Excision repair cross-complementing group-1 (ERCC1) gene induction in peripheral blood mononuclear cells as a marker of outcome in patients with colorectal cancer treated with oxaliplatin.

Abstract

542 Background: Oxaliplatin is a third generation platinum agent that confers tumoricidal effect by forming platinum-DNA adducts and is an integral part of the standard of care regimens for patients with colorectal cancer (CRC). Tissue resistance to oxaliplatin appears to be multifactorial, with the nucleotide excision repair (NER) pathway playing a major role. We have previously demonstrated that Excision Repair Cross-Complementing group-1 (ERCC1), can be induced in colorectal cell lines on exposure to Oxaliplatin and high levels confer resistance to apoptosis. We aim to further this knowledge by analyzing gene expression in vivo, using PBMC as a surrogate, to assess ERCC1 as a biomarker of sensitivity to Oxaliplatin therapy. Methods: Patients with CRC who received oxaliplatin were consented to blood (PBMC) sampling at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy. ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). Clinical benefit from oxaliplatin was determined using the parameters of relapse free survival (RFS) for limited stage and progression free survival (PFS) for mCRC. Results: Fifty-four patients were enrolled on study, 25 (46.3%) had mCRC. Twenty-four patients were included in final analysis based on clinical data. Thirteen (52%) had an increase in ERCC expression from baseline, while 11 (48%) showed no change or decrease. Median PFS was 190 and 237 days respectively (log-rank test HR 2.35, CI 1.005-5.479; p = 0.0182). In the 29 patients with limited stage disease, 19 (65.5%) had an induction of ERCC. However, in these patients change in expression did not correlate with RFS. We did not find any significant correlation of PFS with baseline expression of ERCC1 in either group. Conclusions: We confirm our hypothesis that the ERCC1 gene is induced in vivo in a sub-population of patients on treatment with Oxaliplatin. This induction can serve as a potential marker of resistance to oxaliplatin based chemotherapy in mCRC as evidenced by the significant difference in PFS. Further analyses of the influence of ERCC1 polymorphisms on outcomes is underway.