Fc gamma receptor polymorphisms and KRAS status as predictive biomarkers in patients with metastatic colorectal cancer treated with biweekly cetuximab-based salvage therapy.

Abstract

e13523 Background: Cetuximab has shown a clinically significant antitumor activity against metastatic colorectal cancer (mCRC) both in first and subsequent lines of therapy. Biweekly schedules have shown similar PK/PD behaviour and inhibition of EGFR downstream pathway compared to the weekly schedule. Several molecular factors have been found to predict response to Cetuximab. Among them a role of ADCC has been suggested. We aimed to investigate the association of Fc gamma Receptor (Fcg R) polymorphisms and KRAS mutation with the outcome of mCRC patients (pts) treated with salvage biweekly Cetuximab-based therapy. Methods: Tumor from 66 mCRC pts was screened for KRAS mutations using a sensitive multiplex assay. Fcg RIIa and Fcg RIIIa polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). The results were correlated with objective response (OR), disease control rate (CR+PR+SD>6 months) and progression-free survival (PFS). Results: KRAS mutations were associated with a lower OR (52,9% vs 29%, p=0.04), a lower DCR (68,6% VS 29%, p=0.001) and a shorter PFS (6.6 vs 4.0 months, p=0.0007). Whereas no correlation was found for FCg RII and clinical outcome, pts with V-containing FCg RIII polymorphism had a longer PFS (5.5 vs 3.2 p=0.001) and a significantly higher OR and DCR. The difference in PFS remained significant in both KRAS wild type (wt)(6.7 vs 3.2 months, p=0,036) and mutated pts (4.8 vs 2.6 months, p=0.024), all favouring the V-containing FCg RIII genotype. KRAS mutated pts carrying any V-containing Fcg RIII genotype had a longer PFS than KRAS wt pts with the PP-Fcg RIII allele. Considering KRAS wt and any V-containing FCg RIII genotype as favourable factors, median PFS was 6.7, 4.6 and 2.6 (p=0.002) in pts harbouring 2, 1 or none of them. In the multivariate model, considering clinically relevant parameters, KRAS, Fcg RIII and Köhne index were all significantly associated with PFS. Conclusions: Fcg RIII polymorphisms have a clinically relevant role in cetuximab efficacy, even in KRAS mutated pts. Strategies aimed at enhancing activation of NK cell effector functions in this subset of pts seem warranted. No significant financial relationships to disclose.