Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in non-metastatic colon cancer (CC) patients. We studied this phenotype in stage III CC characterized for mismatch repair (MMR), RAS and BRAF status and treated with adjuvant FOLFOX-based regimen. Experimental Design: Tumor samples of 1907 patients enrolled in the PETACC-8 adjuvant phase 3 trial were analyzed. 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 recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 ± cetuximab). Results: CIMP status was successfully determined in 1867 patients (97.9%): 275 (14.7%) tumors were CIMP+. Compared to 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%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 non-significant 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 stage III CC patients, CIMP+ phenotype is associated with a shorter OS and SAR but not to DFS.
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