The BEACON CRC study is exploring new predictors of response to therapy in metastatic colorectal cancer.

According to the Spanish Society of Medical Oncology (SEOM), the most frequently diagnosed cancers in Spain in 2024 will be colorectal cancer, with a total of 44,294 new cases. In this sense, the determination of diagnostic markers, response to treatment and prognosis of the disease is important meaning. Therefore, a new study published in Natural medicine presented new data on the molecular profile of metastatic colorectal cancer with BRAF-V600E mutation in the phase 3 BEACON CRC study. This is the largest retrospective exploratory analysis of biomarkers in previously treated colorectal cancer patients with these mutations.

BRAF-V600E mutations occur in about 10 percent of tumors. in patients with metastatic colorectal cancer and are associated with poor prognosis compared with BRAF tumors. Given these data, a thorough understanding of the biological landscape of BRAF mutants and prognostic and prognostic determinants is key to optimizing patient care.

Predictive biomarkers

According to information from the BEACON CRC study, the transcriptional profile of colorectal cancer tumors has allowed the identification of subtypes with similar biological characteristics, such as consensus molecular subtypes (CMS) and BM subtypes. These subtypes may be useful in predicting prognosis and response to treatment in patients with these tumor types. In previously treated patients and BRAF V600E mutation acquired resistance changes in the MAPK pathway and MET enhancement following treatment with BRAF inhibitor combinations. Currently, the clinical relationships between molecular subtypes and mechanisms of acquired resistance following treatment with BRAF inhibitors in combination with an anti-EGFR antibody, with or without MEK inhibitors, compared with cytotoxic chemotherapy in combination with an anti-EGFR antibody are not well understood. has not been studied in large randomized trials.

Therefore, the BEACON CRC study aims to identify molecular associations of clinical outcomes and identify resistance mechanisms acquired after treatment. The comprehensive analysis of tumor and plasma molecular characteristics performed in this study provides comprehensive data on BRAF-V600E mutation-positive colorectal cancer.

Development of new therapeutic combinations.

Of the 665 patients included in the full analysis, 621 were included in the biomarker analysis set. To assess the molecular landscape of basal tumors, 503 patients were analyzed by whole exome sequencing (WES) and 441 by whole transcriptome sequencing (WTS). For genomic profiling via circulating tumor DNA (ctDNA), 544 patients were studied at baseline and 320 with paired samples at the end of treatment. Biomarker analysis was carried out among a representative patient population, the number of patients was evenly distributed among three therapeutic sleeves: Enco+Bini+Cetux, Enco+Cetux and control for all subgroups of biomarker analysis.

Genomic profiling of basal tumor tissue and circulating tumor DNA (cDNA) showed that the BRAF-V600E mutation was identified by whole exome sequencing (WES) in 476 of 503 patients (94.6 percent) and in 492 of 544 patients (90.4 percent). ) using ctDNA. . Of patients tested in both sample types, 368 of 404 (91.1 percent) were positive for BRAF-V600E in both conditions. Additionally, when comparing patients with BRAF-V600E detected in ctDNA, patients with this undetectable mutation had smaller tumors. Regarding genes associated with cancerIn tumor tissue, the most frequently mutated proteins were TP53 (70 percent), APC (36 percent), SMAD4 (28 percent), FAT1 (27 percent), RNF43 (26 percent), and LRP1B (25 percent).

Enko+Cetux±Bini

Primary analysis of the BEACON CRC study showed that combinations of encorafenib (Enco) and cetuximab (Cetux) with or without binimetinib (Bini)significantly improved overall survival in patients with metastatic colorectal cancer with a BRAF-V600 mutation compared with control treatment (Cetux with irinotecan or FOLFIRI combination).

The clinical benefits observed with Enco+Bini+Cetux and Enco+Cetux were maintained. consistent across all molecular subtypes regardless of specific genetic mutations, microsatellite instability (MSI) or tumor mutational burden (TMB). These subtypes have become key paradigms in colorectal cancer and were analyzed to contextualize the results. In addition, the results were confirmed by unbiased differential expression analysis and gene set enrichment analysis (GSEA), which highlighted that immunological characteristics of the tumor microenvironment are potential determinants of treatment benefit.

Although most metastatic colorectal cancers (mCRCs) are microsatellite stable (MSS) and are considered unresponsive to cold, mCRCs with MSS and the BRAF-V600E mutation show some degree of immune activation. It is suggested that immune signatures may be enriched in the BM1 and CMS1/CMS4 subtypes, which present a more robust immune profile and stronger inflammatory response compared to other colorectal cancer subtypes.

In the study, the researchers agree that knowledge of the static signature and evolution of the molecular characteristics of the disease will allow in the future to identify new therapeutic combinations, minimize treatment resistance, and improve survival and quality of life of patients with metastatic colorectal cancer. previously treated cancer.

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