title: EGFR and K-Ras mutations in women with lung adenocarcinoma: implications for treatment strategy definition.
abstract: BACKGROUND
  We aimed at investigating the outcomes of female patients with stage IIIB-IV adenocarcinoma of the lung according to EGFR and K-Ras mutational status.
  
  
  METHODS
  One hundred and three consecutive female patients genotyped at a single Italian Institution were analyzed. Patients were planned to receive first-line platinum-based chemotherapy (CT) and a salvage treatment with anti-EGFR tyrosine-kinase inhibitors (TKIs) was proposed irrespective of tumor mutational status. EGFR (exons 18-21) and K-Ras (exon 2, codons 12-13) mutations were evaluated by real-time PCR and pyrosequencing. The association of mutational status with clinical variables and treatment benefit was investigated by chi-square test and log-rank test.
  
  
  RESULTS
  EGFR and K-Ras mutations were found in 31 (30%) and 13 (15%) cases, respectively. Sixty-six patients received platinum CT: no correlation was observed between EGFR or K-Ras mutational status and response rate (RR) (p > 0.05). However, patients treated with first-line CT harboring EGFR activating mutations experienced a significantly reduced progression-free survival (PFS) in comparison with wild-type ones (4.4 vs. 6.4 months, respectively; HR 0.597, 95% CI 0.287-0.975; p = 0.048). Thirty-nine patients received salvage treatment with erlotinib: EGFR activating mutations were significantly correlated with RR (60% vs. 12.5%; p = 0.004) and PFS (11.4 vs. 4.5 months; HR 0.491, 95% CI 0.216-0.936; p = 0.044). Responses to erlotinib were not reported among women with K-Ras mutant tumors, while 50% of those with wild-type K-Ras achieved an objective remission (p = 0.296). Median PFS (3.5 vs. 8.8 months; HR 0.284, 95% CI 0.015-0.510; p = 0.010) and OS (3.9 vs. 19.8 months; HR 0.158, 95% CI 0.001-0.075; p < 0.001) were significantly shorter among K-Ras mutant patients treated with TKI.
  
  
  CONCLUSIONS
  In our population of Caucasian women with advanced lung adenocarcinoma we observed that the presence of EGFR activating mutations correlates with a significant reduction in the benefit from first-line platinum-based CT, emphasizing the importance of an upfront use of anti-EGFR TKIs in this patient subset. K-Ras mutations seem to correlate with a detrimental effect from anti-EGFR TKI, but this finding deserves further investigation.
authors.forename: Virginia
authors.initials: V
authors.lastname: Rotella
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fornaro
authors.forename: Enrico
authors.initials: E
authors.lastname: Vasile
authors.forename: Carmelo
authors.initials: C
authors.lastname: Tibaldi
authors.forename: Laura
authors.initials: L
authors.lastname: Boldrini
authors.forename: Antonio
authors.initials: A
authors.lastname: Chella
authors.forename: Armida
authors.initials: A
authors.lastname: D'Incecco
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cirigliano
authors.forename: Aldo
authors.initials: A
authors.lastname: Chioni
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lupi
authors.forename: Elisa
authors.initials: E
authors.lastname: Sensi
authors.forename: Laura
authors.initials: L
authors.lastname: Ginocchi
authors.forename: Simona
authors.initials: S
authors.lastname: Giovannelli
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Pennucci
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.forename: Editta
authors.initials: E
authors.lastname: Baldini
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016879:Salvage Therapy; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins