Thanh Hue Dellinger, MD from the City of Hope discusses an ASCO 2020 abstract entitled Whole transcriptome changes correlate to exceptional ovarian cancer responders: A sub-analysis of a HIPEC Phase I trial.
Context:
Patients with advanced stage ovarian cancer benefit from hyperthermic intraperitoneal chemotherapy (HIPEC), which prolongs their overall survival by almost 12 months. But HIPEC-triggered molecular changes are not well characterized and no molecular response signatures are identified. We studied improvements in early gene expression in ovarian tumors following treatment with HIPEC.
Approaches:
This is an interval subgroup study of a single Phase I institution trial using HIPEC at the time of optimum cytoreduction with cisplatin 75 mg / m2. Snap-frozen tumor biopsies and normal peritoneum from 20 patients with ovarian cancer prior to and after HIPEC underwent full transcriptome sequencing using NovaSeq 6000 from Illumina for paired 100 base-pair reads. Analysis of differential expression comparing post and pre-samples was performed to classify significantly modified genes, and analysis of the pathways was performed using GSEA.
Reviews:
Sixty-three genes were differentially expressed between pre- and post-HIPEC tumors (P < 0.05, fold shift < 2). Analysis of these genes by hierarchical clustering indicated that all tumors and normal tissues were clustered on the basis of pre-HIPEC versus post-HIPEC status and not on the basis of patient origin. Post-HIPEC tumors have shown substantial upregulation in immune pathways (TNFA signaling via NFKB, coagulation, complement), followed by epithelial-mesenchymal transformation, inflammation, apoptosis, hypoxia, angiogenesis, KRAS signaling and JAK/STAT3 signaling. Gene set enrichment study using a series of 50 ‘hallmark’ gene sets. In comparison, post-HIPEC normal tissues displayed upregulation (Myc targets V2, G2 M checkpoint) in cell cycle pathways. As predicted, upregulation of genes related to inflammatory response was shared by both the post-HIPEC tumor and normal samples. Finally, normal post-HIPEC samples revealed downregulation of growth and metabolism pathways; cell cycle or DNA repair pathways in post-HIPEC tumors, on the other hand, were downregulated. The most significant improvements in gene expression were shown by two exceptional respondents with chronic platinum-sensitive disease (continuing PFS 47 and 12 + months).
Findings:
Exceptional ovarian cancer responders to HIPEC are distinguished by extensive changes in gene expression; in particular, early molecular changes induced by HIPEC are closely correlated with changes in the immune pathways, which suggests a role in ovarian cancer after HIPEC for immunotherapy. Details on clinical trials: NCT01970722