Abstract
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 Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine 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 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 could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (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)).In conclusion, DCR1 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.
Highlights
RESULTSThe outcome of patients with colorectal cancer (CRC) strongly depends on tumor stage at time of diagnosis
We tested for correlation of the methylation status of the candidate genes and progression free survival (PFS) after treatment with capecitabine plus irinotecan (CAPIRI) therapy of metastatic CRC patients participating to the phase III CAIRO trial [12], which identified Decoy Receptor 1 (DCR1) as a candidate marker
Because patients treated with CAP alone were used as a control group, this analysis showed DCR1 methylation as a potential negative predictive marker for response to irinotecan-based therapy
Summary
RESULTSThe outcome of patients with colorectal cancer (CRC) strongly depends on tumor stage at time of diagnosis. When unresectable distant metastases develop, palliative systemic therapy is the only treatment option available to these patients. The backbone of this is a fluoropyrimidine, e.g. capecitabine (CAP) or 5-fluorouracil (5-FU) in combination with either oxaliplatin or irinotecan [2]. Addition of targeted agents directed against vascular epithelial growth factor (VEGF) (bevacizumab) or epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) has been demonstrated to give additional outcome benefit.[3] Only a subset of patients benefit from these regimens, while those patients that do not, may still suffer from considerable toxicity. With the exception of KRAS/NRAS mutation status that predicts resistance to EGFR-targeted therapy [4, 5], no other biomarkers exist that adequately predict treatment response in metastatic CRC. Predictive biomarkers are urgently needed to identify the subset of patients who will benefit from a specific treatment
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