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Introduction Demonstrating human papillomavirus vaccine impact is critical for informing guidelines to increase vaccination and decrease human papillomavirus‒related outcomes, particularly in states with suboptimal vaccination coverage, such as Tennessee. This study examines the trends in high-grade cervical lesion incidence among Tennessee Medicaid-enrolled women aged 18–39 years and the subset of women who were screened for cervical cancer. Methods Using a validated claims-based model to identify incident cervical intraepithelial neoplasia Grades 2 or 3 or adenocarcinoma in situ events, annual age group‒specific incidence rates from Tennessee Medicaid billing data, 2008–2018, were calculated. Significant trends were determined by Joinpoint. Analyses were conducted in 2020. Results From 2008 to 2018, high-grade cervical lesion incidence significantly declined in women aged 18–20 years (average annual percentage change= −31.9, 95% CI= −38.6, −24.6), 21–24 years (average annual percentage change= −12.9, 95% CI= −22.3, −2.4), and 25–29 years (average annual percentage change= −6.4, 95% CI= −8.1, −4.6). Among screened women, rates significantly declined for ages 18–20 years (average annual percentage change= −20.3, 95% CI= −25.3, −15.0), 21–24 years (average annual percentage change= −10.2, 95% CI= −12.6, −7.8), and 25–29 years (average annual percentage change= −2.6, 95% CI= −3.9, −1.2). Trends from 2008 to 2018 were stable for older age groups (30–34 and 35–39 years). Conclusions Results show reductions in high-grade cervical lesion incidence among ages most likely to have benefited from the human papillomavirus vaccine. Declines among young, screened women suggest causes other than reduction in screening. Evidence of vaccine impact in populations with low-vaccination coverage, such as Tennessee, is promising.

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.

Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer—colorectal, lung, ovary, prostate, pancreas, and melanoma—by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.

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.

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.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

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.

Studies have shown an increased risk of breast cancer associated with diabetes which may be due to differences in mammography use among women who have diabetes compared with women who do not have diabetes. Baseline data was used from the Southern Community Cohort Study – a prospective cohort study conducted primarily among low-income persons in the southeastern United States – to examine the association between diabetes and mammography use. In-person interviews collected information on diabetes and mammography use from 14,665 white and 30,846 black women aged 40–79 years between 2002 and 2009. After adjustment for potential confounding, white women with diabetes were no more likely (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.85–1.06) to undergo mammography within the past 12 months than white women without diabetes. Nor was there an association between diabetes and mammography use among black women (OR 1.00, 95% CI 0.93–1.07). An increase in mammography use was seen within one year following diabetes diagnosis, more so among white than black women, but this was offset by decreases thereafter. Although there was some evidence of an increase in mammography use within one year of diabetes diagnosis, these results suggest that mammography use is not related to diabetes.

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: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.