( promoter hypermethylation and response to irinotecan in metastatic colorectal cancer.

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated ( did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, =0.6), validation set: HR=0.9 (95%CI 0.6-1.4, =0.5)), whereas patients with unmethylated did (discovery set: HR=0.4 (95%CI 0.3-0.6, =0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, =0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated for FOLFIRI over 5FU treatment (methylated : HR=0.7 (95%CI 0.5-0.9, =0.01), unmethylated : HR=0.8 (95%CI 0.6-1.2, =0.4)). In conclusion, promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials.