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. 2023 Jul;30(7):4459-4470.
doi: 10.1245/s10434-023-13463-x. Epub 2023 Apr 21.

Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases

Ahmed B Hamed  1   2 , Yongli Shuai  3 , Joshua Derby  1 , Matthew P Holtzman  1 , Melanie Ongchin  1 , David L Bartlett  4 , James F Pingpank  1 , Reetesh Pai  5 , Aatur Singhi  5 , Haroon A Choudry  6
Affiliations

Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases

Ahmed B Hamed et al. Ann Surg Oncol. 2023 Jul.

Abstract

Background: Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival.

Methods: This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors.

Results: A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival.

Conclusions: Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.

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Figures

FIG. 1
FIG. 1
Study enrollment flowchart
FIG. 2
FIG. 2
Distribution of key pathologic variables and genomic alterations in patients with CRPM who underwent CRS-HIPEC; (WHO grade: pathologic grade, CC-score: cytoreduction completeness score)
FIG. 3
FIG. 3
Exploratory associations of primary tumor site, RAS mutation, BRAF mutation, MMR/MSI status, and PIK3CA mutation with survival after CRS-HIPEC; associations of primary tumor site, RAS mutation, and BRAF mutation with survival (a, b). Association of BRAF mutation and MMR/MSI status with survival (c); association of BRAF and PIK3CA mutations with survival (d); p-Value: logrank test p-value; OS overall survival, WT wildtype, M/mut mutated; the mutant category in a, b includes cases with either RAS mutation or BRAF mutation and the wildtype category includes cases that were wildtype for both genes
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