학술논문
Hyperthermic Intraperitoneal Chemotherapy–Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.
Document Type
Article
Author
Dellinger, Thanh H.; Han, Ernest S.; Raoof, Mustafa; Lee, Byrne; Wu, Xiwei; Cho, Hyejin; He, Ting-Fang; Lee, Peter; Razavi, Marianne; Liang, Winnie S.; Schmolze, Daniel; Priceman, Saul J.; Lee, Stephen; Lin, Wei-Chien; Lin, Jeff F.; Kebria, Mehdi; Hakim, Amy; Ruel, Nora; Stewart, Daphne B.; Wang, Edward W.
Source
Subject
*OVARIAN cancer
*HYPERTHERMIC intraperitoneal chemotherapy
*HEAT shock proteins
*OVARIAN epithelial cancer
*CHEMOTHERAPY complications
*CYTOREDUCTIVE surgery
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Language
ISSN
2473-4284
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. [ABSTRACT FROM AUTHOR]