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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.

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.

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.

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.

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

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.

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 Tumor-infiltrating lymphocytes (TILs) have emerged as predictive biomarkers for cancer prognosis. The clinicopathological significance of spatial TIL subpopulations is not well studied due to lack of high-throughput scalable methodology for large population studies.Methods We established a fluorescent multiplex immunohistochemistry (mIHC) method coupled with computer-assisted high-throughput quantitative analysis. We then evaluated associations of six TILs markers (CD3, CD8, CD20, CD56, FOXP3, and PD-L1) with breast cancer prognosis among 188 tumor samples from the Nashville Breast Health Study. Results Our 5-plex fluorescent mIHC workflow was reliable, highly sensitive, non-interfering, and balanced labeling for three biomarkers per tissue section, which is applicable for high-throughput imaging quantification of spatial TILs in regular laboratory settings. In this study we found that the increased intratumoral CD56+ cells were associated with worse overall survival (OS) (HR, 4.89; 95% CI: 1.26-18.95, highest vs lowest tertiles; Ptrend = 0.022), suggesting the subset of immunosuppressive NK cell phenotypes within tumor bed. Increased stromal PD-L1+ cells (HR, 0.01; 95% CI, 0.00-0.89; Ptrend = 0.042) and a high stromal CD8+/FOXP3+ ratio (HR, 0.00; 95% CI, 0.00-0.12; Ptrend = 0.036) were associated with more favorable OS in stage III-IV breast cancer patients. Conclusion We established a reliable 5-plex fluorescent mIHC and showed that CD56+, PD-L1, and CD8+/FOXP3+ ratio may be important biomarkers for breast cancer prognosis. Further studies with a larger sample size are warrant to further elucidate the association between TILs and breast cancer outcomes.

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.

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...

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.

Background The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context. Methods We assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression. Results Among 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p = 0.004) and death (HR: 1.70, p = 0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors. Conclusions This is the first study to demonstrate that p52, a major component of non-canonical NF-κB signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-κB signaling should be explored as novel ovarian cancer therapies are needed.

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 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.

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.

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.

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

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.

Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. Because chemokine network is involved in OC progression, we evaluated associations between chemokine expression and survival in tumor suppressor protein p53 (TP53) wild-type (TP53WT) and mutant (TP53m) OC datasets. TP53 was highly mutated in OC compared to other cancer types. Among OC subtypes, CXCL14 was predominantly expressed in clear cell OC, and CCL15 and CCL20 in mucinous OC. TP53WT endometrioid OC highly expressed CXCL14 compared to TP53m, showing better progression-free survival but no difference in overall survival (OS). TP53m serous OC highly expressed CCL8, CCL20, CXCL10 and CXCL11 compared to TP53WT. CXCL12 and CCL21 were associated with poor OS in TP53WT serous OC. CXCR2 was associated with poor OS in TP53m serous OC, while CXCL9, CCL5, CXCR4, CXCL11, and CXCL13 were associated with better OS. Taken together, specific chemokine signatures may differentially influence OS in TP53WT and TP53m OC.

Oral contraceptive use is associated with reduced ovarian cancer risk; however associations with other contraceptive methods such as intrauterine device (IUD) and tubal ligation are less clear. Women in China differ from western women in regard to mechanisms and duration of use of contraception. This study was undertaken to evaluate associations between contraceptive methods and ovarian cancer risk using data from the prospective Shanghai Womens Health Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. A total of 174 epithelial ovarian cancer cases were found to occur among 70259 women who were followed-up for a total of 888258 person-years. The majority of women had ever used any contraception (77.0%) including IUD (55.6%) oral contraceptive (20.4%) tubal ligation (14.7%) or contraceptive shots (2.6%). Ever use of any contraception was associated with a nonsignificant reduction in ovarian cancer risk (HR: 0.86 95% CI: 0.60-1.24). Longer duration of IUD use was associated with lower ovarian cancer risk (p-value for trend = 0.04). Compared with never users women with durations of IUD use longer than the median (20 years) were 38% less likely to develop ovarian cancer (HR: 0.62 95% CI: 0.40-0.97). Based on the high prevalence and long duration of IUD use among Chinese women we estimate a preventive fraction of 9.3% corresponding to approximately 16 ovarian cancer cases. High prevalence of long-term IUD use may therefore contribute to the low incidence of ovarian cancer observed in China. (c) 2014 UICC.

Background Causes of racial disparities in breast cancer incidence and mortality between white and African American women remain unclear. This study evaluated associations of menstrual and reproductive factors with breast cancer risk by race and cancer subtypes. Patients and Methods Included in the study were 1866 breast cancer cases and 2306 controls recruited in the Nashville Breast Health Study, a population-based case-control study. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results African American women were more likely to have estrogen receptor-negative (ER − ), progesterone receptor-negative (PR − ), and triple-negative (ER − PR − HER2 − ) breast cancer than white women. Age at menarche (≥ 14 years) and multiparity (≥ 3 live births) were inversely associated with ER + tumors only, whereas late age at first live birth (> 30 years) and nulliparity were associated with elevated risk; such associations were predominantly seen in white women (OR = 0.70, 95% CI = 0.55-0.88; OR = 0.72, 95% CI = 0.56-0.92; OR = 1.42, 95% CI = 1.13-1.79; OR = 1.32, 95% CI = 1.06-1.63, respectively). Age at menopause between 47 and 51 years was associated with elevated risk of ER − tumors in both white and African American women. Among women who had natural menopause, positive association between ever-use of hormone replacement therapy and breast cancer risk was seen in white women only (OR = 1.39, 95% CI = 1.03-1.87). Conclusion This study suggests that certain hormone-related factors are differentially associated with risk of breast cancer subtypes, and these associations also differ by race.

Physical activity, a protective factor for breast cancer, increases the level of DNA methylation. Fibroblast growth factor receptor 2 (FGFR2), a confirmed breast cancer susceptibility gene, is predisposed to be methylated. Therefore, DNA methylation related genes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and DNA methyltransferase (DNMT), together with physical activity and FGFR2, may interact with each other to effect breast cancer risk.A total of 839 incident breast cancer cases and 863 age-matched controls from Guangzhou, China were included in this study. We used questionnaires to assess physical activity in metabolic equivalent (MET)-h/week/year and a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform to ascertain genotypes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models.Exercise activity and FGFR2 rs2981582 were confirmed to be associated with breast cancer risk, and were found to significantly interact (P for multiplicative and additive interactions = 0.045 and 0.021, respectively). Women who had CT/TT genotypes of FGFR2 rs2981582 and experienced exercise activity3 MET-h/week/year had significantly increased risk (OR = 3.15, 95% CI = 2.28-4.35) compared to women with CC genotype and ≥ 3 MET-h/week/year. There was also a significant interaction between FGFR2 rs2981582 and MTHFR rs1801133 on breast cancer risk (P for multiplicative and additive interactions = 0.039 and 0.023, respectively).We found both a gene-environment (FGFR2-exercise activity) and a gene-gene (FGFR2-MTHFR) interaction on breast cancer risk. Our results suggest that environmental factors, such as physical activity, may be able to counteract genetic susceptibility to breast cancer.

The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).

Purpose: To examine potential modifying effects of body weight and bilateral oophorectomy on the association of hormone replacement therapy (HRT) with risk of breast cancer, overall and by subtypes according to status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) among postmenopausal women. Experimental Design: This analysis included 2,510 postmenopausal white women recruited in the Nashville Breast Health Study, a population-based case–control study of breast cancer. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) for associations between HRT use and risk of breast cancer overall and by subtypes, adjusted for age and education. Results: Among women with natural menopause and body mass index (BMI) < 25 kg/m2, ever-use of HRT was associated with increased breast cancer risk (OR, 1.95; 95% CI, 1.32–2.88). Risk was elevated with duration of HRT use (P for trend = 0.002). Similar association patterns were found for ER+, ER+PR+, and luminal A cancer subtypes but not ER−, ER−PR−, and triple-negative cancer. In contrast, ever-HRT use in overweight women (BMI ≥ 25 kg/m2) showed no association with risk of breast cancer overall or by subtypes; interaction tests for modifying effect of BMI were statistically significant. Ever-HRT use was associated with decreased breast cancer risk (OR, 0.70; 95% CI, 0.38–1.31) among women with prior bilateral oophorectomy but elevated risk (OR, 1.45; 95% CI, 0.92–2.29) among those with hysterectomy without bilateral oophorectomy (P for interaction = 0.057). Similar associations were seen for virtually all breast cancer subtypes, although interaction tests were statistically significant for ER+ and luminal A only. Conclusion: Body weight and bilateral oophorectomy modify associations between HRT use and breast cancer risk, especially the risk of hormone receptor–positive tumors. Clin Cancer Res; 20(5); 1169–78. ©2014 AACR.

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.

Introduction: To facilitate research on personalized cancer medicine, we developed the DeepPhe system for deep phenotype extraction of computable longitudinal summaries from electronic medical records (EMR). DeepPhe provides an advanced natural language processing (NLP) pipeline capable of extracting cancer details from clinical notes, storage and export of the resulting details, and a visualization tool with interactive graphical capabilities at both the cohort and individual patient levels. Our initial software release included training and evaluation of breast cancer specific attributes (Savova et al. Cancer Research 2017). As part of our iterative process of testing and improving DeepPhe, we have recently expanded to ovarian cancer. Methods: We used DeepPhe to extract ovarian cancer characteristics from EMR, including tumor location(s), laterality, temporality, and clinical and pathologic components of stage of disease at diagnosis. Tool performance was quantified by F1 scores, defined as the harmonic mean between precision and recall, with F1=1.00 indicating perfect performance, compared to the gold standard of information from manual data abstraction. Results: Among a test set of 26 primary epithelial ovarian cancer cases with 1,675 annotated notes from UPMC, the overall F1 was 0.9327. F1 scores for attributes of tumor location, laterality, and temporality were 0.8621, 0.5000, and 1.000, respectively. Performance was perfect for all clinical stage of disease components (T, N, and M), while pathologic components scored 0.7879, 0.7692, and 0.9200, respectively. Evaluation of 16 additional UPMC cases is currently underway and ovarian cancer specific attributes are being expanded to include degree of surgical cytoreduction (debulking) and presence of residual disease. Generalizability will be further assessed by evaluating DeepPhe’s performance on EMR for 427 ovarian cancer cases from the Vanderbilt University Medical Center. Conclusions: Our results demonstrate that DeepPhe can be adapted to additional cancer types without losing good-to-excellent performance characteristics. While some concepts, such as laterality, remain challenging for extraction, current results are considered adequate for semi-automated abstraction approaches. Further refinement and expansion to additional clinical and tumor characteristics, including genomics, tumor biomarkers, treatments, and patient outcomes are currently underway. Open-source and freely available for research use, DeepPhe tools (https://github.com/DeepPhe/DeepPhe-Release) can facilitate large-scale extraction of detailed information from EMR systems for research on cancer. Citation Format: Alicia Beeghly-Fadiel, Jeremy L. Warner, Sean Finan, James Masanz, Harry Hochheiser, Guergana Savova. Deep phenotype extraction to facilitate cancer research: Extending DeepPhe to ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5114.

Introduction: Despite advances in treatment, ovarian cancer associated mortality has not substantially improved over the last 50 years. Understanding mechanisms that underlie disease progression is crucial to the development of new treatments for ovarian cancer. Mediated by a family of transcription factors, the canonical and non-canonical nuclear factor-kappaB signaling pathways have known roles in cell proliferation, as well as immune, inflammatory, and neoplastic processes. Non-canonical NF-kappaB signaling requires processing of a cytoplasmic p100/RelB dimer to a mature p52/RelB complex, capable of nuclear translocation to activate transcription of target genes. Prior studies on canonical NF-kappaB expression and ovarian cancer survival have been inconsistent, but no studies to date have evaluated the role of non-canonical NF-kappaB transcription factors. Methods: We conducted immunohistochemical staining for p52, a component of the non-canonical NF-kappaB signaling pathway, on a clinically annotated tissue microarray of ovarian tumors collected from 1994-2004 at the Vanderbilt University Medical Center. Nuclear and cytoplasmic p52 staining in tumors was semi-quantified by H-score and expression was 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: Among 194 ovarian cancer cases, p52 expression was predominantly cytoplasmic, with a relatively smaller proportion of tumor cells showing nuclear staining (median H-scores: 135.6 vs. 1.0). Cytoplasmic and nuclear p52 H-scores were significantly higher among high grade, advanced stage, and serous tumors (all Wilcoxon rank sum p Conclusions: This is the first study to demonstrate that nuclear p52, representing active non-canonical NF-kappaB signaling, may be an independent prognostic factor for epithelial ovarian cancer. Thus, interventions that inhibit non-canonical NF-kappaB signaling should be explored as novel therapies to limit ovarian cancer progression. Citation Format: Demetra Hufnagel, Andrew J. Wilson, Jamie Saxon, Timothy Blackwell, Dineo Khabele, Marta A. Crispens, Alicia Beeghly-Fadiel, Fiona Yull. Non-canonical NF-kappaB signaling in the tumor microenvironment in relation to ovarian cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1573.

While there is clear evidence for an association between later age at first live birth and increased breast cancer risk, associations with the timing of other reproductive events are less clear. As breast tissues undergo major structural and cellular changes during pregnancy, we examined associations between reproductive time events and intervals with breast cancer risk among parous women from the population-based Shanghai Breast Cancer Study (SBCS). Unconditional logistic regression was used to evaluate associations with breast cancer risk for 3,269 cases and 3,341 controls. In addition to later age at first live birth, later ages at first pregnancy and last pregnancy were significantly associated with increased breast cancer risk (p-trend = 0.002, 0.015, 0.008, respectively); longer intervals from menarche to first or last live birth were also associated with increased risk (p-trend

Background : Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown. Methods : A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS). Results : Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study. Conclusions : No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer. Impact : Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.

Background Thrombocytosis has been associated with poor ovarian cancer prognosis. However, comparisons of thresholds to define thrombocytosis and evaluation of relevant timing of platelet measurement has not been previously conducted. Methods We selected Tumor Registry confirmed ovarian, primary peritoneal, and fallopian tube cancer cases diagnosed between 1995–2013 from the Vanderbilt University Medical Center. Laboratory measured platelet values from electronic medical records (EMR) were used to determine thrombocytosis at three thresholds: a platelet count greater than 350, 400, or 450 × 109/liter. Timing was evaluated with 5 intervals: on the date of diagnosis, and up to 1, 2, 4, and 8 weeks prior to the date of diagnosis. Cox regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for association with overall survival; adjustment included age, stage, grade, and histologic subtype of disease. Results Pre-diagnosis platelet measures were available for 136, 241, 280, 297, and 304 cases in the five intervals. The prevalence of thrombocytosis decreased with increasing thresholds and was generally consistent across the five time intervals, ranging from 44.8–53.2 %, 31.6–39.4 %, and 19.9–26.1 % across the three thresholds. Associations with higher grade and stage of disease gained significance as the threshold increased. With the exception of the lowest threshold on the date of diagnosis (HR350: 1.55, 95 % CI: 0.97–2.47), all other survival associations were significant, with the highest reaching twice the risk of death for thrombocytosis on the date of diagnosis (HR400: 2.01, 95 % CI: 1.25–3.23). Conclusions Our EMR approach yielded associations comparable to published findings from medical record abstraction approaches. In addition, our results indicate that lower thrombocytosis thresholds and platelet measures up to 8 weeks before diagnosis may inform ovarian cancer characteristics and prognosis.

B vitamins and methionine have been postulated to have potential effects on carcinogenesis; however, findings from previous epidemiologic studies on B vitamins, methionine, and lung cancer risk are inconsistent. We investigated associations of dietary intakes of B vitamins (i.e., riboflavin, niacin, vitamin B6, folate, and vitamin B12) and methionine with lung cancer risk among female never smokers.The Shanghai Women's Health Study, a population-based, prospective cohort study, included 74,941 women. During a median follow-up of 11.2 years, 428 incident lung cancer cases accrued among 71,267 women with no history of smoking or cancer at baseline. Baseline dietary intakes were derived from a validated, interviewer-administered food frequency questionnaire. Cancer incidence and vital status were ascertained through annual linkage to the Shanghai Cancer Registry and Shanghai Vital Statistics Registry databases and through biennial in-person follow-ups with participants. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox regression.Dietary riboflavin intake was inversely associated with lung cancer risk (HR = 0.62; 95 % CI = 0.43-0.89; p trend = 0.03 for the highest quartile compared with the lowest). A higher than median intake of methionine was associated with lower risk of lung cancer (HR = 0.78; 95 % CI = 0.60-0.99); however, there was no dose-response relation. Intakes of other B vitamins were not associated with lung cancer risk.Our study suggests that dietary riboflavin intake may be inversely associated with lung cancer risk among female never smokers, which warrants further investigation.

Nine previously reported associations between single nucleotide polymorphisms (SNPs) and breast cancer outcomes from the Shanghai Breast Cancer Study (Stage 1) were further evaluated in relation to disease-free survival (DFS) and overall survival (OS) among 5,192 additional breast cancer patients (Stage 2).Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by proportional hazards regression in models adjusted for age, disease stage, estrogen and progesterone receptor status, and treatment regimens.Two SNPs had generally consistent results and significant associations with OS in combined analyses. Compared to women with MMP7 rs11225297 AA genotypes, OS was moderately better for women with AT genotypes (HR: 0.8, 95% CI: 0.7-1.0) and much better for women with TT genotypes (HR: 0.4, 95% CI: 0.2-0.8). Compared to women with MMP8 rs11225395 CC genotypes, OS was slightly better for women with CT genotypes (HR: 0.9, 95% CI: 0.7-1.1) and moderately better for women with TT genotypes (HR: 0.6, 95% CI: 0.4-0.9). Joint analysis showed significant dose-response relationships with increasing numbers of rare alleles for both OS (p0.001) and DFS (p = 0.001).A functional variant in MMP8 and a SNP in high linkage disequilibrium with a functional variant in MMP7 were significantly associated with breast cancer survival in a large two-stage survival study among Chinese women. This supports the hypothesis that SNPs in matrix metalloproteinase genes may influence breast cancer prognosis; additional research on these and other SNPs in genes important in metastasis, angiogenesis, and the regulation of the tumor microenvironment is warranted.

Introduction: With an overall five-year survival rate of only 46%, ovarian cancer is the most lethal gynecologic malignancy. Treatment includes surgical cytoreduction (debulking) followed by chemotherapy with platinum and taxane agents, and prognosis generally depends upon clinical characteristics, such as stage of disease at diagnosis, success of surgical debulking, and histologic subtype. However, even among women with comparable clinical characteristics, there can be variation in survival. Part of this variability may be due to inherited genetic variation in genes related to the absorption, distribution, metabolism, and excretion (ADME) of pharmacologic agents commonly used to treat ovarian cancer. Approach: To test the hypothesis that pharmacogenetic variants influence ovarian cancer prognosis, we assembled a clinical cohort of confirmed epithelial ovarian cancer cases from electronic medical records (EMR) at the Vanderbilt University Medical Center (VUMC) with banked DNA samples available. Clinical characteristics were abstracted from EMR using natural language processing (NLP)-assisted EMR review and a REDCap data collection instrument. Genotyping was conducted on the Sequenom iPLEX ADME PGx panel at the Vanderbilt Technologies for Advanced Genomics (VANTAGE) core facility. Associations with overall survival were evaluated using multivariable proportional hazards regression. Results: We identified a total of 391 epithelial ovarian cancer cases with banked DNA from VUMC EHR. Clinical characteristic abstracted by NLP followed expected distributions; the majority of cases were Caucasian (87%), with serous histology (63%), late-stage (62%), high-grade (60%) disease. Most common treatments included surgical cytoreduction (93%) and chemotherapy with a platinum (83%) and/or taxane agent (82%) agent. DNA was successfully pulled, plated, and genotyped for 327 cases (81.3%) for 73 common ADME variants in 30 genes. To prevent population stratification, genetic analyses were restricted to 287 Caucasians, where five nominally significant overall survival associations were identified: ABCB1 rs1045642, ABCC2 rs2273697, CYP2A6 rs1801272, CYP2E1 rs2070673, and SLCO2B1 rs2306168. Additional analyses, including for gene and drug scores, are currently under way. Conclusions: Individual variation in ADME genes may contribute to variation in ovarian cancer survival. Future steps include testing associations for replication, and evaluation of response to treatment. In addition, this research demonstrates that EMR-based study populations, in concert with linked biorepositories, can facilitate research on ovarian cancer. Citation Format: Ayush Giri, Rebecca T. Levinson, Spencer Keene, Gwendolyn Holman, Stacy D. Smith, Leshaun Clayton, Whitney Lovett, Samantha P. Stansel, Malcolm-Robert Bringhurst Snyder, Jason T. Fromal, Gabriella D. Cozzi, Dineo Khabele, Alicia Beeghly-Fadiel. Preliminary results from the Pharmacogenetics Ovarian Cancer Knowledge to Individualize Treatment (POCKIT) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4229.

The epithelial transmembrane glycoprotein E-cadherin (CDH1) is necessary for intercellular adhesion, cell signaling, and maintenance of cellular differentiation; reduced expression contributes to cell proliferation, invasion, and cancer progression. Functional or potentially functional single nucleotide polymorphisms (SNPs) in E-cadherin have been previously identified and evaluated in relation to cancer risk; however, studies on breast cancer have been sparse. Forty-six SNPs were genotyped to capture genetic variation of the CDH1 gene among 2,290 Phase 1 and 1,944 Phase 2 participants of the Shanghai Breast Cancer Study (SBCS), a large, population-based, case-control study. No overall associations between E-cadherin SNPs and breast cancer risk were observed. When stratified by menopausal status, associations that were consistent between Phases 1 and 2 and significant when data from both phases were combined were observed for several SNPs. Although none of these associations retained statistical significance after correcting for the total number of polymorphisms evaluated, this study suggests that genetic variation in CDH1 may be associated with breast cancer risk, and that this relationship may vary by menopausal status.

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases which are involved in normal cellular processes and also in cancer development and progression. The purpose of this study was to evaluate polymorphisms in the TIMP-2 and TIMP-3 genes for their associations with breast cancer susceptibility and survival. Using data from the Shanghai Breast Cancer Study, 19 SNPs for each gene were evaluated for associations with breast cancer risk among 1,062 cases and 1,069 controls; associations with disease-free and overall survival were evaluated among the cases. For TIMP-2, women with the rs7501477 TT genotype were 3 times more likely to be breast cancer cases than women with the CC genotype (OR: 2.9, 95% CI: 1.2–7.0). For TIMP-3, women with the rs9609643 AA genotype were 60% less likely to be breast cancer cases than women with the GG genotype (OR: 0.4, 95% CI: 0.2–1.0), whereas women with the rs8136803 TT genotype were 5 times more likely to be cases than women with the GG genotype (OR: 5.1, 95% CI: 1.1–24.3). Further, breast cancer cases with rs8136803 TT were almost 4 times more likely to have decreased disease-free survival (HR: 3.9, 95% CI: 1.4–10.6) and had a trend toward decreased overall survival (HR: 1.9, 95% CI: 0.6–6.1). An important study limitation was that these 3 SNPs (rs7501477, rs9609643, rs8136803) had low minor allele frequencies which resulted in small numbers of homozygote individuals. Genetic variation in the TIMP-2 and TIMP-3 genes may contribute to individual differences in breast cancer susceptibility and survival. © 2009 UICC

The matrix metalloproteinases (MMP) function as regulators of the dynamic tissue remodeling that occurs in the endometrial lining of the uterus during the normal human menstrual cycle; dysregulation of the MMPs is thought to contribute to the development of both endometriosis and endometrial cancer