Effect of tumor-specific KRAS mutational status on impact of anti-EGFR therapy in non-small cell lung cancer (NSCLC).

Abstract

7564 Background: The RAS/RAF/MEK/ERK pathway is a therapeutic target in both colorectal (CRC) and NSCLC cancer, but while mutated KRAS is a negative prognostic marker and a negative predictor for anti-EGFR therapy in CRC, its role in lung cancer is quite ambiguous. KRAS is a pool of mutations mostly occurring in codons 12 and 13 but differing for the replaced basis and for the aminoacid substitution. In CRC the most expressed KRAS mutation is G12D. We hypothesized a different KRAS mutational status in NSCLC patients, bearing a potential different profile in the tumour response to treatment which we tested in vitro. Methods: TAILOR (NCT00637910) is a multicenter Italian phase III trial powered to evaluate a differential effect of all biological markers in selecting patients for erlotinib and docetaxel as second line. Consecutive patients are registered and molecularly profiled centrally. KRAS and EGFR mutations were detected by direct sequencing. Therefore, we identified all KRAS mutations types. The EGFR-wt NCI-H1299 lung cell line was transfected with expression plasmids encoding all different identified KRAS mutations and tested in vitro for the activity of cisplatin, taxanes, erlotinib and pemetrexed. Results: To date, KRAS and EGFR mutational status is available on 161 of 256 patients registered into the trial. We found six types of KRAS mutation in 35 patients (20%): G12C (45.7%) G12D (20%) G12V (20%) G12A (5.7%) G13C (5.7%) G13D (2.8%). Preliminary data, in the NCI- H1299 transfected cell lines, indicate that specific KRAS mutations are associated to different sensitivity or resistance drug profiles. Conclusions: Final results will be presented at the congress and clearly suggest that the specific mutational status of KRAS gene in NSCLC seems to differ from that reported for CRC. This clinical observation, with in vitro results suggesting different patterns of sensitivity/resistance to EGFR inhibition in transfected cell lines, might explain the ambiguous role of KRAS as a predictor to anti-EGFR therapy in NSCLC. Final results of the randomized TAILOR study will definetely allow to verify this suggestive hypothesis. No significant financial relationships to disclose.