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

• Published in: Annals of oncology Vol. 34; no. 6; pp. 543 - 552
• Main Authors: Ros, J., Matito, J., Villacampa, G., Comas, R., Garcia, A., Martini, G., Baraibar, I., Saoudi, N., Salvà, F., Martin, Á., Antista, M., Toledo, R., Martinelli, E., Pietrantonio, F., Boccaccino, A., Cremolini, C., Dienstmann, R., Tabernero, J., Vivancos, A., Elez, E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2023
• Subjects: Alleles; anti-EGFR; BRAF inhibitor; BRAF-V600E mutation; Colonic Neoplasms - genetics; colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Humans; MEK inhibitor; mutant allele fraction; Mutation; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Rectal Neoplasms - genetics; anti-EGFR; BRAF-V600E mutation; BRAF inhibitor; mutant allele fraction; MEK inhibitor; colorectal cancer
• ISSN: 0923-7534; 1569-8041; 1569-8041
• DOI: 10.1016/j.annonc.2023.02.016

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.
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.
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).
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.
•Plasmatic BRAF AF has a prognostic role for survival in mCRC treated with BRAF inhibitors.•ddPCR, applied in a cohort including a real-world population, mirrored those of the BEACON clinical trial using next-generation sequencing (NGS).•ddPCR detects BRAF AF in circulating tumor DNA (ctDNA) with high reproducibility and sensitivity, offering a validated alternative to NGS.•Identifying prognostic factors in BRAF-mutant mCRC is crucial to stratify patients and guide treatment strategies.