There are conflicting results concerning the prognostic value of the methylator phenotype (CIMP+ for “CpG island methylator phenotype”) in non-metastatic colon cancer (CC) patients (pts). We studied this phenotype in stage III CC pts having undergone R0 resection, characterized for MSI, RAS and BRAF mutation status and treated with adjuvant FOLFOX-based treatment.
Tumor samples of 1910 pts enrolled in the PETACC-8 adjuvant phase 3 trial were analysed. The method used was methylation-specific PCR where CIMP+ status was defined by methylation of at least three of the five following genes: IGF2, CACNA1G, NEUROG1, SOCS1 and RUNX3. Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after relapse (SAR) was assessed by Cox model and adjusted for prognostic factors (including MSI, BRAF and RAS mutation status) and treatment arm (FOLFOX or FOLFOX plus cetuximab). CIMP status was analyzed according to treatment efficacy.
Determination of CIMP status was successful in 1870 pts (98%): 275 (14.7%) tumors were classified CIMP+. Compared to CIMP- pts, CIMP+ pts were significantly older (p = 0.002), with more frequently women (p = 0.04). CIMP+ tumors were more frequently right-sided (p
In a large clinically and molecularly well defined stage III CC population treated with standard adjuvant therapy, methylator phenotype is a prognostic biomarker for OS and SAR. However, no impact of CIMP status on DFS was observed. Finally, we did not find any predictive value of the CIMP status for the efficacy of FOLFOX versus FOLFOX plus cetuximab.
Clinical trial identification
PETACC8 Trial (EuDRACT number: 2005-003463-23)
Legal entity responsible for the study
J. Taieb: Consulting or/and advisory boards: Merck KGaA, Sanofi, Roche Genentech, Pfizer, Amgen. J. Tabernero: Consulting or/and advisory boards: Amgen, ImClone Systems, Lilly, Millennium, Novartis, Roche/Genentech, Sanofi, Celgene, Chugai Pharma, Taiho Pharmaceutical, Boehringer Ingelheim, Merck KGaA. J-F. Seitz: Grants for consultancy: Celgene, Lilly, Merck, Novartis Oncology, Pfizer, Sanofi, Roche; grants: Roche; payments for development of educational presentations: Amgen, Lilly; travel grants: Ipsen Pharma, Merck. T. Aparicio: Personal grants consultancy: Pierre Fabre; grants: Roche, Amgen; payments for development of educational presentations: Novartis Oncology, Pfizer, Sanofi, Roche; travel grants: Ipsen Pharma, Novartis Oncology, Sanofi, Roche. G. Folprecht: Consulting or/and advisory boards: Merck KGaA, Roche/Genentech, Sanofi-Aventis, Bayer, Lilly, Servier, BMS. C. Lepage: Personal grants for board membership: AAA; grants: Novartis; travel grants: Ipsen Pharma, Amgen, Bayer. J.F. Emile: Honoraria: Amgen, Merck KGaA. P. Laurent-Puig: Consulting or/and advisory boards: Sanofi, Merck KGaA, Amgen, Roche, Genomic Health, Myriad Genetics, Pfizer. All other authors have declared no conflicts of interest.