Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

Causes of Childhood Cancer: A Review of the Recent Literature: Part I-Childhood Factors.

PURPOSE: To review the childhood risk factors for pediatric cancer (diagnosis before age 20). METHODS: We conducted literature searches using Ovid Medline and Scopus to find primary research studies, review articles, and meta-analyses published from 2014 to 3 March 2021. RESULTS: Strong evidence indicates that an array of genetic and epigenetic phenomena, structural birth defects, and chromosomal anomalies are associated with an increased risk of various childhood cancers. Increased risk is also associated with prior cancer, likely due to previous treatment agents and therapeutic ionizing radiation. Convincing evidence supports associations between several pediatric cancers and ionizing radiation, immunosuppression, and carcinogenic virus infection both in healthy children and in association with immune suppression following organ transplantation. Breastfeeding and a childhood diet rich in fruits and vegetables appears to reduce the risk of pediatric leukemia but the evidence is less strong. Childhood vaccination against carcinogenic viruses is associated with a lower risk of several cancers; there is less strong evidence that other childhood vaccinations more broadly may also lower risk. Ultraviolet (UV) radiation is associated with increased melanoma risk, although most melanomas following childhood UV exposure occur later, in adulthood. Evidence is weak or conflicting for the role of body mass index, other childhood infections, allergies, and certain treatments, including immunomodulator medications and human growth therapy.

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

An Update on Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Intraepithelial Lesions of the Lower Genital Tract.

Women with prenatal diethylstilbestrol exposure are excluded from less frequent cervical cancer screening because of their increased neoplasia risk. We report the results of a prospective follow-up study of prenatal diethylstilbestrol exposure and lower genital tract high-grade (grade 2 or higher) squamous intraepithelial lesions (HSIL). The age-adjusted risk of HSIL among diethylstilbestrol-exposed women (n=4,062) was higher than among the diethylstilbestrol unexposed (n=1,837) through age 44 years (hazard ratio 2.03, 95% CI, 1.31-3.14) but not age 45 years or older. Elevated HSIL risk remained higher in diethylstilbestrol-exposed women, after accounting for frequency of cervical cancer screening. Compared with unexposed women, HSIL risk was higher among women with earlier gestational and high-dose diethylstilbestrol exposure. These data confirm the appropriateness of more frequent screening among diethylstilbestrol-exposed women through age 44 years. Whether those aged 45 years or older should continue to have increased screening will require careful weighing of possible risks and benefits.

A framework for assessing interactions for risk stratification models: the example of ovarian cancer.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

In utero exposure to diethylstilbestrol and blood DNA methylation in adult women: Results from a meta-analysis of two cohort studies.

BACKGROUND: Prenatal exposure to diethylstilbestrol (DES) is associated with several adverse health outcomes. Animal studies have shown associations between prenatal DES exposure and DNA methylation. OBJECTIVE: The aim of this study was to explore blood DNA methylation in women exposed and unexposed to DES in utero. METHODS: Sixty women (40 exposed and 20 unexposed) in the National Cancer Institute's Combined DES Cohort Study and 199 women (99 exposed and 100 unexposed women) in the Sister Study Cohort were included in this analysis. Within each study, robust linear regression models were used to assess associations between DES exposure and blood DNA methylation. Study-specific associations were combined using fixed-effect meta-analysis with inverse variance weights. Our analysis focused on CpG sites located within nine candidate genes identified in animal models. We further explored whether in utero DES exposure was associated with age acceleration. RESULTS: Blood DNA methylation levels at 10 CpG sites in six of the nine candidate genes were statistically significantly associated with prenatal DES exposure (P < 0.05) in this meta-analysis. Genes included EGF, EMB, EGFR, WNT11, FOS, and TGFB1, which are related to cell proliferation and differentiation. The most statistically significant CpG site was cg19830739 in gene EGF, and it was associated with lower methylation levels in women prenatally exposed to DES compared with those not exposed (P < 0.0001; false discovery rate<0.05). The association between prenatal DES exposure in utero and age acceleration was not statistically significant (P = 0.07 for meta-analyzed results). CONCLUSIONS: There are few opportunities to investigate the effects of prenatal DES exposure. These findings suggest that in utero DES exposure may be associated with differential blood DNA methylation levels, which could mediate the increased risk of several adverse health outcomes observed in exposed women. Our findings need further evaluation using larger data sets.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Effects of risk factors for ovarian cancer in women with and without endometriosis.

OBJECTIVE: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. DESIGN: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. SETTING: Population-based. PATIENT(S): We included 8,500 women with ovarian cancer, 13,592 control women. INTERVENTION(S): Ten well-established ovarian cancer risk factors. MAIN OUTCOME MEASURE(S): Risk of ovarian cancer for women with and without endometriosis. RESULT(S): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). CONCLUSION(S): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

Evidence of intergenerational transmission of diethylstilbestrol health effects: hindsight and insight.

This review summarizes key findings from the US National Cancer Institute (NCI) diethylstilbestrol (DES) Combined Cohort Study with a focus on the results of the NCI Third Generation Study, a cohort of DES-exposed and -unexposed granddaughters. Findings to date from the Third Generation Study are discussed in the context of other research efforts and case reports, suggesting an intergenerational heritability of DES-related effects. The DES story serves as a model for the influence of endocrine disrupting chemicals on human health. It also serves as a warning of the special hazards of pregnancy exposures, and more broadly, of the potential for invisible health consequences arising from new or changing exposures.

Common Analgesic Use for Menstrual Pain and Ovarian Cancer Risk.

Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18-0.94 and OR, 0.43; 95% CI, 0.21-0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain (P interaction ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer. PREVENTION RELEVANCE: This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.

Prenatal Diethylstilbestrol Exposure and Cancer Risk in Males.

BACKGROUND: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers. METHODS: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age. RESULTS: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77-1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68-1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23-1.00). CONCLUSIONS: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men. IMPACT: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk.

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Association of Second-Opinion Strategies in the Histopathologic Diagnosis of Cutaneous Melanocytic Lesions With Diagnostic Accuracy and Population-Level Costs.

IMPORTANCE: Diagnostic variation among pathologists interpreting cutaneous melanocytic lesions could lead to suboptimal care. OBJECTIVE: To estimate the potential association of second-opinion strategies in the histopathologic diagnosis of cutaneous melanocytic lesions with diagnostic accuracy and 1-year population-level costs in the US. DESIGN, SETTING, AND PARTICIPANTS: Decision analysis with 1-year time horizon including melanocytic lesion diagnoses available from US pathologists participating in the Melanoma Pathology Study (M-Path) and from the study panel of reference pathologists who classified cases using the MPATH-Dx classification tool. M-Path data collection occurred from July 2013 through March 2015; analyses for the present study were performed between April 2015 and January 2021. EXPOSURES: Various second-opinion strategies for interpretation of melanocytic cutaneous lesions. MAIN OUTCOMES AND MEASURES: Estimated accuracy of pathologists' diagnoses, defined as concordance with the reference panel diagnoses, and 1-year postbiopsy medical costs under various second-opinion strategies. Expected percentage of concordant diagnoses, including percentages of overinterpretation and underinterpretation, and 1-year costs of medical care per 100 000 in the US population. RESULTS: Decision-analytic model parameters were based on diagnostic interpretations for 240 cases by 187 pathologists compared with reference panel diagnoses. Without second opinions, 83.2% of diagnoses in the US were estimated to be accurate-ie, concordant with the reference diagnosis; with overinterpretation (8.0%) or underinterpretation (8.8%), and 16 850 misclassified diagnoses per 100 000 biopsies. Accuracy increased under all second-opinion strategies. Accuracy (87.4% concordance with 3.6% overinterpretation and 9.1% underinterpretation) and cost (an increase of more than $10 million per 100 000 biopsies per year) were highest when second opinions were universal (eg, performed on all biopsies), relative to no second opinions. A selective second-opinion strategy based on pathologists' desire or institutional requirements for a second opinion was most accurate (86.5% concordance; 4.4% overinterpretation; 9.1% underinterpretation) and would reduce costs by more than $1.9 million per 100 000 skin biopsies relative to no second opinions. Improvements in diagnostic accuracy with all second-opinion strategies were associated with reductions in overinterpretation but not underinterpretation. CONCLUSIONS AND RELEVANCE: In this decision-analytic model, selective second-opinion strategies for interpretation of melanocytic skin lesions showed the potential to improve diagnostic accuracy and decrease costs relative to no second opinions or universal second opinions.

Intrauterine device use and risk of ovarian cancer: Results from the New England Case-Control study and Nurses' Health Studies.

Results of studies assessing intrauterine device (IUD) use and ovarian cancer risk are inconsistent. We examined the association between IUD use, including duration, type and timing of use, and ovarian cancer risk using three population-based studies. Data from the New England Case-Control Study (NEC) and two prospective cohort studies, the Nurses' Health Studies (NHS/NHSII), were included in the analysis. Information on IUD use was collected by in-person interview in NEC and by biennial questionnaire in NHS/NHSII. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) in NEC and Cox regression to calculate hazard ratios (HR) and 95% CI in NHS/NHSII. We used meta-analysis to combine the NEC and the pooled NHS/NHSII results. Overall, IUD use was not associated with epithelial ovarian cancer risk (OR = 0.96, 95% CI: 0.81-1.14 in NEC; HR = 0.89, 95% CI: 0.69-1.15 in NHS/NHSII; combined RR = 0.94, 95% CI: 0.81-1.08). Among IUD users, older age at first use was associated with increased ovarian cancer risk (P-trend = .03). We did not observe significant associations by IUD type or duration of use. In conclusion, IUD use was not associated with ovarian cancer risk in our study.

Depot-Medroxyprogesterone Acetate Use Is Associated with Decreased Risk of Ovarian Cancer: The Mounting Evidence of a Protective Role of Progestins.

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 (P trend < 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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies.

Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6-51 and HR = 7.0, 95% CI 1.5-33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88-1.5) or diabetes (HR = 1.1, 95% CI 0.9-1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84-20) or general population (SIR: 1.9, 95% CI 1.0-3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

Peripheral Blood Leukocyte Telomere Length and Endometriosis.

Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers' license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (ORT3/T1 = 2.56, 95% CI = 1.16-5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR T3/T1 = 3.50, 95% CI = 1.12-10.97). In NHANES, the data suggested a similar but attenuated association (ORT3/T1 = 1.29, 95% CI = 0.85-1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.

Association Between Breastfeeding and Ovarian Cancer Risk.

Importance: 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. Objective: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. Design, Setting, and Participants: 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. Exposures: 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. Main Outcomes and Measures: Diagnosis of epithelial ovarian cancer. Results: 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). Conclusions and Relevance: 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.