592 Background: The CpG island methylator phenotype (CIMP) has previously been shown to be a predictive biomarker for 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL) adjuvant chemotherapy in stage III colon cancer patients. It is unknown if CIMP serves as a biomarker for standard-of-care oxaliplatin-based adjuvant therapy. Methods: HE6C05 randomized 441 patients with stage II/III colorectal adenocarcinoma to adjuvant oxaliplatin with either capecitabine (XELOX) or 5-FU/LV (mFOLFOX6) between November 2005 and January 2008. The primary objective was disease-free survival (DFS); overall survival (OS) was a secondary objective. The study closed early due to poor accrual with last follow-up in November 2013. Isolated DNA from 293 tumor samples was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. Cox univariate and multivariate models were used to assess the effects of CIMP on DFS and OS, accounting for interactions with TNM stage; site (right vs. left); KRAS, BRAF, and mismatch repair (MMR) status; tumor T-cell ratio (CD3/CD8); and treatment arm. Results: Of the tumor samples available for CIMP analysis, 28 (9.6%) were CIMP-positive. The CIMP-positive tumors were more likely to be right-sided and have BRAF mutations (chi-square, p<0.001). In the univariate analysis, no significant differences in DFS or OS were observed between individuals with CIMP-positive vs. negative tumors (OS hazard ratio 1.27, Wald’s p=0.55). In addition, CIMP had no predictive value for response to the treatments administered in the two arms of the trial (XELOX vs. mFOLFOX6). In the multivariate model, only TNM stage and primary site were associated with survival outcome (Wald’s p=0.0002 and p=0.006, respectively); CIMP did not improve treatment response prediction. Conclusions: In this exploratory analysis, unlike what we have seen with IFL, CIMP does not appear to serve as a predictive biomarker for treatment response to oxaliplatin-based therapy. CIMP analysis in an irinotecan vs. oxaliplatin trial may offer additional insight.
Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer