The impact of molecular and mismatch repair status on the survival outcomes of surgically treated patients with colorectal peritoneal metastases

Background: Stratification of patients with colorectal peritoneal metastases (CRPM) using RAS/BRAF mutational status may refine patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This study aimed to analyse the association of RAS/BRAF status and their variants, with clinicopathological variables and survival outcomes in patients who have undergone CRS +/- HIPEC. Methods: A single centre, peritonectomy database was interrogated for patients with CRPM who underwent peritonectomy procedures between 2010 and 2020. Results: During the study period, 174 patients were included. Molecular status was obtained on 169 patients, with 68 (40.5%) KRAS, 25 (14.8%) BRAF and 6 (3.6%) NRAS mutations detected. Patients with BRAF mutations were more likely to be mismatch repair deficient (dMMR) (BRAF 20%, KRAS 4.4%, wild type 8.6%, p = 0.015). Most common BRAF and KRAS variants were, V600E (80%) and G12D (39.7%), respectively. BRAF V600E was independently associated with worse overall (median: 28 months, multivariate: HR 2.29, p = 0.026) and disease-free survival (median: 8 months, multivariate: HR 1.8, p = 0.047). KRAS G12V was a strong prognostic factor associated with disease-free survival (median: 9 months, HR 2.63, p = 0.016). dMMR patients (14/161, 8.7%) exhibited worse median overall survival compared to those with proficient MMR (dMMR 27 months, pMMR 29 months p = 0.025). Conclusion: This study highlights the importance of molecular analysis in CRPM stratification. BRAF V600E mutations predict poor outcomes post CRS and HIPEC and may help refine patient selection for this procedure. Molecular analysis should be performed preoperatively to characterise prognosis and guide perioperative therapeutic options.