Endometriosis Typology and Ovarian Cancer Risk.

Importance: Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. Objective: To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. Design, Setting, and Participants: Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. Exposures: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. Main Outcomes and Measures: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. Results: In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). Conclusions and Relevance: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.

Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Molecular subtypes of high-grade serous ovarian cancer across racial groups and gene expression platforms.

BACKGROUND: High-grade serous carcinoma (HGSC) gene expression subtypes are associated with differential survival. We characterized HGSC gene expression in Black individuals and considered whether gene expression differences by self-identified race may contribute to poorer HGSC survival among Black versus White individuals. METHODS: We included newly generated RNA-Seq data from Black and White individuals, and array-based genotyping data from four existing studies of White and Japanese individuals. We used K-means clustering, a method with no predefined number of clusters or dataset-specific features, to assign subtypes. Cluster- and dataset-specific gene expression patterns were summarized by moderated t-scores. We compared cluster-specific gene expression patterns across datasets by calculating the correlation between the summarized vectors of moderated t-scores. Following mapping to The Cancer Genome Atlas (TCGA)-derived HGSC subtypes, we used Cox proportional hazards models to estimate subtype-specific survival by dataset. RESULTS: Cluster-specific gene expression was similar across gene expression platforms and racial groups. Comparing the Black population to the White and Japanese populations, the immunoreactive subtype was more common (39% versus 23%-28%) and the differentiated subtype less common (7% versus 22%-31%). Patterns of subtype-specific survival were similar between the Black and White populations with RNA-Seq data; compared to mesenchymal cases, the risk of death was similar for proliferative and differentiated cases and suggestively lower for immunoreactive cases (Black population HR=0.79 [0.55, 1.13], White population HR=0.86 [0.62, 1.19]). CONCLUSIONS: While the prevalence of HGSC subtypes varied by race, subtype-specific survival was similar. IMPACT: HGSC subtypes can be consistently assigned across platforms and self-identified racial groups.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Reproductive risk factors for breast cancer and association with novel breast density measurements among Hispanic, Black, and White women.

PURPOSE: There are differences in the distributions of breast cancer incidence and risk factors by race and ethnicity. Given the strong association between breast density and breast cancer, it is of interest describe racial and ethnic variation in the determinants of breast density. METHODS: We characterized racial and ethnic variation in reproductive history and several measures of breast density for Hispanic (n = 286), non-Hispanic Black (n = 255), and non-Hispanic White (n = 1694) women imaged at a single hospital. We quantified associations between reproductive factors and percent volumetric density (PVD), dense volume (DV), non-dense volume (NDV), and a novel measure of pixel intensity variation (V) using multivariable-adjusted linear regression, and tested for statistical heterogeneity by race and ethnicity. RESULTS: Reproductive factors most strongly associated with breast density were age at menarche, parity, and oral contraceptive use. Variation by race and ethnicity was most evident for the associations between reproductive factors and NDV (minimum p-heterogeneity:0.008) and V (minimum p-heterogeneity:0.004) and least evident for PVD (minimum p-heterogeneity:0.042) and DV (minimum p-heterogeneity:0.041). CONCLUSION: Reproductive choices, particularly those related to childbearing and oral contraceptive use, may contribute to racial and ethnic variation in breast density.

Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study.

PURPOSE: Prior studies indicate that the physiologic response to stress can affect gene expression. We evaluated differential gene expression in breast cancers collected from Black women with high versus low exposure to psychosocial stressors. METHODS: We analyzed tumor RNA sequencing data from 417 Black Women's Health Study breast cancer cases with data on early life trauma and neighborhood disadvantage. We conducted age-adjusted differential gene expression analyses and pathway analyses. We also evaluated Conserved Transcriptional Response to Adversity (CTRA) contrast scores, relative fractions of immune cell types, T cell exhaustion, and adrenergic signaling. Analyses were run separately for estrogen receptor positive (ER+; n = 299) and ER- (n = 118) cases. RESULTS: Among ER+ cases, the top differentially expressed pathways by stress exposure were related to RNA and protein metabolism. Among ER- cases, they were related to developmental biology, signal transduction, metabolism, and the immune system. Targeted analyses indicated greater immune pathway enrichment with stress exposure for ER- cases, and possible relevance of adrenergic signaling for ER+ cases. CTRA contrast scores did not differ by stress exposure, but in analyses of the CTRA components, ER- breast cancer cases with high neighborhood disadvantage had higher pro-inflammatory gene expression (p = 0.039) and higher antibody gene expression (p = 0.006) compared to those with low neighborhood disadvantage. CONCLUSION: There are multiple pathways through which psychosocial stress exposure may influence breast tumor biology. Given the present findings on inflammation and immune response in ER- tumors, further research to identify stress-induced changes in the etiology and progression of ER- breast cancer is warranted.

Molecular subtypes of high-grade serous ovarian cancer across racial groups and gene expression platforms.

Introduction: High-grade serous carcinoma (HGSC) gene expression subtypes are associated with differential survival. We characterized HGSC gene expression in Black individuals and considered whether gene expression differences by race may contribute to poorer HGSC survival among Black versus non-Hispanic White individuals. Methods: We included newly generated RNA-Seq data from Black and White individuals, and array-based genotyping data from four existing studies of White and Japanese individuals. We assigned subtypes using K-means clustering. Cluster- and dataset-specific gene expression patterns were summarized by moderated t-scores. We compared cluster-specific gene expression patterns across datasets by calculating the correlation between the summarized vectors of moderated t-scores. Following mapping to The Cancer Genome Atlas (TCGA)-derived HGSC subtypes, we used Cox proportional hazards models to estimate subtype-specific survival by dataset. Results: Cluster-specific gene expression was similar across gene expression platforms. Comparing the Black study population to the White and Japanese study populations, the immunoreactive subtype was more common (39% versus 23%-28%) and the differentiated subtype less common (7% versus 22%-31%). Patterns of subtype-specific survival were similar between the Black and White populations with RNA-Seq data; compared to mesenchymal cases, the risk of death was similar for proliferative and differentiated cases and suggestively lower for immunoreactive cases (Black population HR=0.79 [0.55, 1.13], White population HR=0.86 [0.62, 1.19]). Conclusions: A single, platform-agnostic pipeline can be used to assign HGSC gene expression subtypes. While the observed prevalence of HGSC subtypes varied by race, subtype-specific survival was similar.

Pathways to lung cancer diagnosis among individuals who did not receive lung cancer screening: a qualitative study.

BACKGROUND: Although early detection of lung cancer through screening is associated with better prognosis, most lung cancers are diagnosed among unscreened individuals. We therefore sought to characterize pathways to lung cancer diagnosis among unscreened individuals. METHODS: Participants were individuals with lung cancer who did not undergo asymptomatic lung cancer screening (n = 13) and healthcare providers who may be involved in the pathway to lung cancer diagnosis (n = 13). We conducted semi-structured interviews to identify themes in lung cancer patients' narratives of their cancer diagnoses and providers' personal and/or professional experiences of various pathways to lung cancer diagnoses, to identify delays in diagnosis. We audio-recorded, transcribed, and coded interviews in two stages. First, we conducted deductive coding using three time-period intervals from the Models of Pathways to Treatment framework: appraisal, help-seeking, and diagnostic (i.e., excluding pre-treatment). Second, we conducted inductive coding to identify themes within each time-period interval, and classified these themes as either barriers or facilitators to diagnosis. Coding and thematic summarization were completed independently by two separate analysts who discussed for consensus. RESULTS: Eight of the patient participants had formerly smoked, and five had never smoked. We identified eight barrier/facilitator themes within the three time-period intervals. Within the appraisal interval, the barrier theme was (1) minimization or misattribution of symptoms, and the facilitator theme was (2) acknowledgment of symptoms. Within the help-seeking interval, the barrier theme was (3) hesitancy to seek care, and the facilitator theme was (4) routine care. Within the diagnosis interval, barrier themes were (5) health system challenges, and (6) social determinants of health; and facilitator themes were (7) severe symptoms and known risk factors, and (8) self-advocacy. Many themes were interrelated, including minimization or misattribution of symptoms and hesitancy to seek care, which may collectively contribute to care and imaging delays. CONCLUSIONS: Interventions to reduce hesitancy to seek care may facilitate timely lung cancer diagnoses. More prompt referral to imaging-especially computed tomography (CT)-among symptomatic patients, along with patient self-advocacy for imaging, may reduce delays in diagnosis.

Menopausal hormone therapy use and risk of ovarian cancer by race: the ovarian cancer in women of African ancestry consortium.

BACKGROUND: Most studies examining post-menopausal menopausal hormone therapy (MHT) use and ovarian cancer risk have focused on White women and few have included Black women. METHODS: We evaluated MHT use and ovarian cancer risk in Black (n = 800 cases, 1783 controls) and White women (n = 2710 cases, 8556 controls), using data from the Ovarian Cancer in Women of African Ancestry consortium. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MHT use with ovarian cancer risk, examining histotype, MHT type and duration of use. RESULTS: Long-term MHT use, ≥10 years, was associated with an increased ovarian cancer risk for White women (OR = 1.38, 95%CI: 1.22-1.57) and the association was consistent for Black women (OR = 1.20, 95%CI: 0.81-1.78, pinteraction = 0.4). For White women, the associations between long-term unopposed estrogen or estrogen plus progesterone use and ovarian cancer risk were similar; the increased risk associated with long-term MHT use was confined to high-grade serous and endometroid tumors. Based on smaller numbers for Black women, the increased ovarian cancer risk associated with long-term MHT use was apparent for unopposed estrogen use and was predominately confined to other epithelial histotypes. CONCLUSION: The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.

Impact of age, race, and family history on COVID-19-related changes in breast cancer screening among the Boston mammography cohort study.

PURPOSE: We studied women enrolled in the Boston Mammography Cohort Study to investigate whether subgroups defined by age, race, or family history of breast cancer experienced differences in the incidence of screening or diagnostic imaging rates during the COVID-19 lockdown and had slower rebound in the incidence of these rates during reopening. METHODS: We compared the incidence of monthly breast cancer screening and diagnostic imaging rates over during the pre-COVID-19 (January 2019-February 2020), lockdown (March-May 2020), and reopening periods (June-December 2020), and tested for differences in the monthly incidence within the same period by age (< 50 vs ≥ 50), race (White vs non-White), and first-degree family history of breast cancer (yes vs no). RESULTS: Overall, we observed a decline in breast cancer screening and diagnostic imaging rates over the three time periods (pre-COVID-19, lockdown, and reopening). The monthly incidence of breast cancer screening rates for women age ≥ 50 was 5% higher (p = 0.005) in the pre-COVID-19 period (January 2019-February 2020) but was 19% lower in the reopening phase (June-December 2020) than that of women aged < 50 (p < 0.001). White participants had 36% higher monthly incidence of breast cancer diagnostic imaging rates than non-White participants (p = 0.018). CONCLUSION: The rebound in screening was lower in women age ≥ 50 and lower in non-White women for diagnostic imaging. Careful attention must be paid as the COVID-19 recovery continues to ensure equitable resumption of care.

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. RESULTS: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. CONCLUSIONS: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

Familial risk of epithelial ovarian cancer after accounting for gynaecological surgery: a population-based study.

BACKGROUND: Uptake of risk-reducing surgery has increased among women at high risk of epithelial ovarian cancer. We sought to characterise familial risk of epithelial ovarian cancer histotypes in a population-based study after accounting for gynaecological surgeries, including bilateral oophorectomy. METHODS: We compared risk of epithelial ovarian cancer in relatives of 3536 epithelial ovarian cancer cases diagnosed in 1966-2016 and relatives of 35 326 matched controls. We used Cox competing risk models, incorporating bilateral oophorectomy as a competing risk, to estimate the relative risk of ovarian cancer in first-degree (FDR), second-degree (SDR) and third-degree (TDR) relatives from 1966 to 2016. We also estimated relative risks in time periods before (1966-1994, 1995-2004) and after (2005-2016) formal recommendations were made for prophylactic oophorectomy among women with pathogenic variants in BRCA1/2. RESULTS: The relative risks of epithelial ovarian cancer in FDRs, SDRs and TDRs of cases versus controls were 1.68 (95% CI 1.39 to 2.04), 1.51 (95% CI 1.30 to 1.75) and 1.34 (95% CI 1.20 to 1.48), respectively. Relative risks were greatest for high-grade serous, mucinous and 'other epithelial' histotypes. Relative risks were attenuated for case FDRs, but not for SDRs or TDRs, from 2005 onwards, consistent with the timing of recommendations for prophylactic surgery. CONCLUSION: Familial risk of epithelial ovarian cancer extends to TDRs, especially for high-grade serous and mucinous histotypes. Distant relatives share genes but minimal environment, highlighting the importance of germline inherited genetics in ovarian cancer aetiology. Increased ovarian cancer risk in distant relatives has implications for counselling and recommendations for prophylactic surgeries that, from our data, appear only to reach FDRs.

Pathways to ovarian cancer diagnosis: a qualitative study.

BACKGROUND: Ovarian cancer is often diagnosed at a late stage, when survival is poor. Qualitative narratives of patients' pathways to ovarian cancer diagnoses may identify opportunities for earlier cancer detection and, consequently, earlier stage at diagnosis. METHODS: We conducted semi-structured interviews of ovarian cancer patients and survivors (n = 14) and healthcare providers (n = 11) between 10/2019 and 10/2021. Interviews focused on the time leading up to an ovarian cancer diagnosis. Thematic analysis was conducted by two independent reviewers using a two-phase deductive and inductive coding approach. Deductive coding used a priori time intervals from the validated Model of Pathways to Treatment (MPT), including self-appraisal and management of symptoms, medical help-seeking, diagnosis, and pre-treatment. Inductive coding identified common themes within each stage of the MPT across patient and provider interviews. RESULTS: The median age at ovarian cancer diagnosis was 61.5 years (range, 29-78 years), and the majority of participants (11/14) were diagnosed with advanced-stage disease. The median time from first symptom to initiation of treatment was 2.8 months (range, 19 days to 4.7 years). The appraisal and help-seeking intervals contributed the greatest delays in time-to-diagnosis for ovarian cancer. Nonspecific symptoms, perceptions of health and aging, avoidant coping strategies, symptom embarrassment, and concerns about potential judgment from providers prolonged the appraisal and help-seeking intervals. Patients and providers also emphasized access to care, including financial access, as critical to a timely diagnosis. CONCLUSION: Interventions are urgently needed to reduce ovarian cancer morbidity and mortality. Population-level screening remains unlikely to improve ovarian cancer survival, but findings from our study suggest that developing interventions to improve self-appraisal of symptoms and reduce barriers to help-seeking could reduce time-to-diagnosis for ovarian cancer. Affordability of care and insurance may be particularly important for ovarian cancer patients diagnosed in the United States.

Exposure to natural vegetation in relation to mammographic density in a Massachusetts-based clinical cohort.

Inverse associations between natural vegetation exposure (i.e., greenness) and breast cancer risk have been reported; however, it remains unknown whether greenness affects breast tissue development or operates through other mechanisms (e.g., body mass index [BMI] or physical activity). We examined the association between greenness and mammographic density-a strong breast cancer risk factor-to determine whether greenness influences breast tissue composition independent of lifestyle factors. Methods: Women (n = 2,318) without a history of breast cancer underwent mammographic screening at Brigham and Women's Hospital in Boston, Massachusetts, from 2006 to 2014. Normalized Difference Vegetation Index (NDVI) satellite data at 1-km2 resolution were used to estimate greenness at participants' residential address 1, 3, and 5 years before mammogram. We used multivariable linear regression to estimate differences in log-transformed volumetric mammographic density measures and 95% confidence intervals (CIs) for each 0.1 unit increase in NDVI. Results: Five-year annual average NDVI was not associated with percent mammographic density in premenopausal (ß = -0.01; 95% CI = -0.03, 0.02; P = 0.58) and postmenopausal women (ß = -0.02; 95% CI = -0.04, 0.01; P = 0.18). Results were similar for 1-year and 3-year NDVI measures and in models including potential mediators of BMI and physical activity. There were also no associations between greenness and dense volume and nondense volume. Conclusions: Greenness exposures were not associated with mammographic density. Impact: Prior observations of a protective association between greenness and breast cancer may not be driven by differences in breast tissue composition, as measured by mammographic density, but rather other mechanisms.

Body Mass Index and Mammographic Density in a Multiracial and Multiethnic Population-Based Study.

BACKGROUND: Mammographic density (MD) is strongly associated with breast cancer risk. We examined whether body mass index (BMI) partially explains racial and ethnic variation in MD. METHODS: We used multivariable Poisson regression to estimate associations between BMI and binary MD [Breast Imaging Reporting and Database System (BI-RADS) A&B versus BI-RADS C&D] among 160,804 women in the Utah mammography cohort. We estimated associations overall and within racial and ethnic subgroups and calculated population attributable risk percents (PAR%). RESULTS: We observed the lowest BMI and highest MD among Asian women, the highest BMI among Native Hawaiian and Pacific Islander women, and the lowest MD among American Indian and Alaska Native (AIAN) and Black women. BMI was inversely associated with MD [RRBMI≥30 vs. BMI<25 = 0.43; 95% confidence interval (CI), 0.42-0.44] in the full cohort, and estimates in all racial and ethnic subgroups were consistent with this strong inverse association. For women less than 45 years of age, although there was statistical evidence of heterogeneity in associations between BMI and MD by race and ethnicity (P = 0.009), magnitudes of association were similar across groups. PAR%s for BMI and MD among women less than 45 years were considerably higher in White women (PAR% = 29.2, 95% CI = 28.4-29.9) compared with all other groups with estimates ranging from PAR%Asain = 17.2%; 95% CI, 8.5 to 25.8 to PAR%Hispanic = 21.5%; 95% CI, 19.4 to 23.6. For women ≥55 years, PAR%s for BMI and MD were highest among AIAN women (PAR% = 37.5; 95% CI, 28.1-46.9). CONCLUSIONS: While we observed substantial differences in the distributions of BMI and MD by race and ethnicity, associations between BMI and MD were generally similar across groups. IMPACT: Distributions of BMI and MD may be important contributors to breast cancer disparities.

Identification of novel epithelial ovarian cancer loci in women of African ancestry.

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

Urinary PGE-M Levels and Risk of Ovarian Cancer.

BACKGROUND: Regular aspirin use may lower ovarian cancer risk by blocking the cyclooxygenase enzymes, resulting in lower expression of prostaglandins, including prostaglandin E2 (PGE2). We evaluated whether higher prediagnosis PGE-M (a urinary biomarker of PGE2) was associated with increased ovarian cancer risk in three prospective cohorts. METHODS: We conducted a case-control study nested in the Nurses' Health Study (NHS), NHSII, and Shanghai Women's Health Study. Our analyses included 304 cases of epithelial ovarian cancer diagnosed from 1996 to 2015 and 600 matched controls. We measured urinary PGE-M using LC/MS with normalization to creatinine. Measures from each study were recalibrated to a common standard. We estimated ORs and 95% confidence intervals (CI) using conditional logistic regression, with PGE-M levels modeled in quartiles. Multivariable models were adjusted for ovarian cancer risk factors. RESULTS: There was no evidence of an association between urinary PGE-M levels and ovarian cancer risk for women with PGE-M levels in the top versus bottom quartile (OR = 0.80; 95% CI, 0.51-1.27; P trend = 0.37). We did not observe heterogeneity by histotype (P = 0.53), and there was no evidence of effect modification by body mass index (P interaction = 0.82), aspirin use (P interaction = 0.59), or smoking (P interaction = 0.14). CONCLUSIONS: Prediagnosis urinary PGE-M levels were not significantly associated with ovarian cancer risk. Larger sample sizes are needed to consider a more modest association and to evaluate associations for specific tumor subtypes. IMPACT: Systemic prostaglandin levels do not appear strongly associated with ovarian cancer risk. Future research into aspirin use and ovarian cancer risk should consider local prostaglandins and prostaglandin-independent mechanisms.

Anti-Inflammatory Drug Use and Ovarian Cancer Risk by COX1/COX2 Expression and Infiltration of Tumor-Associated Macrophages.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use may affect ovarian cancer risk via prostaglandin synthesis and tumor-associated macrophage (TAM) infiltration. We evaluated if associations between aspirin or non-aspirin NSAID use and ovarian cancer risk differed by tumor expression of prostaglandin-related (COX1, COX2) and TAM-related (CD68, CD163) markers. METHODS: We evaluated cases and matched controls from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (NECC). Cases with IHC data on COX1 and COX2 (n = 532) or CD68 and CD163 (n = 530) were included. We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate OR for NSAID use and ovarian cancer risk by marker level. RESULTS: Recent aspirin use had a nonsignificant inverse association and recent non-aspirin NSAID use had no association with ovarian cancer risk. NSAID use was not differentially associated with ovarian cancer by COX1 or COX2 expression. However, recent aspirin use was associated with lower ovarian cancer risk for high [OR 0.54; 95% confidence interval (CI), 0.37-0.78], but not low (OR 1.50; 95% CI, 0.97-2.31), CD163 density (P heterogeneity < 0.001). Similar results were observed for aspirin duration and tablets and for recent non-aspirin NSAID use. Results were not clearly different by macrophage density defined by the less specific macrophage marker, CD68. CONCLUSIONS: NSAID use was inversely associated with risk of ovarian cancer with high density CD163, a marker for M2-type, immunosuppressive macrophages. However, the relationship did not differ by prostaglandin synthesis markers. IMPACT: Future research should explore prostaglandin-independent mechanisms for the association between NSAID use and ovarian cancer risk, including immune mechanisms.