BRAF Non-V600 Mutations in Metastatic Colorectal Cancer

Simple Summary Metastatic Colorectal cancer (CRC) is an aggressive and complex disease influenced by gene changes, including BRAF mutations. While previous work has largely spotlighted the BRAF V600 mutation, there remains much to uncover about its lesser-studied non-V600 counterparts. Through examining their characteristics, clinical relevance, and emerging treatment possibilities, this review bridges some knowledge gaps and paints a clearer picture of the BRAF non-V600 mutations. By understanding these intricacies, healthcare professionals and researchers can be better equipped to explore targeted treatments, potentially enhancing care for metastatic CRC patients.Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite advancements in detection and therapeutic options, patients with metastatic CRC continue to face poor survival rates. The heterogeneity of oncogenic alterations, including BRAF mutations, poses a substantial challenge in identifying optimal treatment approaches. Notably, BRAF non-V600 mutations, encompassing class II and class III mutations, exhibit the distinct patterns of the signaling pathways and responses to targeted therapies compared to BRAF V600 mutations (class I). Nevertheless, the current classification system may underestimate the complexity and heterogeneity of BRAF-mutant CRC. Ongoing clinical trials are actively investigating targeted therapies for BRAF non-V600 mutations, but they are being confronted with patient recruitment obstacles due to the genetic diversity of these alterations. Continued research is needed to refine mutation subtyping, identify effective treatment strategies, and improve outcomes for patients with BRAF non-V600-mutant CRC. Enhancing our understanding and management of this specific subgroup of CRC is crucial for developing personalized treatment approaches and advancing patient care. This manuscript provides a comprehensive overview of the recent advances in and perspectives on BRAF non-V600 alterations in colorectal cancer, including relevant ongoing clinical trials.