Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803

Shuji Ogino*, Kaori Shima, Jeffrey A. Meyerhardt, Nadine J. McCleary, Kimmie Ng, Donna Hollis, Leonard B. Saltz, Robert J. Mayer, Paul Schaefer, Renaud Whittom, Alexander Hantel, Al B. Benson, Donna Spiegelman, Richard M. Goldberg, Monica M. Bertagnolli, Charles S. Fuchs

*Corresponding author for this work

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAFmutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR=0.52;95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). Conclusions: BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

Original languageEnglish (US)
Pages (from-to)890-900
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2012

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Microsatellite Instability
Colonic Neoplasms
irinotecan
Mutation
Leucovorin
Fluorouracil
Neoplasms
Adjuvant Chemotherapy
Microsatellite Repeats
Survival
Mitogen-Activated Protein Kinase Kinases
Proportional Hazards Models
Colorectal Neoplasms
Carcinogenesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ogino, Shuji ; Shima, Kaori ; Meyerhardt, Jeffrey A. ; McCleary, Nadine J. ; Ng, Kimmie ; Hollis, Donna ; Saltz, Leonard B. ; Mayer, Robert J. ; Schaefer, Paul ; Whittom, Renaud ; Hantel, Alexander ; Benson, Al B. ; Spiegelman, Donna ; Goldberg, Richard M. ; Bertagnolli, Monica M. ; Fuchs, Charles S. / Predictive and prognostic roles of BRAF mutation in stage III colon cancer : Results from intergroup trial CALGB 89803. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 3. pp. 890-900.
@article{a6a60f9a63de4ac0bb1895ae74fbddad,
title = "Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803",
abstract = "Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95{\%} CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAFmutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR=0.52;95{\%} CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95{\%} CI: 0.72-1.46). Conclusions: BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.",
author = "Shuji Ogino and Kaori Shima and Meyerhardt, {Jeffrey A.} and McCleary, {Nadine J.} and Kimmie Ng and Donna Hollis and Saltz, {Leonard B.} and Mayer, {Robert J.} and Paul Schaefer and Renaud Whittom and Alexander Hantel and Benson, {Al B.} and Donna Spiegelman and Goldberg, {Richard M.} and Bertagnolli, {Monica M.} and Fuchs, {Charles S.}",
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Ogino, S, Shima, K, Meyerhardt, JA, McCleary, NJ, Ng, K, Hollis, D, Saltz, LB, Mayer, RJ, Schaefer, P, Whittom, R, Hantel, A, Benson, AB, Spiegelman, D, Goldberg, RM, Bertagnolli, MM & Fuchs, CS 2012, 'Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803', Clinical Cancer Research, vol. 18, no. 3, pp. 890-900. https://doi.org/10.1158/1078-0432.CCR-11-2246

Predictive and prognostic roles of BRAF mutation in stage III colon cancer : Results from intergroup trial CALGB 89803. / Ogino, Shuji; Shima, Kaori; Meyerhardt, Jeffrey A.; McCleary, Nadine J.; Ng, Kimmie; Hollis, Donna; Saltz, Leonard B.; Mayer, Robert J.; Schaefer, Paul; Whittom, Renaud; Hantel, Alexander; Benson, Al B.; Spiegelman, Donna; Goldberg, Richard M.; Bertagnolli, Monica M.; Fuchs, Charles S.

In: Clinical Cancer Research, Vol. 18, No. 3, 01.02.2012, p. 890-900.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Predictive and prognostic roles of BRAF mutation in stage III colon cancer

T2 - Results from intergroup trial CALGB 89803

AU - Ogino, Shuji

AU - Shima, Kaori

AU - Meyerhardt, Jeffrey A.

AU - McCleary, Nadine J.

AU - Ng, Kimmie

AU - Hollis, Donna

AU - Saltz, Leonard B.

AU - Mayer, Robert J.

AU - Schaefer, Paul

AU - Whittom, Renaud

AU - Hantel, Alexander

AU - Benson, Al B.

AU - Spiegelman, Donna

AU - Goldberg, Richard M.

AU - Bertagnolli, Monica M.

AU - Fuchs, Charles S.

PY - 2012/2/1

Y1 - 2012/2/1

N2 - Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAFmutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR=0.52;95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). Conclusions: BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

AB - Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAFmutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR=0.52;95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). Conclusions: BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

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U2 - 10.1158/1078-0432.CCR-11-2246

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