title: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described.
  
  
  METHODS
  Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses.
  
  
  RESULTS
  EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients.
  
  
  CONCLUSIONS
  EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.
authors.affiliation: Department of Pathology, Genentech Inc., San Francisco, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.forename: Audrey D
authors.initials: AD
authors.lastname: Goddard
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Heldens
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: William L
authors.initials: WL
authors.lastname: Ince
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.forename: David H
authors.initials: DH
authors.lastname: Johnson
authors.forename: Pam
authors.initials: P
authors.lastname: Klein
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ostland
authors.forename: David A
authors.initials: DA
authors.lastname: Ramies
authors.forename: Dragan
authors.initials: D
authors.lastname: Sebisanovic
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Stinson
authors.forename: Yu R
authors.initials: YR
authors.lastname: Zhang
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Hillan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D010919:Placebos; D011237:Predictive Value of Tests; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D010919:Placebos; D011799:Quinazolines; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017239:Paclitaxel