Background: 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. Methods: 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. Results: 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 < 0.0001)), with histopathology grade 3-4 (p < 0.0001), pN2 (p = 0.001), MSI (p < 10e-4), BRAF mutated (p < 0.0001) and RAS wild-type (p < 0.0001). In multivariate analysis, CIMP+ status was associated with shorter OS (HR: 1.4; 95% CI 1.02 – 1.9; p = 0.04) and SAR (HR: 1.8; 95% CI 1.2 – 2.6; p < 0.0004); but DFS was not significantly different between CIMP+ and CIMP– pts (HR: 1.1; 95% CI 0.8 1.5; p = 0.34). Theses results were independent of the treatment received. No benefit or detrimental effect of cetuximab was observed in CIMP+ patients for OS and DFS. Conclusions: 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)
Prognostic value of methylator phenotype in stage III colon cancer treated with oxaliplatin-based adjuvant chemotherapy / Gallois, C.; Taieb, J.; Le Corre, D.; Le Malicot, K.; Tabernero, J.; Mulot, C.; Seitz, J-F.; Aparicio, T.; Folprecht, G.; Lepage, C.; Mini, E.; Van Laethem, J-L.; Emile, J.F.; Laurent-Puig, P.. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - ELETTRONICO. - 28:(2017), pp. 161-161. [10.1093/annonc/mdx393.007]
Prognostic value of methylator phenotype in stage III colon cancer treated with oxaliplatin-based adjuvant chemotherapy
Mini, E.;
2017
Abstract
Background: 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. Methods: 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. Results: 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 < 0.0001)), with histopathology grade 3-4 (p < 0.0001), pN2 (p = 0.001), MSI (p < 10e-4), BRAF mutated (p < 0.0001) and RAS wild-type (p < 0.0001). In multivariate analysis, CIMP+ status was associated with shorter OS (HR: 1.4; 95% CI 1.02 – 1.9; p = 0.04) and SAR (HR: 1.8; 95% CI 1.2 – 2.6; p < 0.0004); but DFS was not significantly different between CIMP+ and CIMP– pts (HR: 1.1; 95% CI 0.8 1.5; p = 0.34). Theses results were independent of the treatment received. No benefit or detrimental effect of cetuximab was observed in CIMP+ patients for OS and DFS. Conclusions: 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)
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