Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial
Copyright policy )Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial
AbstractThe 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
- National Cancer Center Hospital East Japan
- Imperial College London United Kingdom
- KU Leuven Belgium
- The University of Texas System United States
- Memorial Sloan Kettering Cancer Center United States
Male, Proto-Oncogene Proteins B-raf, DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms, Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia, TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada, ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols, Cetuximab, Quimioteràpia combinada, Article, Còlon - Càncer - Tractament, ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales, Recte - Càncer - Tractament, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Neoplasm Metastasis, FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación, Sulfonamides, Other subheadings::Other subheadings::Other subheadings::/drug therapy, Gene Expression Profiling, Middle Aged, Gene Expression Regulation, Neoplastic, Anomalies cromosòmiques, Drug Resistance, Neoplasm, PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation, Mutation, Azetidines, Female, Carbamates, Colorectal Neoplasms
Male, Proto-Oncogene Proteins B-raf, DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms, Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia, TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada, ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols, Cetuximab, Quimioteràpia combinada, Article, Còlon - Càncer - Tractament, ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales, Recte - Càncer - Tractament, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Neoplasm Metastasis, FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación, Sulfonamides, Other subheadings::Other subheadings::Other subheadings::/drug therapy, Gene Expression Profiling, Middle Aged, Gene Expression Regulation, Neoplastic, Anomalies cromosòmiques, Drug Resistance, Neoplasm, PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation, Mutation, Azetidines, Female, Carbamates, Colorectal Neoplasms
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