Prognostic Value of Methylator Phenotype in Stage III Colon Cancer Treated with Oxaliplatin-based Adjuvant Chemotherapy.

Abstract

Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen.Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3 Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 ± cetuximab).Results: CIMP status was successfully determined in 1,867 patients (97.9%): 275 (14.7%) tumors were CIMP+ Compared with CIMP- patients, CIMP+ patients were more frequently older (P = 0.002), females (P = 0.04), with right-sided (P < 0.0001), grade 3-4 (P < 0.0001), pN2 (P = 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMP+ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02-1.94; P = 0.04] and SAR [HR, 1.76; 95% CI, 1.20-2.56; P < 0.0004]; but not DFS [HR, 1.15; 95% CI, 0.86-1.54; P = 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMP+ tumors for OS, DFS, and SAR.Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMP+ phenotype is associated with a shorter OS and SAR but not to DFS. Clin Cancer Res; 24(19); 4745-53. ©2018 AACR.

• Authors: Claire Gallois, Julien Taieb, Delphine Le Corre, Karine Le Malicot, Josep Tabernero, Claire Mulot, Jean-François Seitz, Thomas Aparicio, Gunnar Folprecht, Côme Lepage, Enrico Mini, Jean-Luc Van Laethem, Jean-François Emile, Pierre Laurent-Puig, PETACC8 investigators
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 19 Pg. 4745-4753 (10 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29921730 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Organoplatinum Compounds
• Oxaliplatin
• Leucovorin
• Fluorouracil

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Chemotherapy, Adjuvant (adverse effects)
• Colonic Neoplasms (drug therapy, genetics, pathology)
• CpG Islands (drug effects)
• DNA Methylation (drug effects, genetics)
• DNA Mismatch Repair (genetics)
• Disease-Free Survival
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Humans
• Kaplan-Meier Estimate
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Mutation
• Neoplasm Recurrence, Local (drug therapy, genetics, pathology)
• Neoplasm Staging
• Organoplatinum Compounds (administration & dosage, adverse effects)
• Oxaliplatin (administration & dosage, adverse effects)
• Phenotype
• Prognosis