TY - JOUR
T1 - Prognostic value of methylator phenotype in stage III colon cancer treated with oxaliplatin-based adjuvant chemotherapy
AU - Gallois, Claire
AU - Taieb, Julien
AU - Le Corre, Delphine
AU - Le Malicot, Karine
AU - Tabernero, Josep
AU - Mulot, Claire
AU - Seitz, Jean François
AU - Aparicio, Thomas
AU - Folprecht, Gunnar
AU - Lepage, Côme
AU - Mini, Enrico
AU - Van Laethem, Jean Luc
AU - Emile, Jean François
AU - Laurent-Puig, Pierre
PY - 2018/10/1
Y1 - 2018/10/1
N2 - © 2018 American Association for Cancer Research. 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 CIMPþ 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 CIMPþ. Compared with CIMP patients, CIMPþ patients were more frequently older (P ¼ 0.002), females (P ¼ 0.04), with right-sided (P < 0.0001), grade 3-4 (P < 0.0001), pN2 (P ¼ 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMPþ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02-1.94; P ¼ 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 ¼ 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMPþ tumors for OS, DFS, and SAR. Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMPþ phenotype is associated with a shorter OS and SAR but not to DFS.
AB - © 2018 American Association for Cancer Research. 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 CIMPþ 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 CIMPþ. Compared with CIMP patients, CIMPþ patients were more frequently older (P ¼ 0.002), females (P ¼ 0.04), with right-sided (P < 0.0001), grade 3-4 (P < 0.0001), pN2 (P ¼ 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMPþ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02-1.94; P ¼ 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 ¼ 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMPþ tumors for OS, DFS, and SAR. Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMPþ phenotype is associated with a shorter OS and SAR but not to DFS.
U2 - 10.1158/1078-0432.CCR-18-0866
DO - 10.1158/1078-0432.CCR-18-0866
M3 - Article
C2 - 29921730
VL - 24
SP - 4745
EP - 4753
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
ER -