Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer

// Linda J.W. Bosch 1, 2 , Geert Trooskens 3, * , Petur Snaebjornsson 1, 2, * , Veerle M.H. Coupé 4 , Sandra Mongera 1 , Josien C. Haan 1 , Susan D. Richman 5 , Miriam Koopman 6 , Jolien Tol 7 , Tim de Meyer 3 , Joost Louwagie 8 , Luc Dehaspe 8, 9 , Nicole C.T. van Grieken 1 , Bauke Ylstra 1 , Henk M.W. Verheul 10 , Manon van Engeland 11 , Iris D. Nagtegaal 12 , James G. Herman 13 , Philip Quirke 5 , Matthew T. Seymour 14 , Cornelis J.A. Punt 15 , Wim van Criekinge 1, 2, 3, 8 , Beatriz Carvalho 1, 2 and Gerrit A. Meijer 1, 2 1 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3 Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium 4 Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands 5 Pathology and Tumour Biology, University of Leeds, Leeds, UK 6 Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands 7 Department of Internal Medicine, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands 8 MDxHealth, SA, Liège, Belgium 9 Genomics Core Facility, UZ Leuven, Leuven, Belgium 10 Department of Oncology, VU University Medical Center, Amsterdam, The Netherlands 11 Department of Pathology, GROW - School for Oncology and Developmental Biology and Maastricht University Medical Center, Maastricht, The Netherlands 12 Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands 13 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA 14 St James’s Institute of Oncology, St James’s University Hospital, Leeds, UK 15 Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands * These authors have contributed equally to this Work Correspondence to: Gerrit A. Meijer, email: g.meijer@nki.nl Keywords: TNFRSF10C, biomarker, predictive, chemotherapy, CAIRO Received: January 04, 2017 Accepted: May 23, 2017 Published: June 27, 2017 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.