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

Michael P Flood; Anshini Jain; Catherine Mitchell; Chelsee Hewitt; Robert Ramsay; Michael Michael; Alexander G Heriot; Jeanne Tie

doi:10.1016/j.ejso.2022.06.014

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

Eur J Surg Oncol. 2022 Oct;48(10):2218-2225. doi: 10.1016/j.ejso.2022.06.014. Epub 2022 Jun 18.

Authors

Michael P Flood¹, Anshini Jain², Catherine Mitchell³, Chelsee Hewitt³, Robert Ramsay², Michael Michael⁴, Alexander G Heriot², Jeanne Tie⁴

Affiliations

¹ Peter MacCallum Cancer Centre, Division of Surgical Oncology, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia. Electronic address: Michael.flood@petermac.org.
² Peter MacCallum Cancer Centre, Division of Surgical Oncology, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia.
³ Peter MacCallum Cancer Centre, Department of Molecular Pathology, Australia.
⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia; Peter MacCallum Cancer Centre, Division of Medical Oncology, Australia.

PMID: 35750576
DOI: 10.1016/j.ejso.2022.06.014

Abstract

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.

Keywords: BRAF; Colorectal peritoneal metastases; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; KRAS; Molecular analysis.

MeSH terms

Colorectal Neoplasms* / pathology
Cytoreduction Surgical Procedures
DNA Mismatch Repair*
Humans
Hyperthermia, Induced
Peritoneal Neoplasms* / secondary
Peritoneal Neoplasms* / therapy
Prognosis
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins p21(ras) / genetics
Retrospective Studies
Survival Rate

Substances

Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)