Brandy Heckman-Stoddard

Pilot Study of Daily Exemestane in Women with Endometrial Intraepithelial Neoplasia or Low-Grade Endometrial Cancer

Abstract Purpose: To evaluate exemestane, an aromatase inhibitor, as a preventive intervention for endometrial cancer. Experimental Design: This is a multicenter, single-arm, “window of opportunity” pilot study of exemestane (25 mg daily for 21–42 days) in postmenopausal individuals undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer. The primary objective is to determine the change in proliferation, measured by Ki-67 expression, in pre- and posttreatment endometrial tissue specimens. Secondary outcomes include measurement of circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety, and adverse effects. Results: Forty participants were accrued to the study. The mean body mass index was 40.3 (range, 22.8–60.5, SD = 9.8). Preoperative diagnoses included EIN (n = 11, 27.5%), grade 1 endometrial cancer (n = 26, 65%), and grade 2 endometrial cancer (n = 3, 7.5%). Median Ki-67 score decreased from 40.7% [IQR (33.9, 50.3)] at baseline to 18.1% [IQR (8.8, 31.8)] at surgery, representing a median absolute change from baseline of 20.4% [IQR (−29.9, −6.7), P < 0.001]. In a matched historic control cohort, participants also had a decrease in Ki-67 score with a median absolute change from baseline of −6.7% [IQR (−12.7, −1.3), P< 0.001]. However, the decrease in Ki-67 was greater in the study participants than the historic controls, with a median difference between the groups of −13.4% [IQR (−23.3, 6.9), P ≤ 0.01]. Both tissue estrogen receptor and progesterone receptor expression declined significantly with exemestane treatment (P < 0.001). However, serum estradiol levels did not change between baseline and after treatment (P = 0.16). Conclusions: In this pilot study, exemestane demonstrated antiproliferative effects in EIN and low-grade endometrial cancer. This agent warrants further evaluation for the prevention of endometrial cancer.

Trends in uterine cancer incidence and mortality: insights from a natural history model

Abstract Background Uterine cancer incidence and mortality are increasing, with concomitant disparities in outcomes between racial groups. Natural history modeling can evaluate risk factors, predict future trends, and simulate approaches to reducing mortality and disparities. Methods We designed a natural history model of uterine cancer using a multistage clonal expansion design. The model is informed by National Health and Nutrition Examination Survey, National Health Examination Survey, age, time period, birth cohort, and birth certificate data on reproductive histories and body mass index (BMI). We fit and calibrated the model to Surveillance, Epidemiology, and End Results data by race and ethnicity as well as histologic subgroup. We projected future incidence and estimated the degree of contribution of BMI, reproductive history, and competing hysterectomy to excess uterine cancer incidence. Results The model accurately replicated Surveillance, Epidemiology, and End Results incidence for endometrioid, nonendometrioid, and sarcoma subgroups for non-Hispanic Black and non-Hispanic White patients. For endometrioid, nonendometrioid, and sarcomas, BMI-attributable risks are greater for non-Hispanic White than for non-Hispanic Black patients; reproductive history–attributable risks are greater for non-Hispanic Black patients. Between 2018 and 2050, endometrioid incidence is projected to rise by 64.9% in non-Hispanic Black individuals and17.5% in non-Hispanic White individuals; the projected rise for the nonendometrioid subgroup is 41.4% in non-Hispanic Black individuals and 22.5% in non-Hispanic White individuals; the sarcoma incidence projected increase is 36% in non-Hispanic Black individuals and 29.2% in non-Hispanic White individuals. Conclusions Uterine cancer risk is substantially explained by reproductive history and BMI, with differences observed between non-Hispanic Black and non-Hispanic White individuals and future projections indicating perpetuation of disparities. Lower rates of hysterectomy and rising obesity rates will likely contribute to continued increases in uterine cancer incidence.

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy

Abstract Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Projected Trends in the Incidence and Mortality of Uterine Cancer in the United States

Abstract Background: To develop a natural history model for uterine cancer calibrated to population-based incidence and mortality data to project future trends in the disease through 2050. Methods: We developed a state-transition microsimulation model of uterine cancer. The model begins at 18 years of age and simulates Black and White patients, includes transition states for precursor lesions, and separately models endometrioid and nonendometrioid tumors. The model was calibrated to population-based incidence and mortality data using parameter extrapolation. Results: The model closely fit population-based incidence and mortality data of uterine cancer. From 2020 to 2050, the incidence of uterine cancer is projected to increase in White women to 74.2 cases per 100,000 (compared with 57.7 cases per 100,000 in 2018) and increase to 86.9 per 100,000 (compared with 56.8 cases per 100,000 in 2018) in Black women. Among White women, incidence-based mortality will increase from 6.1 per 100,000 in 2018 to 11.2 per 100,000 in 2050, whereas incidence-based mortality in Black women will increase from 14.1 per 100,000 to 27.9 per 100,000. Endometrioid tumors are expected to increase considerably in both White and Black women; White women will experience only a slight increase in nonendometrioid tumors, whereas the incidence of these tumors will increase substantially in Black women. Conclusions: The incidence and mortality of uterine cancer are projected to increase substantially over the next three decades. Black women will experience a disproportionate increase in the disease. Impact: Projecting the incidence and mortality of uterine cancer can facilitate future cancer control efforts.