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Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

Objective To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. Methods We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). Results Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). Conclusions The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.

Background: Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but previous studies have been underpowered. Methods: The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case–control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted. Results: Ever use of DMPA was associated with a 35% decreased risk of ovarian cancer overall (OR, 0.65; 95% confidence interval, 0.50–0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (Ptrend < 0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk. Conclusions: DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted. Impact: The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices that have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.

Author(s): Lee, Alice W; Rosenzweig, Stacey; Wiensch, Ashley; Australian Ovarian Cancer Study Group; Ramus, Susan J; Menon, Usha; Gentry-Maharaj, Aleksandra; Ziogas, Argyrios; Anton-Culver, Hoda; Whittemore, Alice S; Sieh, Weiva; Rothstein, Joseph H; McGuire, Valerie; Wentzensen, Nicolas; Bandera, Elisa V; Qin, Bo; Terry, Kathryn L; Cramer, Daniel W; Titus, Linda; Schildkraut, Joellen M; Berchuck, Andrew; Goode, Ellen L; Kjaer, Susanne K; Jensen, Allan; Jordan, Susan J; Ness, Roberta B; Modugno, Francesmary; Moysich, Kirsten; Thompson, Pamela J; Goodman, Marc T; Carney, Michael E; Chang-Claude, Jenny; Rossing, Mary Anne; Harris, Holly R; Doherty, Jennifer Anne; Risch, Harvey A; Khoja, Lilah; Alimujiang, Aliya; Phung, Minh Tung; Brieger, Katharine; Mukherjee, Bhramar; Pharoah, Paul DP; Wu, Anna H; Pike, Malcolm C; Webb, Penelope M; Pearce, Celeste Leigh | Abstract: BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend l .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

Background Breast cancer is the most common cancer in women worldwide, with a great diversity in outcomes among individual patients. The ability to accurately predict a breast cancer outcome is important to patients, physicians, researchers, and policy makers. Many models have been developed and tested in different settings. We systematically reviewed the prognostic models developed and/or validated for patients with breast cancer. Methods We conducted a systematic search in four electronic databases and some oncology websites, and a manual search in the bibliographies of the included studies. We identified original studies that were published prior to 1st January 2017, and presented the development and/or validation of models based mainly on clinico-pathological factors to predict mortality and/or recurrence in female breast cancer patients. Results From the 96 articles selected from 4095 citations found, we identified 58 models, which predicted mortality (n = 28), recurrence (n = 23), or both (n = 7). The most frequently used predictors were nodal status (n = 49), tumour size (n = 42), tumour grade (n = 29), age at diagnosis (n = 24), and oestrogen receptor status (n = 21). Models were developed in Europe (n = 25), Asia (n = 13), North America (n = 12), and Australia (n = 1) between 1982 and 2016. Models were validated in the development cohorts (n = 43) and/or independent populations (n = 17), by comparing the predicted outcomes with the observed outcomes (n = 55) and/or with the outcomes estimated by other models (n = 32), or the outcomes estimated by individual prognostic factors (n = 8). The most commonly used methods were: Cox proportional hazards regression for model development (n = 32); the absolute differences between the predicted and observed outcomes (n = 30) for calibration; and C-index/AUC (n = 44) for discrimination. Overall, the models performed well in the development cohorts but less accurately in some independent populations, particularly in patients with high risk and young and elderly patients. An exception is the Nottingham Prognostic Index, which retains its predicting ability in most independent populations. Conclusions Many prognostic models have been developed for breast cancer, but only a few have been validated widely in different settings. Importantly, their performance was suboptimal in independent populations, particularly in patients with high risk and in young and elderly patients. Electronic supplementary material The online version of this article (10.1186/s12885-019-5442-6) contains supplementary material, which is available to authorized users.

Background: Ovarian cancer incidence rates in the U.S. decreased since the early 1970s, which was largely attributed to increasing parity among birth cohorts through 1935 and the introduction of combined oral contraceptives (COCs) in the 1960s. However, COC use prevalence has dramatically declined among 20-34 year-olds since the early 2000s as has parity. Ovarian cancer histotypes share many risk factors, including parity and COC use, but the magnitude of the effects differs by histotype. In addition, the prevalence of these risk factors differs by race/ethnicity. Understanding the trends in ovarian cancer incidence by histotype and race/ethnicity will allow us to consider the impact of changes in risk factor profiles. Methods: Ovarian cancer incidence rates in 1992-2017 were obtained from the Surveillance, Epidemiology, and End Results (SEER) 13 registry. Age-standardized ovarian cancer incidence trends for the three most common histotypes (high-grade serous (HGS), endometrioid and clear cell) and four racial/ethnic groups (Hispanic, Asian/Pacific Islander (API), non-Hispanic Black (NHB), and non-Hispanic White (NHW)) were analyzed using joinpoint regression. Temporal trends of each histotype were analyzed using age-period-cohort models. Results: Joinpoint regression analysis: NHW had the highest incidence rates for HGS and endometrioid cancers, while API had the highest rate for clear cell cancer. HGS cancer incidence declined in all racial/ethnic groups during 1992-2017; NHW had the greatest reduction. Endometrioid cancer incidence decreased in NHW and NHB but increased in Hispanics in recent years. All racial/ethnic groups showed an increasing trend of clear cell cancer incidence. Age-period-cohort analysis: HGS cancer incidence has been decreasing in NHW and API by birth cohort, but not in NHB or Hispanics. There is a decreasing trend in HGS cancer incidence by period in NHW, but no clear period-specific pattern was observed among other racial/ethnic groups. Endometrioid cancer incidence has been decreasing in NHW and API, but increasing in NHB and Hispanics in recent cohorts. Clear cell cancer incidence has been increasing by birth cohort in all racial/ethnic groups. Conclusions: HGS and endometrioid cancer incidence has been decreasing overall, but clear cell cancer incidence has been increasing. This may be due to an improvement in diagnosis with a shift from classifying “carcinoma, not otherwise specified” to clear cell cancer. It is also possible that the impact of shifting patterns of lower COC use and parity are having a bigger impact on clear cell cancer given that these exposures are more protective for this histotype. Further, the introduction of opportunistic salpingectomy may balance any impact of COC use or parity changes for HGS cancer. There are differences in the ovarian cancer incidence trends by histotype and race/ethnicity, highlighting the impact of different preventive strategies. Citation Format: Minh Tung Phung, Celeste Leigh Pearce, Rafael Meza, Jihyoun Jeon. Trends of ovarian cancer incidence by histotype and race/ethnicity in the U.S.: 1992-2017 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 794.

Background: Ovarian cancer is the eighth-most common cancer among women. Although a number of established risk factors exist for this disease, analyses of these exposures have largely not taken into account potential interactions. We present an interaction analysis of eight ovarian cancer risk factors, followed by the creation of modifiable and non-modifiable risk scores for the disease. Methods: Data used in this analysis come from nine studies in the Ovarian Cancer Association Consortium (OCAC): one from Australia, one from Europe and seven from the US. Analyses were restricted to pre-menopausal women without first-degree family histories of ovarian cancer, leading to a final study population of 1504 cases and 3515 controls. Five potentially modifiable predictors (oral contraceptive (OC) use duration, body mass index, tubal ligation, hysterectomy and breastfeeding) and three non-modifiable predictors (parity, incomplete pregnancies and history of endometriosis) were considered. A complete analysis of interactions between the eight variables as well as with age, race/ethnicity, education level and study site was conducted. No statistically significant pairwise interactions were found with likelihood ratio statistics, thus suggesting no departure from multiplicativity in the odds ratios. The modifiable and non-modifiable risk scores were calculated as the product of the odds ratios for each group of exposures. Logistic regression was used to model the association between ovarian cancer and the risk scores. Age, race/ethnicity, education level and study site were included in the model. Results: The associations between the second, third and fourth quartiles of the modifiable risk score compared to the lowest quartile were 1.67 (95% CI 1.35-2.09), 2.18 (95% CI 1.76-2.71) and 3.72 (95% CI 3.04-4.57), respectively. The odds ratios for the non-modifiable risk score were 1.17 (95% CI 0.95-1.44), 1.24 (95% CI 0.99-1.54) and 2.06 (95% CI 1.68-2.53), respectively for the second, third and fourth quartiles compared to the first. Women in the highest quartiles of both the modifiable and non-modifiable risk scores, representing 14.6% of the women, had a 7.67-fold increased risk of ovarian cancer (95% CI 4.68-11.39) compared to women in the lowest quartiles for both risk scores (3.6% of the women). Conclusions: Pre-menopausal women in the highest risk quartiles have a substantially elevated risk of ovarian cancer based on these eight exposures. Modifiable factors contribute more than non-modifiable factors to ovarian cancer risk among pre-menopausal women with no family history in our study. Women in the highest risk group (fourth quartile of both risk scores) could reduce their risk by intervening on the modifiable exposures; for example, 63% of women in this group had not used oral contraceptives and 93% had not had tubal ligation. However, careful consideration of the risks and benefits of such prevention measures is needed. Citation Format: Minh Tung Phung, Bhramar Mukherjee, Alice W. Lee, Penelope M. Webb, Harvey A. Risch, Jennifer Anne Doherty, Holly R. Harris, Marc T. Goodman, Roberta B. Ness, Francesmary Modugno, Allan Jensen, Susanne K. Kjaer, Kathryn L. Terry, Daniel W. Cramer, Argyrios Ziogas, Hoda Anton-Culver, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Ovarian cancer risk factors multiply to create high risk in pre-menopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3498.

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.