Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer

Julien Taieb, Karine Le Malicot, Qian D Shi, Frédérique Penault Lorca, Olivier Bouché, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Jean Luc Van Laethem, Daniel J. Sargent, Steven Robert Alberts, Jean Francois Emile, Pierre Laurent Puig, Frank A Sinicrope

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Abstract

Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P <. 001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P <. 001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02, 95% CI = 2.32 to 3.93, P <. 001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P <. 001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P <. 001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients. Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

Original languageEnglish (US)
Article numberdjw272
JournalJournal of the National Cancer Institute
Volume109
Issue number5
DOIs
StatePublished - May 1 2017

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Microsatellite Repeats
Colonic Neoplasms
Mutation
Confidence Intervals
Recurrence
Survival
Neoplasms
DNA Mismatch Repair
Therapeutics
Codon
Colon
Clinical Trials
Carcinoma

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer. / Taieb, Julien; Le Malicot, Karine; Shi, Qian D; Lorca, Frédérique Penault; Bouché, Olivier; Tabernero, Josep; Mini, Enrico; Goldberg, Richard M.; Folprecht, Gunnar; Van Laethem, Jean Luc; Sargent, Daniel J.; Alberts, Steven Robert; Emile, Jean Francois; Puig, Pierre Laurent; Sinicrope, Frank A.

In: Journal of the National Cancer Institute, Vol. 109, No. 5, djw272, 01.05.2017.

Research output: Contribution to journalArticle

Taieb, J, Le Malicot, K, Shi, QD, Lorca, FP, Bouché, O, Tabernero, J, Mini, E, Goldberg, RM, Folprecht, G, Van Laethem, JL, Sargent, DJ, Alberts, SR, Emile, JF, Puig, PL & Sinicrope, FA 2017, 'Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer', Journal of the National Cancer Institute, vol. 109, no. 5, djw272. https://doi.org/10.1093/jnci/djw272
Taieb, Julien ; Le Malicot, Karine ; Shi, Qian D ; Lorca, Frédérique Penault ; Bouché, Olivier ; Tabernero, Josep ; Mini, Enrico ; Goldberg, Richard M. ; Folprecht, Gunnar ; Van Laethem, Jean Luc ; Sargent, Daniel J. ; Alberts, Steven Robert ; Emile, Jean Francois ; Puig, Pierre Laurent ; Sinicrope, Frank A. / Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer. In: Journal of the National Cancer Institute. 2017 ; Vol. 109, No. 5.
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title = "Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer",
abstract = "Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95{\%} confidence interval [CI] = 1.23 to 1.92, P <. 001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95{\%} CI = 1.40 to 1.83, P <. 001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02, 95{\%} CI = 2.32 to 3.93, P <. 001, and HR = 1.20, 95{\%} CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95{\%} CI = 1.56 to 2.57, P <. 001) and KRAS-mutant patients (HR = 1.62, 95{\%} CI = 1.38 to 1.91, P <. 001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients. Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.",
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T1 - Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer

AU - Taieb, Julien

AU - Le Malicot, Karine

AU - Shi, Qian D

AU - Lorca, Frédérique Penault

AU - Bouché, Olivier

AU - Tabernero, Josep

AU - Mini, Enrico

AU - Goldberg, Richard M.

AU - Folprecht, Gunnar

AU - Van Laethem, Jean Luc

AU - Sargent, Daniel J.

AU - Alberts, Steven Robert

AU - Emile, Jean Francois

AU - Puig, Pierre Laurent

AU - Sinicrope, Frank A

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P <. 001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P <. 001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02, 95% CI = 2.32 to 3.93, P <. 001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P <. 001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P <. 001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients. Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

AB - Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials. Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors. Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P <. 001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P <. 001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02, 95% CI = 2.32 to 3.93, P <. 001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P <. 001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P <. 001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients. Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

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