Evaluating the potential of progestins to promote the development or progression of mammary tumors

University Of New Mexico Health Scis Ctr, Albuquerque NM

Investigators

Abstract

Endometrial cancer (EC) is the most common gynecological cancer in the developed world, accounting for more than 60,000 cases in the United States each year. Alarmingly, it represents one of the only cancers in the United States with increasing diagnosis and death rates each year. Therefore, the current approaches for preventing and treating EC are failing. The standard of care for EC treatment, or prevention of atypical endometrial hyperplasia (AEH) progression, is hysterectomy. However, women with comorbidities that preclude surgery or those who desire future fertility and wish to keep their reproductive organs intact are treated with synthetic progesterone, termed progestins. While progestins are effective in the treatment of EC, with up to 75% of tumors initially responding to progestin treatment, progression is seen in 20-40% of cases. There are a wide variety of FDA approved progestins across multiple indications, and which progestin to use is currently based on physician’s choice. No systematic comparison has been done for available progestins to determine which progestin is associated with the best treatment response and lowest risk of recurrence. Moreover, little is known about differential patient response to different progestins, and no clinical biomarkers for response have been identified. Finally, despite being successful in the treatment of EC-AEH, progestin use has been shown to increase the risk of developing breast cancer by more than 25%. Multiple clinical trials and animal models have clearly shown progestins, most commonly medroxyprogesterone acetate (MPA), are associated with the development of breast/mammary tumors. Given the widespread use of multiple progestins, there is a critical need to identify the ideal progestin(s) that provides the best efficacy in the uterus, while not promoting tumors in the breast. Our objective in Project 3 is to comprehensively evaluate the effects of each progestin on the spectrum of mammary tumor growth from initiating events to tumor progression. Our hypothesis is that progestins can be identified for the treatment of EC-AEH that have minimal effects on tumor initiation and progression in the mammary gland. We will test this hypothesis in the following Aims: 1) Define the effects of progestins on promoting tumorigenesis in the normal mammary gland. 2) Define the effects of progestins on promoting the progression of early-stage mammary gland tumors. Identifying the ideal progestins that are effective at preventing the progression from AEH to EC, preventing early-stage EC progression to late stage, and preventing the development of breast cancer in women taking these progestins will make a significant impact in how women are treated with progestins and EC-AEH. The number of women electing progestin treatment/prevention for EC is growing, either due to fertility sparing or obesity-related comorbidities contraindicating surgery. This project is anticipated to provide the first comparative analysis of progestins in breast cancer development and progression. A side-by-side evaluation for putative breast tumor-promoting effects of progestins will dictate future treatment decisions for patients with EC-AEH.