Aim 4: Prevention
Identify the molecular expression patterns associated with the chemoprotective effects of progestin as well as the profiles that are associated with.
Epidemiological studies have demonstrated that OCP use lowers the risk of subsequent endometrial and ovarian cancer. Although the biologic mechanism(s) underlying the protective effect of OCP's on the risk of both of these cancers have not been well defined, there is evidence to suggest that biologic effects related to the progestin component may underlie the cancer preventive effects of the OCP.
Recent studies have reported the
progestin-mediated activation of apoptosis in endometrial cancer cell lines and
endometrial hyperplasias. The finding that progestin activates the apoptosis
pathway in endometrial cells raises the possibility that this may be a major
mechanism underlying the therapeutic effect of progestins against endometrial
hyperplasia. It is interesting that tumors arising from the ovary and
endometrium share common epidemiological risk factors, and that both the
endometrium and ovarian surface epithelium share a common embryological
precursor. It is thus plausible that progestins activate similar molecular
pathways relevant to cancer prevention in both of these organ sites.
Investigators from Walter Reed are currently collecting uterine, fallopian tube and ovarian specimens from patients enrolled in a randomized placebo controlled study that is being conducted with Northwestern University. Patients are given progestin or placebo for four weeks prior to undergoing an indicated hysterectomy for benign disease. This study evaluates the molecular changes that occur in the endometrium as a result of progestin treatment. Using the specimens collected in this trial, investigators from the Gynecologic Disease Program will also analyze fallopian tube and ovary to improve our understanding of the molecular processes involved with hormonal chemoprevention.
The relationship between obesity and endometrial cancer has been documented in numerous epidemiological studies. Women who are 30 pounds over ideal weight have a three-fold increased risk of developing endometrial cancer, and those 50 pounds or more over ideal weight have a 10-fold increase in risk. Investigators from the American Cancer Society also reported last year in the New England Journal of Medicine that obesity increased the risk of cancer related death in endometrial cancer to a greater extent than for any other type of cancer evaluated in this analysis. These findings suggest the need for a chemopreventive agent in these high-risk patients.
The Gynecologic Disease Center at Walter Reed recently completed a study in collaboration with the Centers for Disease Control, Duke University, and the National Cancer Institute. This case-control study involved approximately 3000 patients and revealed that oral certain types of oral contraceptive are more protective in obese patients. Using this information, investigators from the Gynecologic Disease Program have developed experiments aimed at improving our understanding of the hormonal prevention of endometrial cancer and the interplay that it has with dietary intake.