Advancing Hormone Therapy for Endometrial Cancer

– OVERALL Advancing Hormone Therapy for Endometrial Cancer Uterine endometrial cancer (EC) is the only cancer with significantly worse outcomes today compared to 50 years ago. There is an urgent need to improve clinical management of EC patients and patients with precancerous atypical endometrial hyperplasia (AEH) through the development of safer and more effective prevention and treatment strategies. This multi-institutional P01 application seeks to improve outcomes for ECAEH patients by identifying improved strategies to: 1) prevent the transition of AEH to EC, 2) prevent the progression of EC after initial treatment, and 3) prevent treatment-associated breast cancer. First used in the 1970s, progestins (synthetic compounds that target progesterone receptor) are still the only FDA-approved pharmacological agent for early-stage/low-grade EC treatment, representing the majority of EC tumors. Despite being a relatively safe and effective clinical tool, progestin use is very limited. We propose that progestins are under-utilized for three reasons: 1) despite FDA approval of >20 progestins for contraception and hormone replacement therapy, they have not been systematically evaluated for prevention and treatment of EC-AEH, and as a result the most effective progestin is not known; 2) there are no clinical or molecular biomarkers that predict progestin efficacy much less the use of specific progestins; and 3) the safety of long-term progestin use has been called into question by multiple clinical studies linking progestin use to increased breast cancer risk. The ideal progestin would be at least or more effective than the current standard of care in EC-AEH, but with an improved profile for cancer initiation and progression in the breast. Accordingly, the goals of this collaborative project are to identify the ideal progestin(s) for EC-AEH prevention and treatment, and to use them more effectively by understanding their mechanism and identifying patients who will benefit from their use. To achieve our goals, we have assembled an exceptional team of investigators with extensive expertise in endometrial cancer, breast cancer, and steroid hormone signaling to systematically evaluate progestin efficacy on a phenotypic (Project 1), molecular (Project 2), and clinical (Project 4) level, while counterbalancing efficacy with the potential for unwanted effects in the breast (Project 3). To aid in the success of these Projects, the Administrative Core will provide critical organizational and administrative support to all Projects, the Biospecimen Core will provide important sample and pathology services to all Projects, and the Data Analysis Core will provide biostatistics and bioinformatics support essential for all Projects. Our understanding of the mechanism of action and the effectiveness of progestins lags far behind their extensive clinical use in women. By working as a collaborative team, we hope to establish a new paradigm for prevention and treatment of EC-AEH by identifying the optimal progestin(s) to be used in clinical practice, as well as which patients are most likely to derive benefit. The four Projects and three Cores are highly synergistic, supporting an in-depth analysis of progestin action and clinical effectiveness within the same program.