PURPOSE: Menopausal hormone therapy's influence on ovarian and endometrial cancers remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone on ovarian and endometrial cancer incidence and mortality in the Women's Health Initiative randomized, placebo-controlled clinical trials. MATERIALS AND METHODS: Postmenopausal women, age 50-79 years, were entered on two randomized clinical trials evaluating different menopausal hormone therapy regimens. In 16,608 women with a uterus, 8,506 were randomly assigned to once daily 0.625 mg of CEE plus 2.5 mg once daily of MPA and 8,102 placebo. In 10,739 women with previous hysterectomy, 5,310 were randomly assigned to once daily 0.625 mg of CEE-alone and 5,429 placebo. Intervention was stopped for cause before planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Outcomes include incidence and mortality from ovarian and endometrial cancers and deaths after these cancers. RESULTS: After 20-year follow-up, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041%] v 17 [0.020%]; hazard ratio [HR], 2.04 [95% CI, 1.14 to 3.65]; P = .014) and ovarian cancer mortality ( P = .006). By contrast, CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] v 63 [0.045%]; HR, 1.14 [95% CI, 0.82 to 1.59]; P = .44) or ovarian cancer mortality but did significantly lower endometrial cancer incidence (106 cases [0.073%] v 140 [0.10%]; HR, 0.72 [95% CI, 0.56 to 0.92]; P = .01). CONCLUSION: In randomized clinical trials, CEE-alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not. By contrast, CEE plus MPA significantly reduced endometrial cancer incidence.

Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant with a promising role in anti-cancer treatment. In endometrial cancer (EC), in vitro studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) with megestrol acetate (MA), a common treatment for EC. This is a randomized phase II clinical trial (NCT03671811) of PT+MA vs. MA for three weeks prior to scheduled hysterectomy. The primary objective is to determine the antiproliferative effect of PT+MA vs. MA using Ki-67 index. The secondary objectives are toxicity, histological response, transcriptional changes, and lipid metabolism. A total of 44 patients were enrolled between January 2019 and November 2022 with 23 randomized to Arm 1 (PT+MA) and 21 to Arm 2 (MA). Toxicities included one G3 thromboembolic event (PT+MA) and one G3 hypertension event (MA). Histological responses were high in both arms (>90%). There was no difference in Ki-67 changes, although, when restricted to endometroid subtype, the relative decrease in Ki67 was 33.8% in PT+MA vs. 20.1% in MA alone (p = 0.14). Whole transcriptomic gene profiling of samples before and after PT+MA exposure demonstrated the activation of interferon alpha response pathway and suppression of mTORC1 signaling, hypoxia, oxidative phosphorylation, and IL2-STAT5 signaling. Lipid metabolism analyses did not reveal any significant changes between arms. PT is well-tolerated in the preoperative treatment of EC and demonstrated in vivo anti-cancer effects on the transcriptomic level.

Living in a food desert is a known negative health risk, with recent literature finding an associated higher mortality in patients with cancers. Gynecologic cancers have not specifically been studied. We aimed to describe patients with gynecologic cancers who live in a food desert and determine if there is an association between living in a food desert and gynecologic cancer mortality. The 2013–2019 California Cancer Registry (CCR) was used to identify patients with endometrial, ovarian, or cervical cancers. Patient residential census tract was linked to food desert census tracts identified by the 2015 United States Department of Agriculture Food Access Research Atlas. Comorbidity data were obtained from the California Office of Statewide Health Planning and Development database (OSHPD). Treatment, diagnosis, and survival outcomes were obtained from the CCR’s variables and compared by food desert status. Five-year disease-specific survival was analyzed by applying Cox proportional hazards analysis. 40,340 gynecologic cancer cases were identified. 60.1 % had endometrial cancer, 23.2 % had ovarian cancer, and 15.9 % had cervical cancer. The average age of the cohort was 59.4 years, 48.0 % was non-Hispanic White, 50.3 % was privately insured, and 6.8 % of lived in a food desert. Living in a food desert was associated with higher disease-specific mortality for patients with gynecologic cancers (endometrial cancer HR 1.43p < 0.001 95 % CI 1.22–1.68; ovarian cancer HR 1.47p < 0.001 95 % CI 1.27–1.69; cervical cancer HR 1.24p = 0.045 95 % CI 1.01–1.54). Patients living in food deserts had worse disease-specific survival, making access to food a modifiable risk factor that may result in mitigating gynecologic cancer disparities.

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, PARP inhibitor treatment highly increased intracellular PD-L1 accumulation in both ovarian cancer-patient tumor samples and cell lines. We investigated whether intracellular PD-L1 might play a critical role in ovarian cancer progression. Mutating the PD-L1 acetylation site in PEO1 and ID8^Brca1−/− ovarian cancer cells significantly decreased PD-L1 levels and impaired colony formation, which was accompanied by cell cycle G2/M arrest and apoptosis induction. PEO1 and ID8^Brca1−/− tumors with PD-L1 acetylation site mutation also exhibited significantly reduced growth in mice. Furthermore, targeting intracellular PD-L1 with a cell-penetrating antibody effectively decreased ovarian tumor-cell intracellular PD-L1 level and induced tumor-cell growth arrest and apoptosis, as well as enhanced DNA damage and STING activation, both in vitro and in vivo. In conclusion, we have shown the critical role of intracellular PD-L1 in ovarian cancer progression.