight the importance of integration of clinicopathologic considerations and adherence to recently promulgated Guideline recommendations for molecular testing in lung cancer.

Author Manuscript

Keywords SCLC; EGFR; Adenocarcinoma; Molecular; Guideline; Pathology

1. Introduction Activating mutations in the gene that encodes the epidermal growth factor receptor (EGFR) have been identified in 10–15% of non-small cell lung cancers (NSCLCs) [1–3], most notably lung adenocarcinomas. Rare, however, are reports of EGFR mutations occurring in small cell lung cancer (SCLC). Cases of resistance to EGFR tyrosine kinase inhibitor (TKI)

Author Manuscript

Address for correspondence: Dara L. Aisner, M.D., Ph.D, University of Colorado Department of Pathology, 12801 E. 17th Ave, Mail Stop 8104, Aurora, CO 80045, Phone: (303)724-3495, Fax: (303)724-3096, [email protected] Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of Interest M.J.E. reports consulting activities with Eli Lilly, grants from BMS, grants and consulting activities with Genentech, grants from Novartis, grants from Peregrine, grants from Clovis, consulting with Hospira, and grants from Adaptimmune. D.A.R. reports personal fees from AstraZeneca, Clovis Oncology, Oxford Oncology, Casdin Capital, and Illumina. In addition, D.A.R. has a patent pending for a Pneumatic Cell Collector. B.H.C. reports personal fees from Lilly Oncology. B.J.S., K.S., W.Z., O.I., and W.A.F. have nothing to disclose.

Siegele et al.

Page 2

Author Manuscript

therapy have been associated with transformation from adenocarcinoma to SCLC. Exceedingly scarce are cases of EGFR mutations occurring de novo in SCLCs. While improvements in progression free survival with tyrosine kinase inhibitor (TKI) therapy have been shown in NSCLCs with EGFR gene mutations compared to those with the wild type gene [4], the medical literature remains very limited with regard to the clinical impact of TKI therapy in the setting of SCLCs. Here we report two separate cases of SCLC harboring EGFR mutations and review the current literature on the prevalence and clinical implications of EGFR mutations in SCLC.

2. Case Series 2.1. Case 1

Author Manuscript

An 82 year-old male, 35-pack year smoker with a past medical history significant for locally advanced head and neck squamous cell carcinoma previously treated with radiation therapy presented for evaluation for recurrent disease. A positron emission tomography/computed tomography (PET/CT) scan revealed an unanticipated fluorodeoxyglucose (FDG)-avid nodule in the right upper lobe of the lung. A right upper lobe sublobar resection with thoracic lymphadenectomy yielded a 1.8 cm lung tumor.

Author Manuscript

Microscopic evaluation of hematoxylin and eosin (H&E) stained slides of the lung nodule demonstrated a mixed population of hyperchromatic cells with a “salt-and-pepper” chromatin pattern in a sheet-like architecture, as well as a smaller population of glandforming cells. (Figure 1a). A preliminary pathologic diagnosis was given of combined small cell lung cancer (small cell lung cancer [90%] and adenocarcinoma [10%]). Immunochemical studies revealed tumor cells to be positive for staining by cytokeratin AE1/3 monoclonal antibody clone AE1/AE3 (Dako, Carpinteria, CA), synaptophysin monoclonal antibody clone 27G12 (Leica Biosystems, Buffalo Grove, IL), chromogranin monoclonal antibody (Cell Marque, Rocklin, CA), CD56 monoclonal antibody clone CD564 (Leica Biosystems, Buffalo Grove, IL), and TTF-1 monoclonal antibody clone 8G7G3/1 (Dako, Carpinteria, CA), with a Mib-1/Ki-67 proliferative index of up to 90% in the small cell lung cancer component by monoclonal antibody clone MIB-1 (Dako, Carpinteria, CA). Lymph nodes were negative for malignant involvement.

Author Manuscript

Formalin-fixed paraffin-embedded tissue sections were manually microdissected as previously described, [5] with targeted malignant cells isolated from surrounding tissue with the aid of a dissecting microscope. The SCLC and adenocarcinoma components were separately microdissected, isolated malignant cells were digested, and DNA was subsequently extracted and purified. Sanger sequencing was performed, demonstrating a guanine to cytosine point mutation in Exon 21 of the EGFR gene (c.2563G>C) resulting in an aspartate to histidine missense mutation in amino acid 855 (p.D855H) in both the small cell lung carcinoma and the adenocarcinoma cell populations. (Figure 1b). Non-tumor tissue from the patient was separately analyzed, without identification of the p.D855H mutation (data not shown). The final pathologic diagnosis of combined small cell lung cancer (small cell lung cancer and adenocarcinoma) with a p.D855H mutation in the EGFR gene was rendered.

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 3

Author Manuscript

The patient transferred his oncologic care to a local facility for convenience and received adjuvant cisplatin and etoposide chemotherapy. The patient was subsequently lost to clinical follow up. 2.2. Case 2 A 68 year-old Caucasian female never-smoker with no significant past medical history was incidentally discovered to have liver masses on a diagnostic ultrasound of the kidneys. A CT of the chest and abdomen demonstrated a right upper lobe lung mass with a right pleural effusion, as well as extensive mediastinal lymphadenopathy. A fine needle aspirate of the liver demonstrated cells consistent with a diagnosis of small cell lung cancer. Immunochemical studies revealed tumor cells to be positive for staining by CD56 monoclonal antibody clone CD564 (Leica Biosystems, Buffalo Grove, IL) and TTF-1 monoconal antibody clone SPT24 (Leica Biosystems, Buffalo Grove, IL).

Author Manuscript

Additional tumor tissue was retrieved by mediastinoscopic biopsy of the 4R lymph node. The diagnosis of small cell lung cancer was confirmed (Figure 1c), and, given the patient’s never-smoking history, tissue was submitted for testing for an EGFR gene mutation. Formalin-fixed paraffin-embedded tissue sections were microdissected, with isolated malignant cells digested and DNA extracted and purified, as described above for Case 1. Sanger sequencing demonstrated the presence of a tyrosine to guanine point mutation in Exon 21 of the tyrosine kinase domain of the EGFR gene (c.2573T>G) resulting in a leucine to arginine missense mutation in amino acid 858 (p.L858R). (Figure 1d). The final pathologic diagnosis of small cell lung cancer with a p.L858R mutation in the EGFR gene was rendered.

Author Manuscript

The patient was treated with several chemotherapy regimens prior to molecular analysis, experiencing an initial response followed by progressive spread of the tumor locally within the chest and distantly to the brain. Whole brain radiotherapy and, subsequently, topotecan were initiated concurrent with submission of material for molecular analysis. Unfortunately the patient experienced rapid deterioration and died prior to the final results of molecular testing.

3. Review of the Literature and Discussion 3.1. Literature Review

Author Manuscript

A review of the English language medical literature performed on PubMed including all dates, utilizing the keywords “small cell lung cancer” or “SCLC” and “epidermal growth factor receptor” or “EGFR” and excluding the keyword “non-small”, revealed 26 studies, yielding, when including the cases from this report, a total of 59 reported cases of EGFR mutations in small cell lung carcinomas. Results of the literature review are listed in Tables 1 and 2.

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 4

3.2. Discussion

Author Manuscript Author Manuscript

We present two cases of patients with de novo SCLC and EGFR mutations. Case 1 represents the case of combined small cell lung cancer and adenocarcinoma harboring an EGFR mutation arising in the absence of prior targeted therapy. In this case, because complete sampling demonstrated the presence of an adenocarcinoma component, mutation testing was performed revealing a novel p.D855H mutation in Exon 21 of the EGFR gene. This mutation has not been previously described (including evaluation of the COSMIC database and data from The Cancer Genome Atlas via cBioPortal), though the DIRECT database does report a p.D855G mutation in EGFR, coupled with p.F712S and p.E868G mutations, in a case of lung adenocarcinoma demonstrating a partial response to gefitinib therapy.[6] In silico models demonstrating high-energy hydrogen bonds between gefitinib and the wild-type D855 residue suggest that the aspartic acid to histidine substitution may disrupt gefitinib binding and impair its efficacy in this novel mutational setting.[7, 8] To date, however, treatment of cancer bearing a mutation at position p.D855 with tyrosine kinase inhibitor therapy remains largely untested. Case 2 similarly represents an uncommon finding of EGFR mutation positivity in a small cell lung cancer specimen. Typically, small cell lung cancer is not considered for EGFR mutation testing unless a component of adenocarcinoma is also identified. The added clinical history of the patient’s never-smoker status was an additional factor prompting molecular analysis.

Author Manuscript Author Manuscript

A review of the literature demonstrates 59 reported cases of EGFR mutations in SCLC (Tables 1, 2). There is a greater than 3:1 female:male predominance in cases of EGFRmutated SCLC. Unlike the general findings in SCLC in which the population is heavily enriched for those with a smoking history, the finding of concomitant SCLC and EGFR mutation demonstrates a marked preponderance of never-smokers. The original reports of EGFR mutations in SCLC were seen in the setting of small cell transformation as a mechanism of resistance to tyrosine kinase inhibitors.[9, 10] In contrast, in the cases that are the subject of the current report, combined with those summarized in Table 1, 28 of 53 cases (53%) were in patients who presented with a de novo diagnosis of SCLC. The nature of EGFR mutations in these SCLC cases is similar in nature to the type and frequency of mutations seen in adenocarcinomas of the lung, with Exon 19 deletions and point mutations at L858R accounting for the majority of cases. Importantly, the impact of these findings with regard to patient outcomes is not well established. Low numbers of total patients in which this observation has been recorded, combined with the low availability of tracking of subsequent therapy and outcomes makes evaluation of the therapeutic implications of these findings challenging. In 2013, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) jointly sponsored the formulation and publication of the consensus “Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors” (the Guidelines). The Guidelines, based on review of the existing medical literature, recommended testing for epidermal growth factor receptor (EGFR) gene mutations for all advanced-stage primary adenocarcinomas of the lung. Testing for EGFR mutations in small Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 5

Author Manuscript

cell lung cancers was advised to be limited to cases demonstrating combined small cell lung carcinoma-adenocarcinoma histology and cases with limited biopsy material in circumstances otherwise clinically suggestive of the presence of an associated adenocarcinoma component (e.g. young age, lack of smoking history, documented preceding adenocarcinoma).[1] Fifteen of the 26 reports described were published subsequent to the Guidelines.

Author Manuscript

Of note, both cases described here would be considered appropriate for testing based on the Guidelines recommendations for testing, in one case based on never-smoking status, and in the other based on the combined adenocarcinoma component. Table 1 summarizes selected data from the 59 cases of SCLC with EGFR mutations identified. It is noteworthy that, in the overwhelming majority of cases, fifty-four of fifty-eight (93.1%), the Guidelines recommendations would have elicited testing in these EGFR mutation-positive SCLC cases. For one case, reported clinical information available is too limited to determine whether, pursuant to the Guideline recommendations, EGFR testing would have been performed.[11]

Author Manuscript

In the context of this high rate for which testing would have been considered indicated by the Guidelines recommendations, the cases reviewed here also suggest that that the criteria set forth for testing would not result in inclusion of every EGFR mutation-harboring primary small cell lung cancer. We identified three reports in the literature of de novo EGFR mutations in SCLCs in biopsies from patients without clinical histories that would have prompted mutational testing. Tatematsu, et al.[12] reported two cases, one of an 81 year-old Asian male heavy-smoker and one of an 89 year-old Asian female light-smoker, found to harbor G719A and L858R EGFR mutations, respectively, on lung biopsies showing SCLC. The first patient was treated with gefitinib and achieved a partial response. The latter refused treatment and was lost to follow-up. Shiao, et al., [13] likewise, presented the case of a 63 year-old Asian male heavy-smoker with SCLC, identified by biopsy and fine needle aspiration, demonstrating an EGFR exon 19 deletion. The patient refused radiotherapy and so received standard chemotherapy including etoposide and cisplatin, with a partial response obtained after transition to topotecan. Additionally, Lu, et al. [14] recently reported the case of a 61 year-old heavy-smoker with an EGFR exon 19 deletion found on the lobectomy removal of a combined small cell lung carcinoma, with small cell and squamous cell histologic features. In the absence an adenocarcinoma component to the surgically resected tumor this last case likewise would not have prompted EGFR mutational testing under the Guidelines.

Author Manuscript

Recent large scale sequencing studies by Peifer, et al. of 29 exomes, 15 transcriptomes, and 2 genomes of human SCLCs utilizing samples from a global lung cancer genome research consortium, by Rudin, et al. of 36 human SCLC tumors utilizing a collection of commercial samples and samples from North American repositories, and by George et al. of 110 whole genomes, 81 transcriptomes, and 142 SNP arrays of human SCLCs from a Caucasianpredominant, heavy-smoking patient population enriched for early stage lesions revealed just four total EGFR mutations, T446K, I643V, H893R, and L1167V, all of uncertain clinical relevance.[15–17]

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 6

Author Manuscript

4. Conclusions

Author Manuscript

The two cases presented here, in conjunction with the review of the current medical literature, underscore the importance of integration of clinicopathologic considerations in mutation testing in cases of small cell lung cancer. The presence of an adenocarcinoma component in case 1, in spite of the patient’s smoking history, prompted molecular testing which revealed a novel EGFR gene mutation, although the impact on therapy in this case is not clear. In case 2, it was the patient’s never-smoker clinical history that led to testing and the discovery of a potentially targetable EGFR gene mutation. Review of the literature demonstrates that EGFR mutation is a rare, but identifiable event in SCLC in the absence of a definitive NSCLC component (often related to limited sampling), and can be seen in cases not associated with small cell transformation as a mechanism of resistance to tyrosine kinase inhibitor therapy. Additional studies are needed to better appreciate the clinical implications of EGFR mutation in SCLC.

Acknowledgments We would like to gratefully acknowledge the efforts of Lisa Litzenberger in assistance with generation of figures. Molecular analysis supported in part by the Molecular Pathology Shared Resource of Colorado’s NIH/NCI Cancer Center Support Grant P30CA046934

References

Author Manuscript Author Manuscript

1. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013; 137:828–860. [PubMed: 23551194] 2. Boch C, Kollmeier J, Roth A, Stephan-Falkenau S, Misch D, Gruning W, et al. The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study. BMJ Open. 2013; 3 3. van Zandwijk N, Mathy A, Boerrigter L, Ruijter H, Tielen I, de Jong D, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18:99–103. [PubMed: 17060486] 4. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947–957. [PubMed: 19692680] 5. Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol. 2013; 37:685–698. [PubMed: 23552385] 6. Hsieh MH, Fang YF, Chang WC, Kuo HP, Lin SY, Liu HP, et al. Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non-small cell lung cancer. Lung Cancer. 2006; 53:311–322. [PubMed: 16870303] 7. Wan S, Coveney PV. Rapid and accurate ranking of binding affinities of epidermal growth factor receptor sequences with selected lung cancer drugs. J R Soc Interface. 2011; 8:1114–1127. [PubMed: 21227963] 8. Zhong H, Tran LM, Stang JL. Induced-fit docking studies of the active and inactive states of protein tyrosine kinases. J Mol Graph Model. 2009; 28:336–346. [PubMed: 19767223] 9. Zakowski MF, Ladanyi M, Kris MG, Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome G. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006; 355:213–215. [PubMed: 16837691] 10. Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K, et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer. 2007; 58:411–413. [PubMed: 17601631]

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 7

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

11. Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 2015; 6:6377. [PubMed: 25758528] 12. Tatematsu A, Shimizu J, Murakami Y, Horio Y, Nakamura S, Hida T, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res. 2008; 14:6092–6096. [PubMed: 18829487] 13. Shiao TH, Chang YL, Yu CJ, Chang YC, Hsu YC, Chang SH, et al. Epidermal growth factor receptor mutations in small cell lung cancer: a brief report. J Thorac Oncol. 2011; 6:195–198. [PubMed: 21178714] 14. Lu HY, Sun WY, Chen B, Zhang YP, Cai JF, Su D, et al. Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China. Neoplasma. 2012; 59:100–104. [PubMed: 22103903] 15. Peifer M, Fernandez-Cuesta L, Sos M, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature Genetics. 2012; 44:1104–1110. [PubMed: 22941188] 16. Rudin C, Durinck S, Stawiski E, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature Genetics. 2012; 44:1111–1116. [PubMed: 22941189] 17. George J, Lin JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015; 524:47–53. [PubMed: 26168399] 18. Okamoto I, Araki J, Suto R, Shimada M, Nakagawa K, Fukuoka M. EGFR mutation in gefitinibresponsive small-cell lung cancer. Ann Oncol. 2006; 17:1028–1029. [PubMed: 16357019] 19. Fukui T, Tsuta K, Furuta K, Watanabe S, Asamura H, Ohe Y, et al. Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung. Cancer Sci. 2007; 98:1714–1719. [PubMed: 17784875] 20. Alam N, Gustafson KS, Ladanyi M, Zakowski MF, Kapoor A, Truskinovsky AM, et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinibresponsive adenocarcinoma of the lung. Clin Lung Cancer. 2010; 11:E1–4. [PubMed: 20837450] 21. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011; 3:75ra26. 22. Kurahara Y, Kawaguchi T, Tachibana K, Atagi S, Hayashi S, Kitaichi M, et al. Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke. Clin Lung Cancer. 2012; 13:75–79. [PubMed: 21729654] 23. Ma AT, Chan WK, Ma ES, Cheng T, Cheng PN. Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung. Acta Oncol. 2012; 51:557–559. [PubMed: 22129360] 24. van Riel S, Thunnissen E, Heideman D, Smit EF, Biesma B. A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol. 2012; 23:3188–3189. [PubMed: 23079729] 25. Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O’Brien M. Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFRmutant lung adenocarcinoma. Lung Cancer. 2013; 80:1–4. [PubMed: 23312887] 26. Takagi Y, Nakahara Y, Hosomi Y, Hishima T. Small-cell lung cancer with a rare epidermal growth factor receptor gene mutation showing “wax-and-wane” transformation. BMC Cancer. 2013; 13:529. [PubMed: 24195468] 27. Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A, et al. Transformation to smallcell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer. 2013; 82:370–372. [PubMed: 24012411] 28. Norkowski E, Ghigna MR, Lacroix L, Le Chevalier T, Fadel E, Dartevelle P, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol. 2013; 8:1265–1271. [PubMed: 24457237]

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 8

Author Manuscript Author Manuscript

29. Lu HY, Lu ZY, Cheng QY, Cai JF, Wang XJ, Zhang YP, et al. Identifying EGFR mutations from SCLC patient plasma by mutant-enriched liquidchip technology. Adv Clin Exp Med. 2014; 23:191–195. [PubMed: 24913109] 30. Wakuda K, Kenmotsu H, Serizawa M, Koh Y, Isaka M, Takahashi S, et al. Molecular profiling of small cell lung cancer in a Japanese cohort. Lung Cancer. 2014; 84:139–144. [PubMed: 24657128] 31. Bordi P, Tiseo M, Barbieri F, Bavieri M, Sartori G, Marchetti A, et al. Gene mutations in small-cell lung cancer (SCLC): results of a panel of 6 genes in a cohort of Italian patients. Lung Cancer. 2014; 86:324–328. [PubMed: 25453846] 32. Asai N, Ohkuni Y, Matsuda M, Kaneko N. Small-cell lung cancer with epidermal growth factor receptor mutation: Case report and review of literature. Indian J Cancer. 2014; 51:384–385. [PubMed: 25494153] 33. Varghese AM, Zakowski MF, Yu HA, Won HH, Riely GJ, Krug LM, et al. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014; 9:892–896. [PubMed: 24828667] 34. Ross JS, Wang K, Elkadi OR, Tarasen A, Foulke L, Sheehan CE, et al. Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer. J Clin Pathol. 2014; 67:772–776. [PubMed: 24978188] 35. Sun JM, Choi YL, Ji JH, Ahn JS, Kim KM, Han J, et al. Small-cell lung cancer detection in neversmokers: clinical characteristics and multigene mutation profiling using targeted next- generation sequencing. Ann Oncol. 2015; 26:161–166. [PubMed: 25355724] 36. Le X, Desai NV, Majid A, Karp RS, Huberman MS, Rangachari D, et al. De novo pulmonary small cell carcinomas and large cell neuroendocrine carcinomas harboring EGFR mutations: Lack of response to EGFR inhibitors. Lung Cancer. 2015; 88:70–73. [PubMed: 25700797] 37. Piotrowska Z, Niederst MJ, Karlovich CA, et al. Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a ThirdGeneration EGFR Inhibitor. Cancer Discov. 2015; 5:713–722. [PubMed: 25934077]

Author Manuscript Author Manuscript Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 9

Author Manuscript

Highlights •

We report a case of SCLC harboring a novel D855H point mutation in the EGFR gene.



We report a case of SCLC demonstrating a L858R point mutation in the EGFR gene.



We review the literature and note 59 reported SCLCs with EGFR mutations.



Only 4 EGFR mutations would not have been identified based on recent Guidelines



These findings support the Guideline recommendations for EGFR testing in SCLC

Author Manuscript Author Manuscript Author Manuscript Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 10

Author Manuscript Author Manuscript

Fig. 1.

Author Manuscript

Histology and Sanger Sequencing Results. Case 1. (a) Histologic features of combined SCLC. Hematoxylin & eosin stain with low power image (10×) of adenocarcinoma (40× [inset above]) and SCLC components (40× [inset below]). (b) Sanger sequencing chromatograms demonstrating a guanine to cytosine point mutation in Exon 21 of the EGFR gene at position 2563 (c.2563G.C) resulting in an aspartate to histidine missense mutation in amino acid 855 (p.D858H) shared by the adenocarcinoma tissue component (above) and small cell tissue component (below). Case 2. (c) Histologic features of pure SCLC. Hematoxylin & eosin stain with low power (10×) and high power (40× [inset]) image of SCLC. (d) Sanger sequencing chromatogram demonstrating a tyrosine to guanine point mutation in Exon 21 of the tyrosine kinase domain of the EGFR gene at position 2573 (c. 2573T>G) resulting in a leucine to arginine missense mutation in amino acid 858 (p.L858R).

Author Manuscript Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Author Manuscript

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

w acquired TKI resistance*

56 40 61

F F

54

67

63

54

73

62

46

F

F

F

Sequist, et al.[21] (2011)

Series of 37 lung cancers

M

F M

(2011) Series of 76 SCLCs*

65

M

F

89

M

Shiao, et al.[13]

69

F

Tatematsu, et al.[12](2008) Series of 122 SCLCs*

F

2.5

81

F

Fukui, et al.[19] (2007) Series of 6 patients with combined SCLC*

Alam, et al. [20](2010) Case Report

32

36

F

N/A

N/A

N/A

N/A

N/A

Heavy smoker

0

0

67.5

40

0

0

0

0

Morinaga, et al.[10] (2007) Case Report

45

F

0

Zakowski, et al.[9] (2006) Case Report

72

F

Smoking (pyh)

Okamoto, et al.[18] (2006) Case Report

Age

Combined SCLC & ADC SCLC Combined SCLC & ADC

de novo

de novo de novo

ADC (Erlotinib)

ADC (Erlotinib)

ADC (Erlotinib)

ADC (Erlotinib)

SCLC

SCLC

SCLC

SCLC

SCLC

SCLC

de novo ADC (Erlotinib)

SCLC

de novo

SCLC

SCLC

de novo

ADC (Gefitinib; erlotinib)

Combined SCLC & ADC

Combined SCLC & ADC

SCLC

SCLC

SCLC

Diagnosis

ADC (Gefitinib)

de novo

ADC (Gefitinib)

ADC (Erlotinib; gefitinib)

de novo

Prior Diagnosis (& TKI Treatment)

Author Manuscript Sex

Subcutaneous nodule FNA

Chest wall mass excision

Lung biopsy

Mediastinal LN bx

Lingula biopsy

FNA & lung bx

Lung biopsy

Liver biopsy

Surgical resection of primary tumor

Lung biopsy

Lung biopsy

Lung biopsy

Surgical resection of primary tumor

Lobectomy LN dissection

Brain metastasis resection Lung biopsy

Lung biopsy

Transbronchial biopsy

SCLC Diagnosis Specimen Type

Author Manuscript

Review of the Literature

N/A

N/A

N/A

N/A

N/A

LD

LD

ED

IIa

LD

Ia

ED

IV

IIIb

ED

N/A

N/A

Stage

L858R

Exon 19 del

L858R

Exon 19 del

L858R

Exon 19 del

Exon 19 del

L858R

Exon 19 del

L858R

L858R

G719A

L858R

L858R

Exon 19 del

Exon 19 del

Exon 19 del

SCLC EGFR Mutation

N/A

N/A

N/A

N/A

N/A

10

17

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

~7

N/A

Overall Survival (mos)

Author Manuscript

Table 1 Siegele et al. Page 11

Author Manuscript

Lung Cancer. Author manuscript; available in PMC 2017 July 24. F

F

M

M

Norkowski et al.[28] (2013) Case Series of 9 cases*

M

62

F

Watanabe, et al.[27] (2013) Case Report

Wakuda, et al.[30] (2014) Study of 60 SCLCs*

55

F

Takagi, et al.[26] (2013) Case Report

F

50

F

Popat, et al.[25] (2013) Case Report

Lu, et al.[29] (2014) Study of EGFR mutations in plasma

60

F

van Riel, et al.[24] (2012) Case Report

73

57

52

70

46

42

F

65

65

61

M

F

62

F

Ma, et al. [23](2012) Case Report

Kurahara, et al.[22] (2012) Case Series of SCLC in 4 Never-Smokers*

Lu, et al.[14] (2012) Series of 40 SCLCs*

Heavy smoker

0

0

70

0

0

0

0

0

0

0

0

Heavy smoker

0

de novo

Combined SCLC & ADC

SCLC

Combined SCLC & ADC

de novo

N/A

Combined SCLC & ADC

Combined SCLC & ADC

Combined SCLC & ADC

SCLC

Combined SCLC & ADC

Combined SCLC & NSCLC with NE morphology

SCLC

SCLC

ADC

ADC (Erlotinib)

ADC (Erlotinib)

ADC (Erlotinib)

de novo

ADC (Erlotinib)

ADC (Erlotinib)

ADC (Gefitinib)

SCLC

Combined SCLC & SqCC

de novo

de novo

Combined SCLC & ADC

Diagnosis

de novo

Prior Diagnosis (& TKI Treatment)

Author Manuscript Smoking (pyh)

N/A

Transbronchial bx

Tumor resection Mediastinal LN dissection

Lobectomy LN dissection

Tumor Resection Mediastinal LN dissection

Lobectomy Adrenalectomy

Lung biopsy

Transbronchial bx

Liver biopsy

Supraclavicular lymph node biopsy

Pleural biopsy

Transbronchial biopsy

Lobectomy

Lobectomies LN dissection

SCLC Diagnosis Specimen Type

Author Manuscript

Age

Ilb

ED

IIIa

IIIa

IV

IV

ED

IV

IV

N/A

N/A

ED

IIa

IIIa

Stage

G719A

Exon 19 del

G719A Exon 21 L833_V834d el

Exon 19 del

Exon 19 del

E872K

Exon 19 del

L861Q

Exon 19 del

Exon 19 del

L858R

L858R

Exon 19 del

Exon 19 del

SCLC EGFR Mutation

N/A

N/A

>8

N/A

>9

8

N/A

N/A

~7

9

N/A

16

>16

>22

Overall Survival (mos)

Author Manuscript

Sex

Siegele et al. Page 12

Lung Cancer. Author manuscript; available in PMC 2017 July 24. 55 73

F M

Acquired TKI Resistance*

69

F

Adenocarcinomas with

65

52

F

F

(2015) Series of 19

Niederst, et al. [11]

N/A

N/A

N/A

N/A

N/A

N/A

0

0

N/A

F N/A

0 0

N/A

N/A

N/A

N/A

N/A

N/A

0

0

0

0

0

0

0

0

0

N/A

N/A

N/A

F N/A

N/A

F

Study of 391 SCLCs*

N/A

N/A

M

Sun, et al.[35] (2015)

by Next-Gen Sequencing*

F

(2014) Study of 98 SCLCs

N/A

F N/A

N/A

F

F

N/A

F

Ross, et al.[34]

N/A

N/A

F

M

Varghese, et al.[33] (2014) Study of 23 never

68

N/A

F

Asai, et al.[32] (2014) Case Report

66

62

M

F

Study of mutations in 54 SCLCs

smokers with SCLC*

F

Author Manuscript

Bordi, et al.[31] (2014)

SCLC SCLC

de novo de novo

SCLC SCLC

de novo

SCLC

SCLC

TKI

TKI

TKI

SCLC

SCLC

TKI

SCLC

de novo

N/A

N/A

N/A

N/A

N/A

SCLC

Combined SCLC & ADC

Combined SCLC, ADC & NE

SCLC

SCLC

Combined SCLC & ADC

de novo

N/A

N/A

N/A

N/A

N/A

TKI

TKI

TKI

TKI

de novo

de novo

SCLC

SCLC

de novo de novo

SCLC

Diagnosis

de novo

Prior Diagnosis (& TKI Treatment)

Author Manuscript Smoking (pyh)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

Transbronchial bx

N/A

N/A

SCLC Diagnosis Specimen Type

Author Manuscript

Age

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

ED

ED

ED

ED

ED

ED

N/A

LD

LD

Stage

Exon 19 del

L858R

Exon 19 del

Exon 19 del

Exon 19 del

G719A

Exon 19 del

L858R

L858R

Exon 19 del

Exon 19 del

L858R; T790M

L858R

Exon 19 del

Exon 19 del

Exon 19 del

Exon 19 del

Exon 19 del

Exon 19 del

L858R

Exon 19 del

L858R

Exon 19 del

SCLC EGFR Mutation

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

21

21

Overall Survival (mos)

Author Manuscript

Sex

Siegele et al. Page 13

82

68

F

F

F

(2015) Series of 12 Adenocarcinomas with TKI Resistance*

Current Cases

0

35

N/A

N/A

0

SCLC

Combined SCLC & ADC SCLC

de novo

de novo

Combined SCLC & ADC

SCLC

TKI

TKI

de novo

Diagnosis

Liver FNA Mediastinal LN bx

Sublobar resection Thoracic lymphadenectomy

Pleural bx

RLL & Liver bxs

Transbronchial bx Mediastinal LN FNA

SCLC Diagnosis Specimen Type

ED

Ia

N/A

N/A

ED

Stage

L858R

D855H

Exon 19 del

L858R

Exon 19 del

SCLC EGFR Mutation

~0‡

N/A

N/A

N/A

~3

Overall Survival (mos)

Only case(s) with identified EGFR mutations and/or SCLC transformation included from larger case series.

Patient died before completion of molecular analysis and identification of EGFR mutation



*

ADC=Adenocarcinoma; SCLC=Small cell lung cancer; NSCLC=Non-small cell lung cancer; SqCC=Squamous cell carcinoma; NE=Neuroendocrine; pyh=Pack year history; TKI=Tyrosine kinase inhibitor; FNA=Fine needle aspiration; LN=Lymph node; bx=Biopsy

46

52

F

Piotrowska, et al. [37]

63

F

Author Manuscript

Le, et al. [36] (2015) Case Report

Prior Diagnosis (& TKI Treatment)

Author Manuscript Smoking (pyh)

Author Manuscript

Age

Author Manuscript

Sex

Siegele et al. Page 14

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 15

Table 2

Author Manuscript

Summary of Clinical Characteristics for EGFR-mutated SCLC Patients Evaluated in Review of the Medical Literature (Overall N=59; Papers Reviewed=26) plus Current Case Series N=59

%

Age (years) Median (Range)

61 (36–82)

Gender Male

12

(22)

Female

43

(78)

33

(79)

9

(21)

Smoking history Never Smoker

Author Manuscript

Median (pack years) (Range)

41 (2.5–70)

Prior Tyrosine Kinase Inhibitor Therapy +

25

(47)



28

(53)

36*

(67)

Histology Small cell carcinoma, no evidence of other component Biopsy, cytology specimens

16*

Surgical resection specimens

0*

Combined w Adenocarcinoma

18

(33)

16

(29)

Author Manuscript

Biopsy, cytology specimens

3

Surgical resection specimens

9

w Squamous Cell Carcinoma

1

(2)

w NSCLC with Neuroendocrine Morphology

1

(2)

LD

5

(26)

ED

14

(74)

I (Ia,Ib)

2 (2,0)

(14)

II (IIa,IIb)

3 (2,1)

(21)

III (IIIa,IIIb)

4 (3,1)

(29)

5

(36)

Exon 19 deletion

33

(53)

L858R

19

(31)

G719A

4

(6)

T790M

1

(2)

Stage (“Pure” SCLC)

Stage (Combined SCLC)

IV

Author Manuscript

EGFR Mutation

Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Siegele et al.

Page 16

Author Manuscript

N=59

%

D855H

1

(2)

E872K

1

(2)

L861Q

1

(2)

Exon 21 L833_ V834delins

1

(2)

Exon 19 del

5

(32)

L858R

5

(32)

G719A

2

(12)

E872K

1

(6)

D855H

1

(6)

L861Q

1

(6)

Exon 21 L833_V834del

1

(6)

NSCLC with neuroendocrine fts

Exon 19 del

1

(100)

SqCC

Exon 19 del

1

(100)

ADC & neuroendocrine

Exon 19 del

1

(100)

Exon 19 del

22

(61)

L858R

12

(33)

G719A

2

(6)

14

(61)

L858R

8

(35)

E872K

1

(4)

12

(43)

L858R

9

(31)

G719A

4

(14)

D855H

1

(4)

L861Q

1

(4)

Exon 21 L833_V834del

1

(4)

Exon 19 del

1

(100)

EGFR Mutation by SCLC Histology Combined SCLC ADC

Author Manuscript

“Pure” SCLC

EGFR Mutation by SCLC Etiology Prior TKI Treatment

Author Manuscript

De novo

Other

Exon 19 del

Exon 19 del

*

Sources of the remaining 15 specimens with small cell histology, with no other component identified, were not reported.

Author Manuscript Lung Cancer. Author manuscript; available in PMC 2017 July 24.

Epidermal growth factor receptor (EGFR) mutations in small cell lung cancers: Two cases and a review of the literature.

Activating mutations in the epidermal growth factor receptor (EGFR) gene are exceedingly rare in small cell lung cancer (SCLC). We present two cases o...
214KB Sizes 2 Downloads 11 Views