Association of RNF43 Genetic Alterations With BRAF^V600E and MSI^high in Colorectal Cancer

Abstract

PURPOSE Recent studies have provided evidence for a predictive value of RNF43 genetic alterations (GAs) as biomarkers for targeted therapies in microsatellite-stable (MSS) colorectal cancer (CRC). These data have the potential to prioritize treatment strategies in patients with BRAFV600E-mutant CRC and help to identify a subgroup that is more likely to derive benefit versus those patients for whom alternative treatment approaches are needed. We were therefore interested in defining the precise frequency of BRAF V600E and RNF43 GAs and their respective overlap in a large cohort of patients with CRC. METHODS To address this question, we performed a retrospective analysis that included 52,969 patients diagnosed with CRC from the FoundationCORE database. RESULTS We observed a striking association of RNF43 GAs with MSI and tumor mutational burden status and BRAFV600E mutations. Overall, 23% of MSS patients with confirmed BRAFV600E mutation harbor an RNF43 GA—which accounts for 1.1% of all patients with CRC and for 15.7% of all CRC BRAFV600E cases. CONCLUSION Ongoing phase III clinical trials, such as BREAKWATER, should aim to incorporate broader genetic profiling to further validate the superior sensitivity of patients with RNF43-mutant, MSS BRAF V600E CRC to anti–EGFR-/BRAFi-based therapies.