Risk Of Invasive Ovarian Cancer Research Articles

Subfertility, use of fertility treatments and BRCA mutation status and the risk of ovarian cancer

The objective of the study is to evaluate the possible association between history of subfertility, fertility treatments, BRCA mutations and the risk of ovarian cancer. This Israeli National Case-Control study included 1269 consecutive ovarian cancer cases and 2111 individually matched healthy controls. All participants were interviewed and molecular analysis of BRCA mutations were performed to 896 cases. The main outcome measure was reported history of subfertility and exposure to fertility treatments. The rate of reported subfertility was 15.1% and 14.3% in ovarian cancer cases and controls, respectively. However, subfertility was more prevalent in cases with borderline ovarian cancer (but not for invasive ovarian cancer cases) than controls. Multivariate conditional logistic regression revealed that the risk of borderline ovarian cancer was elevated in both women treated for subfertility and those that were not treated for subfertility, (OR = 1.74; 95% CI 0.9-3.36 and OR = 1.79; 95% CI 0.98-3.26, respectively). In non-carriers of BRCA1/2 mutations, fertility treatments were associated with a decreased risk of invasive ovarian cancer while a significant increased risk of borderline ovarian cancer was observed (OR = 2.92, 95%CI 1.67-5.10). Reported subfertility and exposure to fertility treatments were associated with borderline but not with invasive ovarian tumors. This association was more prominent in women who are non-carriers of a BRCA mutation.

First- and second-degree family history of ovarian and breast cancer in relation to risk of invasive ovarian cancer in African American and white women.

Family history (FH) of ovarian cancer and breast cancer are well-established risk factors for ovarian cancer, but few studies have examined this association in African American (AA) and white women by histotype. We assessed first- and second-degree FH of ovarian and breast cancer and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium. Analyses included 1052 AA cases, 2328 AA controls, 2380 white cases and 3982 white controls. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with adjustment for covariates. Analyses were stratified by histotype (high-grade serous vs others). First-degree FH of ovarian cancer was associated with high-grade serous carcinoma in AA (OR = 2.32, 95% CI: 1.50, 3.59) and white women (OR = 2.48, 95% CI: 1.82, 3.38). First-degree FH of breast cancer increased risk irrespective of histotype in AAs, but with high-grade serous carcinoma only in white women. Associations with second-degree FH of ovarian cancer were observed for overall ovarian cancer in white women and with high-grade serous carcinoma in both groups. First-degree FH of ovarian cancer and of breast cancer, and second-degree FH of ovarian cancer is strongly associated with high-grade serous ovarian carcinoma in AA and white women. The association of FH of breast cancer with high-grade serous ovarian carcinoma is similar in white women and AA women, but may differ for other histotypes.

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies.

Parity 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. A 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. Ever 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 < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Incomplete 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.

Abstract C038: First- and second-degree family history of ovarian and breast cancers in relation to risk of invasive ovarian cancer in African American and White women

Abstract Background: Family history of ovarian and breast cancers is a well-established risk factor for ovarian cancer and recent findings suggest that the risk of ovarian cancer may be higher for African American (AA) women compared to other racial/ethnic groups. Few studies have been able to examine this association in both AA and White participants taking into account histotype. Methods: The Ovarian Cancer in Women of African Ancestry Consortium harmonized data from four case-control studies and two case-control studies nested within cohort studies. Each study collected self-reported first-degree family history of ovarian and breast cancers; the four case-control studies also collected self-reported data on second-degree family history of ovarian and breast cancers. For cases, data on age at diagnosis, tumor grade, and tumor histology were abstracted from medical records and cancer registry reports. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with control for covariates. Results: Our sample included 1,052 AA cases, 2,328 AA controls, 2,380 White cases, and 3,982 White controls. The prevalence of first-degree history of ovarian or breast cancer was higher among AA than White ovarian cancer cases (28% vs. 21%) and similar among AA and White controls (15% vs. 16%). The prevalence of second-degree family history of ovarian or breast cancer was similar among AA and White ovarian cancer cases (38% vs. 34%) and among AA and White controls (28% vs. 32%). First-degree family history of ovarian cancer was significantly associated with high-grade serous ovarian cancer in both AA (OR=2.33; 95% CI: 1.48, 3.69) and White participants (OR=2.86; 95% CI: 2.03, 4.02). In AA women, first-degree family history of breast cancer was associated with increased risk of high-grade serous ovarian cancer (OR=1.80; 95% CI: 1.38, 2.34) and all other histotypes combined (OR=1.62; 95% CI: 1.16, 2.25). In White women, first degree family history of breast cancer was associated with high-grade serous ovarian cancer only (OR=1.40; 95% CI: 1.16, 1.68). Second-degree family history of ovarian cancer was associated with high-grade serous ovarian cancer among White women (OR=1.95; 95% CI: 1.32, 2.90) and second-degree family history of breast cancer was associated with high-grade serous ovarian cancer in AA women (OR=1.48; 95% CI: 1.11, 1.98). Second-degree family history of ovarian or breast cancer was not associated with the other histotypes. Estimates across studies were compatible with overall estimates (pheterogeneity&amp;gt;0.05). Conclusion: First-degree family history of ovarian cancer may be more strongly associated with high-grade serous ovarian cancer than other histotypes in AA and White women. Second-degree family history of cancer may differ by race in the associations with ovarian cancer, but potential underreporting of second-degree family history and inability to account for family size limit interpretation of these data. Citation Format: Traci N. Bethea, Heather M. Ochs-Balcom, Elisa V. Bandera, Alicia Beeghly-Fadiel, Fabian Camancho, Emily K. Cloyd, Holly R. Harris, Charlotte E. Joslin, Evan Myers, Patricia G. Moorman, Lauren C. Peres, Veronica W. Setiawan, Anna H. Wu, Lynn Rosenberg, Joellen M. Schildkraut. First- and second-degree family history of ovarian and breast cancers in relation to risk of invasive ovarian cancer in African American and White women [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C038.

Association Between Breastfeeding and Ovarian Cancer Risk

Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent. To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019. Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies. Diagnosis of epithelial ovarian cancer. A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02). Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

Abstract DP-007: POLYCYSTIC OVARY SYNDROME AND OVARIAN CANCER RISK: A MENDELIAN RANDOMIZATION ANALYSIS

Abstract 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&amp;lt;0.05) with oral contraceptives and the association with ovarian cancer was not materially changed. 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.

Abstract 640: Breastfeeding pattern and ovarian cancer risk: Results from the Ovarian Cancer Association Consortium

Abstract Background: Ovarian cancer is the fifth leading cause of cancer deaths in US women with few modifiable risk factors. Breastfeeding has been observed to be associated with reduced risk of ovarian cancer in multiple studies. However, prior studies reporting the association between breastfeeding pattern and ovarian cancer risk by histologic subtypes have reported inconsistent findings, likely due to small sample size and lack of details on breastfeeding patterns. The objective of this study is to evaluate the association between breastfeeding patterns and ovarian cancer risk by histologic subtypes using individual questionnaire data from the Ovarian Cancer Association Consortium (OCAC). Method: We evaluated breastfeeding patterns in relation to invasive ovarian cancer risk in 9,807 cases and 12, 971 controls from 13 studies in the OCAC. We performed pooled unconditional logistic regression to evaluate the association between breastfeeding and ovarian cancer risk and used multinomial logistic regression to evaluate the association by histologic subtype. We restricted the analysis to parous women and adjusted for study site, age, body mass index, race, education, oral contraceptive use, number of full-term births, family history of ovarian cancer, and birth decade (to account for change in breastfeeding practice over time). We additionally adjusted for age at first and last births simultaneously when examining the association between first and last age at breastfeeding and ovarian cancer risk. Results: Women who reported ever breastfeeding had a 24% decreased risk of overall invasive ovarian cancer compared to women who never breastfed (OR=0.76, 95%CI: 0.71-0.81) and this association did not differ significantly by histologic subtypes (p-heterogeneity=0.09). Considering only episodes when women breastfed, we observed lower risk of ovarian cancer in women who had longer average duration per episode compared to women who breastfed &amp;lt; 6 months on average per episode (OR=0.85, 95%CI: 0.77-0.93 for 6-12 months; OR=0.77, 95%CI: 0.66-0.89 for &amp;gt; 12 months; p-trend &amp;lt;0.0001). Older age at first and last breastfeeding was significantly associated with lower risk of ovarian cancer compared to women who never breastfed (OR=0.65, 95%CI: 0.58-0.73 for age &amp;gt;30 years at first breastfeeding; OR=0.60, 95%CI: 0.53-0.69 for age &amp;gt;35 years at last breastfeeding). Compared to women who never breastfed, women who last breastfed &amp;lt; 10 years ago had 54% reduction of risk (OR= 0.46, 95%CI: 0.39-0.56) while women who last breastfed ≥ 30 years ago had 19% reduction of risk (OR=0.81, 95%CI: 0.74-0.88). Conclusion: Breastfeeding regardless of age or duration was associated with reduced risk of ovarian cancer. Our findings support the benefit of breastfeeding as modifiable risk factor for ovarian cancer regardless of histologic subtypes, which has the potential for reducing the incidence this deadly disease. Citation Format: Naoko Sasamoto, Ana Babic, Susan Jordan, Harvey Risch, Holly Harris, Mary Anne Rossing, Jennifer Doherty, Marc Goodman, Pamela Thompson, Susanne K. Kjær, Allan Jensen, Joellen Schildkraut, Linda Titus, Daniel Cramer, Elisa Bandera, Weiva Sieh, Valerie McGuire, Rebecca Sutphen, Celeste L. Pearce, Anna H. Wu, Malcolm Pike, Penelope Webb, Francesmary Modugno, Kathryn Terry. Breastfeeding pattern and ovarian cancer risk: Results from the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 640.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility.

This is an updated version of the original Cochrane Review published in the Cochrane Library in 2013 (Issue 8) on the risk of ovarian cancer in women using infertility drugs when compared to the general population or to infertile women not treated. The link between fertility drugs and ovarian cancer remains controversial. To evaluate the risk of invasive ovarian cancer and borderline ovarian tumours in women treated with ovarian stimulating drugs for subfertility. The original review included published and unpublished observational studies from 1990 to February 2013. For this update, we extended the searches from February 2013 to November 2018; we evaluated the quality of the included studies and judged the certainty of evidence by using the GRADE approach. We have reported the results in a Summary of findings table to present effect sizes across all outcome types. In the original review and in this update, we searched for randomised controlled trials (RCTs) and non-randomised studies and case series including more than 30 participants. At least two review authors independently conducted eligibility and 'Risk of bias' assessments and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We conducted no meta-analyses due to expected methodological and clinical heterogeneity. We included 13 case-control and 24 cohort studies (an additional nine new cohort and two case-control studies), which included a total of 4,684,724 women.Two cohort studies reported an increased incidence of invasive ovarian cancer in exposed subfertile women compared with unexposed women. One reported a standardised incidence ratio (SIR) of 1.19 (95% confidence interval (CI) 0.54 to 2.25) based on 17 cancer cases. The other cohort study reported a hazard ratio (HR) of 1.93 (95% CI 1.18 to 3.18), and this risk was increased in women remaining nulligravid after using clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) versus multiparous women (HR 1.52, 95% CI 0.67 to 3.42) (very low-certainty evidence). The slight increase in ovarian cancer risk among women having between one and three cycles of in vitro fertilisation (IVF) was reported, but this was not clinically significant (P = 0.18). There was no increase in risk of invasive ovarian cancer after use of infertility drugs in women with the BRCA mutation according to one cohort and one case-control study. The certainty of evidence as assessed using GRADE was very low.For borderline ovarian tumours, one cohort study reported increased risk in exposed women with an SIR of 3.61 (95% CI 1.45 to 7.44), and this risk was greater after treatment with clomiphene citrate (SIR 7.47, 95% CI 1.54 to 21.83) based on 12 cases. In another cohort study, the risk of a borderline ovarian tumour was increased, with an HR of 4.23 (95% CI 1.25 to 14.33), for subfertile women treated with IVF compared with a non-IVF-treated group with more than one year of follow-up. A large cohort reported increased risk of borderline ovarian tumours, with HR of 2.46 (95% CI 1.20 to 5.04), and this was based on 17 cases. A significant increase in serous borderline ovarian tumours was reported in one cohort study after the use of progesterone for more than four cycles (risk ratio (RR) 2.63, 95% CI 1.04 to 6.64). A case-control study reported increased risk after clomiphene citrate was taken, with an SIR of 2.5 (95% CI 1.3 to 4.5) based on 11 cases, and another reported an increase especially after human menopausal gonadotrophin was taken (odds ratio (OR) 9.38, 95% CI 1.66 to 52.08). Another study estimated an increased risk of borderline ovarian tumour, but this estimation was based on four cases with no control reporting use of fertility drugs. The certainty of evidence as assessed using GRADE was very low.However, although some studies suggested a slight increase in risks of ovarian cancer and borderline ovarian tumour, none provided moderate- or high-certainty evidence, as summarised in the GRADE tables. Since the last version of this review, only a few new relevant studies have provided additional findings with supporting evidence to suggest that infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated with infertility drugs when compared to the general population or to subfertile women not treated. The risk is slightly higher in nulliparous than in multiparous women treated with infertility drugs, and for borderline ovarian tumours. However, few studies have been conducted, the number of cancers is very small, and information on the dose or type of fertility drugs used is insufficient.

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22406 with invasive disease, 3103 with borderline disease and 40941 controls). An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

Abstract A18: Metabolomic analysis of ovarian cancer risk in the Nurses’ Health Studies: Metabolite associations are more pronounced in non-serous tumors

Abstract Background: To identify potential novel risk factors for ovarian cancer, we assessed the role of metabolites and lipids in the development of ovarian cancer. Prior research suggests that lipid synthesis and metabolism are dysregulated in ovarian tumors. Furthermore, studies show that lysophosphatidylcholines (LPC), PCs, and sphingomyelins (SM) are differentially expressed in ovarian cancer cases versus controls. We used a validated metabolomics platform to assess prediagnosis measures of these lipid classes with ovarian cancer risk and conduct a discovery-based analysis of other metabolites. Methods: LC-MS/MS targeted metabolomics were measured at the Broad Institute (Cambridge, MA, USA). 300 cases were matched to one control on age, menopause status/hormone therapy use, fasting, season, and time of day of blood draw. 348 metabolites and lipids passed QC. Metabolites were transformed using probit scores for normality. We used conditional logistic regression to identify metabolites and lipids associated with total invasive ovarian cancer risk. We used unconditional logistic regression, adjusting for matching factors, in histotype-specific analyses including all available controls, thus increasing power. All analyses adjusted for known risk factors: oral contraceptive use, parity, and tubal ligation. Results: We found 18 metabolites that were associated with risk of invasive ovarian cancer (p≤0.05). These included sphingosine, C3-DC-CH3 carnitine, choline, cytosine, triacylglycerols (TAG), C18:1 SM, lysophosphatidylinositol (LPI), mono hydroxyoctadecadienoic acid, phosphatidylethanolamine (PE), and taurine. The odds ratios ranged between 0.73 and 0.84 per 1 standard deviation (SD) increase in metabolite value. None of the metabolites remained significant after multiple testing correction (false discovery rate (FDR) corrected p≥0.85). In histotype analysis, 13 metabolites were associated with serous disease (p≤0.05). These included C3-DC-CH3 carnitine, 7 TAGs, choline, symmetric dimethylarginine (SDMA), citrulline, cytosine, and 6-deoxodolichosterone. Odds ratios ranged between 0.75 and 0.82 for 1 SD increase in the metabolite values. No metabolites remained significant after multiple testing correction (FDR-corrected p≥0.75). Interestingly, 40 metabolites were associated with non-serous ovarian cancer at p≤0.05. Nearly all were different than those found for total invasive or serous disease. These included pregnanediol-3-glucuronide, laserpitin, trihydroxyecdysone, docosahexaenoic acid, decosapentaenoic acid, niacinamide, testosterone sulfate, alanine, taurine, eicosapentaenoic acid, thiamine, 1-methyladenosine, cajaisoflavone, kurilensoside H, and multiple lipid classes (cholesterol ester (CE), PCs, PE and PC plasmalogens, TAGs, carnitines, SMs, DAG, LPI, lysophosphatidic acid (LPA), lysophosphatidylethanolamine (LPE), PE, TAGs, and diacylglycerols (DAGs)). Odds ratios for protective metabolites ranged between 0.49 and 0.74 while for harmful metabolites they ranged between 1.38 and 1.48 for 1 SD increase in the metabolite values. However, FDR-corrected p-values were ≥0.41. Conclusion: While several metabolites differed between ovarian cancer cases and controls on a nominal p-value scale, none remained significant after multiple testing correction. However, this test does not account for the high correlation between many of the metabolites. Notably, distinct markers were associated with different histotypes and more metabolites were associated with non-serous tumors, which have been associated more strongly with BMI and other metabolic risk factors. For nonserous disease, we observed associations with LPCs, PCs, and SM lipids, which were part of our a priori hypotheses, as well as sex hormone metabolites. Ongoing analyses include adjusting for BMI at age 18 and adolescent somatotype to account for early life adiposity, consideration of other multiple testing correction methods, and pathway analyses. Citation Format: Oana A. Zeleznik, Elizabeth M. Poole, Clary Clish, Heather A. Eliassen, Peter Kraft, Shelley S. Tworoger. Metabolomic analysis of ovarian cancer risk in the Nurses’ Health Studies: Metabolite associations are more pronounced in non-serous tumors. [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 A18.

Abstract B21: C-reactive protein and ovarian cancer risk in the Ovarian Cancer Cohort Consortium

Abstract Background: C-reactive protein (CRP), a general marker of inflammation, has been consistently associated with increased ovarian cancer risk. However, few studies have had the ability to evaluate differences in association by ovarian tumor subtype. Thus, we leveraged previously measured CRP levels in prediagnostic specimens from 6 studies in the Ovarian Cancer Cohort Consortium (OC3). Methods: We pooled data on CRP and ovarian cancer risk among nested case-control studies conducted in CLUEII, EPIC, NHS, NHSII, NYUWHS, and PLCO; invasive ovarian cancer cases were matched to one or two controls on age, menopausal status, hormone therapy (HT) use, and fasting status. Due to variability in CRP distributions across studies in part due to different assays, we regressed CRP levels on study (with EPIC as the reference), adjusting for predictors of CRP, including age, menopause/HT status, fasting status, BMI, aspirin use, and smoking. Levels for each study (except EPIC) were recalibrated based on the beta coefficient for that study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for natural log-transformed CRP (continuous), quartiles (based on control distributions) and clinical cutpoints (&amp;lt;1, 1-&amp;lt;10, ≥10mg/L) using conditional logistic regression, which implicitly accounts for matching factors. We examined associations for all invasive cancer and by histotype (serous [n=740], endometrioid [n=109], mucinous [n=69], clear cell [n=47]). Primary analyses (model 1) adjusted for reproductive risk factors (oral contraceptive use, number of pregnancies, and tubal ligation); model 2 additionally adjusted for known predictors of CRP, including BMI, smoking, and aspirin use, that also may be related to ovarian cancer risk. Results: There was a marginally significant linear association between CRP and total invasive ovarian cancer risk among 1,135 cases and 2,124 controls (p-trend=0.05), which was slightly attenuated when adjusting for BMI, smoking, and aspirin use (p-trend=0.08). The model 1 OR (95% CI) was 1.24 (0.99-1.54) comparing the top to bottom quartile and 1.90 (1.28-2.81) for ≥10 to &amp;lt;1 mg/L. The corresponding OR (95% CI) for model 2 was 1.21 (0.96-1.53) and 1.86 (1.24-2.79), respectively. Results were generally similar across histotypes with the strongest associations comparing CRP levels ≥10 vs. &amp;lt;1mg/L, although no associations reached statistical significance. Interestingly, the impact of adjusting for BMI, smoking, and aspirin differed across subtypes. For example, the OR (95% CI) comparing the top versus bottom quartile for serous tumors increased from 1.25 (0.95-1.65) in model 1 (reproductive factors) to 1.31 (0.97-1.75) in model 2 (reproductive factors and predictors of CRP). Conversely, the association was largely attenuated for endometrioid tumors when adjusting for predictors of CRP (model 1: OR=1.37 [0.72-2.58]; model 2: OR=1.06 [0.52-2.18]). Conclusion: Our results confirm that CRP, particularly very high levels, is positively associated with risk of ovarian cancer. The association for serous tumors appeared to be independent of reproductive exposures and other factors that are associated with CRP and ovarian cancer; however, the relationship observed for endometrioid tumors was largely explained by BMI. Given that fewer risk factors have been identified for serous tumors, our work supports further exploration of inflammation and immunity in the etiology of this histotype. Further analyses will explore associations by other tumor factors (e.g., grade) and participant characteristics (e.g., menopausal status). Citation Format: Britton Trabert, Renee Fortner, Elizabeth Poole, Nicolas Wentzensen, Shelley Tworoger. C-reactive protein and ovarian cancer risk in the Ovarian Cancer Cohort Consortium. [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 B21.

Polycystic Ovary Syndrome, Oligomenorrhea, and Risk of Ovarian Cancer Histotypes: Evidence from the Ovarian Cancer Association Consortium.

Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies.Methods: We analyzed data from 14 case-control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression.Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58-0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65-1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001).Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype.Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174-82. ©2017 AACR.

Abstract 2293: Oligomenorrhea, polycystic ovary syndrome, and risk of ovarian cancer histotypes, evidence from the Ovarian Cancer Association Consortium

Abstract Background: Oligomenorrhea, defined as infrequent or irregular periods has been shown to be associated with epithelial ovarian cancer risk in some but not all studies. Polycystic ovary syndrome (PCOS), which is characterized by oligomenorrhea and abnormal hormone levels including hyperandrogenism, hyperinsulinemia, and gonadotropin imbalance, has been suggested to increase ovarian cancer risk. However, these associations have been rarely examined by histologic subtype. We sought to examine these associations among 14 studies participating in the Ovarian Cancer Association Consortium. Methods: Participants included 16,594 patients with invasive (n=13,719) or borderline (n=2,875) ovarian cancers and 17,718 controls who had answered questions regarding menstrual cycle irregularity, menstrual cycle length, and/or PCOS. Study specific odds ratios (ORs; 95% confidence intervals [95% CI]), adjusted for ovarian cancer risk factors, were calculated and then combined using a random-effects meta-analysis. Pooled histologic subtype specific ORs (95% CI) were calculated using polytomous logistic regression. Results: Women reporting menstrual cycle length &amp;gt;35 days had decreased risk of invasive ovarian cancer compared to women reporting cycle length ≤35 days (OR=0.70; 95% CI=0.58-0.84). Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared to women with regular cycles (OR=0.83; 95% CI=0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR=0.87; 95% CI=0.65-1.15). For menstrual cycle length &amp;gt;35 days, decreased risk was observed for all invasive histotypes: low grade serous (OR=0.48; 95% CI=0.25-0.92), high grade serous (OR=0.62; 95% CI=0.48-0.80), mucinous (OR=0.38; 95% CI=0.19-0.76), endometrioid (OR=0.75; 95% CI=0.54-1.06), and clear cell (OR=0.70; 95% CI=0.43-1.13) but not for serous borderline tumors (OR=1.18; 95% CI=0.87-1.59) (pheterogeneity=0.006). An increased risk of serous borderline disease was observed among women reporting irregular cycles (OR=1.34; 95% CI=1.16-1.55) (pheterogeneity&amp;lt;0.0001). No statistically significant differences by histologic subtype were observed for self-reported PCOS. Conclusion: In this large consortium analysis we observed a decreased risk of most invasive epithelial ovarian cancer histotypes among women reporting longer or irregular menstrual cycles. In contrast, such cycles were associated with increased risk of the serous borderline tumors. Citation Format: Holly R. Harris, Susan Jordan, Harvey Risch, Mary Anne Rossing, Marc T. Goodman, Francesmary Modugno, Susanne Krüger Kjær, Joellen M. Schildkraut, Elisa V. Bandera, Nicolas Wentzensen, Catherine Phelan, Hoda Anton-Culver, Anna H. Wu, Kathryn L. Terry. Oligomenorrhea, polycystic ovary syndrome, and risk of ovarian cancer histotypes, evidence from the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2293. doi:10.1158/1538-7445.AM2017-2293

Fertility drugs and cancer: a guideline.

Methodological limitations in studying the association between the use of fertility drugs and cancer include the inherent increased risk of cancer in women who never conceive, the low incidence of most of these cancers, and that the age of diagnosis of cancer typically is many years after fertility drug use. Based on available data, there does not appear to be a meaningful increased risk of invasive ovarian cancer, breast cancer, or endometrial cancer following the use of fertility drugs. Several studies have shown a small increased risk of borderline ovarian tumors; however, there is insufficient consistent evidence that a particular fertility drug increases the risk of borderline ovarian tumors, and any absolute risk is small. Given the available literature, patients should be counseled that infertile women may be at an increased risk of invasive ovarian, endometrial, and breast cancer; however, use of fertility drugs does not appear to increase this risk.

BRCA1/2 negative status predicts no extended risk of invasive ovarian cancer

<scp>BRCA1</scp>/2 negative status predicts no extended risk of invasive ovarian cancer

A Prospective Study of Circulating C-Reactive Protein, Interleukin-6, and Tumor Necrosis Factor α Receptor 2 Levels and Risk of Ovarian Cancer

Chronic inflammation may play a role in ovarian carcinogenesis. We examined associations between 3 plasma biomarkers of inflammation-C-reactive protein (CRP), interleukin 6, and tumor necrosis factor α receptor 2-and risk of invasive epithelial ovarian cancer in prospectively collected samples from the Nurses' Health Study (NHS; 1989-2010), Nurses' Health Study II (NHS II; 1996-2009), and the Women's Health Study (WHS; 1992-2011) and performed a meta-analysis including data from previous publications. Associations with ovarian cancer risk were calculated using logistic regression (NHS/NHS II; n = 217 cases) or Cox proportional hazards regression (WHS; n = 159 cases). Study-specific results were combined using random-effects meta-analysis. In the NHS/NHS II and WHS, we observed a 53% increased risk of invasive ovarian cancer when comparing women in the fourth quartile of CRP with women in the first quartile (95% confidence interval (CI): 1.05, 2.23). A CRP level of >10 mg/L versus a level of ≤1 mg/L was associated with a 2.16-fold increased risk (95% CI: 1.23, 3.78). In a meta-analysis of published studies, women in the third tertile of CRP had a 35% increased risk (95% CI: 1.10, 1.67) compared with women in the first tertile. There were no significant associations between interleukin 6 or tumor necrosis factor α receptor 2 and risk in the NHS/NHS II. Our results support the hypothesis that higher levels of circulating CRP are associated with increased risk of ovarian cancer, indicating that the role of inflammation in ovarian cancer requires further elucidation.

Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility

The use of assisted reproductive techniques is increasing, but the possible link between fertility drugs and ovarian cancer remains controversial. To evaluate the risk of ovarian cancer in women treated with ovulation stimulating drugs for subfertility. We searched for published and unpublished observational studies from 1990 to February 2013. The following databases were used: the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, MEDLINE (to February week 4 2013), EMBASE (to 2013 week 09) and databases of conference abstracts. We also scanned reference lists of retrieved articles. The search was not restricted by language of publication. We searched for randomised controlled trials (RCTs) and non-randomised studies, and case series including more than 30 participants, reporting on women with exposure to ovarian stimulating drugs for treatment of subfertility and histologically confirmed borderline or invasive ovarian cancer. At least two review authors independently conducted eligibility and 'Risk of bias' assessment, and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We expressed findings as adjusted odds ratio (OR), risk ratio (RR), hazard ratio (HR) or crude OR if adjusted values were not reported and standardised incidence ratio (SIR) where reported. We conducted no meta-analyses due to expected methodological and clinical heterogeneity. We included 11 case-control studies and 14 cohort studies, which included a total of 182,972 women.Seven cohort studies showed no evidence of an increased risk of invasive ovarian cancer in subfertile women treated with any drug compared with untreated subfertile women. Seven case-control studies showed no evidence of an increased risk, compared with control women of a similar age. Two cohort studies reported an increased incidence of invasive ovarian cancer in subfertile women treated with any fertility drug compared with the general population. One of these reported a SIR of 5.0 (95% confidence interval (CI) 1.0 to 15), based on three cancer cases, and a decreased risk when cancer cases diagnosed within one year of treatment were excluded from the analysis(SIR 1.67, 95% CI 0.02 to 9.27). The other cohort study reported an OR of 2.09 (95% CI 1.39 to 3.12), based on 26 cases.For borderline ovarian tumours, exposure to any fertility drug was associated with a two to three-fold increased risk in two case-control studies. One case-control study reported an OR of 28 (95% CI 1.5 to 516), which was based on only four cases. In one cohort study, there was more than a two-fold increase in the incidence of borderline tumours compared with the general population (SIR 2.6, 95% CI 1.4 to 4.6) and in another the risk of a borderline ovarian tumour was HR 4.23 (95% CI 1.25 to 14.33) for subfertile women treated with in vitro fertilisation (IVF) compared with a non-IVF treated group with more than one year of follow-up.There was no evidence of an increased risk in women exposed to clomiphene alone or clomiphene plus gonadotrophin, compared with unexposed women. One case-control study reported an increased risk in users of human menopausal gonadotrophin (HMG)(OR 9.4, 95% CI 1.7 to 52). However, this estimate is based on only six cases with a history of HMG use. We found no convincing evidence of an increase in the risk of invasive ovarian tumours with fertility drug treatment. There may be an increased risk of borderline ovarian tumours in subfertile women treated with IVF. Studies showing an increase in the risk of ovarian cancer had a high overall risk of bias, due to retrospective study design, lack of accounting for potential confounding and estimates based on a small number of cases. More studies at low risk of bias are needed.

Ovarian cancer among 8005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2

BackgroundMutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative...

Pelvic inflammatory disease and risk of invasive ovarian cancer and ovarian borderline tumors

The aim of the study was to examine the potential association between a history of pelvic inflammatory disease (PID) and risk of epithelial ovarian cancer or ovarian borderline tumors. In a population-based case-control study in Denmark, we included 554 women with invasive ovarian cancer, 202 with ovarian borderline tumors, and 1,564 controls aged 35-79 years. The analyses were performed in multiple logistic regression models. We found a significantly increased risk of ovarian borderline tumors among women with a history of PID (OR = 1.50; 95% CI 1.08-2.08) but no apparent association between PID and risk of invasive ovarian cancer (OR = 0.83; 95% CI 0.65-1.05). We found no effect of age at time of first PID or time since first PID on the risk for either condition. Our results suggest that a history of PID is associated with an increased risk of ovarian borderline tumors, which may support the hypothesis that inflammation is an etiological factor. The lack of an association between previous PID and invasive ovarian cancer may indicate an etiological difference between ovarian borderline tumors and invasive ovarian cancer. However, an important limitation of the study is the use of self-reported PID.

Nonsteroidal anti‐inflammatory drugs and risk of ovarian cancer: systematic review and meta‐analysis of observational studies

Several observational studies have investigated the association between nonsteroidal anti-inflammatory drug (NSAID) use and ovarian cancer risk, but with conflicting results. We performed a systematic review and meta-analysis of the association between NSAID use and ovarian cancer risk. Systematic review and meta-analysis of observational studies published until September 2012. Studies were identified from the PubMed database. Fourteen case-control and seven cohort studies were included. Pooled relative risks (RRs) with corresponding 95% confidence intervals (CI) for aspirin and non-aspirin NSAIDs, separately, were calculated. Both fixed and random effect models were applied, but only random effect pooled RRs are presented. Risk estimates for invasive and borderline ovarian tumors combined and for invasive ovarian tumors only were calculated. Furthermore, heterogeneity and publication bias were evaluated. Ovarian cancer. In the combined analysis, a slight inverse association between use of aspirin (RR 0.93; 95% CI 0.84-1.02) and non-aspirin NSAIDs (RR 0.94; 95% CI 0.84-1.06) and ovarian cancer risk was found, although it was not statistically significant. However, the risk of invasive ovarian cancer was significantly reduced with use of aspirin (RR 0.88; 95% CI 0.79-0.98). A similar tendency was observed for non-aspirin NSAIDs, but the results were not significant. This meta-analysis showed a slight inverse association between NSAIDs and risk of ovarian cancer. However, data suggest that a chemopreventive effect of NSAIDs may be restricted to invasive ovarian tumors. Further research on NSAIDs and ovarian cancer is needed before definite conclusions can be drawn.