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Multicenter Study
. 2023 Jun;34(6):543-552.
doi: 10.1016/j.annonc.2023.02.016. Epub 2023 Mar 14.

Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments

J Ros  1 , J Matito  2 , G Villacampa  3 , R Comas  2 , A Garcia  2 , G Martini  4 , I Baraibar  5 , N Saoudi  5 , F Salvà  5 , Á Martin  6 , M Antista  7 , R Toledo  2 , E Martinelli  4 , F Pietrantonio  7 , A Boccaccino  8 , C Cremolini  8 , R Dientsmann  2 , J Tabernero  5 , A Vivancos  2 , E Elez  9
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Free article
Multicenter Study

Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments

J Ros et al. Ann Oncol. 2023 Jun.
Free article

Erratum in

Abstract

Background: Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations.

Patients and methods: A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi-anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n= 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations.

Results: Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01).

Conclusions: Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF-V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies.

Keywords: BRAF inhibitor; BRAF-V600E mutation; MEK inhibitor; anti-EGFR; colorectal cancer; mutant allele fraction.

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Conflict of interest statement

Disclosure JR declares personal speaker honoraria from Sanofi and AMGEN, and accommodation expenses from Pierre-Fabre, Servier, Amgen, and Merck. GV declares personal speaker honoraria from Sanofi and AMGEN, and accommodation expenses from Pierre-Fabre, Servier, Amgen, and Merck. GM declares personal speaker honoraria from Servier. IB declares to have received honoraria from Sanofi; and to have received travel and accommodations expenses from Amgen, Sanofi, Merck, and Servier. NS declares to have received honoraria from Amgen. FS declares personal financial interests, honoraria for advisory role, travel grants, research grants (past 5 years): Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, Servier, Bristol-Myers Squibb. Institutional financial interests, honoraria due to investigator contribution in clinical trials from: Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune. RT holds a Miguel Servet-I research contract by Institute of Health Carlos III (ISCIII) of the Ministry of Economy [grant number CP17/00199] and Competitiveness from the Spanish government and is supported by an Olga Torres Foundation emerging researcher grant, by the Swiss Bridge Award, and received a research grant from Novartis, Astrazeneca, Beigene. EM has served as adviser and speaker for AstraZeneca, Amgen, Bayer, Merck-Serono, Roche, Sanofi, Servier, Pierre Fabre. FP reports personal fees from Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, MSD, and Lilly; grants and personal fees from AstraZeneca and BMS; and grants from Incyte. CC declares honoraria: Roche, Amgen, Bayer, Servier, MSD, Merck, Pierre Fabre, Organon; consulting or advisory role: Roche, Bayer, Amgen, MSD, Pierre Fabre, Nordic Pharma; speakers’ bureau: Servier, Merck, Pierre Fabre; research funding: Merck, Bayer, Roche, Servier. RD reports receiving honoraria for speaker activities from Roche, Ipsen, Amgen, Sanofi, Servier Laboratories, Merck and Sharp & Dohme; an advisory role at Roche and Boehringer Ingelheim; and research grants from Merck and Pierre Fabre. JT reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). AV declares to be stockholder of Reveal Genomics, consultants of Reveal Genomics, reports personal fees from Bayer, personal fees from Bristol Meyers Squibb, personal fees from Guardant Health, personal fees from Merck, personal fees from Novartis, personal fees from Roche, personal fees from Incyte, and has a patent O2015145388A3 licensed. EE has received personal speaker honoraria from Organon and Novartis; and personal advisory board honoraria from Amgen, Bayer, Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD, and Servier. Her institution has received research funding from Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc. She held/holds non-remunerated roles as Coordinator of the SEOM +MIR Section of Residents and Young Assistants of the Sociedad Española de Oncología Médica (SEOM), speaker of the ESMO Academy of the European Society for Medical Oncology (ESMO), and volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy of the American Society of Clinical Oncology (ASCO). All other authors have declared no conflicts of interest.

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