Division of Gynecologic Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA.
Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA.
JCO Precis Oncol. 2022 Mar;6:e2100239. doi: 10.1200/PO.21.00239.
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.
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.
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.
Distinct transcriptomic signatures identify responders to HIPEC, and preclinical model findings are confirmed for the first time in a human cohort.
腹腔内热灌注化疗（HIPEC）在卵巢上皮癌（EOC）和临床前模型中均具有生存获益。然而，HIPEC 诱导的分子变化尚未在人体中得到证实。
一项可行性试验评估了在诊断为 III 期、IV 期或复发性 EOC 的患者中，在最佳减瘤手术（CRS）期间进行顺铂 HIPEC 的临床和安全性结果。在 HIPEC 前后进行了全面的基因组和转录组测序分析，以确定与反应相关的突变和 RNAseq 特征；对肿瘤微环境进行了分析，以确定潜在的免疫生物标志物；并比较了 HIPEC 前后肿瘤和正常样本的转录特征，以研究 HIPEC 诱导的急性转录变化。
35 名患者在最佳 CRS 时接受了 HIPEC；所有患者均进行了最佳 CRS。原发性患者的中位无进展生存期（PFS）为 24.7 个月，复发性患者为 22.4 个月。无 4 级或 5 级不良事件。贫血是最常见的 3 级不良事件（43%）。层次聚类分析确定了与 HIPEC 反应良好和反应不良的患者之间存在明显的转录组特征，分别与 29.9 个月和 7.3 个月的 PFS 相关。在反应良好的患者中，显著的 HIPEC 诱导的分子变化包括免疫途径上调和 DNA 修复途径下调。在肿瘤岛内，HIPEC 后 CD8+T 细胞中程序性死亡蛋白 1 的表达显著增加。一名异常反应者（PFS 58 个月）表现出最高的程序性死亡蛋白 1 增加。热休克蛋白是 HIPEC 治疗肿瘤中上调最明显的差异基因。
独特的转录组特征可识别对 HIPEC 有反应的患者，并且首次在人类队列中证实了临床前模型的发现。
