Differential gene expression analysis of a phase II randomized clinical trial of patients with endometrial cancer (EC) treated with megestrol acetate ± pterostilbene.

e17601 Background: The oral antioxidant pterostilbene (PT) (3,5-dimethoxy-40-hydroxystilbene) has demonstrated synergistic antiproliferative effect with megestrol acetate (MA) in endometrial cancer (EC). We conducted a preoperative (window of opportunity) study enrolling endometrial cancer patients scheduled for hysterectomy, who were randomized to preoperative PT+MA vs MA alone. Methods: This prospective, randomized phase II clinical trial (NCT03671811) enrolled patients who were surgical candidates for hysterectomy. Patients were randomized 1:1 to each arm and were treated for 3 weeks with either PT+MA (arm 1) or MA alone (arm 2). Exploratory objectives included histologic response by GOG 211 criteria, and transcriptional changes using whole transcriptome analysis. For the RNA-seq analysis, differential expression analysis used the “limma” R limma package. The differentially expressed genes were selected based on the cutoff values of p-value = 1.5. The gene set enrichment analysis was performed using GSEA software v. 4.3.2 to identify the affected Hallmark and KEGG pathways, using the pre-ranked gene list ranked by the -log10(p-value) with a sign determined by the fold change direction. Results: This prospective, randomized phase II clinical trial (NCT03671811) enrolled patients who were surgical candidates for hysterectomy. Patients were randomized 1:1 to each arm and were treated for 3 weeks with either PT+MA (arm 1) or MA alone (arm 2). Exploratory objectives included histologic response by GOG 211 criteria, and transcriptional changes using whole transcriptome analysis. For the RNA-seq analysis, differential expression analysis used the “limma” R limma package. The differentially expressed genes were selected based on the cutoff values of p-value = 1.5. The gene set enrichment analysis was performed using GSEA software v. 4.3.2 to identify the affected Hallmark and KEGG pathways, using the pre-ranked gene list ranked by the -log10(p-value) with a sign determined by the fold change direction. Conclusions: In endometrial cancer, the oral antioxidant Pterostilbene increases innate immune system pathway expression, while reducing mTOR pathway expression, potentially serving as a useful adjunct to progestin hormonal therapy in EC. Clinical trial information: NCT03671811 .