EGFR, KRAS, PIK3CA mutations and response to tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients.

22003 Background: Molecular alterations of the EGFR pathway are considered the major determinant of clinical outcome in response to EGFR TKIs in non small cell lung cancer (NSCLC) patients (pts).The aim of this study was to determine the clinical implication of EGFR, KRAS, PIK3CA gene mutations in pts with advanced NSCLC who had been treated with gefitinib or erlotinib after failure of 1 or 2-line platinum-based chemotherapy.,Genomic DNA was isolated from paraffin- embedded tumor specimens, amplified for EGFR (exons 18, 19, 20 and 21), PIK3CA (exons 9 and 20) KRAS (exon 2) by nested polymerase chain reaction and sequenced in both sense and antisense directions. RECIST criteria were used to assess response to TKIs.,From July 2002 to December 2007 128 pts have been treated with TKIs in our Institution. EGFR mutations were detected in 25.4% of pts; 16.4% had deletional mutations in exon 19, 4.7% point mutations in exon 20 and 4.7% in exon 21. KRAS and PIK3CA mutations were detected in 5.7% and in 2.7% of pts, respectively. Overall, pts with EGFR mutations had a response rate (RR) of 58.4% vs 19.7% (p=0.001), disease control rate of 74.2% vs 49.4% (p=0.02) median time to progression of 8 months vs 3 months (p=0.06), with respect to EGFR non mutated pts. No difference in overall median survival was observed. However when we considered 25 pts with TKI-sensitive EGFR mutations (deletion in exon 19, missense L858R) we observed a significant longer TTP (p=0.008, median 8 vs 3 months in non mutants) and a better OS (p=0.07, median not reached vs 11 months in non mutants). In this setting the RR was 88% (22 of 25) and TTP was significantly better also the multivariate analysis (p=0.03). All pts with KRAS mutations did not responded to TKIs treatment as the pts with PIK3CA mutations.,In this experience we confirmed that EGFR mutations (deletion in exon 19, missense L858R) are the most important predictor of TKI sensitivity. In addition the evaluation of KRAS and PIK3CA mutations could contribute to identify lung cancer patients who are most suitable for TKIs treatment. No significant financial relationships to disclose.