Impact of hyperthermic intraperitoneal chemotherapy on genomic heterogeneity of peritoneal metastases in stage IV gastroesophageal adenocarcinoma.
Authors: Sood Divya , Fefferman Marie L. , Reizine Natalie Marie , Morgan Ryan B. , Ong Cecilia T. , Dhiman Ankit , Turaga Kiran , Catenacci Daniel V.T. , Eng Oliver 
Published: January 2022

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Background: Programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) are potential biomarkers for response to therapy. Heterogeneity of PD-L1 and TMB has been demonstrated in gastroesophageal adenocarcinoma (GEA) in response to systemic chemotherapy. With the increased use of hyperthermic intraperitoneal chemotherapy (HIPEC) for GEA peritoneal metastases (PM), we aimed to determine the effects of HIPEC on genomic heterogeneity of PM. Methods: This is a retrospective review of a prospectively maintained database of patients with stage IV GEA who underwent iterative laparoscopic HIPEC (mitomycin C 30 mg + cisplatin 200 mg, 60 minutes) between 2017 and 2021. PD-L1 status and TMB levels were reviewed from peritoneal tumor specimens collected prior to each HIPEC. PD-L1 status was defined as positive if combined positive score (CPS) was 1 or greater using the 22C3 pharmDx assay. TMB levels were defined as low, intermediate, or high for up to 5, 5 to 15, or over 15 mutations per megabase (m/MB), respectively. Potentially actionable and biologically relevant variants were reviewed, as well as overall survival, defined as time from diagnosis with stage IV disease to death from any cause. Results: 16 patients completed at least one HIPEC during the study period. Median age was 55.5 years (range 43-79), 50% were female, and 62.5% were Caucasian. All patients received at least one line of systemic chemotherapy after stage IV diagnosis and prior to first HIPEC. Median peritoneal cancer index at first HIPEC was 15 (range 3-39). Three patients completed only one HIPEC. Of the 13 who completed at least two HIPECs, 5 had sufficient tumor tissue for genomic analysis at two timepoints. Of those 5 patients, one exhibited a change in PD-L1 expression from positive to negative after HIPEC, and one exhibited an increase in TMB from low to intermediate. All 5 patients exhibited a change in the profile of potentially actionable or biologically relevant genetic variants, including gain or loss of mutations in DNA repair genes (RAD51), proto-oncogenes (MET), and tumor suppressor genes (ERBB3, IRS2). Median overall survival amongst the full cohort was 27.4 months, with median follow-up of 26.1 months. Overall survival was higher amongst those who underwent at least 2 HIPECs compared to only one, but this was not statistically significant. Conclusions: Amongst our cohort, only one patient exhibited a change in PD-L1 expression and one in TMB after HIPEC. However, HIPEC was associated with a change in genetic variant profiles in all evaluable patients. If confirmed in larger studies, this temporal genomic heterogeneity could inform the role of PD-L1, TMB, and other genetic variants as predictive biomarkers for therapy after HIPEC. Iterative laparoscopic HIPEC warrants further investigation as a treatment option after systemic therapy for GEA with peritoneal metastases.