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Background: Combined oral contraceptive use is associated with a decreased risk of ovarian carcinoma (cancer). However, the relationship between progestin-only contraceptives and ovarian cancer risk is unclear. Two previous studies have suggested a protective effect whereas another reported a non-statistically significant increased risk of ovarian cancer. The current study examined the association between use of depot medroxyprogesterone acetate (DMPA), a progestin-only injectable contraceptive, and ovarian cancer risk, using data from seven case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Methods: A pooled analysis examining the relationship between DMPA use and ovarian cancer risk was conducted using 7,679 invasive ovarian cancer cases and 11,136 controls from six studies from the United States and one from Australia. Combined oral contraceptive use, parity, education level, age, and race/ethnicity were considered important a priori confounders and were included in all statistical models. OCAC study site was also included in all models. The impact of additional exposures, including a personal history of endometriosis, first-degree family history of ovarian cancer, tubal ligation, breastfeeding, body mass index, and menopausal hormonal therapy use on the association between DMPA use and ovarian cancer were considered. None of these variables was found to impact the DMPA use-ovarian cancer association by >10% and thus not included in the final models. Odds ratios (OR) and 95% confidence intervals (CI) were generated from logistic regression models. The association between duration of DMPA use, categorized as never use, Results: The frequency of DMPA use among controls ranged from 1.25% to 3.53% across the seven studies. DMPA use was more common in controls than in cases in all of the studies. Overall, ever use of DMPA was associated with a 26% decreased risk of ovarian cancer (95% CI 0.58-0.94), after taking into account combined oral contraceptive use, parity, education level, age, race/ethnicity, and OCAC study site. A significant trend with duration of use was observed in the two studies with these data (p=0.02). Conclusions: DMPA use appears to be associated with a decreased risk of ovarian cancer. The finding provides additional evidence that progestins may be protective for ovarian cancer. Further evaluation of the role of DMPA as a potential primary prevention strategy for ovarian cancer, especially in women for whom combined oral contraceptive use is contraindicated due to concerns about estrogen-induced thromboembolic events, is warranted. Citation Format: Minh Tung Phung, Penelope M. Webb, Jennifer Anne Doherty, Holly R. Harris, Pamela J. Thompson, Marc T. Goodman, Kirsten Moysich, Francesmary Modugno, Roberta B. Ness, Joellen M. Schildkraut, Andrew Berchuck, Daniel W. Cramer, Kathryn L. Terry, Linda Titus, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Use of progestin-only injectable contraceptive is associated with reduced risk of ovarian cancer in the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B38.

Background: Endometriosis is a common gynecologic disorder that affects approximately 10% of women of reproductive age. It is also a well-established risk factor for ovarian cancer. Whether hormonal-related and other risk factors for ovarian cancer (e.g., parity, oral contraceptive use) are the same for women with and without endometriosis is currently unknown. Methods: We pooled questionnaire information from 10 population-based case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Data from 8,172 women with invasive epithelial ovarian cancer and 12,464 controls were included in our analysis. Associations of body mass index (BMI), parity, oral contraceptive use, breastfeeding, menopausal hormone therapy use, first-degree family history of ovarian cancer, tubal ligation, and hysterectomy with risk of ovarian cancer were stratified by history of endometriosis and analyzed using logistic regression. All models were conditioned on age, race/ethnicity, education, and OCAC study site. We fit an endometriosis interaction term for each risk factor to evaluate statistical interactions. Results: Among women with no history of endometriosis, those who had hysterectomies showed a 12% increased risk of ovarian cancer compared to those with intact uteri (OR=1.12, 95% CI 1.01-1.24); an increased risk was not observed among women with endometriosis (OR=0.74, 95% CI 0.53-1.05; p-interaction=0.009). Use of estrogen-progestin hormone therapy was associated with decreased risk ovarian cancer for women with histories of endometriosis (OR=0.69, 95% CI 0.47-1.02), but not for those without endometriosis (OR=0.96, 95% CI 0.87-1.07; p-interaction=0.02). We did not observe any significant statistical interactions for the other risk factors considered, and no interactions were significant after consideration of multiple comparisons. Conclusions: The associations of hysterectomy and menopausal estrogen-progestin hormone therapy use with risk of ovarian cancer seemed to differ by endometriosis status, suggesting interactions that may need to be considered in ovarian cancer risk profiling strategies. Future investigations into the biology underlying these interactions would be relevant. Citation Format: Aruna Muthukumar, Lilah Khoja, Penelope M. Webb, Harvey Risch, Jennifer Doherty, Holly Harris, Marc Goodman, Roberta Ness, Francesmary Modugno, Susanne K. Kjaer, Allan Jensen, Joellen Schildkraut, Andrew Berchuck, Kathryn L. Terry, Daniel Cramer, Linda J. Titus, Hoda Anton-Culver, Argyrios Ziogas, Anna H. Wu, Malcolm C. Pike, Celeste L. Pearce, Alice W. Lee. Are ovarian cancer risk factors different for women with endometriosis? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B32.

Background: An estimated 38 million American women currently use contraception, a critical key to women’s health with respect to preventing unwanted pregnancies and reducing maternal morbidity and mortality. Additionally, oral contraceptives (OC) reduce ovarian cancer risk by an estimated 15-30% and are credited with the decreasing ovarian cancer incidence over recent decades. However, contraceptive patterns are changing, with OC use decreasing in favor of intrauterine devices (IUDs). Studies regarding IUD use and ovarian cancer risk are inconsistent, with most reporting decrease in risk or no association. Differences between these studies could be attributable to IUD type, duration of use, age at first use, or type of ovarian cancer. Here we examined the association between IUD use, including duration, type, and timing of use, and ovarian cancer risk using three population-based studies. Methods: In the New England Case-Control Study, a population-based study enrolling participants in New Hampshire and Eastern Massachusetts from 1992 to 2008, 2,323 ovarian cancer cases and 2,339 frequency-matched population-based controls were included in the analysis. Information on IUD use was collected using questionnaire data at time of enrollment. Unconditional logistic regression adjusted for potential confounders including age, body mass index, smoking status, age at menarche, parity, OC use, tubal ligation, genital powder use, endometriosis, family history of ovarian cancer, center, and study phase was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). In the Nurses’ Health Studies (NHS/NHSII), prospective cohort studies established in 1976 and 1989 enrolling 121,700 and 116,429 registered nurses residing in 11 and 14 US states, 1,761 ovarian cancer cases were confirmed through 2015. Information on IUD use was collected in biennial questionnaires from 1976 to 1982. Cox regression adjusted for potential confounders listed above was used to calculate the hazard ratios (HRs) and 95% CIs. NHS and NHSII cohorts were pooled and models were adjusted for cohort. Polytomous logistic regression was used to evaluate the association by histotypes. Results: Overall, IUD use was not associated with ovarian cancer risk (OR=0.99, 95%CI: 0.83-1.17 in NEC; HR=0.89, 95%CI: 0.69-1.15 in NHS/NHSII). While histotype specific associations were not significantly different, IUD use was suggestively associated with increased risk of serous borderline tumors (OR=1.42, 95% CI: 1.00-2.02 in NEC). There was no significant difference by IUD type, duration, or age at first IUD use. The association between IUD use and ovarian cancer risk did not differ when stratified by parity. Conclusion: IUD use was not significantly associated with ovarian cancer risk, although the current study was limited by small sample size to investigate the association between detailed IUD use and risk. Larger studies are warranted to further investigate the association between patterns of IUD use and ovarian cancer risk. Citation Format: Naoko Sasamoto, Jiaxi Yang, Ana Babic, Allison F. Vitonis, Daniel W. Cramer, Linda J. Titus, Shelley S. Tworoger, Kathryn L. Terry. Intrauterine device use and ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B42.

Among the limited studies assessing the association between physical activity and ovarian cancer survival, results have been inconsistent. Therefore, we investigated the relation of pre- and postdiagnosis physical activity with risk of death among women with ovarian cancer in two prospective cohort studies, the Nurses’ Health Study (NHS) and NHSII. Analyses included 1,113 women with confirmed invasive, stage I-III epithelial ovarian cancer (611 ovarian cancer specific deaths). We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by physical activity levels, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index, and nonsteroidal anti-inflammatory use (postdiagnosis models only). Neither prediagnosis physical activity (assessed a median of 12 months before diagnosis) nor postdiagnosis physical activity (assessed a median of 19 months after diagnosis) was significantly associated with risk of ovarian cancer death. For example, comparing women participating in ≥27 vs. Citation Format: Tianyi Wang, Mary Townsend, Heather Eliassen, Kathryn Terry, Mingyang Song, Shelley Tworoger. Physical activity and survival following diagnosis with ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B47.

BACKGROUND: Cancer antigen 125 (CA125) is a membrane bound glycosylated mucin which has been reported to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening with CA125 and transvaginal ultrasound to usual care have shown no clinically significant difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity and variation between individuals by personal characteristics. Identifying personal characteristics that influence CA125 levels could be used to create personalized thresholds for CA125 thereby improving its performance as an ovarian cancer screening biomarker. We developed and conducted internal and external validation of two prediction models (linear and dichotomous) of circulating CA125 among postmenopausal women using 28,842 controls without ovarian cancer in four large population-based studies. METHODS: We identified controls from three prospective cohort studies, including Prostate, Lung, Colorectal, and Ovarian (PLCO, n=26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n=861), and the Nurses' Health Studies (NHS, n=164) as well as one population-based case-control study, the New England Case Control Study (NEC, n=1,000). CA125 was measured using the CA125II assay in PLCO, NHS, and NEC. Meso Scale Discovery (MSD) platform was used to measure CA125 in EPIC. The MSD assay values were recalibrated to the CA125II scale based on 534 NEC controls with both measurements. CA125 levels were log-transformed to achieve normal distribution or dichotomized by the upper limit of normal (35 U/ml). The prediction models were developed and internally validated using postmenopausal controls in PLCO, and then were externally validated using postmenopausal controls in EPIC, NHS and NEC. The prediction models were developed using stepwise linear or logistic regression with RESULTS: The linear CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, parity, age at menopause, and duration of HRT use as predictors, explaining 5% of the variability of log-transformed CA125 levels. The correlation coefficient of the measured and predicted log-transformed CA125 was 0.18 in the PLCO testing dataset, and showed comparable correlations across the independent validation datasets (0.14-0.16). The dichotomous CA125 prediction model included age, race, BMI, duration of HRT use, and hysterectomy as predictors with an AUC of 0.63 in the PLCO testing dataset and 0.71 in NEC. CONCLUSION: We developed linear and dichotomous circulating CA125 prediction models in postmenopausal women that can form the foundation for creating personalized thresholds of CA125. However, other factors should be considered to increase the predictive capacity of the model. Citation Format: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Renée T. Fortner, Allison F. Vitonis, Hidemi Yamamoto, Raina N. Fichorova, Daniel W. Cramer, Rudolf Kaaks, Shelley S. Tworoger, Kathryn L. Terry. DEVELOPMENT AND VALIDATION OF CIRCULATING CA125 PREDICTION MODEL IN POSTMENOPAUSAL WOMEN WITHOUT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-013.

BACKGROUND: Polycystic ovary syndrome (PCOS), a complex endocrine disorder that has an estimated prevalence of 4-21% in reproductive aged women, is characterized by oligomenorrhea (i.e. infrequent or irregular periods) and abnormal hormone levels including hyperandrogenism, hyperinsulinemia, and gonadotropin imbalance which could influence ovarian cancer risk. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a non-significant decreased risk of invasive ovarian cancer among women with self-reported PCOS. When infrequent and irregular periods were examined as a proxy for PCOS, women reporting these characteristics had a decreased risk of invasive ovarian cancer that was consistent across most histotypes. However, given the limitations of self-reported PCOS, potential confounding, and that oligomenorrhea only captures one facet of PCOS, the causality of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization (MR), the analytical method that capitalizes on the random assortment of genes from parents to offspring, to examine the association between PCOS and ovarian cancer independent of exposure misclassification and confounding variables. METHODS: We conducted a literature search to identify single nucleotide polymorphisms (SNPs) associated with PCOS for use as instrumental variables. Using summary statistics from a previously conducted genome wide association study (GWAS) of ovarian cancer among European ancestry women within OCAC (22,406 invasive cases and 40,941 controls), we assessed the association between genetically predicted PCOS and ovarian cancer risk using an inverse-variance weighted method. The associations were examined overall and by histotype. In addition, as oral contraceptives have a well-established protective effect on ovarian cancer risk and are a first-line treatment for women with PCOS to manage menstrual irregularities, hyperandrogenism, and acne, we evaluated the association between PCOS-associated SNPs and oral contraceptive use using publicly available GWAS data. RESULTS: We identified 7 SNPs that were associated with PCOS on genome-wide significance levels in European populations. A statistically significant inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk with an odds ratio (OR) of 0.89 (95% confidence interval [CI] = 0.82-0.97; p=0.006). When results were examined by histotype, there was a statistically significant inverse association between genetically predicted PCOS and the high-grade serous (OR=0.88; 95% CI=0.79-0.97; p=0.012; cases=13,307) and endometrioid (OR=0.73; 0.60-0.88; p=0.001; cases=2,810) histotypes. None of our instrument SNPs were associated with ever use of oral contraceptives after adjusting for number of tests. We conducted a sensitivity analyses of our MR analyses excluding two SNPs that showed nominal association (p CONCLUSION: Our study provides evidence for a causal relationship between PCOS and ovarian cancer risk, with PCOS reducing risk of most histotypes of ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand the mechanisms underlying this association. Citation Format: Holly R. Harris, Kara L. Cushing-Haugen, Sara Lindström, Kathryn L. Terry. POLYCYSTIC OVARY SYNDROME AND OVARIAN CANCER RISK: A MENDELIAN RANDOMIZATION ANALYSIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-007.

CA125 has proven to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound (TVU) to usual care have shown no clinically important difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity, which could be due in part to its expression on variety of tissues, including the lung, pancreas, stomach, liver, endometrium, and breast. In addition, CA125 levels vary between individuals based on demographic, reproductive, and lifestyle characteristics. We hypothesize that, independent of ovarian cancer, genetic variation may influence CA125 levels and identification of genetic predictors of CA125 may be used to develop individualized cut-off points, in combination with personal characteristics, to improve the predictive value of CA125 as an ovarian cancer screening biomarker. Furthermore, studies showing that CA125 binds to natural killer cells and monocytes, dampening immune response, suggest that CA125 may contribute to ovarian cancer progression through immune dysregulation. Thus, identifying genetic variants associated with CA125 levels could add another layer of understanding of the biologic role of elevated CA125 in ovarian cancer progression. To test our hypothesis, we evaluated the association between common germline genetic variants across the genome in relation to serum levels of CA125 among 347 women without ovarian cancer recruited as population-based controls in the New England Case Control Study, a population-based study of ovarian cancer that enrolled participants between 1992 and 2008 in eastern Massachusetts and New Hampshire. We used linear regression to identify SNPs associated with CA125 using the Rare variant (RV) test. To account for multiple testing, a p-value threshold of 5x10-8 was used. We adjusted for age and three principal components to account for potential population stratification. While there were no GWAS-significant SNPs, rs12602627 on chromosome 17 was associated with a 75% increase in CA125 per additional variant allele of rs12602627 (p=6.47x10-8). Furthermore, there were two SNPs (rs12602169 and rs73990427) in close proximity that were nearly GWAS significant (p=7.12x10-8 and 8.97x10-8, respectively). rs12602627 explained 8% of the variability of CA125. Monocyte to macrophage differentiation associated (MMD) is the closest gene to rs12602627. MMD encodes a protein expressed in differentiated mature macrophages and is involved in macrophage activation, suggesting it may play an important role in immune response. This is the first GWAS study to assess SNPs directly associated with circulating levels of CA125 in women without ovarian cancer. Validation studies are currently under way. Results from these analyses may provide important insights into genetic determinants of CA125 levels, improved ovarian cancer screening, and better understanding of how CA125 contributes to ovarian cancer pathogenesis and progression. *Coauthors. Citation Format: Naoko Sasamoto, Lai Jiang, Allison F. Vitonis, Raina N. Fichorova, Paul Pharaoh, Daniel W. Cramer, Peter Kraft, Kathryn L. Terry. Genome-wide association study of cancer antigen 125. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B19.

Introduction: Prostaglandin E2 (PGE2) is thought to influence ovarian carcinogenesis by increasing cell proliferation, tumor cell invasiveness, and angiogenesis. PGE-M is the major metabolite of PGE2 and a marker of systemic PGE2 production. Prior research has reported positive associations between urinary PGE-M and risk of colorectal, gastric, lung, pancreatic, and breast cancer; however, this is the first study to evaluate the association between urinary PGE-M and risk of ovarian cancer. Methods: We conducted a prospective case-control study nested in the Nurses’ Health Study (NHS) and NHSII cohorts. We included 194 cases of invasive epithelial ovarian cancer and 387 matched controls. All cases were diagnosed between the time of urine specimen collection (1996-97 NHSII; 2000-2002 NHS) and the end of follow-up (2015). Controls were selected using incidence density sampling and matched to cases on year of birth, menopausal status at collection and diagnosis, date and time of day of collection, hormone therapy use at collection, and fasting status. We measured PGE-M levels using LC/MS methods, and used the PGE-M distribution among controls to identify tertile cutpoints. We estimated the association between prediagnosis urinary PGE-M (in tertiles) and risk of ovarian cancer using conditional logistic regression. Results: We observed a suggestively lower risk of ovarian cancer for those with the highest PGE-M levels in NHS (OR=0.66; 95%CI=0.36-1.21; p-trend=0.15; n=123 cases), and no association in NHSII (OR=1.15; 95%CI=0.50-2.67; p-trend=0.75; n=71 cases). When results from the two cohorts were pooled, we observed nonsignificant, lower odds of ovarian cancer among those in the highest tertile of PGE-M compared to the lowest tertile (OR=0.80; 95%CI=0.50-1.27; p-trend=0.34), particularly after restricting our analysis to study participants who provided first morning urine samples (OR=0.68; 95%CI=0.40-1.14; p-trend=0.13). However, when we examined quartiles, no clear association was observed, although power was limited. Conclusions: Overall, our results suggest that higher prediagnosis PGE-M levels are not associated with an increased risk of ovarian cancer. Further analyses are under way to evaluate the potential for effect modification by menopausal status, BMI, and NSAID use. Citation Format: Mollie E. Barnard, A. Heather Eliassen, Bernard A. Rosner, Kathryn L. Terry, Ginger L. Milne, Shelley S. Tworoger. Urinary PGE-M levels and risk of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B08.

BACKGROUND: One recent model of ovarian cancer development divides ovarian cancer into two types. Type II tumors are fast growing, potentially arising from the fallopian tubes, and characterized by tubal precursor lesions with p53 mutations. Type I tumors are slow–growing, arising from the ovary, and characterized by KRAS, BRAF, and PTEN mutations. The purpose of this study was to evaluate the association between selected lifestyle and reproductive risk factors and risk of ovarian cancer defined by expression of p53 (as a marker of Type II disease) and mitogen–activated protein kinase (MAPK), which is upregulated by KRAS and BRAF (as a marker of Type I disease). METHODS: Epithelial ovarian cancer cases with available tumor blocks and cancer–free controls were identified from the Nurses' Health Study (NHS) and NHS II prospective cohorts, and from the population–based New England Case–Control (NECC) study of ovarian cancer. We performed immunohistochemical assays for p53 and MAPK expression. Age– and multivariable–adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between each lifestyle or reproductive risk factor (e.g. parity, oral contraceptive use, tubal ligation, age at menarche, menopausal status, age at menopause, hormone therapy use, and family history of ovarian cancer) and ovarian cancer using polytomous logistic regression. RESULTS: 249 cases and 1051 controls from the NHS/NHS II and 77 cases and 857 controls from the NECC study were included in the analyses. Overall there were few significant differences in lifestyle or reproductive risk factors by p53 or MAPK tumor expression. Increasing parity was associated with a greater decreased risk of p53 negative tumors (OR=0.40; 95% CI=0.26–0.62) than p53 positive tumors (OR=0.85; 95% CI=0.46–1.57) (pheterogeneity=0.03). Family history of ovarian cancer was associated with risk of developing MAPK negative (OR=1.87; 95% CI=1.28–2.74) but not MAPK positive tumors (OR=0.76; 95% CI=0.46–1.23) (pheterogeneity CONCLUSIONS: These findings provide evidence that parity and family history may be associated with tumor subtypes defined by p53 and MAPK expression. However, in future studies other immunohistochemical markers that more clearly define these subtypes should be considered. Citation Format: Holly R. Harris, Megan S. Rice, Amy L. Shafrir, Elizabeth M. Poole, Jonathan L. Hecht, Kathryn L. Terry, Shelley S. Tworoger. LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-008.

Introduction: Ovarian cancer survival is poor particularly for women with platinum-resistant disease. Therefore evaluating pre-diagnostic risk factors that are associated with ovarian cancer survival and platinum resistance in particular may help identify women who will not benefit from standard therapy. However, limited research has assessed pre-diagnostic reproductive and hormonal factors in relation to ovarian cancer survival and no studies have assessed these factors with platinum resistance. Objective: To evaluate the association of pre-diagnostic reproductive and hormonal factors with both ovarian cancer survival and platinum resistance among ovarian cancer patients. Methods: We included 1,648 cases of invasive epithelial ovarian cancer from a population-based case-control study with cases and controls recruited in Eastern Massachusetts and New Hampshire from 1992-2008. Reproductive and hormonal factors, including oral contraceptive use, parity, tubal ligation and endometriosis, were assessed during in-person interviews. Invasive ovarian cancer cases who received platinum chemotherapy and had medical record follow-up data (n=610) were included in the analyses on platinum resistance, which was defined as a recurrence within the first six months after the end of platinum-based chemotherapy. We used Cox proportional hazards models to calculate overall ovarian cancer survival and platinum resistance controlling for age, enrollment wave, reproductive factors, and tumor histology and stage. The same reproductive and hormonal factors were assessed for ovarian cancer survival and platinum resistance. As the cause of death was not known for all cases, we also restricted follow-up to the first five years when the vast majority of deaths should be from ovarian cancer in a secondary analysis. Results: We observed 906 deaths during 13,920 person-years of follow-up. Self-report of a physician diagnosis of endometriosis was associated with a 28% (95% CI: 0.55-0.95; p=0.02) decreased risk of death from ovarian cancer. We observed no association between oral contraceptive use, parity, age at first birth, and ovulatory years and ovarian cancer survival (p>0.17). Restricting analyses to the first five years did not substantially change the results. In preliminary analyses, 162 of the 610 women with platinum-based therapy had a disease recurrence within six months of ending treatment over 3,216 person-months of follow-up. Ever having a spontaneous or induced abortion was associated with a 44% (95% CI: 1.00-2.07; p=0.05) increased risk of platinum resistance but was not associated with overall ovarian cancer survival (p=0.18). Additionally, there was a suggestion that increasing age at menarche (Hazard ratio (HR): 1.13; 95% CI: 0.99-1.29 per year; p=0.07) and physician-diagnosed endometriosis (HR: 0.45; 95% CI: 0.19-1.05; p=0.06) were associated with platinum resistance. No association was observed for oral contraceptive use, parity, age at first birth, and ovulatory years (p>0.53), although the results were based on a small sample size. Conclusion: Increasing age at menarche and ever having a spontaneous or induced abortion were associated with an increased risk of platinum chemotherapy resistance. Additionally, physician-diagnosed endometriosis was associated with a reduced risk of ovarian cancer death and a suggestion of a reduced risk of platinum-resistance after adjusting for various factors including tumor histology. Although endometriosis increases the risk of endometrioid and clear cell tumors, which tend to have a more favorable prognosis, our data suggest endometriosis may improve survival through pathways other than tumor histology. Citation Format: Amy L. Shafrir, Ana Babic, Rulla M. Tamimi, Bernard A. Rosner, Shelley S. Tworoger, Kathryn L. Terry. Reproductive and hormonal risk factors in relation to ovarian cancer survival and platinum resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B33.

Background: Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels (SHBG) and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer. Methods: We investigated the association between menstrual cycle characteristics and PCOS among 2071 women with epithelial ovarian cancer and 2100 controls in the New England Case-Control Study (1992-2008). Women self-reported menstrual cycle irregularity, menstrual cycle length, and previous diagnosis of PCOS. We used unconditional logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether the associations differed across histologic subtypes. Results: Overall, we observed no difference in ovarian cancer risk between women who reported periods that were never regular and women who did not report menstrual cycle irregularity (multivariable OR=0.87; 95% CI=0.69-1.10). A similar association was observed for those reporting an average menstrual cycle length of greater than 35 days with a multivariable OR of 0.87 (95% CI=0.47-1.60). In addition, no association was observed with self-reported PCOS and ovarian cancer (multivariable OR=0.96; 95% CI=0.60-1.54). When we examined the associations by histologic subtype, we observed significant differences in the association with menstrual cycle irregularity as the exposure (pheterogeneity=0.007) but not for cycle length >35 days or self-reported PCOS. Menstrual cycle irregularity was protective for serous invasive tumors (OR=0.66; 95% CI=0.47-0.91) but was associated with a non-significant increase in risk of serous borderline tumors (OR=1.32; 95% CI=0.86-2.03). Conclusions: Our results suggest that menstrual cycle characteristics may have influences on ovarian cancer risk that vary by histologic subtype. Future research in a large collaborative consortium may help clarify these associations. Citation Format: Holly R. Harris, Linda J. Titus, Daniel W. Cramer, Kathryn L. Terry. Menstrual cycle characteristics, PCOS, and ovarian cancer risk. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B37.

Background: CA125 is elevated in 80% of ovarian cancer cases and has proven utility in assessing response to therapy and prognosis. Unfortunately, CA125 is elevated in a variety of benign conditions and only in 50% of early stage ovarian cancers, resulting in a sensitivity and specificity unacceptable for population-based screening. Therefore, understanding factors that influence CA125 at presentation could provide important insights for interpreting CA125 values. Methods: Using pre-treatment CA125 and detailed epidemiologic data from 12 studies participating in the Ovarian Cancer Association Consortium (OCAC), we evaluated factors previously reported to influence CA125 levels, including age, race, oral contraceptive use, parity, tubal ligation, endometriosis, body mass index (BMI), personal history of breast cancer, or a family history of breast or ovarian cancer. We used linear regression to estimate the association between each variable and CA125 probit scores, which we used to standardize values between studies. Secondary analyses included adjustment for histologic subtype. We also estimated the associations within each study using log-transformed CA125 as the outcome and estimated summary measures using random effects meta-analyses. Results: Of the 4417 cases included in the analysis, 2918 (66%) were serous, 227 (5%) were mucinous, 484 (11%) were endometrioid, and 258 (6%) were clear cell carcinomas. Median CA125 values varied between studies with a high of 831 U/mL and a low of 271 U/mL. We observed no association between race, oral contraceptive use, tubal ligation, endometriosis, prior breast cancer, and family history of breast cancer and pre-treatment CA125. However, we observed increased pre-treatment CA125 levels with older age (>70 vs. < 50, p=0.03), parity (p=0.01), number of children (p=0.02), obesity (BMI>30 vs. 21-25, p=0.03), and family history of ovarian cancer (p=0.05). Results were similar but attenuated when we calculated summary estimates of the association using meta-analysis of study specific estimates of the association with log-transformed CA125 rather than probit scores. Age and BMI remained predictive of pre-treatment CA125 values after adjustment for histologic subtype. Our data are limited by between site variability in CA125 assays; therefore, validation of these findings is needed with adjustment for type of assay used or in a study population in which all cases had pre-treatment CA125 values measured with the same assay. Conclusions: Despite these limitations, results from this analysis of over 4000 ovarian cancer cases suggest that age and body size may influence pre-treatment CA125 values. Citation Format: KL Terry, A Babic, BY Karlan, MT Goodman, D Lambrechts, F Heitz, K Matsuo, I McNeish, T Pejovic, S Kruger Kjaer, PM Webb, E Hogdall, EL Goode, DW Cramer, for the Ovarian Cancer Association Consortium. Epidemiologic predictors of pre-treatment CA125 in women with ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS13.