Hyperthermic Intraperitoneal Chemotherapy-Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.

Abstract

PURPOSE:

Hyperthermic intraperitoneal chemotherapy (HIPEC) confers a survival benefit in epithelial ovarian cancer (EOC) and in preclinical models. However, the molecular changes induced by HIPEC have not been corroborated in humans.

PATIENTS AND METHODS:

A feasibility trial evaluated clinical and safety outcomes of HIPEC with cisplatin during optimal cytoreductive surgery (CRS) in patients with EOC diagnosed with stage III, IV, or recurrent EOC. Pre- and post-HIPEC biopsies were comprehensively profiled with genomic and transcriptomic sequencing to identify mutational and RNAseq signatures correlating with response; the tumor microenvironment was profiled to identify potential immune biomarkers; and transcriptional signatures of tumors and normal samples before and after HIPEC were compared to investigate HIPEC-induced acute transcriptional changes.

RESULTS:

Thirty-five patients had HIPEC at the time of optimal CRS; all patients had optimal CRS. The median progression-free survival (PFS) was 24.7 months for primary patients and 22.4 for recurrent patients. There were no grade 4 or 5 adverse events. Anemia was the most common grade 3 adverse event (43%). Hierarchical cluster analyses identified distinct transcriptomic signatures of good versus poor responders to HIPEC correlating with a PFS of 29.9 versus 7.3 months, respectively. Among good responders, significant HIPEC-induced molecular changes included immune pathway upregulation and DNA repair pathway downregulation. Within cancer islands, % programmed cell death protein 1 expression in CD8+ T cells significantly increased after HIPEC. An exceptional responder (PFS 58 months) demonstrated the highest programmed cell death protein 1 increase. Heat shock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors.

CONCLUSION:

Distinct transcriptomic signatures identify responders to HIPEC, and preclinical model findings are confirmed for the first time in a human cohort.

• Authors: Thanh H Dellinger, Ernest S Han, Mustafa Raoof, Byrne Lee, Xiwei Wu, Hyejin Cho, Ting-Fang He, Peter Lee, Marianne Razavi, Winnie S Liang, Daniel Schmolze, Saul J Priceman, Stephen Lee, Wei-Chien Lin, Jeff F Lin, Mehdi Kebria, Amy Hakim, Nora Ruel, Daphne B Stewart, Edward W Wang, Benjamin I Paz, Mark T Wakabayashi, Mihaela C Cristea, Lorna Rodriguez-Rodriguez
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 6 Pg. e2100239 (03 2022) ISSN: 2473-4284 [Electronic] United States
• PMID: 35357903 (Publication Type: Clinical Trial, Journal Article)

Topics

• Carcinoma, Ovarian Epithelial (drug therapy)
• Feasibility Studies
• Female
• Humans
• Hyperthermic Intraperitoneal Chemotherapy (adverse effects)
• Neoplasm Recurrence, Local (drug therapy)
• Ovarian Neoplasms (drug therapy)
• Tumor Microenvironment