Journal Article

Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study

Kahl, Christoph, Karthaus, Meinolf, Pihusch, Rudolf, Stintzing, Sebastian, Kaiser, Florian, Heinrich, Kathrin, Heinemann, Volker, Schroers, Roland, Modest, Dominik P., Held, Swantje, Müller, Christian, Klein‐Scory, Susanne, Stauch, Martina, Schmiegel, Wolff, Burkart, Christof, Mika, Thomas, Schwaner, Ingo, Baraniskin, Alexander, Tougeron, David, Eucker, Jan

2025

Overview

The randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell‐free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE‐4.5 included mCRC patients with BRAF V600E mutation detected by tissue‐based analyses. Liquid biopsies (LBs) were collected at baseline (pre‐treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)‐certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression‐free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild‐type patients. Follow‐up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild‐type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E‐mutated mCRC. Liquid biopsy evaluating circulating tumor DNA as a prognostic and predictive biomarker is informative and may help to guide treatment in patients with BRAF V600E mutated colorectal cancer. In patients with a detectable BRAF V600E variant in ctDNA, chemotherapy with bevacizumab showed superiority in terms of PFS and OS, while this was not the case in BRAF wild‐type patients.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: 5-Fluorouracil / Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bevacizumab / Biomarkers, Tumor - blood / Biomarkers, Tumor - genetics / Biopsy / Cancer / Cancer and Oncology / Cancer therapies / cetuximab / circulating tumor DNA / Circulating Tumor DNA - blood / Circulating Tumor DNA - genetics / Clinical Trials / Colorectal Cancer / Colorectal carcinoma / Colorectal Neoplasms - blood / Colorectal Neoplasms - diagnosis / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Comparative analysis / Decision making / Disease control / DNA / Female / FOLFOXIRI / Folinic acid / Gene frequency / Gene mutations / Genetic aspects / Humans / Irinotecan / Laboratories / liquid biopsy / Male / Medical prognosis / Metastases / Metastasis / Middle Aged / Monoclonal antibodies / Mutants / Mutation / mutational load / Oncology, Experimental / Oxaliplatin / Patients / Plasma / Prognosis / Protein-serine/threonine kinase / Proto-Oncogene Mas / Proto-Oncogene Proteins B-raf - genetics / Raf protein / Reproducibility / Response rates / Software / Tumors