Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials

Abstract

Importance: The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial.

Objective: To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX.

Design, setting, and participants: The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009.

Interventions: Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study.

Main outcomes and measures: Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status.

Results: Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03).

Conclusions and relevance: The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy.

Trial registration: clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Zaanan has participated in consulting and/or advisory boards for Roche, Merck Serono, Amgen, Sanofi and Lilly; Dr Taieb for Merck, Sanofi, Roche Genentech, Pfizer, and Amgen; Dr Julie for Roche and Merck Sereno; Mr Tabernero for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai Pharma, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho Pharmaceutical and Takeda; Mr Goldberg for Biothera, Sanofi and Merck; Dr Folprecht for Merck, Roche, Lilly, Bristol-Myers Squibb, Baxalta; Dr Sargent for Abbvie, Acerta Pharma, Ariad, Astellas Pharma, AstraZeneca, Biothera, Celldex, Exelixis, Genentech, Incyte, Kyowa Hakko Kirin, Medivation, Merck, Merrimack, Nektar, Novartis, Pharmacyclics, Pique, Spiration, Xbiotech, Celgene, Roche; Mr Laurent-Puig for Sanofi, Merck Serono, Amgen, Roche, Genomic Health, Myriad Genetics, and Pfizer; Dr Sinicrope for Illumina, Gilead, Ventana Medical Systems, EMD Serono, and Ventana Medical Systems. No other conflicts are reported.

Figures

Figure 1.. Participant Enrollment Flowchart

Included are participants in the NCCTG N0147 and PETACC8 phase 3 trials evaluating the impact of mismatch repair (MMR) phenotype in patients with stage III colon cancer treated with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy.

Figure 2.. Disease-Free Survival

Disease-free survival by MMR phenotype, deficient (dMMR) vs proficient (pMMR), in patients with stage III colon cancer treated with adjuvant FOLFOX (folinic acid, fluorouracil, and oxaliplatin). Survival curves and hazard ratio (HR) with 95% confidence intervals (CIs) are adjusted for age, sex, tumor grade, ECOG (Eastern Cooperative Oncology Group) performance status, pT/pN stage, primary tumor location, and BRAF V600E mutational status.