DCR1 promoter hypermethylation and response to irinotecan in metastatic colorectal cancer

Diversity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. 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. The discovery and initial validation set consisted of primary tumors of 185 and 166 metastatic CRC patients, respectively, from the phase III CAIRO trial. An external validation set consisted of 467 primary tumors from the phase III FOCUS study. Methylation status in tumor tissue was correlated to progression free survival (PFS) by first-line treatment regimen, containing either single-agent fluorouracil (i.e. CAP in CAIRO or 5FU in FOCUS) or combination chemotherapy (i.e. CAP or 5FU plus irinotecan (CAPIRI in CAIRO / FOLFIRI in FOCUS)). In the discovery and initial validation set, patients with methylated DCR1 tumors did not significantly benefit from CAPIRI treatment over CAP treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 tumors did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results, however, could not be validated in the external data set, where a similar effect size was found in patients with methylated and unmethylated DCR1 (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). DCR1 promoter methylation was identified and initially validated as a potential negative predictive biomarker for response to irinotecan-based therapy, but external validation could not validate these findings. These results underline the importance of extensive clinical evaluation of candidate biomarkers. 6 DCR1 methylation and response to irinotecan in CRC | 109