Mutational signatures as potential predictors of HIPEC response and recurrence in ovarian cancer.

Abstract

e17577 Background: While Hyperthermic intraperitoneal chemotherapy (HIPEC) has demonstrated overall survival benefit in advanced ovarian cancer (OC) patients, no predictive biomarkers exist for optimal patient selection. Methods: A cohort of 41 patients with primary or recurrent ovarian cancer underwent HIPEC with cisplatin 75 mg/m2 (60 minutes, 42°C at optimal cytoreductive surgery, CRS) at COH between 2012 and 2022 (NCT01970722). Tumor and normal samples or buffy coat were collected at time of HIPEC CRS and subjected to genomic DNA isolation. Whole exome sequencing (WES) genomic libraries were constructed. HIPEC response was defined by the following progression-free survival (PFS) cut-off values to distinguish good vs poor responders: 18 months in primary EOC patients (based on KGOG, CARCINO-HIPEC trials), and 12 months in recurrent EOC patients (based on MSK, CHIPOR HIPEC trials). Recurrence type was defined as peritoneal-only (only within the peritoneal cavity) vs. extraperitoneal recurrence (any type of recurrence which included extraperitoneal metastases). Mutational signatures for single and doublet-base substitutions (DBSs) and indels were analyzed using SigProfiler (Github, UC San Diego, CA) and fitted to the COSMIC v3.1 database, excluding noncontributory signatures. The Wilcoxon signed-rank test was used to compare cosmic mutational burden between good and poor responders, and peritoneal-only vs extraperitoneal recurrences. Results: A total of 36 EOC tumor samples were analyzed, after exclusion of 5 samples due to lack of exonic variants, or absent normal samples. 21 (58%) were primary EOC, and 15 (42%) were recurrent EOC. Eighteen (50%) patients were identified as good responders, and 18 (50%) as poor responders, with OS of NR (46.5, NR), and NR (27.2, NR), respectively (p=0.02). BRCA1/2 mutation was present in 11.2% of patients. Peritoneal-only recurrence occurred in 23 (64%) of patients, and extraperitoneal recurrence occurred in 13 (36%). Median PFS in the peritoneal-only group was 15.3 months (95%CI, 11.6, 19.5) vs 14.3 months (9.7, 20.8) in the extraperitoneal group. The most common gene mutation in the entire cohort was TP53 (47%). Top OncoPathways included TP53, RTK-RAS, NOTCH, and PI3K. The cosmic mutational signature SBS5 (unknown etiology) was enriched in good HIPEC responders compared to poor responders (p=0.017). Patients with peritoneal-only recurrence had higher SBS15 (DNA mismatch repair) mutational burden compared to patients with extraperitoneal recurrence (p=0.048). Conclusions: SBS5 cosmic signature in EOC tumors is associated with HIPEC response in ovarian cancer and could be validated as a prognostic biomarker in a larger validation cohort. DNA mismatch repair signature SBS15 is associated with peritoneal only recurrence after HIPEC in ovarian cancer, and its absent mutational burden may predict increased risk of extraperitoneal recurrence.