Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial Journal Article
| Authors: | Kopetz, S.; Murphy, D. A.; Pu, J.; Ciardiello, F.; Desai, J.; Van Cutsem, E.; Wasan, H. S.; Yoshino, T.; Saffari, H.; Zhang, X.; Hamilton, P.; Xie, T.; Yaeger, R.; Tabernero, J. |
| Article Title: | Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial |
| 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 © The Author(s) 2024. |
| Keywords: | cancer chemotherapy; controlled study; treatment response; middle aged; unclassified drug; gene mutation; major clinical study; overall survival; genetics; mutation; clinical trial; antineoplastic agent; metastasis; gene expression profiling; tumor volume; randomized controlled trial; antineoplastic combined chemotherapy protocols; drug resistance; pathology; drug resistance, neoplasm; cetuximab; protein p53; tumor marker; colorectal neoplasms; cd7 antigen; sulfonamide; colorectal tumor; sulfonamides; microsatellite instability; neoplasm metastasis; reactive oxygen metabolite; dna fingerprinting; ras protein; phase 3 clinical trial; transcription factor t bet; mutation rate; drug therapy; protein kinase; b raf kinase; apc protein; benzimidazole derivative; benzimidazoles; carbamic acid; carbamates; proto-oncogene proteins b-raf; braf protein, human; scatter factor receptor; tumor microenvironment; protein pik3ca; metastatic colorectal cancer; clinical outcome; exploratory research; peptides and proteins; toll like receptor 7; humans; human; male; female; article; circulating tumor dna; binimetinib; whole exome sequencing; gene set enrichment analysis; encorafenib; biomarkers, tumor; azetidine derivative; azetidines; tumor mutational burden; molecular fingerprinting; whole transcriptome sequencing; protein map2k1; protein rnf43 |
| Journal Title: | Nature Medicine |
| Volume: | 30 |
| Issue: | 11 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-11-01 |
| Start Page: | 3261 |
| End Page: | 3271 |
| Language: | English |
| DOI: | 10.1038/s41591-024-03235-9 |
| PUBMED: | 39313594 |
| PROVIDER: | scopus |
| PMCID: | PMC11564101 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus |
