Regulation of Age-Related Lipid Metabolism in Ovarian Cancer.

Although a lot of effort has been dedicated to ovarian cancer (OC) research, the mortality rate is still among the highest in female gynecologic malignancies. The effects of the aged tumor microenvironment are still being undermined despite age being the highest risk factor in ovarian cancer development and progression. In this study, we have conducted RNA sequencing and lipidomics analysis of gonadal adipose tissues from young and aged rat xenografts before and after ovarian cancer formation. We have found significantly higher tumor formation rates and volumes in aged OC xenograft rat models compared to their young counterparts (p<0.05), suggesting the aged adipose microenvironment (AME) is more susceptible to OC outgrowth. We have revealed significant shifts in the gene expression enrichment from groups of young vs. aged rats before tumor formation, groups of young vs. aged rats when the tumor formed, and groups of aged rats before and after tumor formation. We also observed shifts in the lipid components of the gonadal adipose tissues between young and aged rat xenografts when tumors were generated. Additionally, we found that the aged AME was associated with age-related changes in the immune cell composition, especially inflammation-related cells. The top hits showing the most differences between aged and young adipose tissues were eight genes including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3, 22 lipids including multiple isoforms of free fatty acids (FFA) and triglyceride (TG), as well as four immune cells including neutrophil, myeloid dendritic cell, T cell CD4+ (non-regulatory), and mast cell activation. The functional correlation among S100a8, S100a9, neutrophil, and FFA (18:3) was also determined. Furthermore, FFA (18:3), which was shown to be downregulated in aged xenograft rats, was capable of inhibiting OC cell proliferation. In conclusion, our study suggested that aging promoted OC proliferation through changes in genes/pathways, lipid metabolism, and immune cells. Targeting the aging adipose microenvironment, particularly lipid metabolism reprogramming, holds promise as a therapeutic strategy for OC, which warrants further investigation. Significance: Aging microenvironment of OC may be regulated by S100a8 and S100a9 secreted by adipocytes, preadipocytes, or neutrophils through affecting the lipid metabolism, such as FFA (18:3).

Oncolytic adenovirus MEM-288 encoding membrane-stable CD40L and IFNß induces an anti-tumor immune response in high grade serous ovarian cancer.

Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor and immune stimulatory effects of an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L and IFNß. We demonstrated this virus successfully infects HGSOC cell lines and primary human ascites samples in vitro. We evaluated the anti-tumor and immunostimulatory activity in vivo in immune competent mouse models. Intraperitoneal delivery of MEM-288 decreased ascites and solid tumor burden compared to controls, and treatment generated a systemic anti-tumor immune response. The tumor microenvironment had a higher proportion of anti-tumor macrophages and decreased markers of angiogenesis. MEM-288 is a promising immunotherapy agent in HGSOC, with further pre-clinical studies required to understand the mechanism of action in the peritoneal microenvironment and clinical activity in combination with other therapies.

Frailty in patients with ovarian cancer and the role of healthcare access, race, and ethnicity.

OBJECTIVE: Ovarian cancer has poor 5-year survival, particularly among non-Hispanic (NH) Black patients. Efforts to identify patients at high-risk of functional limitations and frailty may improve outcomes. In this study, we examined how healthcare access (HCA) and race/ethnicity relate to frailty among patients with ovarian cancer. METHODS: We identified Hispanic, NH Black, and NH White patients diagnosed at ages ≥6 5 years with ovarian cancer between 2009 and 2015 using SEER-Medicare. Log-binomial regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between HCA and race/ethnicity with pre- or post-diagnosis frailty, adjusting for age and comorbidities. RESULTS: A total of 6041 patients with ovarian cancer were included, including 91.8% NH White, 6.6% NH Black, and 1.7% Hispanic. Pre-diagnosis, 14.7% of patients were defined as frail (NH White: 14.3%; NH Black: 17.9%; Hispanic: 20.8%). Post-diagnosis, frailty prevalence increased to 58.8% (NH White: 58.2%; NH Black: 65.2%; Hispanic: 70.2%). No statistically significant associations were observed between race/ethnicity and pre- or post-diagnosis frailty in fully adjusted models. After adjustment for patient characteristics and healthcare accessibility and availability, higher healthcare affordability was associated with a decreased prevalence of pre-diagnosis frailty (PR: 0.91, 95% CI: 0.8 5, 0.98). CONCLUSIONS: Patients with ovarian cancer have a high prevalence of frailty after diagnosis, particularly NH Black and Hispanic patients. Improving healthcare affordability may prevent or help manage frailty in Medicare patients, improve receipt of cancer treatment, and increase cancer survival.

Pre-diagnosis tea and coffee consumption and survival after a diagnosis of ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Tea and coffee are the most frequently consumed beverages in the world. Green tea in particular contains compounds with potential anti-cancer effects, but its association with survival after ovarian cancer is uncertain. METHODS: We investigated the associations between tea and coffee consumption before diagnosis and survival using data from 10 studies in the Ovarian Cancer Association Consortium. Data on tea (green, black, herbal), coffee and caffeine intake were available for up to 5724 women. We used Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Compared with women who did not drink any green tea, consumption of one or more cups/day was associated with better overall survival (aHR = 0.84, 95% CI 0.71-1.00, p-trend = 0.04). A similar association was seen for ovarian cancer-specific survival in five studies with this information (aHR = 0.81, 0.66-0.99, p-trend = 0.045). There was no consistent variation between subgroups defined by clinical or lifestyle characteristics and adjustment for other aspects of lifestyle did not appreciably alter the estimates. We found no evidence of an association between coffee, black or herbal tea, or caffeine intake and survival. CONCLUSION: The observed association with green tea consumption before diagnosis raises the possibility that consumption after diagnosis might improve patient outcomes.

Metformin use and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada.

OBJECTIVES: There is an active debate regarding whether metformin use improves survival in people with ovarian cancer. We examined this issue using methods designed to avoid immortal time bias-as bias that occurs when participants in a study cannot experience the outcome for a certain portion of the study time. METHODS: We used time-dependent analyses to study the association between metformin use for all 4,951 patients diagnosed with ovarian cancer in 1997 through 2018 in the province of British Columbia, Canada. Cox proportional hazards models were run to estimate the association between metformin and survival in the full cohort of ovarian cancer patients and among a cohort restricted to patients with diabetes. RESULTS: Metformin use was associated with a 17 % better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.83 (95 %CI 0.67, 1.02)), and a 16 % better ovarian cancer survival for serous cancers patient's cohort (aHR = 0.84 (95 %CI 0.66, 1.07)), although both were not significant. However, a statistically significant protective effect was observed when restricting to the diabetic cohort (aHR = 0.71 (95 %CI 0.54-0.91)), which was also seen among serous cancers (aHR = 0.73 (95 %CI 0.54-0.98)). CONCLUSION: Metformin use was associated with improved ovarian cancer survival. The lack of statistical significance in the full cohort may reflect that diabetes is associated with reduced cancer survival, and thus diabetes itself may offset the benefit of metformin when examining the full cohort. Future research should examine metformin use among non-diabetic ovarian cancer patients.

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

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .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 Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

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 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.

Racial Differences in Vaginal Fluid Metabolites and Association with Systemic Inflammation Markers among Ovarian Cancer Patients: A Pilot Study.

The vaginal microbiome differs by race and contributes to inflammation by directly producing or consuming metabolites or by indirectly inducing host immune response, but its potential contributions to ovarian cancer (OC) disparities remain unclear. In this exploratory cross-sectional study, we examine whether vaginal fluid metabolites differ by race among patients with OC, if they are associated with systemic inflammation, and if such associations differ by race. Study participants were recruited from the Ovarian Cancer Epidemiology, Healthcare Access, and Disparities Study between March 2021 and September 2022. Our study included 36 study participants with ovarian cancer who provided biospecimens; 20 randomly selected White patients and all 16 eligible Black patients, aged 50-70 years. Acylcarnitines (n = 45 species), sphingomyelins (n = 34), and ceramides (n = 21) were assayed on cervicovaginal fluid, while four cytokines (IL-1ß, IL-10, TNF-α, and IL-6) were assayed on saliva. Seven metabolites showed >2-fold differences, two showed significant differences using the Wilcoxon rank-sum test (p < 0.05; False Discovery Rate > 0.05), and 30 metabolites had coefficients > ±0.1 in a Penalized Discriminant Analysis that achieved two distinct clusters by race. Arachidonoylcarnitine, the carnitine adduct of arachidonic acid, appeared to be consistently different by race. Thirty-eight vaginal fluid metabolites were significantly correlated with systemic inflammation biomarkers, irrespective of race. These findings suggest that vaginal fluid metabolites may differ by race, are linked with systemic inflammation, and hint at a potential role for mitochondrial dysfunction and sphingolipid metabolism in OC disparities. Larger studies are needed to verify these findings and further establish specific biological mechanisms that may link the vaginal microbiome with OC racial disparities.

Health Care Access Dimensions and Racial Disparities in End-of-Life Care Quality among Patients with Ovarian Cancer.

This study investigated the association between health care access (HCA) dimensions and racial disparities in end-of-life (EOL) care quality among non-Hispanic Black (NHB), non-Hispanic White (NHW), and Hispanic patients with ovarian cancer. This retrospective cohort study used the Surveillance, Epidemiology, and End Results-linked Medicare data for women diagnosed with ovarian cancer from 2008 to 2015, ages 65 years and older. Health care affordability, accessibility, and availability measures were assessed at the census tract or regional levels, and associations between these measures and quality of EOL care were examined using multivariable-adjusted regression models, as appropriate. The final sample included 4,646 women [mean age (SD), 77.5 (7.0) years]; 87.4% NHW, 6.9% NHB, and 5.7% Hispanic. In the multivariable-adjusted models, affordability was associated with a decreased risk of intensive care unit stay [adjusted relative risk (aRR) 0.90, 95% confidence interval (CI): 0.83-0.98] and in-hospital death (aRR 0.91, 95% CI: 0.84-0.98). After adjustment for HCA dimensions, NHB patients had lower-quality EOL care compared with NHW patients, defined as: increased risk of hospitalization in the last 30 days of life (aRR 1.16, 95% CI: 1.03-1.30), no hospice care (aRR 1.23, 95% CI: 1.04-1.44), in-hospital death (aRR 1.27, 95% CI: 1.03-1.57), and higher counts of poor-quality EOL care outcomes (count ratio:1.19, 95% CI: 1.04-1.36). HCA dimensions were strong predictors of EOL care quality; however, racial disparities persisted, suggesting that additional drivers of these disparities remain to be identified. SIGNIFICANCE: Among patients with ovarian cancer, Black patients had lower-quality EOL care, even after adjusting for three structural barriers to HCA, namely affordability, availability, and accessibility. This suggests an important need to investigate the roles of yet unexplored barriers to HCA such as accommodation and acceptability, as drivers of poor-quality EOL care among Black patients with ovarian cancer.

Role of endometrial sampling to differentiate between advanced endometrial versus ovarian malignancy: retrospective cohort study.

OBJECTIVE: Distinguishing between advanced stage endometrial and ovarian cancer at diagnosis can be challenging, especially when patients do not present with abnormal uterine bleeding. Given emerging systemic therapies specific for ovarian versus endometrial cancers, it has become increasingly critical to establish the correct diagnosis at presentation to ensure appropriate treatment. This study evaluates the frequency with which advanced endometrial cancer is mistakenly presumed to be ovarian cancer. METHODS: A retrospective analysis was performed of patients with a final diagnosis of advanced endometrial cancer treated consecutively at a single academic institution between 2013 and 2022. Variables abstracted included abnormal uterine bleeding, endometrial sampling, and timing of endometrial cancer diagnosis. We quantified incorrect diagnoses made after 2018, when frontline targeted treatments differentiating advanced endometrial from advanced ovarian cancer became available. RESULTS: We identified 270 patients with an ultimate diagnosis of stage III or IV endometrial cancer. The most common presenting symptom was abnormal uterine bleeding (219/270, 81%), followed by abdominal or pelvic pain (48/270, 18%) and bloating (27/270, 10%). Forty-eight patients (18%) received neoadjuvant chemotherapy, of whom 11 (23%) had an incorrect diagnosis of ovarian cancer. Since 2018, six patients have received neoadjuvant chemotherapy for presumed ovarian cancer, three of whom received a systemic regimen specific for ovarian cancer when they, in fact, had endometrial cancer. CONCLUSION: In patients with presumed advanced ovarian cancer dispositioned to neoadjuvant chemotherapy, endometrial sampling can identify some cases that are actually primary endometrial cancers. Correct diagnosis guides the use of appropriate antineoplastic therapies, optimizing response and survival outcomes while minimizing toxicity and cost of unindicated therapies.

Periostin facilitates ovarian cancer recurrence by enhancing cancer stemness.

The lethality of epithelial ovarian cancer (OC) is largely due to a high rate of recurrence and development of chemoresistance, which requires synergy between cancer cells and the tumor microenvironment (TME) and is thought to involve cancer stem cells. Our analysis of gene expression microarray data from paired primary and recurrent OC tissues revealed significantly elevated expression of the gene encoding periostin (POSTN) in recurrent OC compared to matched primary tumors (p = 0.015). Secreted POSTN plays a role in the extracellular matrix, facilitating epithelial cell migration and tissue regeneration. We therefore examined how elevated extracellular POSTN, as we found is present in recurrent OC, impacts OC cell functions and phenotypes, including stemness. OC cells cultured with conditioned media with high levels of periostin (CMPOSTNhigh) exhibited faster migration (p = 0.0044), enhanced invasiveness (p = 0.006), increased chemoresistance (p < 0.05), and decreased apoptosis as compared to the same cells cultured with control medium (CMCTL). Further, CMPOSTNhigh-cultured OC cells exhibited an elevated stem cell side population (p = 0.027) along with increased expression of cancer stem cell marker CD133 relative to CMCTL-cultured cells. POSTN-transfected 3T3-L1 cells that were used to generate CMPOSTNhigh had visibly enhanced intracellular and extracellular lipids, which was also linked to increased OC cell expression of fatty acid synthetase (FASN) that functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors. Additionally, POSTN functions in the TME were linked to AKT pathway activities. The mean tumor volume in mice injected with CMPOSTNhigh-cultured OC cells was larger than that in mice injected with CMCTL-cultured OC cells (p = 0.0023). Taken together, these results show that elevated POSTN in the extracellular environment leads to more aggressive OC cell behavior and an increase in cancer stemness, suggesting that increased levels of stromal POSTN during OC recurrence contribute to more rapid disease progression and may be a novel therapeutic target. Furthermore, they also demonstrate the utility of having matched primary-recurrent OC tissues for analysis and support the need for better understanding of the molecular changes that occur with OC recurrence to develop ways to undermine those processes.

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.

Efficacy of cyclin-dependent kinase 4/6 inhibitors in combination with hormonal therapy in patients with recurrent granulosa cell tumor of the ovary: A case series.

Cyclin-dependent kinase inhibitors are approved in combination with hormonal therapy for treatment of hormone receptor expressing breast cancers. Activity in hormone receptor expressing gynecologic cancers has been postulated. Granulosa cell tumor of the ovary is one such cancer, which is relatively resistant to traditional cytotoxic chemotherapy. We report a case series of 7 heavily pre-treated patients with recurrent granulosa cell tumor of the ovary with a cyclin-dependent kinase inhibitor in combination with hormonal therapy, with 3 patients demonstrating partial response and 2 with stable disease. As of the data cutoff, 3 patients remained on treatment and 5 were alive, with true medians for duration of treatment and overall survival not reached (medians at data cutoff of 64 weeks and 62 months respectively). The treatment was generally well tolerated, with 1 patient choosing to discontinue treatment due to grade 3 fatigue. This regimen represents a possible option in the treatment of granulosa cell tumor of the ovary, warranting further prospective study for this unmet need in this indolent disease which often requires many lines of treatment.

High-fat diet and obesity are associated with differential angiogenic gene expression in epithelial ovarian cancer.

OBJECTIVE: We sought to evaluate the association between diet and angiogenic biomarkers in KpB mice, and the association between these markers, body mass index (BMI), and overall survival (OS) in high-grade serous cancers (HGSC). METHODS: Tumors previously obtained from KpB mice subjected to high-fat diets (HFD, n = 10) or low-fat diets (LFD, n = 10) were evaluated for angiogenesis based on CD-31 microvessel density (MVD). Data from prior microarray analysis (Agilent 244 K arrays) conducted in 10 mice were utilized to assess associations between diet and angiogenetic biomarkers. Agilent (mouse) and Affymetrix Human Genome U133a probes were linked to 162 angiogenic-related genes. The associations between biomarkers, BMI, and OS were evaluated in an HGSC internal database (IDB) (n = 40). Genes with unadjusted p < 0.05 were evaluated for association with OS in the TCGA-OV database (n = 339). RESULTS: There was no association between CD-31 and diet in mice (p = 0.66). Sixteen angiogenic-related genes passed the p < 0.05 threshold for association with HFD vs. LFD. Transforming growth factor-alpha (TGFA) demonstrated 72% higher expression in HFD vs. LFD mice (p = 0.04). Similar to the mouse study, in our HGSC IDB, higher TGFA expression correlated with higher BMI (p = 0.01) and shorter survival (p = 0.001). In the TCGA-OV dataset, BMI data was not available and there was no association between TGFA and OS (p = 0.48). CONCLUSIONS: HFD and obesity may promote tumor progression via differential modulation of TGFA. We were unable to confirm this finding in the TCGA dataset. Further evaluation of TGFA is needed to determine if this is a target unique to obesity-driven HGSC.

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.

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility.

Importance: Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. Objective: To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. Design, Setting, and Participants: We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. Exposures: Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. Main Outcomes and Measures: The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. Results: There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. Conclusions and Relevance: The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.

Factor Analysis of Health Care Access With Ovarian Cancer Surgery and Gynecologic Oncologist Consultation.

Importance: Poor health care access (HCA) is associated with racial and ethnic disparities in ovarian cancer (OC) survival. Objective: To generate composite scores representing health care affordability, availability, and accessibility via factor analysis and to evaluate the association between each score and key indicators of guideline-adherent care. Design, Setting, and Participants: This retrospective cohort study used data from patients with OC diagnosed between 2008 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The SEER Medicare database uses cancer registry data and linked Medicare claims from 12 US states. Included patients were Hispanic, non-Hispanic Black, and non-Hispanic White individuals aged 65 years or older diagnosed from 2008 to 2015 with first or second primary OC of any histologic type (International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3] code C569). Data were analyzed from June 2020 to June 2022. Exposures: The SEER-Medicare data set was linked with publicly available data sets to obtain 35 variables representing health care affordability, availability, and accessibility. A composite score was created for each dimension using confirmatory factor analysis followed by a promax (oblique) rotation on multiple component variables. Main Outcomes and Measures: The main outcomes were consultation with a gynecologic oncologist for OC and receipt of OC-related surgery in the 2 months prior to or 6 months after diagnosis. Results: The cohort included 8987 patients, with a mean (SD) age of 76.8 (7.3) years and 612 Black patients (6.8%), 553 Hispanic patients (6.2%), and 7822 White patients (87.0%). Black patients (adjusted odds ratio [aOR], 0.75; 95% CI, 0.62-0.91) and Hispanic patients (aOR, 0.81; 95% CI, 0.67-0.99) were less likely to consult a gynecologic oncologist compared with White patients, and Black patients were less likely to receive surgery after adjusting for demographic and clinical characteristics (aOR, 0.76; 95% CI, 0.62-0.94). HCA availability and affordability were each associated with gynecologic oncologist consultation (availability: aOR, 1.16; 95% CI, 1.09-1.24; affordability: aOR, 1.13; 95% CI, 1.07-1.20), while affordability was associated with receipt of OC surgery (aOR, 1.08; 95% CI, 1.01-1.15). In models mutually adjusted for availability, affordability, and accessibility, Black patients remained less likely to consult a gynecologic oncologist (aOR, 0.80; 95% CI, 0.66-0.97) and receive surgery (aOR, 0.80; 95% CI, 0.65-0.99). Conclusions and Relevance: In this cohort study of Hispanic, non-Hispanic Black, and non-Hispanic White patients with OC, HCA affordability and availability were significantly associated with receiving surgery and consulting a gynecologic oncologist. However, these dimensions did not fully explain racial and ethnic disparities.

Health-care access dimensions and ovarian cancer survival: SEER-Medicare analysis of the ORCHiD study.

BACKGROUND: Racial and ethnic disparities in ovarian cancer (OC) survival are well-documented. However, few studies have investigated how health-care access (HCA) contributes to these disparities. METHODS: To evaluate the influence of HCA on OC mortality, we analyzed 2008-2015 Surveillance, Epidemiology, and End Results-Medicare data. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HCA dimensions (affordability, availability, accessibility) and OC-specific and all-cause mortality, adjusting for patient characteristics and treatment receipt. RESULTS: The study cohort included 7590 OC patients: 454 (6.0%) Hispanic, 501 (6.6%) Non-Hispanic (NH) Black, and 6635 (87.4%) NH White. Higher affordability (HR = 0.90, 95% CI = 0.87 to 0.94), availability (HR = 0.95, 95% CI = 0.92 to 0.99), and accessibility scores (HR = 0.93, 95% CI = 0.87 to 0.99) were associated with lower risk of OC mortality after adjusting for demographic and clinical factors. Racial disparities were observed after additional adjustment for these HCA dimensions: NH Black patients experienced a 26% higher risk of OC mortality compared with NH White patients (HR = 1.26, 95% CI = 1.11 to 1.43) and a 45% higher risk among patients who survived at least 12 months (HR = 1.45, 95% CI = 1.16 to 1.81). CONCLUSIONS: HCA dimensions are statistically significantly associated with mortality after OC and explain some, but not all, of the observed racial disparity in survival of patients with OC. Although equalizing access to quality health care remains critical, research on other HCA dimensions is needed to determine additional factors contributing to disparate OC outcomes by race and ethnicity and advance the field toward health equity.

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.