Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Prognostic Value of Cutaneous Disease Severity Estimates on Survival Outcomes in Patients With Chronic Graft-vs-Host Disease.

Importance: Prior studies have demonstrated an association between cutaneous chronic graft-vs-host disease (cGVHD) and mortality. Assessment of the prognostic value of different measures of disease severity would assist in risk stratification. Objective: To compare the prognostic value of body surface area (BSA) and National Institutes of Health (NIH) Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of cGVHD. Design, Setting, and Participants: Multicenter prospective cohort study from the Chronic Graft-vs-Host Disease Consortium including 9 medical centers in the US, enrolled from 2007 through 2012 and followed until 2018. Participants were adults and children with a diagnosis of cGVHD requiring systemic immunosuppression and with skin involvement during the study period, who had longitudinal follow-up. Data analysis was performed from April 2019 to April 2022. Exposures: Patients underwent continuous BSA estimation and categorical NIH Skin Score grading of cutaneous cGVHD at enrollment and every 3 to 6 months thereafter. Main Outcomes and Measures: Nonrelapse mortality (NRM) and overall survival (OS), compared between BSA and NIH Skin Score longitudinal prognostic models, adjusted for age, race, conditioning intensity, patient sex, and donor sex. Results: Of 469 patients with cGVHD, 267 (57%) (105 female [39%]; mean [SD] age, 51 [12] years) had cutaneous cGVHD at enrollment, and 89 (19%) developed skin involvement subsequently. Erythema-type disease had earlier onset and was more responsive to treatment compared with sclerosis-type disease. Most cases (77 of 112 [69%]) of sclerotic disease occurred without prior erythema. Erythema-type cGVHD at first follow-up visit was associated with NRM (hazard ratio, 1.33 per 10% BSA increase; 95% CI, 1.19-1.48; P < .001) and OS (hazard ratio, 1.28 per 10% BSA increase; 95% CI, 1.14-1.44; P < .001), while sclerosis-type cGVHD had no significant association with mortality. The model with erythema BSA collected at baseline and first follow-up visits retained 75% of the total prognostic information (from all covariates including BSA and NIH Skin Score) for NRM and 73% for OS, with no statistical difference between prognostic models (likelihood ratio test χ2, 5.9; P = .05). Conversely, NIH Skin Score collected at the same intervals lost significant prognostic information (likelihood ratio test χ2, 14.7; P < .001). The model incorporating NIH Skin Score instead of erythema BSA accounted for only 38% of the total information for NRM and 58% for OS. Conclusions and Relevance: In this prospective cohort study, erythema-type cutaneous cGVHD was associated with increased risk of mortality. Erythema BSA collected at baseline and follow-up predicted survival more accurately than the NIH Skin Score in patients requiring immunosuppression. Accurate assessment of erythema BSA may assist in identifying patients with cutaneous cGVHD at high risk for mortality.

Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma.

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35). CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.

BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Multiplex immunohistochemistry and high-throughput image analysis for evaluation of spatial tumor immune cell markers in human breast cancer.

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.

Racial differences in the association of body mass index and ovarian cancer risk in the OCWAA Consortium.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (ORBMI 30+= 1.62, 95% CI: 1.16, 2.26) and White women with obesity (ORBMI 30+= 1.20, 95% CI: 1.02, 2.42) compared to non-obese. Obesity was associated with higher NHGS risk in White women who never used HT (ORBMI 30+= 1.40, 95% CI: 1.08, 1.82). Higher NHGS ovarian cancer risk was observed for AA women who ever used HT (ORBMI 30+= 2.66, 95% CI: 1.15, 6.13), while in White women, there was an inverse association between recent BMI and risk of EOC and HGS in ever-HT users (EOC ORBMI 30+= 0.81, 95% CI: 0.69, 0.95, HGS ORBMI 30+= 0.73, 95% CI: 0.61, 0.88). CONCLUSION: Obesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

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

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

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

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.

Evaluation of Information Theoretic Network Meta-analysis to Rank First-Line Anticancer Regimens for Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer.

Importance: Hormone receptor-positive, ERBB2 (formerly HER2/neu)-negative metastatic breast cancer (HR-positive, ERBB2-negative MBC) is treated with targeted therapy, endocrine therapy, chemotherapy, or combinations of these modalities; however, evaluating the increasing number of treatment options is challenging because few regimens have been directly compared in randomized clinical trials (RCTs), and evidence has evolved over decades. Information theoretic network meta-analysis (IT-NMA) is a graph theory-based approach for regimen ranking that takes effect sizes and temporality of evidence into account. Objective: To examine the performance of an IT-NMA approach to rank HR-positive, ERBB2-negative MBC treatment regimens. Data Sources: HemOnc.org, a freely available medical online resource of interventions, regimens, and general information relevant to the fields of hematology and oncology, was used to identify relevant RCTs. Study Selection: All primary and subsequent reports of RCTs of first-line systemic treatments for HR-positive, ERBB2-negative MBC that were referenced on HemOnc.org and published between 1974 and 2019 were included. Additional RCTs that were evaluated by a prior traditional network meta-analysis on HR-positive, ERBB2-negative MBC were also included. Data Extraction and Synthesis: RCTs were independently extracted from HemOnc.org and a traditional NMA by separate observers. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for NMA with several exceptions: the risk of bias within individual studies and inconsistency in the treatment network were not assessed. Main Outcomes and Measures: Regimen rankings generated by IT-NMA based on clinical trial variables, including primary end point, enrollment number per trial arm, P value, effect size, years of enrollment, and year of publication. Results: A total of 203 RCTs with 63 629 patients encompassing 252 distinct regimens were compared by IT-NMA, which resulted in 151 rankings as of 2019. Combinations of targeted and endocrine therapy were highly ranked, especially the combination of endocrine therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. For example, letrozole plus palbociclib was ranked first and letrozole plus ribociclib, third. Older monotherapies that continue to be used in RCTs in comparator groups, such as anastrozole (251 of 252) and letrozole (252), fell to the bottom of the rankings. Many regimens gravitated toward indeterminacy by 2019. Conclusions and Relevance: In this network meta-analysis study, combination therapies appeared to be associated with better outcomes than monotherapies in the treatment of HR-positive, ERBB2-negative MBC. These findings suggest that IT-NMA is a promising method for longitudinal ranking of anticancer regimens from RCTs with different end points, sparse interconnectivity, and decades-long timeframes.

Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19.

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19. SIGNIFICANCE: Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171.

Association of Leukocyte Adhesion and Rolling in Skin With Patient Outcomes After Hematopoietic Cell Transplantation Using Noninvasive Reflectance Confocal Videomicroscopy.

Importance: Hematopoietic cell transplantation (HCT) is a potential cure for hematologic cancer but is associated with a risk of relapse and death. Dynamic biomarkers to predict relapse and inform treatment decisions after HCT are a major unmet clinical need. Objective: To identify a quantitative characteristic of leukocyte-endothelial interactions after HCT and test its associations with patient outcomes. Design, Setting, and Participants: In this prospective single-center cohort study from June 2017 to January 2020, patients of any age, sex, race, and ethnicity who had HCT for hematologic cancer were referred by health care professionals as either suspected of having symptoms or not having symptoms of acute graft-vs-host disease between 25 and 161 days after HCT. Patients underwent noninvasive skin videomicroscopy. Videos of dermal microvascular flow were recorded with a reflectance confocal microscope. Two blinded observers (J.R.P. and Z.Z.) counted leukocytes adherent to and rolling along the vessel wall per hour (A&R). Of 57 enrolled patients, 1 relapsed before imaging and was excluded, resulting in 56 patients included in analyses. Main Outcomes and Measures: Relapse of cancer, relapse-free survival, and overall survival. Results: Among the 56 patients (median age, 59 years; 38 [68%] male) who underwent imaging a median of 40 days after HCT, 21 had high A&R and 35 had low A&R. After correcting for the revised Disease Risk Index, patients with high A&R had higher rates of relapse (hazard ratio [HR], 4.24; 95% CI, 1.32-13.58; P = .02), reduced relapse-free survival (HR, 3.29; 95% CI, 1.26-8.55; P = .02), and reduced overall survival (HR, 3.06, 95% CI, 1.02-9.19; P = .05). These associations were preserved after correcting for possible confounders, steroid treatment, and acute graft-vs-host disease status. In the prognostic adequacy calculation by using Cox models, the new imaging biomarker (A&R) accounted for 82% to 95% of the prognostic information to predict each outcome. By contrast, the best existing clinical predictor routinely available, the revised Disease Risk Index, accounted for 10% to 28% of the prognostic information in the same model. Conclusions and Relevance: In this cohort study, leukocyte-endothelial interactions, visualized directly in skin after HCT, were associated with the patient outcomes of relapse, relapse-free survival, and overall survival. Assessing this dynamic marker could help patients at high risk for relapse who may benefit from interventions, such as early withdrawal of immunosuppression.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

A pooled case-only analysis of obesity and breast cancer subtype among Black women in the southeastern United States.

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/m2), 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/m2) 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.

Human Papillomavirus Vaccine Impact on Cervical Precancers in a Low-Vaccination Population.

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.

Learning through a Pandemic: The Current State of Knowledge on COVID-19 and Cancer.

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

High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer.

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.

Increasing Area Deprivation Index negatively impacts ovarian cancer survival.

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.

The Impact of the Human Papillomavirus Vaccine on High-Grade Cervical Lesions in Urban and Rural Areas: An Age-Period-Cohort Analysis.

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.

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

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