Comprehensive Landscape of BRAF Variant Classes, Clonalities, and Co-Mutations in Metastatic Colorectal Cancer Using ctDNA Profiling

Simple Summary Patients with atypical (nonV600) BRAF mutations represent a unique category of metastatic colorectal cancer patients. In the past, these patients were considered to be similar to those with the more common BRAFV600E mutation. However, additional investigation confirmed patients with atypical BRAF mutations have a distinct molecular make up, clinical course, and treatment response to both chemotherapy and targeted therapy, compared to those of patients with BRAFV600E mutations. Here, we report the key characteristics of patients with atypical BRAF mutations identified from a large circulating tumor DNA database and a real-world clinical cohort, highlighting important differences, such as the presence of additional mutations and related survival outcomes. These findings support the need for dedicated research efforts to understand the intricacies of atypical BRAF mutations in colon cancer and promote the discovery of new therapies for these patients.Abstract Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and male. In contrast to BRAFV600E, BRAF class II and III variants and their co-occurrence with KRAS/NRAS mutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypical BRAF mCRC treated at a large academic referral center. While there were no survival differences between atypical BRAF classes, concurrent RAS mutations or liver involvement was associated with poorer prognosis. Notably, patients younger than 50 years of age had extremely poor survival. In these patients, the high-frequency KRAS/NRAS co-mutation and its correlation with poorer prognosis underlines the urgent need for novel therapeutic strategies. This study represents one of the most comprehensive characterizations to date of atypical BRAF variants, utilizing both ctDNA and clinical cohorts.