Evaluating the utility of promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance).

While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of promoter hypermethylation (m) as a prognostic and predictive marker in colon cancer. We examined the association of m with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of m in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. m was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with m compared to unmethylated (unm). There was no significant difference in disease-free or overall survival between patients with m versus unm colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by methylation status. While promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of m as a prognostic and predictive marker.