Whole transcriptome changes correlate to exceptional ovarian cancer responders: A sub-analysis of a HIPEC Phase I trial.

Abstract

6060 Background: Advanced stage ovarian cancer patients benefit from hyperthermic intraperitoneal chemotherapy (HIPEC), prolonging overall survival by nearly 12 months. However, molecular changes triggered by HIPEC are not well characterized, and no molecular signatures of response are known. We analyzed early gene expression changes after HIPEC treatment in ovarian tumors. Methods: This is an interval subgroup analysis of a single institution Phase I trial using HIPEC with cisplatin 75 mg/m2 at time of optimal cytoreduction. Snap-frozen biopsies from tumor and normal peritoneum from 20 patients with ovarian cancer before and after HIPEC underwent whole-transcriptome sequencing using Illumina’s NovaSeq 6000 for paired 100 base-pair reads. Differential expression analysis comparing post and pre-samples was done to identify significantly changed genes, and pathway analysis was conducted using GSEA. Results: Sixty-three genes were differentially expressed (P < 0.05, fold change ≥2) between pre- and post-HIPEC tumors. Hierarchical clustering analysis of these genes confirmed that all tumors and normal tissues clustered based on pre-HIPEC versus post-HIPEC status, and not based on their patient source. Gene set enrichment analysis using a collection of 50 “hallmark” gene sets revealed that post-HIPEC tumors demonstrate significant upregulation in immune pathways (TNFA signaling via NFKB, coagulation, complement), followed by epithelial-mesenchymal transition, inflammation, apoptosis, hypoxia, angiogenesis, KRAS signaling and JAK/STAT3 signaling. In contrast, post-HIPEC normal tissues exhibited upregulation in cell cycle pathways (Myc targets V2, G2M checkpoint). As expected, both post-HIPEC tumor and normal samples shared upregulation of genes related to inflammatory response. Lastly, post-HIPEC normal samples revealed downregulation of growth and metabolism pathways; in contrast, cell cycle or DNA repair pathways were downregulated in post-HIPEC tumors. Two exceptional-responders with recurrent platinum-sensitive disease (ongoing PFS 47 and 12+ months) demonstrated the most substantial changes in gene expression. Conclusions: Exceptional ovarian cancer responders to HIPEC are characterized by extensive gene expression changes; specifically, early HIPEC-induced molecular changes are strongly associated with immune pathways changes, implicating a role for immunotherapy after HIPEC in ovarian cancer. Clinical trial information: NCT01970722.