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

person Thanh Hue Dellinger City of Hope National Comprehensive Cancer Center, Duarte, CA info_outline Thanh Hue Dellinger, Xiwei Wu, Hyejin Cho, Susan Elaine Yost, Nora H. Ruel, Marta Invernizzi, Rosemary Noel Senguttuvan, Paul Henry Frankel, Mehdi Kebria, Ernest Soyoung Han, Mihae Song, Maria De Leon, Melissa Eng, Raechelle Tinsley, Daniel Schmolze, Sue Chang, Javier Arias Stella

Authors person Thanh Hue Dellinger City of Hope National Comprehensive Cancer Center, Duarte, CA info_outline Thanh Hue Dellinger, Xiwei Wu, Hyejin Cho, Susan Elaine Yost, Nora H. Ruel, Marta Invernizzi, Rosemary Noel Senguttuvan, Paul Henry Frankel, Mehdi Kebria, Ernest Soyoung Han, Mihae Song, Maria De Leon, Melissa Eng, Raechelle Tinsley, Daniel Schmolze, Sue Chang, Javier Arias Stella Organizations City of Hope National Comprehensive Cancer Center, Duarte, CA, City of Hope, Duarte, CA, City of Hope National Medical Center, Duarte, CA, City of Hope Comprehensive Cancer Center, Duarte, CA, City of Hope Comprehensive Medical Center, Duarte, CA Abstract Disclosures Research Funding No funding sources reported 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 <= 0.05 and fold change >= 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 <= 0.05 and fold change >= 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.

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