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. 2023 Nov;34(11):1025-1034.
doi: 10.1016/j.annonc.2023.08.006. Epub 2023 Aug 23.

Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials

J Taieb  1 , F A Sinicrope  2 , L Pederson  3 , S Lonardi  4 , S R Alberts  2 , T J George  5 , G Yothers  6 , E Van Cutsem  7 , L Saltz  8 , S Ogino  9 , R Kerr  10 , T Yoshino  11 , R M Goldberg  12 , T André  13 , P Laurent-Puig  14 , Q Shi  3
Affiliations

Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials

J Taieb et al. Ann Oncol. 2023 Nov.

Abstract

Background: The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis.

Patients and methods: We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations.

Results: Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence.

Conclusions: Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

Keywords: BRAF(V600E) mutation; MSI/dMMR; RAS mutation; adjuvant; stage III colon cancer; survival after relapse; time to recurrence.

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Conflict of interest statement

DISCLOSURE

JT has received honoraria for speaker or advisory role from Astellas, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, BMS, Astra Zeneca, Novartis, Takeda, and MSD. FAS reports consulting/advisory funds from Guardant Health and Roche/Genentech; and patent-related royalties from Roche Diagnostics. QS reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics Inc; honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to self); and research funds from Celgene/BMS, Roche/Genentech, Janssen, and Novartis (to institution). RMG reports the receipt of consulting fees from AbbVie, Adaptimmune, Astra Zeneca, Bayer, Compass Therapeutics, Focal Medical, Haystack Oncology, Innovative Cellular Therapeutics, Inspirna, IQVIA, Merck, Sorrento, Taiho, and Takeda; also reports stock options from Compass Therapeutics, Haystack, and Focal Medical; and has served as a paid expert witness for Taiho and Genentech. TJG reports consulting/advisory role from Pfizer/Array, Tempus Labs, and BillionToOne. TA reports honoraria from Amgen, Aptitude Health, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pierre Fabre, Roche/Vantana, Sanofi, and Servier; consulting or advisory roles for Astellas Pharma, Bristol-Myers Squibb, GamaMabs Pharma, Gilead, GlaxoSmithKline, Gritstone Oncology, Merck Sharp & Dohme, Seagen, and Servier; participating in Transgene Speaker’s Bureaus for Bristol-Myers Squibb, Merck Sharp & Dohme, Seagen, and Servier; research funding from Bristol-Myers Squibb and Merck Sharp & Dohme; travel and accommodation expenses covered by Merck Sharp & Dohme and Bristol-Myers Squibb; and nonremunerated activities for the ARCAD Foundation and GERCOR Group. SRA serves as a member of several data monitoring committees for Merck. LS reports consulting role for Genor Biopharma, Ltd. PLP has received honoraria for speaker or advisory role from Sanofi, Merck Serono, Amgen, Servier, Pierre Fabre, and Biocartis; is also the founder of METHYS Dx. SL reports research funding (to institution) from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, and Bristol Myers Squibb; personal honoraria as an invited speaker from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, and Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, and Merck Sharp & Dohme. TY reports honoraria from Bayer, Chugai, Merck Biopharma, MSD, Ono, and Takeda; consulting role from Sumitomo Corp.; research grants from Taiho, Ono, Chugai, Amgen, MSD, Daiichi-Sankyo, Eisai, FALCO Biosystems, Genomedia, Molecular Health, Nippon Boehringer Ingelheim, Pfizer, Roche Diagnostics, Sysmex, and Sanofi. All other authors have declared no conflicts of interest.

Figures

Figure 1.
Figure 1.. Study flowchart.
BRAF MT, mutant for BRAFV600E; KRAS MT, mutant for KRAS exon 2; MSI, microsatellite instability; MSS, microsatellite stable; WT, wild type.
Figure 2.
Figure 2.. The Kaplan—Meier curve for time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) for (A, C, and E) the microsatellite-stable (MSS) population and (B, D, and F) the microsatellite unstable (MSI-high) population by mutational status.
CI, confidence interval; dMMR, deficient mismatch repair; HR, hazard ratio; MT, mutated; WT, wild type.
Figure 3.
Figure 3.. Forest plot for (A) time to recurrence (TTR), (B) overall survival (OS), and (C) survival after recurrence (SAR) for the microsatellite-stable (MSS) population depending on mutations. Kaplan Meier curves for (D) time to recurrence (TTR), (E) overall survival (OS), and (F) SUrvival after recurrence (SAR) for the micro-satellite stable (MSS) population depending on mutations.
HRs and 95% CIs were calculated using the adjusted Cox proportional hazard model. Solid circles represent HR, whereas open-ended horizontal lines represent the 95% CIs. CI, confidence interval; HR, hazard ratio; MT, mutated; WT, wild type.
Figure 3.
Figure 3.. Forest plot for (A) time to recurrence (TTR), (B) overall survival (OS), and (C) survival after recurrence (SAR) for the microsatellite-stable (MSS) population depending on mutations. Kaplan Meier curves for (D) time to recurrence (TTR), (E) overall survival (OS), and (F) SUrvival after recurrence (SAR) for the micro-satellite stable (MSS) population depending on mutations.
HRs and 95% CIs were calculated using the adjusted Cox proportional hazard model. Solid circles represent HR, whereas open-ended horizontal lines represent the 95% CIs. CI, confidence interval; HR, hazard ratio; MT, mutated; WT, wild type.
See this image and copyright information in PMC

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