The role of specific KRAS mutation types in response to treatment by EGFR inhibitors.

Abstract

e18006 Background: KRAS mutations can be found in 15 to 25% of lung cancers, frequently in adenocarcinomas and their presence is associated with smoking. The role of KRAS mutations in biological targeted therapy by EGFR inhibitors is ambiguous. While some reports clearly assigned mutated KRAS as negative prognostic factor and negative predictor, others did not confirm such notion. In our work we aimed to elucidate the role of specific type of KRAS mutation in outcome of patients with advanced NSCLC threated with EGFR-TKI therapy. Methods: 443 patients with NSCLC were examined. 38 patients, threated with erlotinib or gefitinib in maintenance setting, were further evaluated. 30 patients were suffering from adenocarcinoma, 7 patients had squamous cell carcinoma including 1 patient with poorly diferentiated carcinoma. 37 patients were smokers and only 1 patient was never smoker. Statistical significance was scrutinized by a Log rank test at a 95% confidence level. Results: KRAS mutation was detected in 66 patients. Glycine to cystein substitution at codon 12 [G12C] was the most frequent type of KRAS mutation, detected in 24 patients. Outcome of patients with G12C [n=24] and patients with other specific type of mutation [nonG12C] [n=14] was compared. Median of TTP in the G12C group was 4,3 weeks in comparison with 9,0 weeks in the nonG12C group [p 0.009]. Median of TTP among patients with adenocarcinoma in the G12C group was 4,1 weeks in comparison with 9,0 weeks in the nonG12C group [p 0.007]. Median of OS in the G12C group was 9,3 weeks in comparison with 12,1 weeks in the nonG12C group [p 0.068], median of OS among patients with adenocarcinoma in the G12C group was 9,3 weeks in comparison with 10,6 weeks in the nonG12C group [p 0.095]. Analysis of OS was influenced by different oncological threatment after EGFR-TKI, different quality of basic supportive care and higher incidence of brain matestasis in the nonG12C group. Conclusions: G12C KRAS mutation is a strong negative predictor for EGFR-TKI threatment. Other specific types of KRAS mutation didn’t prove such a negative predictive value and TTP was comparable to patients bearing wild type KRAS gene.