Impact of RAS/RAF Mutations on Metastatic Treatment Response Following Total Neoadjuvant Therapy in Patients With Stage IV Rectal Cancer

BACKGROUND: The underlying biology and genetic status of rectal cancer can guide treatment options. However, there is limited understanding of the impact of underlying mutational status of RAS/RAF on TNT response in metastatic rectal cancer. This study aims to determine treatment response to TNT in patients harboring RAS/RAF mutations. METHODS: This prospective multicenter observational study identified patients diagnosed with synchronous metastatic rectal cancer suitable to receive personalized TNT (pTNT) treated with curative intent between 2019 and 2024. Metastatic treatment response to pTNT was compared between patient groups based on RAS/RAF mutational status. Three-year disease free (DFS) and overall survival (OS) were compared. RESULTS: Seventy Stage IV rectal cancer patients were treated with curative intent and 49 had genetic testing available for inclusion. Among them, 27 (55.1%) patients had mutations (mRAS group) and 22 patients (44.9%) were wild-type (wtRAS group). mRAS patients were older than wtRAS patients (median 65.0 [60.0-71.0] vs. 55.5 years [39.0-69.25] respectively, p = 0.037). Synchronous metastases occurred more commonly in the liver than in the lungs (53.1% vs. 16.3%, p = 0.014). Complete metastatic tumor response to TNT was demonstrated in half as many mRAS as wtRAS patients (22.2% vs. 40.9%, p = 0.158) and disease progression was higher in patients harboring RAS mutations (37.0% vs. 22.7%, p = 0.280), but neither were significant. Differences in 3-year DFS and OS between the two groups did not reach significance. CONCLUSION: RAS/RAF mutations may negatively impact metastatic tumor response rates in curative Stage IV rectal cancer patients treated with pTNT. Larger scale studies are needed to verify these results.