KRAS and EGFR status as predictive markers of response and time to progression in EGFR wild-type stage IV non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine-kinase inhibitors.

Abstract

e19000 Background: KRAS mutations on codons 12, 13 and 61 result in the constitutive activation of protein, which may render tumor cells independent of epidermal growth factor receptor (EGFR) signalling and thereby resistant to tyrosine-kinase inhibitor (TKI) therapy in NSCLC patients. This study was aimed to evaluate the associations of KRAS and EGFR copy number alteration and mutations with response and time to progression (TTP) in EGFR TKI-treated patients. Methods: 84 samples from NSCLS patients treated with erlotinib or gefitinib were analyzed for KRAS and EGFR mutation status by cobas KRAS and EGFR Mutation Tests (Roche). EGFR copy number was determined by fluorescent in situ hybridization (FISH, Abbott Molecular) and amplification was defined with three or more gene copies in tumor. Results: KRAS mutation was detected in 15 (17.8%) cases, EGFR mutation in 27 (32.1%) and EGFR amplification in 8 (9.5%). Significant differences were detected in response rates for wild-type (0.2) and mutant KRAS (0.0) (p=0.023), for wild-type (0.12) and mutant EGFR (0.39) (p=0.007), and for non-amplified (0.18) and EGFR-amplified (0.71) patients (p=0.005). Additionally, significant benefit from TKI therapy was observed for KRAS wild-type compared with KRAS-mutated patients (median TTP 7 vs. 3 months, p=0.001), for EGFR-mutated compared with wild-type patients (14 vs. 4 months, p=0.004) and for EGFR-amplification in contrast to non-amplified cases (11 vs. 5 months, p=0.001). KRAS and EGFR mutations or EGFR amplification did not correlated with overall survival (18 vs. 19 months, p=0.406; 16 vs. 21 p=0.094; 25 vs. 17 months, p=0.103, respectively). Combined analysis of favourable status of three biomarkers strongly predicted benefit to TKI therapy (median TTP 15 vs. 3 months, p<0.001). Conclusions: Combined analysis ofKRAS mutation, EGFR mutation and EGFR amplification in EGFR TKI-treated NSCLC might provide superior predictive information than single biomarker study in these patients.