Mihae Song

A Critical Role of Intracellular PD-L1 in Promoting Ovarian Cancer Progression

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 ID8Brca1−/− 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 ID8Brca1−/− 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.

Explainable artificial intelligence analysis of brachytherapy boost receipt in cervical cancer during the COVID-19 era

Brachytherapy is a critical component of the standard-of-care curative radiotherapy regimen for women with locally advanced cervical cancer (LACC). However, existing literature suggests that many patients will not receive the brachytherapy boost. We used machine learning (ML) and explainable artificial intelligence to characterize this disparity. Patients with LACC diagnosed from 2004 to 2020 who received definitive radiation were identified in the National Cancer Database. Five ML models were trained to predict if a patient received a brachytherapy boost. The best-performing model was explained using SHapley Additive exPlanation (SHAP) values. To identify trends that may be attributable to the coronavirus disease 2019 (COVID-19) pandemic, the previous analysis was repeated and limited to 2019 to 2020. A total of 37,564 patients with LACC were identified; 5799 were diagnosed from 2019 to 2020 (COVID cohort). Of these patients, 59.3% received a brachytherapy boost, with 76.4% of patients diagnosed in 2019 to 2020 receiving a boost. The random forest model achieved the best performance for both the overall and COVID cohorts. In the overall cohort, the most important predictive features were the year of diagnosis, stage, age, and insurance status. In the COVID cohort, the most important predictive features were FIGO stage, age, insurance status, and hospital type. Of the 26 patients who tested positive for COVID-19 during their course of radiotherapy, 19 (73.1%) received a brachytherapy boost. A gradual increase in brachytherapy boost utilization has been noted, which did not seem to be significantly impacted by the onset of the COVID-19 pandemic. ML could be considered to identify patient populations where brachytherapy is underutilized, which can provide actionable feedback for improving access.

Menopausal Hormone Therapy and Ovarian and Endometrial Cancers: Long-Term Follow-Up of the Women's Health Initiative Randomized Trials

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.