title: Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib.
abstract: BACKGROUND
  A subset of lung adenocarcinomas appears preferentially sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating mutations and never smoking are associated with response to TKIs.
  
  
  OBJECTIVE
  To describe the morphology of adenocarcinomas responsive to TKIs, compare it to tumors in nonresponding patients, and correlate findings with EGFR mutations, gene copy number, and protein expression.
  
  
  METHODS
  Material from 52 EGFR TKI-treated patients was studied: 29 responders and 23 nonresponders. Adenocarcinoma subtypes and morphologic features were defined in histologic and cytologic material. EGFR mutations were detected by sequencing, copy number by chromogenic in situ hybridization, and expression by immunohistochemistry.
  
  
  RESULTS
  Tumors from TKI responders tended to be better-differentiated adenocarcinomas with bronchioloalveolar carcinoma components. Nonresponders showed more heterogeneous morphology, higher grade, and more subtypes, and were more likely to show solid growth. In nonresponders, the only pure bronchioloalveolar carcinoma was mucinous, a subtype known to be negative for EGFR mutations. Using World Health Organization criteria, all tumors in both groups other than pure bronchioloalveolar carcinomas would be classified as adenocarcinomas, mixed subtype, thereby obscuring some of these distinctions. EGFR mutations were significantly more common in responders (22/29 vs 0/23; P < .001). Immunohistochemistry and chromogenic in situ hybridization results were not significantly correlated with EGFR mutations or response to TKIs in this study.
  
  
  CONCLUSIONS
  Overall, histologic differences exist between tumors that respond to TKIs and those that do not, although sampling affects classification, and there is significant histologic overlap between the 2 groups. Response is strongly associated with EGFR mutations.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. zakowskm@mskcc.org
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: Sanaa
authors.initials: S
authors.lastname: Hussain
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Ginsberg
authors.forename: Robert
authors.initials: R
authors.lastname: Heelan
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Valerie W
authors.initials: VW
authors.lastname: Rusch
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000188:drug therapy* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011799:Quinazolines / Q000627:therapeutic use*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib