Faculty, Staff and Student Publications
Publication Date
11-1-2024
Journal
Nature Medicine
DOI
10.1038/s41591-024-03235-9
PMID
39313594
PMCID
PMC11564101
PubMedCentral® Posted Date
9-23-2024
PubMedCentral® Full Text Version
Post-print
Abstract
The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic profiling. Tumors with higher immune signatures showed a trend towards increased OS benefit with Enco+Bini+Cetux. RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+Cetux±Bini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline TP53 mutation was associated with acquired MET amplification. Acquired mutations were subclonal and polyclonal, with evidence of increased tumor mutation rate with Enco+Cetux±Bini and mutational signatures (SBS17a/b). These findings support treatment with Enco+Cetux±Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224.
Keywords
Female, Humans, Male, Middle Aged, Antineoplastic Combined Chemotherapy Protocols, Azetidines, Biomarkers, Tumor, Carbamates, Cetuximab, Colorectal Neoplasms, Drug Resistance, Neoplasm, Gene Expression Profiling, Mutation, Neoplasm Metastasis, Proto-Oncogene Proteins B-raf, Sulfonamides, Gene Expression Regulation, Neoplastic, Biomarkers, Medical research, Cancer, Genetics, Molecular biology
Published Open-Access
yes
Recommended Citation
Kopetz, Scott; Murphy, Danielle A; Pu, Jie; et al., "Molecular Profiling of Braf-V600E-Mutant Metastatic Colorectal Cancer in the Phase 3 Beacon CRC Trial" (2024). Faculty, Staff and Student Publications. 4633.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4633
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