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Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race.We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models.The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORObesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

PURPOSE. To evaluate the association between obesity and the relative prevalence of tumor subtypes among Black women with breast cancer (BC). METHODS: We conducted a pooled case-only analysis of 1,793 Black women with invasive BC recruited through three existing studies in the southeastern US. Multivariable case-only polytomous logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between obesity, measured by pre-diagnostic body mass index (BMI), and human epidermal growth factor receptor 2+ (HER2+) and triple negative BC (TNBC) subtype relative to hormone receptor (HR)+/HER2− status (referent). RESULTS. Among 359 premenopausal women, 55.4% of cases were HR+/HER2−, 20.1% were HER2+, and 24.5% were TNBC; corresponding percentages among 1,434 postmenopausal women were 59.3%, 17.0%, and 23.6%. Approximately 50–60% of both pre- and postmenopausal women were obese (BMI>30 kg/m(2)), regardless of BC subtype. We did not observe a significant association between obesity and BC subtype. Among postmenopausal women, class I obesity (BMI 35+ kg/m(2)) was not associated with the development of HER2+ BC (OR 0.69; 95% CI 0.42–1.14) or TNBC (OR 0.93; 95% CI 0.60–1.45) relative to HR+/HER2− tumors. Corresponding estimates among premenopausal women were 1.03 (95% CI 0.43–2.48) and 1.13 (95% CI 0.48–2.64). CONCLUSION. In this large study of Black women with BC, there was no evidence of heterogeneity of BMI by BC subtype.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has left patients with current or past history of cancer facing disparate consequences at every stage of the cancer trajectory. This comprehensive review offers a landscape analysis of the current state of the literature on COVID-19 and cancer, including the immune response to COVID-19, risk factors for severe disease, and impact of anticancer therapies. We also review the latest data on treatment of COVID-19 and vaccination safety and efficacy in patients with cancer, as well as the impact of the pandemic on cancer care, including the urgent need for rapid evidence generation and real-world study designs. SIGNIFICANCE: Patients with cancer have faced severe consequences at every stage of the cancer journey due to the COVID-19 pandemic. This comprehensive review offers a landscape analysis of the current state of the field regarding COVID-19 and cancer. We cover the immune response, risk factors for severe disease, and implications for vaccination in patients with cancer, as well as the impact of the COVID-19 pandemic on cancer care delivery. Overall, this review provides an in-depth summary of the key issues facing patients with cancer during this unprecedented health crisis.

BACKGROUND: The clinicopathological significance of spatial tumor-infiltrating lymphocytes (TILs) subpopulations is not well studied due to lack of high-throughput scalable methodology for studies with large human sample sizes. OBJECTIVE: Establishing a cyclic fluorescent multiplex immunohistochemistry (mIHC/IF) method coupled with computer-assisted high-throughput quantitative analysis to evaluate associations of six TIL markers (CD3, CD8, CD20, CD56, FOXP3, and PD-L1) with clinicopathological factors of breast cancer. METHODS: Our 5-plex mIHC/IF staining was shown to be reliable and highly sensitive for labeling three biomarkers per tissue section. Through repetitive cycles of 5-plex mIHC/IF staining, more than 12 biomarkers could be detected per single tissue section. Using open-source software CellProfiler, the measurement pipelines were successfully developed for high-throughput multiplex evaluation of intratumoral and stromal TILs. RESULTS: In analyses of 188 breast cancer samples from the Nashville Breast Health Study, high-grade tumors showed significantly increased intratumoral CD3+CD8+ cytotoxic T lymphocyte density (P= 0.0008, false discovery rate (FDR) adjusted P= 0.0168) and intratumoral PD-L1 expression (P= 0.0061, FDR adjusted P= 0.0602) compared with low-grade tumors. CONCLUSIONS: The high- and low-grade breast cancers exhibit differential immune responses which may have clinical significance. The multiplexed imaging quantification strategies established in this study are reliable, cost-efficient and applicable in regular laboratory settings for high-throughput tissue biomarker studies, especially retrospective and population-based studies using archived paraffin tissues.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Background: NCCN recommends evaluation and treatment of all patients with cancer who have anemia. Few studies have evaluated the prevalence of anemia among patients with gynecologic cancer and compliance with the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Growth Factors. Methods: We performed a single-institution retrospective cohort study of patients diagnosed with primary gynecologic cancer between 2008 and 2018. We identified tumor registry–confirmed patients using ICD-O codes from the Synthetic Derivative database, a deidentified copy of Vanderbilt’s electronic medical records. Patients were included if they were between ages 18 and 89 years, received initial care at Vanderbilt University Medical Center, and had a hemoglobin measurement within the first 6 months of diagnosis. Anemia was defined as a hemoglobin level ≤11 g/dL and was graded using CTCAE version 5.0. Results: A total of 939 patients met inclusion criteria, with a median age of 60 years. The most common malignancy was uterine cancer. At the time of cancer diagnosis, 186 patients (20%) were noted to have anemia. Within 6 months of diagnosis, 625 patients (67%) had anemia, of whom 200 (32%) had grade 3 anemia and 209 (33%) underwent any evaluation of anemia, including 80 (38%) with iron studies performed. Of the patients with iron studies performed, 7 (9%) had absolute iron deficiency and 7 (9%) had possible functional iron deficiency. Among those with anemia within 6 months of diagnosis, 260 (42%) received treatment for anemia, including blood transfusion (n=205; 79%), oral iron (n=57; 22%), intravenous iron (n=8; 3%), vitamin B12 (n=37; 14%), and folate supplementation (n=7; 3%). Patients with ovarian cancer were significantly more likely to have anemia and undergo evaluation and treatment of anemia. Conclusions: Anemia is pervasive among patients with gynecologic cancer, but compliance with the NCCN Guidelines is low. Our data suggest that there are opportunities for improvement in the evaluation and management of anemia.

Black 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.

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

PURPOSE: Women with endometriosis have a 2 to 3-fold greater risk of endometrioid and clear cell ovarian cancer than other women, based on estimates from studies predominantly of White women. Fibroids have not been consistently associated with ovarian cancer risk but are the most common indication for hysterectomies in the U.S. Hysterectomy has been associated with lower ovarian cancer risk in subgroups of women including those with fibroids; thus fibroids may indirectly impact ovarian cancer risk. We evaluated the association of endometriosis and fibroids with ovarian cancer risk among Black and White women, taking into consideration the impact of hysterectomy. METHODS: We used data from six studies in the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. Participants included 2,995 Black women and 5,281 White women. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between endometriosis and fibroids with ovarian cancer risk, overall, by race, and stratified by histotype. We also assessed effect modification by hysterectomy. RESULTS: Overall the prevalences of endometriosis and fibroids were 6.4% and 43.2% among Black women and 7.0% and 21.5% among White women, respectively. Endometriosis was associated with an increased risk of endometrioid and clear cell ovarian cancer in Black and White women. Among Black women the association was strongest for endometrioid tumors (OR=7.06; 95% CI=3.86-12.91) compared to White women (OR=2.17; 95% CI=1.36-3.45) with a significant difference by race (phetereogeneity=0.003). When stratified by hysterectomy the association between endometriosis and ovarian cancer risk in White women was stronger in those who did not report a hysterectomy. However, in Black women, the elevated risk of ovarian cancer among women with endometriosis was present among those with and without hysterectomy. Fibroids were associated with a slightly elevated risk of ovarian cancer in Black (OR=1.34; 95% CI=1.11-1.62) and White women (OR=1.22; 95% CI=1.05-1.41). For both groups, the association was present only in those who did not report a hysterectomy. Black women who had a history of fibroids and no hysterectomy had a 53% greater odds of ovarian cancer (95% CI=1.23-1.89) compared to those without fibroids, while there was no association with fibroids in the hysterectomy group (OR=0.92, 95% CI=0.62-1.36) (pinteraction=0.05). A similar pattern was observed among White women, but the interaction was not significant (pinteraction=0.21). CONCLUSION: Both Black and White women with endometriosis had a higher risk of ovarian cancer, and hysterectomy modified this association only among White women. Fibroids were associated with modestly increased risk of ovarian cancer among Black and White women, with hysterectomy modifying the risk in both groups. Further research is needed to understanding how racial differences in diagnoses of these conditions, and differential access to care and treatment options, impact or modify ovarian cancer risk. Citation Format: Holly Harris, Lauren Peres, Courtney Johnson, Kristin Guertin, Alicia Beeghly-Fadiel, Elisa Bandera, Traci Bethea, Charlotte Joslin, Anna Wu, Patricia Moorman, Heather Ochs-Balcom, Jessica Petrick, Veronica Setiawan, Lynn Rosenberg, Joellen Schildkraut, Evan Myers. Racial differences in the association of endometriosis and fibroids with risk of ovarian cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C105.

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 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.

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

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 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.

Objective. High-grade serous ovarian cancer (HGSOC) is the most common and lethal histological subtype of epithelial ovarian cancer. HGSOC with cyclin E1 gene (CCNE1) amplification and bromodomain and extraterminal 4 (BRD4) amplification have been associated with poor outcomes. Our objective was to evaluate clinical outcomes of HGSOC with co-amplification of CCNE1 and BRD4 and high protein expression of cyclin E and BRD4. Methods. Copy number amplification data were extracted from The Cancer Genome Atlas (TCGA) for 579 HGSOC. Reverse phase protein array (RPPA) TCGA data were used to determine cyclin E and BRD4 protein expression in 482 HGSOC. Cyclin E and BRD4 protein expression by immunohistochemistry (IHC) was evaluated in a tissue microarray (TMA) of 110 HGSOC. Measured clinical outcomes were survival and platinum sensitivity. Results. Of 30% of HGSOC with amplifications in CCNE1 or BRD4, 8% have both CCNE1 and BRD4 amplification. Protein expression of cyclin E and BRD4 are positively correlated, both by RPPA (r = 0.23; p < 0.001) and by IHC (r = 0.21; p = 0.025). Patients with CCNE1 and BRD4 co-amplified HGSOC have worse overall survival than patients without amplifications, 39.94 vs 48.06 months (p = 0.029). High protein expression of cyclin E, but not BRD4, was associated with poor overall survival (HR 1.62, 1.04–2.53, p = 0.033) and platinum resistance (p = 0.016). Conclusion. HGSOC with CCNE1 and BRD4 co-amplification are associated with poor overall survival. Further studies are warranted to determine the use of protein expression by IHC as a surrogate marker for CCNE1 and BRD4 co-amplified HGSOC.

Background Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. Methods Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. Results Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08–1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. Conclusions This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

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; Ptrend = 0.37). We did not observe heterogeneity by histotype (P = 0.53), and there was no evidence of effect modification by body mass index (Pinteraction = 0.82), aspirin use (Pinteraction = 0.59), or smoking (Pinteraction = 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.

Simple Summary Obesity contributes to one-fifth of cancer deaths. Ovarian cancer (OC) progression is frequently asymptomatic, making its early detection difficult and its chance of survival low. OC expresses highly tumorigenic chemokines, CXCL1/8, of which the specific receptor CXCR2 is increased in the adipocytes. So, the CXCL1/8-CXCR2 axis may appear as a molecular link between obesity and OC. Here, we generated adipocyte-specific CXCR2 conditional knockout (cKO) mice to investigate how this CXCR2 cKO affects the peritoneal dissemination of OC under obese conditions. High-fat, diet-induced obese mice had a shorter survival than lean mice. Particularly, obese cKO mice had a reduced tumor burden but increased ascites accumulation, showing a decreased floating tumor burden in ascites, as well as proliferation and macrophage infiltration in tumors compared to obese wild-type mice. Despite the ascites accumulation, adipocyte-specific CXCR2 cKO reduced the obesity-induced tumor burden, likely altering the peritoneal tumor microenvironment of OC. Abstract Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional knockout (cKO) affected the peritoneal tumor microenvironment of OC in a high-fat diet (HFD)-induced obese mouse model. We first generated adipocyte-specific CXCR2 cKO in mice: adipose tissues were not different in crown-like structures and adipocyte size between the wild-type (WT) and cKO mice but expressed lower levels of CCL2/6 compared to the obese WT mice. HFD-induced obese mice had a shorter survival time than lean mice. Particularly, obese WT and cKO mice developed higher tumors and ascites burdens, respectively. The ascites from the obese cKO mice showed increased vacuole clumps but decreased the floating tumor burden, tumor-attached macrophages, triglyceride, free fatty acid, CCL2, and TNF levels compared to obese WT mice. A tumor analysis revealed that obese cKO mice attenuated inflammatory areas, PCNA, and F4/80 compared to obese WT mice, indicating a reduced tumor burden, and there were positive relationships between the ascites and tumor parameters. Taken together, the adipocyte-specific CXCR2 cKO was associated with obesity-induced ascites despite a reduced tumor burden, likely altering the peritoneal tumor microenvironment of OC.

Background: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19. Methods: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed. Results: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity. Conclusions: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship. Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis. Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94). Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed. Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3228.

Transcriptome-wide association studies (TWAS) have been successful in uncovering large numbers of putative disease susceptibility genes. TWAS approaches such as S-PrediXcan, FUSION and TIGAR, show comparable overall performance for susceptibility gene discovery; however, integrating prior disease-specific regulatory information is lacking. To improve accuracy of gene expression prediction by integrating information on susceptible transcription factor (sTF) occupancy in target cells and tissues, we developed an analytical framework, called sTF-TWAS. We evaluated six sets of putative regulatory variants selected from sTF-occupied sites, and performed generalized Berk-Jones (GBJ) analysis to combine sets and quantify overall associations. We demonstrated that sTF-TWAS outperforms S-PrediXcan in both simulation and real data analyses. Using summary statistics data from the Breast Cancer Association Consortium (BCAC), we also incorporated alternative splicing (sp) data in TF-TWAS and identified 76 and 88 significant genes for breast cancer risk at a Bonferroni-corrected P Citation Format: Xingyi Guo, Jingni He, Alicia Beeghly-Fadiel, Zhishan Chen, Chen Cao, Xiao-ou Shu, Wei Zheng, Quan Long. Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5900.

Purpose Data standards and interoperability are critical for improving care for patients with cancer. Recent efforts by ASCO include the Data Standards and Interoperability Summit in 2016, which led to the Omics and Precision Oncology and Advancing Interoperability workshops. To facilitate improved patient care, several recommendations for data sharing and standardization were made to the community. Methods To address these recommendations, we developed SMART Cancer Navigator, a Web application that uses application programming interfaces to gather clinical and genomic data from 11 public knowledge bases ranging from basic to clinical content coverage; three (CIViC, ClinVar, and OncoKB) explicitly linked genomic variants to clinical factors such as prognosis and treatment selection. We illustrated the utility of this application by selecting one of the monthly case studies presented by the ASCO University Molecular Oncology Tumor Board: Ovarian Cancer (BRCA Mutation). We also performed analyses on information from the three clinico-genomic knowledge bases to corroborate previous work and illustrate the state of data sharing among publicly available resources. Results SMART Cancer Navigator aggregates and contextualizes data from 11 different knowledge bases and stores user queries in a lightweight Web application that can link into Fast Healthcare Interoperability Resources–enabled electronic health records. Potentially relevant clinical trials and/or approved treatments were identified for three mutations found in a hypothetical patient with advanced ovarian cancer. A comparison of the three clinico-genomic knowledge bases indicated substantial differences in coverage at the gene and variant levels. Conclusion SMART Cancer Navigator has immediate relevance to practicing oncologists and others. Additional knowledge bases can be added without undue effort. As a first step toward utility, we generalized and disseminated the resulting implementation ( https://smart-cancer-navigator.github.io ) and data sets.

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.

Introduction While individual-level measures of socioeconomic status have been well-studied in relation to ovarian cancer survival, no studies to date have examined both state and national-level Area Deprivation Indices (ADIs), which incorporate neighborhood affluence and resources. Methods We abstracted clinical data from medical records for ovarian cancer cases from the Vanderbilt University Medical Center and obtained ADIs from the Neighborhood Atlas®. Associations with clinical characteristics were assessed with Spearman correlations and Kruskal-Wallis tests; associations with progression-free survival (PFS) and overall survival (OS) were assessed with Cox proportional-hazards regression. Results Among 184 cases, state and national ADIs were highly correlated, but not related to any cancer characteristics. In multivariable adjusted regression models, both were significantly associated with OS; each decile increase in state or national ADI corresponded to a 9 % or 10 % greater risk of death, respectively. Conclusions Increasing area-level deprivation may negatively impact ovarian cancer survival.

Objectives: Identifying new strategies to improve response to poly ADP-ribose polymerase inhibitors (PARPi) in women with homologous recombination (HR)-proficient ovarian cancer is a key clinical challenge. The nuclear orphan receptor NR4A1 has pro-tumor effects in ovarian cancer cells through transcriptional regulation of key genes promoting growth, survival and HR DNA repair. NR4A1 is also expressed in immune cells in the tumor microenvironment and may play a role in inhibiting re-polarization of pro-tumor M2-like tumor-associated macrophages (TAMs) to a more effective anti-tumor M1-like TAM phenotype. Our group has shown that the NF-kappaB (NF-ĸB) pathway is a key regulator of TAM phenotype, with upregulated NF-ĸB signaling promoting M1-like functions. Our goal therefore was to determine whether inhibition of NR4A1 can improve responses to PARPi both by increased tumor DNA damage and apoptosis, and by promoting an anti-tumor M1 phenotype in TAMs by modulating NF-ĸB activity. Methods: Cultured HR-proficient ID8 mouse ovarian cancer cells, mouse ovarian TAMs and mouse bone marrow-derived macrophages were treated with the established NR4A1 antagonist C-DIM-pPHOH (C-DIM) and/or the PARPi olaparib (OLA) for 24-72 hours. C57BL/6 mice with established intra-peritoneal ID8 tumors were treated with vehicle, C-DIM, OLA or combined C-DIM/OLA for 3 weeks. Standard techniques were used to determine cell growth (Sulforhodamine B assay), HR efficiency (BRCA1 and RAD51 foci formation), NF-ĸB activity (nuclear p65, luciferase reporter activity), and expression of markers of DNA damage (pH2AX), apoptosis (cleaved PARP), proliferation (PCNA), and macrophage M1 (CCL3, iNOS) and M2 (CD206, arginase-1) polarization. Statistical significance (p Download : Download high-res image (260KB) Download : Download full-size image Results: In ID8 cells, co-treatment with C-DIM and OLA significantly reduced cell growth and HR efficiency, and increased DNA-damage-induced apoptosis, compared to OLA treatment alone. NR4A1 was highly expressed in macrophages, and C-DIM increased NF-ĸB activity and induced M1 polarization alone and when combined with olaparib. Similar effects of combined treatment were observed in vivo. Compared to mice treated with OLA alone, there was significantly reduced ascites volume and omental tumor mass in C-DIM/OLA mice at the time of sacrifice. Combined treatment also reduced proliferation and increased DNA damage and apoptosis in harvested tumors, and increased M1 polarization of TAMs in ascites fluid, compared to OLA mice. Conclusions: NR4A1 inhibition sensitizes ovarian tumors to PARPi though direct effects on tumors by targeting the HR pathway, and by modulating TAM function towards an anti-tumor phenotype. These findings have important implications for expanding the use of PARPi in women with HR-proficient ovarian tumors, which would benefit a substantial number of women with this devastating disease.

5583Background: Median survival for high-grade serous ovarian cancer (HGSOC) patients is 3-4 years with a wide range of outcomes. Gene expression patterns have been reported to be predictive of out...

Background: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors. Methods: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States. Breast cancers were classified by clinical subtype. Case-only polytomous logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for HER2+ and triple-negative breast cancer (TNBC) status in relation to estrogen receptor–positive (ER+)/HER2− status (referent) for reproductive risk factors. Results: Relative to women who had ER+/HER2− tumors, women who were age 19–24 years at first birth (OR, 1.78; 95% CI, 1.22–2.59) were more likely to have TNBC. Parous women were less likely to be diagnosed with HER2+ breast cancer and more likely to be diagnosed with TNBC relative to ER+/HER2− breast cancer. Postmenopausal parous women who breastfed were less likely to have TNBC [OR, 0.65 (95% CI, 0.43–0.99)]. Conclusions: This large pooled study of Black women with breast cancer revealed etiologic heterogeneity among breast cancer subtypes. Impact: Black parous women who do not breastfeed are more likely to be diagnosed with TNBC, which has a worse prognosis, than with ER+/HER2− breast cancer.

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. ispartof: JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE vol:113 issue:3 pages:329-337 ispartof: location:United States status: published

PURPOSE: The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression. METHODS: We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources. RESULTS: Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83–0.97), RASGRP1 (HR 0.89, 95% CI 0.82–0.97), and SOD2 (HR 0.80, 95% CI 0.66–0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81–0.97) and RASGRP1 (HR 0.87, 95% CI 0.81–0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06–1.22) and GSPT1 (HR 1.33, 95% CI 1.14–1.55) expression was associated with shorter DFS. CONCLUSIONS: We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.

Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation. CXCR2 decreased p53 protein, a regulator of p21, and downregulated p21 promoter activity only in p53WT cells. The p53 responsive element (RE) of p21 promoter played a critical role in this CXCR2-mediated p21 downregulation. Moreover, CXCR2-positive cells activated more Akt than CXCR2-negative cells followed by enhanced murine double minute (Mdm2). Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells. Cell cycle analysis revealed that CXCR2 decreased p21 gene in p53-null cells. Interestingly, romidepsin (histone deacetylase inhibitor)-induced p21 upregulation did not involve the p53 RE in the p21 promoter in p53-null cells. Romidepsin decreased the protein levels of Akt1 and Mdm2, leading to induction of p21 in p53-null cells. CXCR2 reduced romidepsin-induced p21 upregulation by activating Akt-induced Mdm2. Taken together, CXCR2 enhances cell proliferation by suppressing p21 through Akt-Mdm2 signaling in p53-dependent and independent manner.

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Disparities in human papillomavirus (HPV) vaccination exist between urban (metropolitan statistical areas (MSAs)) and rural (non-MSAs) regions. To address whether the HPV vaccine’s impact differs by urbanicity, we examined trends in cervical intraepithelial neoplasia grades 2 or 3 and adenocarcinoma in situ (collectively, CIN2+) incidence in MSAs and non-MSAs among Tennessee Medicaid (TennCare)-enrolled women aged 18–39 years and among the subset screened for cervical cancer in Tennessee, United States. Using TennCare claims data, we identified annual age-group-specific (18–20, 21–24, 25–29, 30–34, and 35–39 years) CIN2+ incidence (2008–2018). Joinpoint regression was used to identify trends over time. Age–period–cohort Poisson regression models were used to evaluate age, period, and cohort effects. All analyses were stratified by urbanicity (MSA versus non-MSA). From 2008–2018, 11,243 incident CIN2+ events (7956 in MSAs, 3287 in non-MSAs) were identified among TennCare-enrolled women aged 18–39 years. CIN2+ incident trends (2008–2018) were similar between women in MSAs and non-MSAs, with largest declines among ages 18–20 (MSA average annual percent change (AAPC): −30.4, 95% confidence interval (95%CI): −35.4, −25.0, non-MSA AAPC: −30.9, 95%CI: −36.8, −24.5) and 21–24 years (MSA AAPC: −14.8, 95%CI: −18.1, −11.3, non-MSA AAPC: −15.1, 95%CI: −17.9, −12.2). Significant declines for ages 18–20 years began in 2008 in MSAs compared to 2010 in non-MSAs. Trends were largely driven by age and cohort effects. These patterns were consistent among screened women. Despite evidence of HPV vaccine impact on reducing CIN2+ incidence regardless of urbanicity, significant declines in CIN2+ incidence were delayed in non-MSAs versus MSAs.

Objectives: Our objective was to determine the prevalence of anemia and to improve compliance with the National Comprehensive Cancer Network (NCCN) recommendations to evaluate and treat anemia among gynecologic oncology patients. Methods: We conducted a prospective healthcare improvement initiative to align our practice with NCCN recommendations. Our intervention included prospective monitoring of lab results of both new patients and patients undergoing chemotherapy. Providers were notified if their patient had hemoglobin ≤11 g/dL and a clinical pharmacist pended iron studies, B12, and folate labs for the provider to review and accept if appropriate. Baseline data from the pre-intervention cohort was collected from 1/1/19-12/31/19; posti-ntervention data was collected from 2/2/2020-7/31/20. The primary outcome was prevalence of anemia and the secondary outcome was compliance with anemia evaluation, including iron, b12, and folate studies. Unadjusted odds ratios (OR) were obtained from logistic regression analysis. Results: We identified a total of 422 patients, 270 in the baseline cohort (69 new and 201 chemotherapy patients), and 152 in the post-implementation cohort (55 new and 97 chemotherapy patients). Prevalence of anemia in the entire study population was N=33/124 (27%) among new patients and N=202/298 (68%) among chemotherapy patients. Among new patients presenting with anemia, compliance with recommendations for evaluation of anemia increased from 37% to 93%, OR 22.3 (95% CI 3.4-451.2; P=0.007). Among anemic patients undergoing chemotherapy, compliance with recommendations for evaluation of anemia increased from 46% to 91%, OR 12.2 (95% CI 5.29-33.2; P Download : Download high-res image (183KB) Download : Download full-size image Conclusions: Anemia is common among gynecologic cancer patients. Implementation of a healthcare improvement program was associated with significant increases in compliance with NCCN guidelines for evaluation of anemia among gynecologic oncology patients.

Purpose of Study: We used multiple mediation analysis to examine why African-American women have poorer ovarian cancer survival compared to white women. Methods: We examined data from the OCWAA consortium which harmonized questionnaire-based data on 1,075 African-American women and 3,272 white women with ovarian cancer from seven U.S. studies. We first selected potential mediators and confounders by examining their association with race and survival and then incorporated these variables into a sequential multiple mediation analysis. We used multiple imputation and bootstrapping to fit and pool natural effects models with counterfactual exposures and survival times. In order to distinguish the effect of race through mediators and otherwise, we implemented log-normal accelerated failure time and Cox proportional hazards (PH) models. Results: In OCWAA, 67.8% (n=729) of African-American women and 69.7% (n=2,282) of white women were deceased. The hazard ratio for African-American compared to white women was 1.29 (95%CI=1.15-1.46). In our final model (Table 1), mediators of this disparity in survival included 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 46.4% (95%CI=30.9-60.0%) of the overall racial disparity, and histotype/stage and PMH duration accounted for the largest fraction. Conclusions: In the OCWAA consortium, almost half of the disparity in ovarian cancer survival between African-American and white women is explained by education, lifestyle factors, diabetes, PMH use, and tumor characteristics. A more complete understanding of the remaining difference in racial disparity is needed in order to ultimately improve outcomes and reduce disparities. Table 1.Sequential multiple mediation of racial differences in ovarian cancer survival in OCWAAStepaMediator(s) AddedIndirect Effect HRbDirect Effect HRcTotal Effect HRd% Mediatede1College graduate1.015 (0.960, 1.073)1.308 (1.265, 1.351)1.327 (1.268, 1.389)4.5 (-16.9, 22.0)2Nulliparity1.018 (0.963, 1.076)1.304 (1.261, 1.347)1.327 (1.268, 1.388)5.8 (-15.6, 22.9)3Smoking1.023 (0.968, 1.082)1.296 (1.254, 1.340)1.326 (1.266, 1.387)7.5 (-13.3, 24.8)4BMI,Diabetes,Diabetes/Race Interaction1.051 (0.995, 1.111)1.263 (1.222, 1.305)1.327 (1.268, 1.389)17.0 (-2.2, 33.2)5PMH Duration,PMH Duration/Race Interaction,PMH Duration/Age Interaction1.086 (1.025, 1.149)1.195 (1.157, 1.235)1.298 (1.238, 1.359)31.0 (11.2, 47.3)6Histotype,Stage1.129 (1.073, 1.189)1.149 (1.114, 1.184)1.297 (1.243, 1.353)46.4 (30.9, 60.0)Abbreviations: OCWAA, Ovarian Cancer in Women of African Ancestry; PMH, Postmenopausal hormone; BMI, body mass index.Bold numbers reflect statistically significant values.aSequential order in which the selected mediators were added to the model. Model also includes variables in all preceding steps.bThe indirect effect is the cumulative indirect effect of the variables selected as mediators in a given step and all preceding steps.cThe direct effect is the remaining direct effect through all other non-mediated pathways.dTotal effect is calculated as log(Indirect Effect HR) + log(Direct Effect HR).ePercent (%) mediated is calculated as log(indirect effect HR)/log(total effect HR). Citation Format: Kristin A. Guertin, Holly R. Harris, Tareq F. Camacho, Courtney E. Johnson, Anna H. Wu, Patricia G. Moorman, Evan Myers, Traci N. Bethea, Elisa V. Bandera, Charlotte E. Joslin, Heather M. Ochs-Balcom, Lauren C. Peres, Will T. Rosenow, Veronica W. Setiawan, Alicia Beeghly-Fadiel, Lauren F. Dempsey, Lynn Rosenberg, Joellen M. Schildkraut. Racial disparities in epithelial ovarian cancer survival: An examination of contributing factors in the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 33.

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC. ispartof: CANCER MEDICINE vol:8 issue:5 pages:2503-2513 ispartof: location:United States status: published

Platelets are critical components of a number of physiologic processes, including tissue remodeling after injury, wound healing, and maintenance of vascular integrity. Increasing evidence suggests that platelets may also play important roles in cancer. In ovarian cancer, thrombocytosis, both at the time of initial diagnosis and at recurrence, has been associated with poorer prognosis. This review describes current evidence for associations between thrombocytosis and ovarian cancer prognosis and discusses the clinical relevance of platelet count thresholds and timing of assessment. In addition, we discuss several mechanisms from in vitro, in vivo, and clinical studies that may underlie these associations and recommend potential approaches for novel therapeutic targets for this lethal disease.

Diagnosed before age 50, early onset pancreatic malignancy (EOPM), is hypothesized to be a distinct subset of disease, although research is limited. To better characterize EOPM, and the effect of age at diagnosis on pancreatic cancer survival, we examined clinical characteristics and survival in EOPM and typical age-at-onset pancreatic malignancy (TOPM) cases. Vanderbilt University Medical Center (VUMC) Cancer Registry confirmed pancreatic adenocarcinomas (PDACs) and malignant pancreatic neuroendocrine tumors (PNETs) were evaluated. Clinical characteristics were compared using χ(2) tests. Overall survival was visualized with Kaplan-Meier functions; Cox proportional hazards regression was used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 1,697 pancreatic malignancies were diagnosed at the VUMC between 1988 and 2013. Of 1,407 PDACs, 118 (8.4%) were EOPM, which was associated with significantly better survival (adjusted HR: 0.82, 95% CI: 0.67-1.00). EOPM and TOPM PDACs significantly differed with regard to having multiple malignancies; survival associations significantly differed by race, stage of disease, treatment and multiple malignancies. Of 190 PNETs, 63 (33.1%) were EOPM, which was not significantly associated with survival (adjusted HR: 0.80, 95% CI: 0.46-1.40). Malignant neuroendocrine EOPM and TOPM cases significantly differed by stage of disease and tumor location; survival associations significantly differed by family history of pancreatic cancer, stage of disease and multiple malignancies. Differences in clinical characteristics and associations with survival were identified, indicating that EOPM is distinct from TOPM, and exists among both pancreatic adenocarcinomas and malignant pancreatic neuroendocrine tumors.

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.\ud Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.\ud Results: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92–0.95, p = 4.13E−13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02–1.06, p = 1.26E−05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95–0.99, p = 8.05E−04).\ud Conclusions: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

Purpose. Although the incidence of epithelial ovarian cancer is highest among non-Hispanic white women, African-American women have the worst survival of all racial/ethnic groups. We hypothesize that differences in the prevalence of known and suspected ovarian cancer risk factors may explain a portion of the differences in incidence of epithelial ovarian cancer between white and African-American women. Methods. We used data from seven U.S. studies in the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium, the North Carolina Ovarian Cancer Study (NCOCS), the Los Angeles Ovarian Cancer Study (LACOCS), the African-American Cancer Epidemiology Study (AACES), the Cook County Case-Control Study (CCCCS), the Black Women's Health Study (BWHS), the Women's Health Initiative (WHI), and the Multiethnic Cohort Study (MEC). The association between each known or suspected ovarian cancer risk factor (age, parity, oral contraceptive use, tubal ligation, body mass index (BMI), family history of ovarian and breast cancer, menopausal status, education, hysterectomy, aspirin use, talcum powder applied to genital areas, endometriosis, and age at menarche) was estimated using logistic regression with study site interactions to capture heterogeneity across studies. Using the Bruzzi method, population attributable risks (PAR) were calculated by race for each risk factor individually and collectively for all risk factors. Results. The comparison of 3,249 white ovarian cancer cases and 9,650 controls to 1,054 African-American cases and 2,410 controls revealed notable differences in the PAR of several risk factors by race. African-American women had a statistically significantly higher PAR for family history of breast cancer and BMI ≥30kg/m2compared to white women (10.0% vs. 2.5% and 8.9% vs. 0.4%, respectively). Although not statistically significant, white women had a higher PAR for oral contraceptive use (duration Conclusions. Our findings suggest that the known and suspected ovarian cancer risk factors investigated in this study may be partially responsible for differences in ovarian cancer incidence between white and African-American women. Although important across both racial groups, collectively, the factors studied accounted for slightly more of the ovarian cancer risk among African-American women than white women. Citation Format: Lauren C. Peres, Tareq F. Camacho, Elisa V. Bandera, Traci N. Bethea, Charlotte E. Joslin, Anna H. Wu, Alicia Beeghly-Fadiel, Emily K. Cloyd, Holly R. Harris, Patricia G. Moorman, Evan Myers, Heather M. Ochs-Balcom, Will L. Rosenow, Veronica W. Setiawan, Lynn Rosenberg, Joellen M. Schildkraut. Estimating the contribution of epidemiologic risk factors to racial differences in epithelial ovarian cancer incidence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1180.

Objective: Mediated by a family of transcription factors, the canonical and noncanonical nuclear factor-kappaB (NF-kB) signaling pathways have key roles in inflammation, innate immunity, and cancer development and progression. As prior ovarian cancer studies have evaluated only canonical NF-kB transcription factors in relation to survival, this study was undertaken to evaluate both canonical and noncanonical NF-kB pathway components in tumor samples from epithelial ovarian cancer cases from the Vanderbilt Tissue Repository for Ovarian Cancer (TROC). Methods: We abstracted clinical data from electronic medical records and assayed p65 (representing the canonical NF-kB pathway) and p52 (representing the noncanonical NF-kB pathway) by immunohistochemistry for 197 TROC samples. Nuclear and cytoplasmic staining in tumor cells was semiquantified by H-scores and dichotomized at median values. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional-hazards regression. Results: Median cytoplasmic and nuclear p65 and p52 H-scores were significantly higher among high-grade and serous cases; median p52 H-scores were also significantly higher among late-stage cases and patients treated with chemotherapy (all Wilcoxon rank sum p Conclusions: This is the first study to demonstrate that p52, representing noncanonical NF-kB signaling, may be an independent prognostic factor for epithelial ovarian cancer. Approaches to inhibit noncanonical NF-kB signaling should be explored as novel therapies for ovarian cancer are needed. Citation Format: Demetra Hufnagel, Andrew J. Wilson, Jamie Saxon, Dineo Khabele, Timothy Blackwell, Marta A. Crispens, Fiona Yull, Alicia Beeghly-Fadiel. Noncanonical NF-kappaB signaling is associated with poor ovarian cancer prognosis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A15.

Objectives: Obesity affects more than one-third of US adults and promotes the development and progression of many cancers. One mechanism by which obesity may influence ovarian cancer is via adipocyte-tumor cell communication, including the production of chemotactic cytokines, or chemokines, in the tumor microenvironment. Our goal was to measure adipogenic chemokine expression and examine associations with body mass index (BMI) and ovarian cancer survival. Methods: We selected 25 chemokines from laboratory experiments that modeled adipogenesis, of which 22 had expression data available for 302 high-grade serous ovarian cancer cases from The Cancer Genome Atlas (TCGA). We measured mRNA expression using Taqman quantitative real-time polymerase chain reaction (QPCR) in 50 high-grade serous tumor samples and ascertained BMI from electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). We also evaluated peri-diagnosis BMI (± 4 weeks) from EMR for 298 tumor registry-confirmed (165 serous and 133 nonserous) cases. Expression data were log transformed and dichotomized at median values; associations with disease-free survival (DFS) and overall survival (OS) were quantified using proportional hazards regression. Results: In TCGA analyses, two ligands and one receptor had significant associations with better (CCL8 and CXCL13) and worse (CX3CR1) OS, respectively. Higher CXCL13 expression was also associated with better DFS in VUMC tumors, but significance was attenuated after adjustment for clinical covariates. CX3CR1 was not expressed in all tumors but was positively associated with BMI (Pearson’s r=0.69, P=0.019). Finally, among all 298 tumor registry-confirmed VUMC cases, BMI was not associated with OS, although higher BMI was associated with a 4% significantly increased risk of death among 133 nonserous cases. Conclusions: Our findings suggest that obesity impacts chemokine expression in the tumor microenvironment and ovarian cancer survival. Further, differences between serous and nonserous subtypes may influence the relationship between obesity and ovarian cancer prognosis. Citation Format: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel. Adipogenic chemokines, body mass index, and ovarian cancer survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B54.

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

Background: Obesity has been implicated in the progression of ovarian cancer, but associations between body mass index (BMI) and survival outcomes are mixed. Studies evaluating pre- or peri-diagnosis BMI have generally found associations between higher BMI and worse overall survival (OS), but studies with post-diagnosis BMI measures are limited. Furthermore, no existing post-diagnosis BMI and ovarian cancer survival studies have conducted analyses stratified by race. Objective: We undertook this study to characterize changes over time in BMI among ovarian cancer cases from the Vanderbilt University Medical Center (VUMC) and to evaluate associations in relation to overall survival (OS); differences by race were examined in stratified analyses. Methods: We assembled a retrospective cohort of Tumor Registry confirmed ovarian cancer cases from VUMC EMR. BMI (kg/m2) at diagnosis, and 6, 12, 18, and 24 months after diagnosis (±8 weeks) were used to classify obesity according to the World Health Organization (WHO) guidelines as underweight (1.05%), decreased ( Citation Format: Alicia Beeghly-Fadiel, Nneka J Anyanwu, Shyria Karam, Demetra Hufnagel, George Bukenya, Sara Duque, Deok Son, Andrew J Wilson, Marta A Crispens. Body mass index, race, and ovarian cancer: Characterizing changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C069.

Objective: Obesity disproportionately affects African American (AA) women, and there is some suggestion that its association with ovarian cancer risk may be stronger among AA compared to white women, but no study to date has been adequately powered to compare risk between the two populations. The Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium provided a unique opportunity to evaluate the association between body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in AA and white women and to estimate the contribution of obesity to ovarian cancer risk in both racial groups. Methods: The OCWAA Consortium is a collaboration of six of the largest epidemiologic studies of ovarian cancer in the United States that include AA women: four case-control and two case-control studies nested within cohort studies. The six studies are the Chicago Case-Control Study, the North Carolina Ovarian Cancer Study, the Los Angeles Ovarian Cancer Case-Control Studies, the African American Cancer Epidemiology Study, the Black Women’s Health Study, and the Multiethnic Cohort. BMI before diagnosis was available in all the studies and data on BMI and relevant confounders were harmonized for analyses. There were 1,144 AA cases, 2,910 AA controls, 3,174 white cases, and 9,160 white controls included. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using random-effects multi-level logistic regression models separately by race and histotype with control for relevant covariates, which included study, age, education, parity, oral contraceptive use, age at menarche and family history of breast/ovarian cancer. Multinomial regression was used for histotype analyses. Population attributable risk (PAR) estimates were computed by race and histotype. Results: The prevalence of obesity (BMI≥30 kg/m2) was higher in AAs compared to white women for both cases (53.2% vs 21.4%) and controls (45.7% vs. 18.4%). For EOC, there was little evidence of an association with obesity for white women. For AAs, risk was elevated for BMI≥30 kg/m2 (ORBMI 30-34=1.37, 95% CI: 1.12, 1.69; ORBMI≥35 = 1.26, 95% CI: 0.74, 2.15) relative to BMI 18.5- Citation Format: Elisa V Bandera, Fabian Camacho, Deanna Chyn, Emily K Cloyd, Traci N Bethea, Alicia Beeghly-Fadiel, Charlotte E Joslin, Evan Myers, Patricia G Moorman, Heather M Ochs-Balcom, Holly R Harris, Lauren C Peres, Veronica Wendy Setiawan, Anna H Wu, Lynn Rosenberg, Joellen M Schildkraut. Racial disparities in body mass index and ovarian cancer risk in the OCWAA Consortium [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C070.

Background: Pseudoangiomatous stromal hyperplasia (PASH) is a proliferative mesenchymal lesion of the breast histologically defined by dense collagenous stroma with spindle-shaped myofibroblasts. Characterization of patients with PASH has largely been limited to histologic and radiographic studies with small sample sizes due to the rarity of this benign condition. Furthermore, no existing studies of PASH have yet to consider race. Objectives: We undertook this study to identify subjects with PASH from electronic medical records (EMR) at the Vanderbilt University Medical Center (VUMC) and evaluate patient characteristics, including differences by race. Approach: We used natural language processing (NLP)-assisted searches to identify 283 subjects with pathology reports containing ‘PASH’ or ‘pseudoangiomatous stromal hyperplasia’. Results: We confirmed PASH by pathology report for 229 subjects (80.9%). The majority were Caucasian women, although 24 African Americans (10.5%) and 4 males (1.7%) with PASH were also identified. A total of 27 (11.8%) had a diagnosis of cancer as some point in their EMR, most frequently breast (74.1%) or thyroid (14.8%) cancer. The median age at PASH diagnosis was 45.4 years (range: 12.9-84.6) but this seemed lower among Asians (31.4 years). PASH was found more frequently in the left breast (54.8%) and was ascertained most often by core needle biopsy (76.0%), stereotactic needle biopsy (11.8%), or excision (7.0%). Among initially biopsied patients, 20 (9.9%) and 39 (19.3%) had subsequent biopsies and excisions, respectively. No significant differences in any of these characteristics by race were identified. Conclusions: This data confirms that PASH is not exclusive to Caucasians and suggests that patient characteristics do not differ by race. Analysis of additional characteristics and patient outcomes, with inclusion of EMR time, is currently underway. Citation Format: George Bukenya, Demetra Hufnagel, Nneka Anyawu, Stephanie Kurita, Alicia Beeghly-Fadiel. Characteristics of patients with pseudoangiomatous stromal hyperplasia (PASH): A retrospective cohort study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B118.

BACKGROUND: A key clinical challenge in ovarian cancer is identifying new strategies to treat patients who do not respond to poly ADP-ribose polymerase (PARP) inhibitor (PARPi) therapy. We previously linked the nuclear orphan receptor NR4A1/TR3 to pro-growth and pro-survival effects in ovarian cancer cells. However, it is unknown whether inhibiting NR4A1 function has therapeutic effects alone or in combination with PARPi in vitro. Moreover, the prognostic value of NR4A1 expression in patient tumors remains ill-defined, as two prior reports had contradictory findings for associations with ovarian cancer survival. OBJECTIVE: We undertook this study to test the therapeutic potential of inhibiting NR4A1 in ovarian cancer cells, and to clarify the prognostic value of NR4A1 expression in patient tumors. METHODS: In a panel of established ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3), we inhibited NR4A1 using the chemical antagonist, 1,1-Bis(3'-indolyl)-1-(p-hydroxyphenyl) methane (C-DIM) and siRNA targeting NR4A1 (siNR4A1). Effects of C-DIM on cell growth, alone and in combination with the PARPi, olaparib and rucaparib, were assessed in sulforhodamine B (SRB) in vitro assays. Markers of apoptosis (cleaved PARP, cleaved caspase-3) and proliferation (Ki67, PCNA, p21) were measured by western blot or immunohistochemistry (IHC). In ovarian tumors, NR4A1 was measured by IHC in 203 clinically annotated formalin-fixed paraffin-embedded (FFPE) tissue samples from the Vanderbilt University Medical Center (VUMC) Tissue Repository for Ovarian Cancer (TROC). Staining intensity (1: weak; 2: moderate; 3: strong) and percent of positive nuclei (0-100) were multiplied to yield an H score for NR4A1 expression. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by Hazards Ratios (HR) and 95% Confidence Intervals (CI) from proportional hazards regression. RESULTS: In ovarian cancer cell lines, C-DIM induced concentration-dependent decreases in cell growth and markers of proliferation, and stimulated apoptosis. These effects were mimicked in cells transfected with siNR4A1 compared to a non-targeting siRNA-transfected control. In combination with PARPi, C-DIM induced synergistic growth inhibition and apoptosis in vitro. In tumors, NR4A1 expression lower than the median (H score CONCLUSIONS: Our current results reconcile the discrepancy between prior NR4A1 reports, as associations differed due to confounding by clinical covariates. Shorter survival among cases with higher NR4A1 expression is supported by experimental evidence showing reduced ovarian cancer cell growth and increased apoptosis following NR4A1 inhibition, both alone and when combined with a PARPi. Together, our findings support further development of NR4A1 inhibition as a novel therapeutic approach that could improve response to PARPi therapy among ovarian cancer patients with chemoresistant disease. Citation Format: Alicia Beeghly-Fadiel, Johnathan Cooks, Dajah Chase, Marta Crispens, Dineo Khabele, and Andrew J Wilson. PROGNOSTIC SIGNIFICANCE OF NR4A1/TR3 EXPRESSION IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-088.