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

Aziz Zaanan, Qian D Shi, Julien Taieb, Steven Robert Alberts, Jeffrey P. Meyers, Thomas Christopher Smyrk, Catherine Julie, Ayman Zawadi, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Jean Luc Van Laethem, Karine Le Malicot, Daniel J. Sargent, Pierre Laurent-Puig, Frank A Sinicrope

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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.

Original languageEnglish (US)
Pages (from-to)379-383
Number of pages5
JournalJAMA oncology
Volume4
Issue number3
DOIs
StatePublished - Mar 1 2018

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oxaliplatin
DNA Repair-Deficiency Disorders
DNA Mismatch Repair
Leucovorin
Adjuvant Chemotherapy
Fluorouracil
Colonic Neoplasms
Randomized Controlled Trials
Disease-Free Survival
Institutional Practice
Phenotype
Neoplasms
Phase III Clinical Trials
Private Practice
Proportional Hazards Models

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Zaanan, Aziz; Shi, Qian D; Taieb, Julien; Alberts, Steven Robert; Meyers, Jeffrey P.; Smyrk, Thomas Christopher; Julie, Catherine; Zawadi, Ayman; Tabernero, Josep; Mini, Enrico; Goldberg, Richard M.; Folprecht, Gunnar; Van Laethem, Jean Luc; Le Malicot, Karine; Sargent, Daniel J.; Laurent-Puig, Pierre; Sinicrope, Frank A.

In: JAMA oncology, Vol. 4, No. 3, 01.03.2018, p. 379-383.

Research output: Contribution to journalArticle

Zaanan, A, Shi, QD, Taieb, J, Alberts, SR, Meyers, JP, Smyrk, TC, Julie, C, Zawadi, A, Tabernero, J, Mini, E, Goldberg, RM, Folprecht, G, Van Laethem, JL, Le Malicot, K, Sargent, DJ, Laurent-Puig, P & Sinicrope, FA 2018, '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', JAMA oncology, vol. 4, no. 3, pp. 379-383. https://doi.org/10.1001/jamaoncol.2017.2899
Zaanan, Aziz ; Shi, Qian D ; Taieb, Julien ; Alberts, Steven Robert ; Meyers, Jeffrey P. ; Smyrk, Thomas Christopher ; Julie, Catherine ; Zawadi, Ayman ; Tabernero, Josep ; Mini, Enrico ; Goldberg, Richard M. ; Folprecht, Gunnar ; Van Laethem, Jean Luc ; Le Malicot, Karine ; Sargent, Daniel J. ; Laurent-Puig, Pierre ; Sinicrope, Frank A. / 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. In: JAMA oncology. 2018 ; Vol. 4, No. 3. pp. 379-383.
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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.",
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T1 - 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

AU - Zaanan, Aziz

AU - Shi, Qian D

AU - Taieb, Julien

AU - Alberts, Steven Robert

AU - Meyers, Jeffrey P.

AU - Smyrk, Thomas Christopher

AU - Julie, Catherine

AU - Zawadi, Ayman

AU - Tabernero, Josep

AU - Mini, Enrico

AU - Goldberg, Richard M.

AU - Folprecht, Gunnar

AU - Van Laethem, Jean Luc

AU - Le Malicot, Karine

AU - Sargent, Daniel J.

AU - Laurent-Puig, Pierre

AU - Sinicrope, Frank A

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

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