New biomarkers to predict response to oxaliplatin-based chemotherapy in metastatic colorectal cancer: KRAS and ERCC1.

Abstract

500 Background: In the present study we have evaluated the possibility that KRAS mutational status might be predictive of the efficacy of oxaliplatin-based chemotherapy. In addition, we explored the possible role of excision repair cross complementing group-1 (ERCC-1) that is envolved in repair of oxaliplatin (OXA) produced DNA-adducts. Methods: We performed a retrospective analysis of 90 patients with metastatic colorectal cancer, who received FOLFOX-6 schedule and FOLFIRI schedule ± Bevacizumab, in first or second line therapy. In sixty out of 90 patients the expression of ERCC-1 was also determined by fluorescence-based real-time detection method. Results: Among 90 patients, 42 (47%) wild-type (wt) and 48 (53%) mutated (mt) KRAS tumors were found. Twenty-two out of 42 wt KRAS patients received FOLFOX-6 as first-line therapy and the other 20 patients as second-line treatment; in the mt KRAS population, 27 and 21 patients received FOLFOX-6 as front-line or second-line, respectively. One complete response (CR) and 10 partial responses (PR) were observed in the wt KRAS group (RR 26%), whereas 2 CR and 25 PR were obtained in the mt KRAS group (56%); the difference is statistically significant in the total sample (p=0.003) and when only patients receiving FOLFOX-6 in first-line are considered (p=0006). PFS was longer in mt than in wt KRAS patients in the entire group of patients (10 vs 8 months, respectively; p=0.001) and in those treated in front-line (10 vs 8 months, respectively; p=0.003). ERCC-1 was over-expressed in 30 out of 60 patients, but the efficacy of FOLFOX-6 was not different in patient showing high ERCC-1 levels in comparison to those with low level of the gene. In ERCC-1 over-expressing patients, however, RR and PFS were higher in mt than in wt patients (40% vs 13% and 10 vs 8 months, respectively); a similar, not significant, trend was also observed in patients not over-expressing ERCC-1. Conclusions: Our data, if confirmed in larger series and in a prospective setting, suggest that activating mutation of KRAS oncogene could be a predictive biomarker of response to oxaliplatin. Basal tumor expression of ERCC-1 doesn’t explain the high efficacy of FOLFOX-6 in mt KRAS patients.