title: De novo pulmonary small cell carcinomas and large cell neuroendocrine carcinomas harboring EGFR mutations: Lack of response to EGFR inhibitors.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) mutations are present in 10-20% of all non-small-cell lung cancers and predict for response to EGFR tyrosine kinase inhibitors (TKIs). However, the incidence of these mutations and their ability to predict response to TKIs in high-grade pulmonary neuroendocrine carcinomas [i.e. small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC)] is unknown.
  
  
  METHODS
  The presence of EGFR mutations, clinicopathologic and anti-cancer therapy response data were retrospectively compiled and analyzed from a cohort of 608 patients-lung tumors to identify EGFR mutated high-grade pulmonary neuroendocrine carcinomas. We identified 126 EGFR-mutated (21.8% of 578 successful genotyped cases) lung cancers and only 2 (1.6%) were high-grade neuroendocrine carcinomas.
  
  
  RESULTS
  Case one was of a 63 year-old white never smoker woman with extensive stage SCLC harboring EGFR-delL747_P753insS but without EGFR protein expression. After progression on carboplatin/etoposide, the patient was treated with erlotinib and developed progressive disease with a survival <3 months from start of erlotinib. Case two was of a 73 year-old Asian 30 pack-year smoker man with metastatic LCNEC harboring EGFR-delL747_P753insQS and also lacking EGFR protein expression. The patient received first line therapy with erlotinib and had progressive disease with a survival of 4 months.
  
  
  CONCLUSIONS
  The lack of response to EGFR TKIs in EGFR mutated de novo SCLC and LCNEC reported here may indicate that tumor differentiation affects tumor dependency on EGFR as a driver oncogene.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Xiuning
authors.initials: X
authors.lastname: Le
authors.affiliation: Department of Medicine, Beverly Hospital, Beverly, MA, United States.
authors.forename: Neelam V
authors.initials: NV
authors.lastname: Desai
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Adnan
authors.initials: A
authors.lastname: Majid
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Karp
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Huberman
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Deepa
authors.initials: D
authors.lastname: Rangachari
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kent
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Sidharta P
authors.initials: SP
authors.lastname: Gangadharan
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Erik
authors.initials: E
authors.lastname: Folch
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. Electronic address: pvanderl@bidmc.harvard.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: VanderLaan
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. Electronic address: dbcosta@bidmc.harvard.edu.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011859:Radiography; D055752:Small Cell Lung Carcinoma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D005047:Etoposide; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; Erlotinib; Large cell neuroendocrine carcinoma; Mutation; Never-smoker; Progression; Resistance; Small cell lung cancer