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

Abstract

Recent studies have provided evidence for a predictive value of <i>RNF43</i> 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 <i>BRAF</i>^V600E-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 <i>BRAF</i>^<i>V600E</i> and <i>RNF43</i> GAs and their respective overlap in a large cohort of patients with CRC. To address this question, we performed a retrospective analysis that included 52,969 patients diagnosed with CRC from the FoundationCORE database. We observed a striking association of <i>RNF43</i> GAs with MSI and tumor mutational burden status and <i>BRAF^V600E</i> mutations. Overall, 23% of MSS patients with confirmed <i>BRAF</i>^V600E mutation harbor an <i>RNF43</i> GA-which accounts for 1.1% of all patients with CRC and for 15.7% of all CRC <i>BRAF</i>^V600E cases. Ongoing phase III clinical trials, such as BREAKWATER, should aim to incorporate broader genetic profiling to further validate the superior sensitivity of patients with <i>RNF43</i>-mutant, MSS <i>BRAF</i>^<i>V600E</i> CRC to anti-EGFR-/BRAFi-based therapies.