P-0199 - Analysis of Molecular Alterations for Predicting Clinical Benefit to Cetuximab Plus Chemotherapy in First-Line Metastatic Colorectal Cancer (MCRC)

Abstract

Introduction: The utility of KRAS gene mutation testing in patients with metastatic colorectal cancer (mCRC) to predict response to anti-EGFR MoAb therapy has been established. However, most patients with KRAS wild-type tumors still do not respond. We study the effect of other downstream mutations on the efficacy of cetuximab in our cohort of patients with mCRC patients selected by KRAS wild-type codons 12 and 13. Methods: We analysed formalin-fixed samples from a cohort of mCRC patients treated with chemotherapy plus cetuximab in first-line by means of additional screening of V600E in BRAF; R88Q, N345K, C420R, E542K, E545X (E545A, E545D, E545G and E545K), Q546X (Q546 E, Q546K, Q546L and Q546R) in exon 9 and M1043I, H1047X (H1047L, H1047 R and H 1047Y) and G1049R in exon 20 of PIK3CA by Cobas Mutation Test (Roche diagnostic), Epiregulin (EREG) and Anfiregulin (AREG) mRNA expression with real time quantitative PCR by TaqMan assays, PTEN expression by inmmunochemistry and EGFR amplification by FISH. We analyzed objective response, progression-free survival (PFS) and overall survival (OS) in molecular defined subgroup of patients. Results: In total, 107 KRAS exon 2 wild-type samples from mCRC patients were analyzed. The median follow-up was 15.8 months. Median PFS and OS were 8.4 and 20.3 months respectively. BRAF mutation was detected in 7.69 (8/104) and 10.1% (10/99) harboured PIK3CA mutation. 83% (70/84) had loss PTEN expression and 17.5% (13/74) had increased gene copy number of EGFR. AREG and EREG were overexpressed in 66% (55/83) and 33% (27/82) respectively. Median PFS was significantly longer in patients with BRAF wild-type compared with BRAF mutated (p= 0.008, HR: 0.38; CI 95% 0.18-0.83) and also in patients with high expression of AREG (p= 0.01, HR: 0.5; CI 95% 0.3-0.8). PIK3CA and PTEN were not associated to PFS or OS. The OS was significantly longer in patients with BRAF wild-type tumors versus mutated BRAF (p= 0.007, HR:0.36; CI 95% 0.16-0.83) and in those with increased gene copy number of EGFR (p= 0.01, HR: 0.3; CI 95% 0.1-0.9). In the multivariate analysis, BRAF wild-type and AREG overexpression were independent factors for OS. Patients with wild-type BRAF and overexpressed AREG had better outcome for PFS. Conclusion: Recent clinical data have provided substantial evidence that KRAS mutational status should be used as a predictive marker of outcome to anti-EGFR therapies in colorectal cancer. We suggest that BRAF mutations are associated with a worse PFS and OS in patients treated with cetuximab. In addition, AREG over-expression and EGFR amplification are associated with better results to cetuximab therapy.