ABSTRACT Contraceptive patterns are changing and the implications for ovarian cancer risk are unknown. Oral contraceptives (OCs), which are an established protective factor for ovarian cancer, are being used less frequently and intrauterine device use (IUD) is on the rise. However, the impact of changing contraceptive patterns on ovarian cancer incidence is unclear. While most studies of IUDs and ovarian cancer risk suggest an inverse association, some studies report no association or even a slight increase in risk. Differences between these studies could be attributable to IUD type, timing, or molecular features of tumors including histotypes. Preliminary data from the New England Case Control (NEC) Study suggest the association between IUDs and ovarian cancer risk vary by histotype, with a non-significant decrease in risk of low-grade serous and clear cell tumors but not for other histotypes. Furthermore, we observed an increased risk of ovarian cancer with low tumor stromal CD163 expression, reflecting heme scavenger receptor expression decreased M2-type macrophage infiltration. These observations suggest the impact of IUD use on ovarian cancer risk may differ by subtype and subgroup, but larger samples sizes are needed. Inflammation is known to play a role in ovarian cancer pathogenesis, and IUDs exert their physiologic effect through local inflammation. However, IUD-associated inflammation may be accompanied by an immune response that could lead to clearance of premalignant cells or local infection. An appreciation of how ovarian cancer risk varies by expression of immune markers within tumors may inform the biologic mechanisms possibly involved (e.g. CD3, CD8, CD4, CD69, FOXP3, CD163). Here we propose to evaluate the association between IUD use and ovarian cancer risk in 17 case control studies and 7 cohort studies with a total of more than 20,000 cases that collected, with varying degrees of detail, data on IUD type and timing of use (e.g. age at use and before/after first birth), as well as detailed histologic data critical for distinguishing ovarian cancer subtypes. Importantly, our proposed research includes a case-control study of African American women enrolled between 2010-2015, reflecting recent contraceptive trends and increasing diversity. The inclusion of cohort studies with updated contraceptive use data and a case-control study which recently completed enrollment will provide information on the contemporary contraceptive use. Furthermore, we will utilize unique resources and innovative platforms to examine the potential mechanisms through which contraceptive choice influences ovarian cancer risk. In more than 3,000 cases with detailed contraceptive data, we will simultaneously measure a panel of immune markers by multiplex immunofluorescence which shows co-localization of marker expression. Both the high prevalence and modifiable nature of contraceptive use make this an important public health question with a significant impact on the population burden of ovarian cancer.

NARRATIVE Changing contraceptive patterns, specifically the decline of oral contraceptives and rise intrauterine devices, could have important implications for future ovarian cancer risk. Leveraging data from 24 population-based studies including more than 700,000 women (>20,000 cases) as well as ovarian cancer tissue (>3,000) to examine local immune mechanisms with cutting-edge multiplex immunofluorescence technology, we will evaluate how this highly prevalent and modifiable risk factor may impact the population burden of this extremely fatal disease.