Lauren C. Peres

Regular Physical Inactivity and Ovarian Cancer Risk in the Ovarian Cancer in Women of African Ancestry Consortium

Abstract Background: Regular physical inactivity may increase ovarian cancer risk, but few studies have investigated whether this association is similar among Black and White women. Methods: In a pooled nested case–control study within the Ovarian Cancer in Women of African Ancestry consortium, logistic regression models evaluated regular recreational physical inactivity with risk of epithelial ovarian cancer among Black (223 cases; 1,472 controls) and White women (985 cases; 6,212 controls) enrolled in four cohort studies. Models were further stratified by histologic type. Results: Regular physical inactivity was not associated with the risk of overall ovarian cancer among Black [OR = 1.16; 95% confidence interval (CI), 0.83–1.61] or White women (OR = 1.03; 95% CI, 0.87–1.23). We did not detect associations according to histologic type. Conclusions: Physical inactivity was not associated with ovarian cancer among Black or White women in a consortium of cohort studies. Impact: These results are counter to case–control-based studies and emphasize the complexity of investigating physical activity prospectively.

An Analytic Pipeline to Obtain Reliable Genetic Ancestry Estimates from Tumor-Derived RNA Sequencing Data

Abstract Background: Germline genetics may influence tumor molecular characteristics and ultimately cancer survival. Studies of tumor characteristics, including our epithelial ovarian cancer (EOC) studies of Black women in the United States, may have RNA sequencing (RNA-seq) data from archival tumor tissue but lack germline DNA for at least some individuals. Incomplete germline DNA measurements impede analyses of important measures such as global genetic ancestry, often used in downstream analyses, by reducing sample sizes. Methods: The study population consists of 184 women who participated in two population-based studies of EOC with both germline and formalin-fixed, paraffin-embedded (FFPE) tumor samples and an additional 58 women diagnosed with EOC from the same two studies with only FFPE tumor tissue. We used tumor RNA-seq data to calculate proportions of African, European, and Asian genetic ancestry using a pipeline built on the packages SeqKit, HISAT2, SAMtools, BCFtools, PLINK, and ADMIXTURE. Women from the 1000 Genomes Project were used as the reference populations, and germline genetic ancestry estimates from blood or saliva were used as the baseline comparison. We evaluated multiple quality control strategies to improve genetic ancestry estimation. Results: Correlations between tumor RNA-seq–derived estimates of genetic ancestry from our pipeline and germline-derived African and European genetic ancestry ranged between 0.76 and 0.94. Conclusions: RNA-seq data from archival FFPE tumor tissue can be confidently and efficiently used to approximate global genetic ancestry in an admixed population when germline DNA is unavailable. Impact: This approach supports analyses of genetic ancestry and cancer when germline samples are not available.

Neighborhood disorder and ovarian cancer survival in Black women

Abstract Ovarian cancer (OC) is the fifth leading cause of cancer mortality among women in the US. Black women experience significantly lower OC survival than White women. Evidence suggests that this disparity is not solely the result of barriers to healthcare access but may also be impacted by other factors, including neighborhood social characteristics. To investigate this further, this study developed an approach for remotely estimating the degree of physical disorder (PD) in neighborhoods using structured audits of Google Street View imagery for participants in the AACES, a multi-site population-based study of Black women newly diagnosed with OC. We then assessed whether neighborhood disadvantage (ND) and PD were associated with overall survival. We fit Weibull accelerated failure time models to assess the association of both PD and ND with survival among 471 Black women with OC (n = 317 deaths). Both PD (event time ratio (ETR), 0.99; 95% CI, 0.98, 1.00) and Area Deprivation Index (ETR: 0.96, 95% CI: 0.94, 1.00) were associated with shorter survival. The results suggest that both physical and social neighborhood characteristics may impact survival in woman with OC, but further research is warranted.

Use of non-prescription analgesic medications and survival among Black women with ovarian cancer

Abstract Background Chronic inflammation and inflammatory-related exposures have been implicated in epithelial ovarian cancer (EOC) prognosis. However, no studies have evaluated whether analgesic medication use impacts survival in Black women with EOC, an understudied population with poor survival. Methods Leveraging data from the African American Cancer Epidemiology Study, we examined the association of pre-diagnostic analgesic medication use (aspirin, non-aspirin non-steroidal anti-inflammatory drugs [naNSAIDs], and acetaminophen) with survival among self-identified Black women diagnosed with EOC ( N  = 541) using multivariable Cox proportional hazards regression. Stratified analyses were conducted by comorbidities and histotype. Results Acetaminophen use was associated with a higher risk of mortality overall (HR = 1.40; 95% CI = 1.00–1.97) and for frequent and chronic use (≥30 days per month: HR = 1.62; 95% CI = 1.12–2.34; >5 years: HR = 1.57; 95% CI = 1.03–2.39). These associations were more pronounced among women with high-grade serous carcinoma (HGSC)/carcinosarcoma and those with comorbidities. Among women with comorbidities, naNSAID use was associated with a decreased risk of mortality (HR = 0.71; 95% CI = 0.51–0.99), but no association was observed among women without comorbidities (HR = 0.99; 95% CI = 0.56–1.75). No associations with survival were observed for aspirin. Conclusion Chronic use of acetaminophen negatively impacted survival among Black women with EOC, while naNSAID use conferred a survival advantage only among women with comorbidities.

Comorbid conditions and survival among Black women with ovarian cancer

AbstractBackgroundBlack women with epithelial ovarian cancer (EOC) have worse survival and a higher burden of comorbid conditions compared with other racial groups. This study examines the association of comorbid conditions and medication use for these conditions with survival among Black women with EOC.MethodsIn a prospective study of 592 Black women with EOC, the Charlson comorbidity index (CCI) based on self‐reported data, three cardiometabolic comorbidities (type 2 diabetes, hypertension, and hyperlipidemia), and medication use for each cardiometabolic comorbidity were evaluated. Cox proportional hazards regression models were used to examine the association of comorbid conditions and related medication use with all‐cause mortality while adjusting for relevant covariates overall and by histotype (high‐grade serous [HGS]/carcinosarcoma vs. non‐HGS/carcinosarcoma) and stage (I/II vs. III/IV).ResultsA CCI of ≥2 was observed in 42% of the cohort, and 21%, 67%, and 34% of women had a history of type 2 diabetes, hypertension, and hyperlipidemia, respectively. After adjusting for prognostic factors, a CCI ≥2 (vs. 0; hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.04–1.71) and type 2 diabetes (HR, 1.42; 95% CI, 1.10–1.84) were associated with an increased risk of mortality. The increased risk of mortality for type 2 diabetes was present specifically among women with HGS/carcinosarcoma (HR, 1.47; 95% CI, 1.10–1.97) and among women with stage III/IV disease (HR, 1.47; 95% CI, 1.10–1.98). The authors did not find evidence that hypertension, hyperlipidemia, or medication use for the cardiometabolic comorbidities meaningfully impacted survival.ConclusionComorbid conditions, especially type 2 diabetes, had a significant adverse impact on survival among Black women with EOC.

Associations between common contraceptive use and circulating inflammatory biomarkers

Abstract Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor α receptor 2 in the Nurses’ Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average of 30.4% (95% CI, –53.6 to 4.4) with every 5 years since initial IUD use (P-trend = .03), while CRP increased an average of 9.9% (95% CI, 5.7, 14.3) with every 5 years of use of OC (P-trend < .0001) as well as differences by body mass index and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time. This article is part of a Special Collection on Gynecological Cancer.

Molecular Subtypes of High-Grade Serous Ovarian Cancer across Racial Groups and Gene Expression Platforms

Abstract 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 sequencing 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. After mapping to The Cancer Genome Atlas–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 with the White and Japanese populations, the immunoreactive subtype was more common (39% vs. 23%–28%) and the differentiated subtype was less common (7% vs. 22%–31%). Patterns of subtype-specific survival were similar between the Black and White populations with RNA sequencing data; compared with 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: Although 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.

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

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. 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. 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, p The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.

Association of inflammation-related exposures and ovarian cancer survival in a multi-site cohort study of Black women

An association was observed between an inflammation-related risk score (IRRS) and worse overall survival (OS) among a cohort of mostly White women with invasive epithelial ovarian cancer (EOC). Herein, we evaluated the association between the IRRS and OS among Black women with EOC, a population with higher frequencies of pro-inflammatory exposures and worse survival. The analysis included 592 Black women diagnosed with EOC from the African American Cancer Epidemiology Study (AACES). Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of the IRRS and OS, adjusting for relevant covariates. Additional inflammation-related exposures, including the energy-adjusted Dietary Inflammatory Index (E-DII A dose-response trend was observed showing higher IRRS was associated with worse OS (per quartile HR: 1.11, 95% CI: 1.01-1.22). Adding the E-DII to the model attenuated the association of IRRS with OS, and increasing E-DII, indicating a more pro-inflammatory diet, was associated with shorter OS (per quartile HR: 1.12, 95% CI: 1.02-1.24). Scoring high on both indices was associated with shorter OS (HR: 1.54, 95% CI: 1.16-2.06). Higher levels of inflammation-related exposures were associated with decreased EOC OS among Black women.

Impact of obesity on chemotherapy dosing of carboplatin and survival of women with ovarian cancer

The study objective is to examine the impact of obesity on frontline carboplatin dosing in the neoadjuvant and adjuvant settings and to evaluate the association of dosing with survival among epithelial ovarian cancer (EOC) patients. We selected 1527 women diagnosed with EOC from January 1, 2011 to October 20, 2021 from a nationwide electronic health record-derived de-identified database. The dose reduction of frontline carboplatin was defined as a relative dose intensity (RDI) < 0.85. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of RDI with survival overall and by histology. Women with a BMI ≥ 30 kg/m In the real-world setting, underdosing of carboplatin in the neoadjuvant setting was associated with inferior survival among women with serous tumours. With the increasing utilisation of neoadjuvant chemotherapy in EOC, actual weight-based dosing of carboplatin may be important to improve outcomes in this patient population.

Racial Differences in Population Attributable Risk for Epithelial Ovarian Cancer in the OCWAA Consortium

Abstract Background The causes of racial disparities in epithelial ovarian cancer (EOC) incidence remain unclear. Differences in the prevalence of ovarian cancer risk factors may explain disparities in EOC incidence among African American (AA) and White women. Methods We used data from 4 case-control studies and 3 case-control studies nested within prospective cohorts in the Ovarian Cancer in Women of African Ancestry Consortium to estimate race-specific associations of 10 known or suspected EOC risk factors using logistic regression. Using the Bruzzi method, race-specific population attributable risks (PAR) were estimated for each risk factor individually and collectively, including groupings of exposures (reproductive factors and modifiable factors). All statistical tests were 2-sided. Results Among 3244 White EOC cases and 9638 controls and 1052 AA EOC cases and 2410 controls, AA women had a statistically significantly higher PAR (false discovery rate [FDR] P &amp;lt; .001) for first-degree family history of breast cancer (PAR = 10.1%, 95% confidence interval [CI] = 6.5% to 13.7%) compared with White women (PAR = 2.6%, 95% CI = 0.8% to 4.4%). After multiple test correction, AA women had a higher PAR than White women when evaluating all risk factors collectively (PAR = 61.6%, 95% CI = 48.6% to 71.3% vs PAR = 43.0%, 95% CI = 32.8% to 51.4%, respectively; FDR P = .06) and for modifiable exposures, including body mass index, oral contraceptives, aspirin, and body powder (PAR = 36.0%, 95% CI = 21.0% to 48.8% vs PAR = 13.8%, 95% CI = 4.5% to 21.8%, respectively; FDR P = .04). Conclusions Collectively, the selected risk factors accounted for slightly more of the risk among AA than White women, and interventions to reduce EOC incidence that are focused on multiple modifiable risk factors may be slightly more beneficial to AA women than White women at risk for EOC.

Predictors of survival trajectories among women with epithelial ovarian cancer

Although ovarian cancer is a deadly disease, approximately a third of women survive ≥9 years after diagnosis. The factors associated with achieving long-term survival are not well understood. In this study, data from the Surveillance, Epidemiology, and End Results (SEER) program were used to determine predictors of survival trajectories among women with epithelial ovarian cancer and across histotype (high-grade serous carcinoma (HGSC) and non-HGSC). Data on 35,868 women diagnosed with epithelial ovarian cancer in 2004-2016 were extracted from SEER. Extended Cox proportional hazards regression was used to estimate overall and histotype-specific associations between patient and tumor characteristics and all-cause mortality within each survival time (t) interval (t 70 years at diagnosis, where a high risk of mortality was observed in both the t < 3 and t ≥ 9 year time periods, and non-Hispanic Asian/Pacific Islanders, where a more pronounced inverse association with mortality was observed in t ≥ 9 years after diagnosis. Similar associations were observed for HGSC, although the waning effect was not apparent for most characteristics. Mortality associations for non-HGSC were more pronounced for stage and race/ethnicity, primarily for non-Hispanic Asian/Pacific Islanders. Most patient and tumor characteristics were more strongly associated with mortality in the years following diagnosis, but have declining impact with increasing survival time. Given this waning effect, it is critical to identify factors impacting risk of mortality as ovarian cancer patients advance through the survival trajectory.

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 &lt; 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.

Scratching Below the Ovarian Cancer GWAS Surface

Abstract Despite recent notable treatment advancements, ovarian cancer survival rates remain poor, with about half of women surviving five years after diagnosis. Uncovering novel prognostic factors is critical to better understand and reduce mortality from this deadly disease. While genome-wide association studies have identified numerous loci associated with risk of epithelial ovarian cancer, the investigation of genetic factors associated with outcomes among women with ovarian cancer has been limited due to several challenges summarized in the present commentary. Using data from the Ovarian Cancer Association Consortium, Quinn and colleagues conducted a genome-wide association study of patients with ovarian cancer receiving debulking surgery and standard chemotherapy as first-line treatment, revealing a locus at 12q24.33 associated with progression-free survival. Experimental evidence suggests that ULK1, a gene coding for a serine/threonine kinase implicated in autophagy, is the target of the association. We discuss the novelty of these findings, unanswered questions, and next steps for the road ahead in translating the work of Quinn and colleagues into clinical practice. See related article by Quinn et al., p. 1669

Genital Powder Use and Risk of Epithelial Ovarian Cancer in the Ovarian Cancer in Women of African Ancestry Consortium

Abstract Background: Genital powder use is more common among African-American women; however, studies of genital powder use and ovarian cancer risk have been conducted predominantly in White populations, and histotype-specific analyses among African-American populations are limited. Methods: We used data from five studies in the Ovarian Cancer in Women of African Ancestry consortium. Participants included 620 African-American cases, 1,146 African-American controls, 2,800 White cases, and 6,735 White controls who answered questions on genital powder use prior to 2014. The association between genital powder use and ovarian cancer risk by race was estimated using logistic regression. Results: The prevalence of ever genital powder use for cases was 35.8% among African-American women and 29.5% among White women. Ever use of genital powder was associated with higher odds of ovarian cancer among African-American women [OR = 1.22; 95% confidence interval (CI) = 0.97–1.53] and White women (OR = 1.36; 95% CI = 1.19–1.57). In African-American women, the positive association with risk was more pronounced among high-grade serous tumors (OR = 1.31; 95% CI = 1.01–1.71) than with all other histotypes (OR = 1.05; 95% CI = 0.75–1.47). In White women, a significant association was observed irrespective of histotype (OR = 1.33; 95% CI = 1.12–1.56 and OR = 1.38; 95% CI = 1.15–1.66, respectively). Conclusions: While genital powder use was more prevalent among African-American women, the associations between genital powder use and ovarian cancer risk were similar across race and did not materially vary by histotype. Impact: This is one of the largest studies to date to compare the associations between genital powder use and ovarian cancer risk, overall and by histotype, between African-American and White women.

Circulating Biomarkers of Inflammation and Ovarian Cancer Risk in the Nurses' Health Studies

AbstractBackground:Chronic inflammation is a well-established mechanism of ovarian carcinogenesis; however, the specific immunogenic processes influencing ovarian tumor development remain unclear. In a case–control study nested within the Nurses' Health Study (NHS) and the NHSII, we examined the association between six inflammatory chemokines and cytokines [B-cell activating factor (BAFF), C-X-C motif chemokine ligand 13 (CXCL13), IL8, soluble(s)IL2-receptor-α(Rα), sIL6Rα] and epithelial ovarian cancer risk.Methods:Among 299 epithelial ovarian cancer cases and 334 matched controls, six inflammatory biomarkers were measured in plasma collected 1–24 years before diagnosis or index date using two custom multiplex Luminex panels. ORs and 95% confidence intervals (CI) were estimated for the association between each biomarker and risk using multivariable conditional logistic regression with adjustment for relevant confounders. We additionally assessed heterogeneity in the risk associations by histotype [high-grade serous carcinoma (HGSC) vs. non-HGSC], body mass index, smoking status, menopausal status, and aspirin use.Results:Women with the highest versus lowest quartile (Q) levels of CXCL13 had a 72% increased ovarian cancer risk (OR = 1.72; 95% CI = 1.04–2.83; Ptrend = 0.007). The positive association with CXCL13 was stronger in magnitude for non-HGSC, overweight or obese women, and postmenopausal women, although only menopausal status demonstrated statistically significant heterogeneity (Pinteraction = 0.04). The remaining biomarkers were not associated with risk.Conclusions:This first evidence that prediagnostic CXCL13, a B-cell chemoattractant, is associated with an increased risk of epithelial ovarian cancer expands current understanding of the role of inflammation in ovarian carcinogenesis.Impact:CXCL13 may represent a novel biomarker for ovarian cancer.

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

AbstractFamily 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.

Race Differences in the Associations between Menstrual Cycle Characteristics and Epithelial Ovarian Cancer

Abstract Background: Menstrual cycle characteristics—including age at menarche and cycle length— have been associated with ovarian cancer risk in White women. However, the associations between menstrual cycle characteristics and ovarian cancer risk among Black women have been sparsely studied. Methods: Using the Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium that includes 1,024 Black and 2,910 White women diagnosed with epithelial ovarian cancer (EOC) and 2,325 Black and 7,549 White matched controls, we investigated associations between menstrual cycle characteristics (age at menarche, age at menstrual regularity, cycle length, and ever missing three periods) and EOC risk by race and menopausal status. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results: Black women were more likely to be &amp;lt;11 years at menarche than White women (controls: 9.9% vs. 6.0%). Compared with ≥15 years at menarche, &amp;lt;11 years was associated with increased EOC risk for White (OR = 1.25; 95% CI, 0.99–1.57) but not Black women (OR = 1.10; 95% CI, 0.80–1.55). Among White women only, the association was greater for premenopausal (OR = 2.20; 95% CI, 1.31–3.68) than postmenopausal women (OR = 1.06; 95% CI, 0.82–1.38). Irregular cycle length was inversely associated with risk for White (OR = 0.78; 95% CI, 0.62–0.99) but not Black women (OR = 1.06; 95% CI, 0.68–1.66). Conclusions: Earlier age at menarche and cycle irregularity are associated with increased EOC risk for White but not Black women. Impact: Associations between menstrual cycle characteristics and EOC risk were not uniform by race.

Racial disparities in epithelial ovarian cancer survival: An examination of contributing factors in the Ovarian Cancer in Women of African Ancestry consortium

AbstractBlack women diagnosed with epithelial ovarian cancer have poorer survival compared to white women. Factors that contribute to this disparity, aside from socioeconomic status and guideline‐adherent treatment, have not yet been clearly identified. We examined data from the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium which harmonized data on 1074 Black women and 3263 white women with ovarian cancer from seven US studies. We selected potential mediators and confounders by examining associations between each variable with race and survival. We then conducted a sequential mediation analysis using an imputation method to estimate total, direct, and indirect effects of race on ovarian cancer survival. Black women had worse survival than white women (HR = 1.30; 95% CI 1.16‐1.47) during study follow‐up; 67.9% of Black women and 69.8% of white women died. In our final model, mediators of this disparity include college education, nulliparity, smoking status, body mass index, diabetes, diabetes/race interaction, postmenopausal hormone (PMH) therapy duration, PMH duration/race interaction, PMH duration/age interaction, histotype, and stage. These mediators explained 48.8% (SE = 12.1%) of the overall disparity; histotype/stage and PMH duration accounted for the largest fraction. In summary, nearly half of the disparity in ovarian cancer survival between Black and white women in the OCWAA consortium is explained by education, lifestyle factors, diabetes, PMH use, and tumor characteristics. Our findings suggest that several potentially modifiable factors play a role. Further research to uncover additional mediators, incorporate data on social determinants of health, and identify potential avenues of intervention to reduce this disparity is urgently needed.

Racial Differences in the Tumor Immune Landscape and Survival of Women with High-Grade Serous Ovarian Carcinoma

Abstract Background: Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts. Methods: The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race. Results: Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant. Conclusions: Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC. Impact: This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.

Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race

Abstract Background: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race. Methods: HRD features were identified using matched tumor–normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race. Results: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43–1.09; White HR = 0.38; 95% CI, 0.14–1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%). Conclusions: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals. Impact: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.

Genomic Characterization of High-Grade Serous Ovarian Carcinoma Reveals Distinct Somatic Features in Black Individuals

Abstract Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole-exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared with historic data from The Cancer Genome Atlas (TCGA). Despite technical differences (e.g., formalin-fixed vs. fresh-frozen tissue), the distribution of mutations and their variant classifications for major HGSC genes were nearly identical across study populations. However, de novo significantly mutated gene analysis identified genes not previously reported in TCGA analysis, including the oncogene KRAS and the potential tumor suppressor OBSCN. The prevalence of the homologous recombination deficiency signature was higher among Black individuals with the immunoreactive gene expression subtype compared with the mesenchymal and proliferative subtypes. These findings were confirmed by comparing the data from Black patients with those from 123 White patients with identical tissue collection and processing. Overall, this study suggests that, although most features of HGSC tumor phenotypes are similar in Black and White populations, there may be clinically relevant differences. If validated, these phenotypes may be important for clinical decision-making and would have been missed by characterizing tumors from White individuals only. Significance: Elucidation of the somatic mutational landscape of high-grade serous ovarian carcinoma in Black individuals, who experience poor survival and are underrepresented in research, could inform patient prognosis and enable precision medicine opportunities.