Abstract
B147
Because there are no effective screening methods for ovarian cancer, most patients are diagnosed at an advanced stage of the disease. Therefore, it is widely accepted that prevention is the key to a reduction in ovarian cancer mortality. Epidemiological studies have suggested that the use of hormonal contraception is protective against ovarian cancer. This protection is thought to be a result of either ovulation suppression or decreased gonadotrophins. There are limited biologic data, however, which support these findings or evaluate a possible mechanism of action. In this study, we examine whether the hormonal components of oral contraceptives and a GnRH agonist could influence ovarian carcinogenesis in a genetically engineered mouse model of ovarian cancer. A mouse model of ovarian carcinoma was recently developed by Dinulescu et al, using recombinant adenovirus expressing Cre recombinase (AdCre) to specifically infect ovarian surface epithelium. Cre-mediated activation of K-ras along with inactivation of Pten results in metastatic endometroid ovarian carcinoma. LSL-K-rasG12D/+PtenloxP/loxP mice were treated with 90-day time release pellets containing placebo (n=13), norethindrone and ethinyl estradiol (n=13), norethindrone alone (n=12) or a GnRH agonist (n=12). Three weeks after beginning treatment ovarian cancer was initiated by injection of adenoviral Cre recombinase into the ovarian bursa. Mice were monitored for 8 weeks and then sacrificed. The majority of the mice in our study (84%) developed ovarian tumors ranging in size from 0.1 to 8 grams. Metastatic nodules to the diaphragm, omentum and small bowel were noted ranging in number from 2 to 25. We found that treatment with the GnRH agonist increased mean tumor volume compared to control (1130 mm3 vs 560 mm3) but the increase did not reach statistical significance (p=0.2). The tumor volume in the combined norethindrone and ethinyl estradiol and the norethindrone alone groups were 444 mm3 and 498 mm3 respectively. There was no difference in mean tumor volume, metastasis or ascites in the mice treated with the various hormonal components as compared to placebo. This study did not confirm the protective effect of hormonal contraception seen in epidemiological studies and even suggests that the GnRH agonist may have resulted in increased tumor burden. Ongoing research aims to determine the molecular changes occurring in the various treatment groups and further explore potential mechanisms of action of the reduced risk of ovarian cancer seen with hormonal contraceptive use.
Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA