Background: The prognostic impact of deficient (d) MMR, including sporadic and familial types, in stage III colon cancer pts receiving standard adjuvant FOLFOX therapy remains unknown. We examined the association of MMR status with clinical outcome in two phase III clinical trials of adjuvant FOLFOX +/- cetuximab. Methods: Prospectively collected tumors from both studies were separately analyzed for MMR protein (MLH1, MSH2, MSH6) expression and mutations in BRAF (V600E). Loss of any MMR protein indicated dMMR. Methylation of the MLH1 gene promoter was studied in tumors with loss of MLH1 and wild-type (WT) BRAF. Associations of MMR status with time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) were analyzed using a stratified Cox proportional hazards model. Multivariate models were adjusted for treatment and covariates (age, sex, tumor grade, T/N stage, tumor location, ECOG PS, BRAF/KRAS). Results: The frequency of dMMR in the overall cohort was 10.7% (499/ 4674). 3-year (yr) DFS for dMMR vs proficient (p) MMR pts was 75% vs 74% (HR = 0.87; 95% CI, 0.71-1.07; padustedj = .196). Among pts with complete biomarker data (N = 4339), there were 405 dMMR tumors of which 265 (65.4%) were categorized as sporadic (BRAF mutation or WT with MLH1 methylation) and 140 (34.6%) as familial (BRAF WT and unmethylated MLH1 or loss of MSH2 or MSH6). DFS rates of pts with sporadic and familial dMMR tumors were similar (HR, 1.15; 95% CI, 0.73-1.81; padjusted = .54). Pts with dMMR tumors had similar DFS rates as did pts with pMMR tumors without BRAF or KRAS mutations (Table). Consistent results were found for biomarkers and TTR and OS. Conclusions: In this large cohort of stage III colon cancer pts enrolled in two adjuvant trials testing FOLFOX +/- cetuximab, MMR status was not prognostic. Similar outcomes were found for sporadic and familial dMMR cases, and when each of these dMMR subtypes was compared to pMMR tumors WT for both BRAF and KRAS genes. Clinical trial information: NCT00079274.
Analysis of DNA mismatch repair (MMR) and clinical outcome in stage III colon cancers from patients (pts) treated with adjuvant FOLFOX +/- cetuximab in the PETACC8 and NCCTG N0147 adjuvant trials / Zaanan, Aziz; Shi, Qian; Taieb, Julien; Alberts, Steven R.; Smyrk, Thomas C.; Julie, Catherine; Zawadi, Ayman; Tabernero, Josep; Mini, Enrico; Goldberg, Richard M.; Folprecht, Gunnar; Van Laethem, Jean L.; Le Malicot, Karine; Sargent, Daniel J.; Laurent-Puig, Pierre; Sinicrope, Frank A.. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 0732-183X. - ELETTRONICO. - 33:(2015), pp. 3506-3506. [10.1200/jco.2015.33.15_suppl.3506]
Analysis of DNA mismatch repair (MMR) and clinical outcome in stage III colon cancers from patients (pts) treated with adjuvant FOLFOX +/- cetuximab in the PETACC8 and NCCTG N0147 adjuvant trials
Mini, Enrico;
2015
Abstract
Background: The prognostic impact of deficient (d) MMR, including sporadic and familial types, in stage III colon cancer pts receiving standard adjuvant FOLFOX therapy remains unknown. We examined the association of MMR status with clinical outcome in two phase III clinical trials of adjuvant FOLFOX +/- cetuximab. Methods: Prospectively collected tumors from both studies were separately analyzed for MMR protein (MLH1, MSH2, MSH6) expression and mutations in BRAF (V600E). Loss of any MMR protein indicated dMMR. Methylation of the MLH1 gene promoter was studied in tumors with loss of MLH1 and wild-type (WT) BRAF. Associations of MMR status with time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) were analyzed using a stratified Cox proportional hazards model. Multivariate models were adjusted for treatment and covariates (age, sex, tumor grade, T/N stage, tumor location, ECOG PS, BRAF/KRAS). Results: The frequency of dMMR in the overall cohort was 10.7% (499/ 4674). 3-year (yr) DFS for dMMR vs proficient (p) MMR pts was 75% vs 74% (HR = 0.87; 95% CI, 0.71-1.07; padustedj = .196). Among pts with complete biomarker data (N = 4339), there were 405 dMMR tumors of which 265 (65.4%) were categorized as sporadic (BRAF mutation or WT with MLH1 methylation) and 140 (34.6%) as familial (BRAF WT and unmethylated MLH1 or loss of MSH2 or MSH6). DFS rates of pts with sporadic and familial dMMR tumors were similar (HR, 1.15; 95% CI, 0.73-1.81; padjusted = .54). Pts with dMMR tumors had similar DFS rates as did pts with pMMR tumors without BRAF or KRAS mutations (Table). Consistent results were found for biomarkers and TTR and OS. Conclusions: In this large cohort of stage III colon cancer pts enrolled in two adjuvant trials testing FOLFOX +/- cetuximab, MMR status was not prognostic. Similar outcomes were found for sporadic and familial dMMR cases, and when each of these dMMR subtypes was compared to pMMR tumors WT for both BRAF and KRAS genes. Clinical trial information: NCT00079274.
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