The Impact of RAS/BRAF Mutation on Pathological Complete Response After Total Neoadjuvant Therapy in Rectal Cancer.

Introduction: Kirsten rat sarcoma viral oncogene (KRAS) mutations account for 86% of all RAS mutations and 30-50% of colorectal cancer mutations (CRC). The KRAS mutation may have prognostic implications in CRC. The impact of RAS/BRAF mutations on pathological complete response (pCR) after total neoadjuvant therapy (TNT) in patients with rectal cancer is unclear. This study aims to assess pCR rates following TNT in RAS/BRAF mutant rectal cancer.

Methods: Adult patients with rectal cancer who underwent TNT and curative surgery at a large academic institution between 2018 and 2023 were retrospectively reviewed. Patients were divided into two groups based on RAS/BRAF mutation status: mutant RAS/BRAF (RAS+) and wild-type RAS/BRAF (RAS-). Patients with other or concurrent mutations were excluded.

Results: Of 146 patients, 69 (47.3%) were RAS+, whereas 77 (52.7%) were RAS-. In the RAS+ group, five patients (7.2%) were BRAF mutants. There was no significant difference in magnetic resonance imaging rate between groups. However, RAS mutation status was significantly associated with differences in pCR; specifically, a higher proportion of RAS- patients achieved pCR (20.8% vs. 8.7%; p = 0.042). Subgroup analysis revealed that RAS+ (20.8%, 8.7%; p = 0.042) and codons 12 and 13 (20.8%, 7.3%; p = 0.033) were associated with a less pathologic complete response rate. Three-year disease-free survival was significantly associated with RAS mutation status, being higher in the RAS- group compared with the RAS+ group (80% vs. 65%; p = 0.038).

Conclusions: In the era of TNT and nonoperative management strategies, RAS/BRAF mutations are more likely associated with a lower pCR rate in locally advanced rectal cancer patients. Moreover, these mutations are associated with worse disease-free survival.