KRAS and BRAF mutational status as response biomarkers to cetuximab combination therapy in advanced gastric cancer patients

e15503 Background: The prognosis of advanced gastric cancer (GC) patients (pt) is still poor despite the introduction of new chemotherapy regimens. In colorectal cancer (CRC) it has been demonstrated that KRAS or BRAF mutations are associated with resistance to treatment with the anti-EGFR mAbs. We have assessed whether, and to what extent, the mutational profile of KRAS and BRAF genes affects the response to cetuximab combination therapy in GC. Methods: We have collected 44 tumor samples from pts affected by locally advanced or metastatic GC undergoing cetuximab combination therapy as first-line treatment in two consecutive phase II studies. Thirteen pts received cetuximab plus FOLFIRI (FOLCETUX Study) and 31 pts cetuximab plus cisplatin and docetaxel (DOCETUX Study). Genomic DNA was extracted from paraffin-embedded tumor specimens from all cases. The mutational status of KRAS (exon 2) and BRAF (exon 15) was ascertained by PCR amplification followed by direct sequencing. The objective response was evaluated every 6 weeks by CT according to RECIST criteria. Results: KRAS and BRAF mutations were detected in 5 (11.4%) and 1 (2.3%), respectively, of the 44 tumors analyzed. These frequencies are consistent with those previously reported in GC. In the case of KRAS, 3 cases displayed amino acid substitutions of codon 12 and 1 of codon 13. One case had the A11V variant that had been reported in hematopoietic and lymphoid tissue of the stomach. The only BRAF mutation found in 1 sample was the classic V600E substitution. As a whole, 13.6 % of the analyzed tumors carried a mutation in either KRAS or BRAF genes. K-RAS and BRAF mutations were, as expected, mutually exclusive. In this pt cohort oncogenic activation of KRAS/BRAF-signaling pathways was not significantly associated to objective response (p= 0.757). Also, we found no correlation between KRAS/BRAF mutations and clinical outcome measured as overall survival. Conclusions: In advanced GC the frequency of mutations in KRAS and BRAF is lower as compared with CRC cancer. In our cases, the mutational status of KRAS and BRAF genes does not correlate with the response to cetuximab-based therapy in advanced gastric cancer patients. No significant financial relationships to disclose.