title: Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project--part 2).
abstract: BACKGROUND
  Epidermal growth factor and v-Ki-ras2 Kirsten ras sarcoma (KRAS) mutation status, although associated with EGFR- tyrosine kinase inhibitor (TKI) efficacy, has not been used in clinical practice until recently. The prospective Evaluation of the EGFR Mutation status for the administration of EGFR-TKIs in non small cell lung Carcinoma (ERMETIC) study aimed to implement these biomarkers in France.
  
  
  METHODS
  Between March 2007 and April 2008, EGFR and KRAS were studied by sequencing DNA tumor specimens from 522 consecutive advanced non-small-cell lung cancer patients treated with EGFR-TKI, mostly in second- or third-line settings. Cox models were used to investigate the impact of patient characteristics and mutations on progression-free survival (PFS) and overall survival (OS). Added value from mutation status was evaluated using likelihood ratio (LR) tests. Classification and regression tree analysis aimed to identify homogeneous groups in terms of survival.
  
  
  RESULTS
  Among the 522 patients, 87% were white, 32% were women, and 18% were never-smokers, with 65% presenting with adenocarcinoma. Biological data were available for 307 patients, showing 44 EGFR mutations (14%) and 42 KRAS (14%) mutations. Median PFS was 2.4 months (interquartile range, 1.4-4.6) and median OS 5.6 months (interquartile range, 2.2-14.0). Factors independently associated with PFS were performance status 1 or 2 to 3 (hazards ratio [HR] = 1.5, 95% confidence interval [CI] 1.1-1.9; and HR = 2.3, CI 1.7-3.1, respectively; p < 0.001); former or current smoker status (HR = 1.8, CI 1.4-2.4 and 2.0,CI 1.4-2.8, respectively; p < 0.001); nonadenocarcinoma histology (squamous cell: HR = 0.9 CI 0.7-1.2]; others: HR = 1.6, 1.3-2.1; p < 0.001); at least two metastatic sites (HR = 1.3, CI 1.1-1.6 and 1.6, CI 1.3-2.1, respectively; p < 0.001); prior taxane-based chemotherapy (HR = 1.3, CI 1.0-1.3, p = 0.01); non-white (HR = 0.7, CI 0.5-0.9, p = 0.009). Similar results were found for OS. In addition, EGFR and KRAS mutations were significantly associated with PFS (HR = 0.5, CI 0.3-0.7 and HR = 1.2, CI 0.8-1.8, respectively, versus no mutation; LR p = 0.001). In the OS model, adjusted HR was 0.7 (0.4-1.0) for EGFR mutation and 1.7 (1.1-2.4) for KRAS (LR p = 0.004). Classification and regression tree analysis revealed EGFR mutation to be the primary factor for identifying homogeneous patient subgroups in terms of PFS.
  
  
  CONCLUSIONS
  EGFR and KRAS status independently impacts outcomes in advanced non-small-cell lung cancer patients treated with EGFR-TKI. However, EGFR status impacts both PFS and OS whereas KRAS only impacts OS. These findings support the nationwide use of EGFR status for patient selection before EGFR-TKI therapy. The role of KRAS mutations remains to be elucidated.
authors.affiliation: Service de Pneumologie-AH-HP Hôpital Tenon, Faculté de Médecine P&M Curie, université Paris 6 Paris, France. jacques.cadranel@tnn.aphp.fr
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.forename: Audrey
authors.initials: A
authors.lastname: Mauguen
authors.forename: Michele
authors.initials: M
authors.lastname: Faller
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Buisine
authors.forename: Virginie
authors.initials: V
authors.lastname: Westeel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Longchampt
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
authors.forename: Bruno
authors.initials: B
authors.lastname: Coudert
authors.forename: Catherine
authors.initials: C
authors.lastname: Daniel
authors.forename: Bruno
authors.initials: B
authors.lastname: Chetaille
authors.forename: Stephane
authors.initials: S
authors.lastname: Michiels
authors.forename: Helene
authors.initials: H
authors.lastname: Blons
authors.forename: Jerome
authors.initials: J
authors.lastname: Solassol
authors.forename: Florence
authors.initials: F
authors.lastname: De Fraipont
authors.forename: Pascal
authors.initials: P
authors.lastname: Foucher
authors.forename: Thierry
authors.initials: T
authors.lastname: Urban
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.forename: Virginie
authors.initials: V
authors.lastname: Poulot
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Quoix
authors.forename: Martine
authors.initials: M
authors.lastname: Antoine
authors.forename: Guillaume
authors.initials: G
authors.lastname: Danton
authors.forename: Franck
authors.initials: F
authors.lastname: Morin
authors.forename: Christos
authors.initials: C
authors.lastname: Chouaid
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000368:Aged; D001859:Bone Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D012307:Risk Factors; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins