KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance)

Harry H Yoon, David Tougeron, Qian D Shi, Steven Robert Alberts, Michelle R. Mahoney, Garth D. Nelson, Suresh G. Nair, Stephen N Thibodeau, Richard M. Goldberg, Daniel J. Sargent, Frank A Sinicrope

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Abstract

Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52;95% confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/ BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting.

Original languageEnglish (US)
Pages (from-to)3033-3043
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2014

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Adjuvant Chemotherapy
Codon
Colonic Neoplasms
Disease-Free Survival
Mutation
Neoplasms
DNA Mismatch Repair
Proportional Hazards Models
Colon
Adenocarcinoma
Research Design
Confidence Intervals
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). / Yoon, Harry H; Tougeron, David; Shi, Qian D; Alberts, Steven Robert; Mahoney, Michelle R.; Nelson, Garth D.; Nair, Suresh G.; Thibodeau, Stephen N; Goldberg, Richard M.; Sargent, Daniel J.; Sinicrope, Frank A.

In: Clinical Cancer Research, Vol. 20, No. 11, 01.06.2014, p. 3033-3043.

Research output: Contribution to journalArticle

@article{be604f1fdaba4fbe92e53f27bd311d5f,
title = "KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance)",
abstract = "Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52;95{\%} confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95{\%} CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/ BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting.",
author = "Yoon, {Harry H} and David Tougeron and Shi, {Qian D} and Alberts, {Steven Robert} and Mahoney, {Michelle R.} and Nelson, {Garth D.} and Nair, {Suresh G.} and Thibodeau, {Stephen N} and Goldberg, {Richard M.} and Sargent, {Daniel J.} and Sinicrope, {Frank A}",
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T1 - KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance)

AU - Yoon, Harry H

AU - Tougeron, David

AU - Shi, Qian D

AU - Alberts, Steven Robert

AU - Mahoney, Michelle R.

AU - Nelson, Garth D.

AU - Nair, Suresh G.

AU - Thibodeau, Stephen N

AU - Goldberg, Richard M.

AU - Sargent, Daniel J.

AU - Sinicrope, Frank A

PY - 2014/6/1

Y1 - 2014/6/1

N2 - Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52;95% confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/ BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting.

AB - Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52;95% confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/ BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting.

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DO - 10.1158/1078-0432.CCR-13-3140

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JF - Clinical Cancer Research

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