Cancer Epidemiology, Biomarkers & Prevention

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Abstract Background: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. Methods: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. Results: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09–1.19). There was significant heterogeneity by study design (Phet &lt; 0.01), with a stronger magnitude of association observed among case–control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. Conclusions: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. Impact: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Cervical Cancer Screening and Treatment Algorithms Using Human Papillomavirus Testing—Lessons Learnt from a South African Pilot Randomized Controlled Trial

Abstract Background: To report quantitative and qualitative results on cervical cancer human papillomavirus (HPV)-based screening and treatment algorithms, with/out triage with visual inspection after acetic acid (VIA), followed by ablative treatment (AT). Methods: Women 30 to 54 years old from Durban, South Africa were recruited, regardless of human immunodeficiency virus (HIV) status, randomized into one of two study arms and screened for HPV. VIA triage arm: HPV-positive women were triaged using VIA, biopsied and received AT if VIA positive and eligible; no triage arm: eligible HPV-positive women received AT. Women ineligible for AT were referred to colposcopy. Women were asked about side effects immediately and 1 week after AT. Retention to screening and treatment algorithms was compared between arms. Results: A total of 350 women [275 HIV-uninfected and 75 women living with HIV, (WLWH)] were allocated to receive HPV testing with VIA triage (n = 175) or no triage (n = 175). HPV prevalence was 28% [95% confidence interval (CI) = 23–33]; WLWH: 52% (95% CI = 40–64) versus HIV-uninfected: 21% (95% CI = 17–27; P &lt; 0.05). Among women who underwent VIA triage with histologic diagnosis, 3/17 were VIA negative with cervical intraepithelial neoplasia (CIN)2+; 14/18 were VIA positive with &lt;CIN2. Retention to screening and treatment algorithms was high (92%). Conclusions: This pilot demonstrated the feasibility of implementing screening and treatment algorithms, including performing triage and treatment in one visit; however, VIA triage did not reduce overtreatment and missed some precancerous lesions. Impact: This study reports on implementation feasibility of two World Health Organization screening and treatment algorithms (with/out VIA triage). Although the retention to screening and treatment algorithms was high in both arms, the question of how best triaging HPV-positive women deserves further consideration, particularly for WLWH. See related In the Spotlight, p. 763

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

Abstract 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 &lt;11 years at menarche than White women (controls: 9.9% vs. 6.0%). Compared with ≥15 years at menarche, &lt;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.

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer

Abstract Background: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Methods: Stage II–IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47–0.95), IR positivity (HR, 0.53; 95% CI, 0.29–0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47–0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02–2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02–1.92) were associated with increased recurrence risk. Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. Impact: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

Mammographic Breast Density and Risk of Ovarian Cancer in Korean Women

Abstract Background: This study aimed to investigate the potential association between mammographic breast density and ovarian cancer risk. Methods: This retrospective cohort study included women ≥40 years of age who underwent a mammography screening from 2009 to 2014. Breast density was assessed using the Breast Imaging-Reporting and Data System. The primary outcome was ovarian cancer development, and the cases were recorded until 2020. Cox proportional hazards regression was used to assess the association between breast density and ovarian cancer development. Subgroup analyses stratified by age, menopausal status, and body mass index (BMI) were conducted. Results: Of the 8,556,914 women included in this study, 9,246 ovarian cancer events were recorded during a median follow-up period of 10 years (interquartile range, 8.1–11.0 years). Compared with women with almost entirely fat density, those with scattered fibroglandular density, heterogeneous density, and extreme density had an increased risk of ovarian cancer with adjusted HRs of 1.08 [95% confidence interval (CI), 1.02–1.15], 1.16 (95% CI, 1.09–1.24), and 1.24 (95% CI, 1.15–1.34), respectively. The strongest association was observed in the ≥60 years age group; subgroup analysis indicated a significant increase in association between the higher-density category and ovarian cancer risk, regardless of BMI or menopausal status. Conclusions: Higher levels of breast density are associated with an increased risk of ovarian cancer. Impact: Breast density may have a relationship with ovarian cancer risk and could be used to assess future risk.

The Effect of Circulating Proteins and Their Role in Mediating Adiposity’s Effect on Endometrial Cancer Risk: Mendelian Randomization and Colocalization Analyses

Abstract Background: Proteomics could enhance our understanding of endometrial carcinogenesis. However, addressing confounding in traditional observational studies remains challenging, especially given the strong impact of adiposity on the plasma proteome and endometrial cancer risk. Methods: Using Mendelian randomization (MR) and colocalization analyses, we examined the causal association between 2,751 unique proteins from the UK Biobank (N proteins = 2,031; N = 52,363) and deCODE (N proteins = 1,667; N = 35,559) with endometrial cancer risk [overall (N cases = 12,270; N controls = 46,126), endometrioid (N cases = 8,758), and nonendometrioid (N cases = 1,230)]. We performed enrichment analyses to explore pathways overrepresented among plasma proteins in endometrioid and nonendometrioid cancer subtypes. We assessed whether circulating proteins mediated the effect of body mass index on endometrial cancer risk using uni- and multivariable MR. Results: Twenty proteins were associated with endometrial cancer risk in MR and colocalization analyses. GSTO1-1 and SKAP1 were positively and MMP10 was negatively associated with overall and endometrioid endometrial cancer; DTYMK and ABO were positively and TSSC4 was negatively associated with overall endometrial cancer; IGF2R was positively associated with endometrioid cancer; and MAPK9 was positively and DNAJB14, IFI16, LCN2, and SCT were negatively associated with nonendometrioid endometrial cancer. Distinct pathways were overrepresented in endometrioid (e.g., platelet-derived growth factor signaling and PTEN gene regulation) and nonendometrioid (e.g., noncanonical NF-κB signaling) cancer subtypes. There was weak evidence of associated proteins mediating the relationship between body mass index and endometrial cancer risk. Conclusions: We identified distinct plasma proteins and pathways associated with endometrioid and nonendometrioid endometrial cancer risk. Impact: Prioritized proteins may support noninvasive methods to differentiate endometrial cancer subtypes.

Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes

Abstract Background: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes. Methods: We pooled data from 11 case–control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models. Results: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only. Conclusions: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes. Impact: The different patterns of associations may provide key information about the etiology of the four subtypes.

Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women

Abstract Background: Distinguishing ovarian cancer from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of ovarian cancer pathogenesis. Accumulating evidence suggests a link between ovarian cancer and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved ovarian cancer diagnosis and prevention. Methods: Here, we profiled the serum lipidome of 208 ovarian cancer, including 93 early-stage patients with ovarian cancer and 117 nonovarian cancer (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning (ML) approaches. Results: We found that lipidome alterations unique to ovarian cancer were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in ovarian cancer in comparison with other gynecological diseases. ML methods selected a panel of 17 lipids that discriminated ovarian cancer from nonovarian cancer cases with an AUC value of 0.85 for an independent test set. Conclusions: This study provides a systemic analysis of lipidome alterations in human ovarian cancer, specifically in Korean women. Impact: Here, we show the potential of circulating lipids in distinguishing ovarian cancer from nonovarian cancer conditions.

Time Trends for Incidence and Net Survival of Cervical Cancer in Sweden 1960–2014—A Nationwide Population-Based Study

Abstract Background: The aim was to investigate time trends for incidence and long-term net survival in the morphologic subtypes and stages of cervical cancer in Sweden during the period 1960 to 2014. Methods: Women with invasive cervical cancer were identified through the Swedish Cancer Registry. Incidence and net survival were calculated according to morphology, age at diagnosis, and FIGO stage at diagnosis. Results: In total, 29,579 cases of invasive cervical cancer between 1960 and 2014 were included. The age-standardized incidence for squamous cell carcinoma (SCC) decreased until 2000; thereafter, the incidence rate stagnated, and a small increase was found in 2014. The incidence of adenocarcinoma continuously increased. The age-standardized 5-year net survival increased. However, decreasing net survival with increasing age was found. A higher stage at diagnosis showed a worse net survival. SCC and adenocarcinoma did not statistically differ as regards net survival in the last years of the study. Conclusions: Age-standardized 5-year net survival improved between 1960 and 2014. A positive trend for short- and long-term net survival was seen for women ages 18 to 64 years but long-term net survival for women ≥75 years decreased. In this study, age and FIGO stage at diagnosis were found to be important prognostic factors in determining net survival. The morphologies, SCC, and adenocarcinoma did not statistically differ as regards net survival in the last years of the study. Impact: This study demonstrates longitudinal data on cervical cancer in Sweden for over 50 years with sub analyses on morphology, age, and stage at diagnosis.

Depot-Medroxyprogesterone Acetate Use Is Associated with Decreased Risk of Ovarian Cancer: The Mounting Evidence of a Protective Role of Progestins

AbstractBackground:Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but previous studies have been underpowered.Methods:The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case–control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted.Results:Ever use of DMPA was associated with a 35% decreased risk of ovarian cancer overall (OR, 0.65; 95% confidence interval, 0.50–0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (Ptrend &lt; 0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk.Conclusions:DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted.Impact:The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices that have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.

Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk—Response

Copy Number Variation and Ovarian Cancer Risk—Letter

Metabolically Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case–control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; &lt;1st tertile) and metabolically unhealthy (MU; ≥1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)&lt;25 kg/m2 or waist circumference (WC)&lt;80 cm or waist-to-hip ratio (WHR)&lt;0.8) and overweight (OW; BMI≥25 kg/m2 or WC≥80 cm or WHR≥0.8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/NW, and (iv) MU/OW. Results: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05–2.10 and ORWHR, 1.68; 95% CI, 1.21–2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73–3.27; ORWC, 2.69; 95% CI, 1.92–3.77 and ORWHR, 1.83; 95% CI, 1.32–2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24–3.04). Conclusions: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity-related pathways are relevant for the development of this cancer beyond insulin. Impact: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se.

Cervical Cancer Screening—Past, Present, and Future

Abstract Cervical cancer screening has undergone a transformation in recent decades. Historically, programs were based on cervical cytology (i.e., “Pap smear”), which had to be repeated often because of its limited sensitivity and reproducibility. In more recent years, the discovery of human papillomavirus (HPV) as the necessary cause of virtually all cervical cancers has led to the introduction of HPV testing into clinical practice, first as a triage test for minor cytologic abnormalities, then in conjunction with cervical cytology (cotesting), and most recently, as a standalone screening test. Multiple randomized trials have shown that HPV-based screening has higher sensitivity compared with cytology, providing great reassurance against cervical precancer and cancer for women testing HPV-negative for many years. Analyses have also been conducted in support of the recent U.S. Preventive Services Task Force guidelines that show that primary HPV screening achieves the greatest balance of benefits and harms compared with other strategies. An added benefit of primary HPV testing is the ability to conduct it from self-collected samples, which is critical for extending coverage among hard-to-reach individuals and could provide a safe and effective alternative to in-person screening visits during the COVID-19 pandemic. See related article by Liang et al., p. 474

Cost-Effectiveness of Offering Cervical Cancer Screening with HPV Self-Sampling among African-American Women in the Mississippi Delta

Abstract Background: African-American women in the United States have an elevated risk of cervical cancer incidence and mortality. In the Mississippi Delta, cervical cancer disparities are particularly stark. Methods: We conducted a micro-costing study alongside a group randomized trial that evaluated the efficacy of a patient-centered approach (“Choice” between self-collection at home for HPV testing or current standard of care within the public health system in Mississippi) versus the current standard of care [“Standard-of-care screening,” involving cytology (i.e., Pap) and HPV co-testing at the Health Department clinics]. The interventions in both study arms were delivered by community health workers (CHW). Using cost, screening uptake, and colposcopy adherence data from the trial, we informed a mathematical model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis comparing the “Choice” and “Standard-of-care screening” interventions among un/underscreened African-American women in the Mississippi Delta. Results: When each intervention was simulated every 5 years from ages 25 to 65 years, the “Standard-of-care screening” strategy reduced cancer risk by 6.4% and was not an efficient strategy; “Choice” was more effective and efficient, reducing lifetime risk of cervical cancer by 14.8% and costing $62,720 per year of life saved (YLS). Screening uptake and colposcopy adherence were key drivers of intervention cost-effectiveness. Conclusions: Offering “Choice” to un/underscreened African-American women in the Mississippi Delta led to greater uptake than CHW-facilitated screening at the Health Department, and may be cost-effective. Impact: We evaluated the cost-effectiveness of an HPV self-collection intervention to reduce disparities.

Will COVID-19 Be the Tipping Point for Primary HPV Self-sampling?

Abstract Self-sampling is poised to be a disruptor for cervical screening. So far, cancer screening has been a causality of COVID-19; however, the opposite may transpire for self-sampling. Self-sampling enables socially distanced cervical screening with an outreach that extends to underserved populations. As evidence mounts that self-sampling is noninferior to clinician-taken samples, the focus for self-sampling is now as a primary screening option for all women. Now, we have evidence from a modeling study (using Australia as an exemplar) to suggest that program effectiveness with primary self-sampling would be better than the current program, even if sensitivity is lower. Regulatory issues, suitable triage strategies, and clear communication about self-sampling are hurdles yet to be overcome. Nevertheless, existing evidence coupled with COVID-19 could be the tipping point for wider introduction of self-sampling. See related article by Smith et al., p. 268

Testing a Population-Based Outreach Intervention for Ovarian Cancer Survivors to Encourage their Close Relatives to Consider Genetic Counseling

Abstract Background: Most relatives of women with ovarian cancer are unaware of their increased risk for cancer and their eligibility for genetic counseling. State cancer registries offer a platform to communicate about inherited risk to this population. Methods: We conducted a two-arm randomized trial to test a theory-based communication intervention—Your Family Connects (YFC)—compared to the standard Georgia Cancer Registry (GCR) contact. A total of 1,938 eligible ovarian cancer survivors were randomly assigned to either the YFC arm (n = 969) or the Standard Care arm (n = 969). We assessed the number of ovarian cancer survivors and their close relatives who logged on to the study website by arm. Results: Survivor reach was significantly higher in the Standard Care arm than YFC (20.8% vs. 15.2%, respectively; P &lt; 0.001). However, reach to relatives was limited to listed relatives in the YFC arm (n = 20, 13.2%), with little participation from those in the Standard Care arm (n = 1, 0.4%). Pooling across arms, minority race, longer time since diagnosis, and older age were all significantly associated with a decreased likelihood that the survivor accessed the website. Conclusions: The YFC intervention showed lower effectiveness for engaging survivors but was more effective than Standard Care in engaging at-risk relatives. Other factors (e.g., time since diagnosis) associated with lower reach must be considered in refining future outreach approaches. Impact: Partnering with a state cancer registry to foster family communication about inherited cancer risk is feasible but the possibility for broad population reach warrants further testing.

Promise and Perils of Primary HPV Testing

Abstract Cervical cancer screening has reduced morbidity and mortality in many countries, but efforts to optimize screening modalities and schedules are ongoing. Using data from a randomized trial conducted in British Columbia, Canada, in conjunction with a provincial screening registry, Gottschlich and colleagues demonstrated that the estimated risk for precancerous disease (cervical intraepithelial neoplasia grades 2 or worse) at 8 years following a negative human papillomavirus (HPV) test was similar to the current standard of care (Pap testing after 3 years). The study supports extending screening intervals for those with a negative HPV test beyond currently recommended 5-year intervals. In an ideal world, the resources saved through less frequent routine cervical screening could be redirected to increasing screening uptake and follow-up of abnormalities to improve equity in cervical cancer prevention. However, implementation of extending screening intervals remains less than straightforward in settings with fragmented healthcare systems that lack information systems to support patient call/recall, such as the United States. To achieve the full promise of primary HPV testing, stakeholders at every level must commit to identifying and addressing the diverse spectrum of barriers that undergird existing inequities in care access, appropriately resource implementation strategies, and improve health information systems. See related article by Gottschlich et al., p. 904

Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race

Abstract Background: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race. Methods: HRD features were identified using matched tumor–normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race. Results: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43–1.09; White HR = 0.38; 95% CI, 0.14–1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%). Conclusions: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals. Impact: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.

Projected Trends in the Incidence and Mortality of Uterine Cancer in the United States

Abstract Background: To develop a natural history model for uterine cancer calibrated to population-based incidence and mortality data to project future trends in the disease through 2050. Methods: We developed a state-transition microsimulation model of uterine cancer. The model begins at 18 years of age and simulates Black and White patients, includes transition states for precursor lesions, and separately models endometrioid and nonendometrioid tumors. The model was calibrated to population-based incidence and mortality data using parameter extrapolation. Results: The model closely fit population-based incidence and mortality data of uterine cancer. From 2020 to 2050, the incidence of uterine cancer is projected to increase in White women to 74.2 cases per 100,000 (compared with 57.7 cases per 100,000 in 2018) and increase to 86.9 per 100,000 (compared with 56.8 cases per 100,000 in 2018) in Black women. Among White women, incidence-based mortality will increase from 6.1 per 100,000 in 2018 to 11.2 per 100,000 in 2050, whereas incidence-based mortality in Black women will increase from 14.1 per 100,000 to 27.9 per 100,000. Endometrioid tumors are expected to increase considerably in both White and Black women; White women will experience only a slight increase in nonendometrioid tumors, whereas the incidence of these tumors will increase substantially in Black women. Conclusions: The incidence and mortality of uterine cancer are projected to increase substantially over the next three decades. Black women will experience a disproportionate increase in the disease. Impact: Projecting the incidence and mortality of uterine cancer can facilitate future cancer control efforts.

History of Infertility and Risk of Endometrial Cancer in the Women’s Health Initiative

Abstract Background: Several studies have suggested an association between infertility and risk of endometrial cancer. However, most studies have evaluated this relationship in premenopausal people, yet the mean age of endometrial cancer is 60 years, after the average age of menopause. Methods: Our study included Women’s Health Initiative participants who self-reported whether they had a history of infertility. Cox proportional hazards models were used to examine the association between infertility and incident endometrial cancer. Given that all infertility diagnoses occurred prior to study enrollment, we conducted secondary analyses using logistic regression examining prevalent endometrial cancer cases diagnosed before study baseline. Results: Approximately 18% of participants reported a history of infertility. No statistically significant association was observed between infertility and risk of incident endometrial cancer overall [incident cases = 1,622; HR = 1.12; 95% confidence interval (CI) = 0.99–1.26]. Although point estimates suggested an increase in risk of endometrial cancer among women with body mass index (BMI) ≥25 (HR = 1.15; 95% CI = 0.99–1.33), none of the associations were statistically significant. There was an association between history of infertility and prevalent endometrial cancer cases (OR = 1.19; 95% CI = 1.06–1.34), with the strongest association for infertility diagnosis due to endometriosis (OR 2.42; 95% CI = 1.83–3.19). Conclusions: In a population of postmenopausal participants, we observed a modest, but not statistically significant, association between overall infertility and incident endometrial cancer, with the suggestion of a higher risk among those with a BMI ≥ 25. Impact: Our findings highlight, as observed in previous studies, that risk factors for endometrial cancer may vary by BMI.

Disparities and Determinants of Testing for Early Detection of Cervical Cancer among Nepalese Women: Evidence from a Population-Based Survey

Abstract Background: Cervical cancer presents a considerable challenge in South Asia, notably in Nepal, where screening remains limited. Past research in Nepal lacked national representation and a thorough exploration of factors influencing cervical cancer screening, such as educational and socioeconomic disparities. This study aims to measure these gaps and identify associated factors in testing for early detection of cervical cancer among Nepalese women. Methods: Data from the 2019 Nepal Noncommunicable Disease Risk Factors survey (World Health Organization STEPwise approach to noncommunicable risk factor surveillance), involving 2,332 women aged 30 to 69 years, were used. Respondents were asked if they had undergone cervical cancer testing through visual inspection with acetic acid, Pap smear, or human papillomavirus test ever or in the past 5 years. The slope index of inequality (SII) and relative concentration index were used to measure socioeconomic and education-based disparities in cervical cancer test uptake. Results: Only 7.1% [95% confidence interval (CI): 5.1–9.9] Nepalese women had ever undergone cervical cancer testing, whereas 5.1% (95% CI: 3.4–7.5) tested within the last 5 years. The ever uptake of cervical cancer testing was 5.1 percentage points higher (SII: 5.1, 95% CI: −0.1 to 10.2) among women from the richest compared with the poorest households. Education-based disparities were particularly pronounced, with a 13.9 percentage point difference between highly educated urban residents and their uneducated counterparts (SII: 13.9, 95% CI: 5.8–21.9). Conclusions: Less than one in ten women in Nepal had a cervical cancer testing, primarily favoring higher educated and wealthier individuals. Impact: Targeted early detection and cervical cancer screening interventions are necessary to address these disparities and improve access and uptake.

Evidence of Decreased Long-term Risk of Cervical Precancer after Negative Primary HPV Screens Compared with Negative Cytology Screens in a Longitudinal Cohort Study

Abstract Background: The growing use of primary human papillomavirus (HPV) cervical cancer screening requires determining appropriate screening intervals to avoid overtreatment of transient disease. This study examined the long-term risk of cervical precancer after HPV screening to inform screening interval recommendations. Methods: This longitudinal cohort study (British Columbia, Canada, 2008 to 2022) recruited women and individuals with a cervix who received 1 to 2 negative HPV screens (HPV1 cohort, N = 5,546; HPV2 cohort, N = 6,624) during a randomized trial and women and individuals with a cervix with 1 to 2 normal cytology results (BCS1 cohort, N = 782,297; BCS2 cohort, N = 673,778) extracted from the provincial screening registry. All participants were followed through the registry for 14 years. Long-term risk of cervical precancer or worse [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)] was compared between HPV and cytology cohorts. Results: Cumulative risks of CIN2+ were 3.2/1,000 [95% confidence interval (CI), 1.6–4.7] in HPV1 and 2.7/1,000 (95% CI, 1.2–4.2) in HPV2 after 8 years. This was comparable with the risk in the cytology cohorts after 3 years [BCS1: 3.3/1,000 (95% CI, 3.1–3.4); BCS2: 2.5/1,000 (95% CI, 2.4–2.6)]. The cumulative risk of CIN2+ after 10 years was low in the HPV cohorts [HPV1: 4.7/1,000 (95% CI, 2.6–6.7); HPV2: 3.9 (95% CI, 1.1–6.6)]. Conclusions: Risk of CIN2+ 8 years after a negative screen in the HPV cohorts was comparable with risk after 3 years in the cytology cohorts (the benchmark for acceptable risk). Impact: These findings suggest that primary HPV screening intervals could be extended beyond the current 5-year recommendation, potentially reducing barriers to screening.

Reproductive and Hormonal Factors and Risk of Ovarian Cancer by Tumor Dominance: Results from the Ovarian Cancer Cohort Consortium (OC3)

Abstract Background: Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells. Methods: We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and nondominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance. Results: Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were nondominant. Parity was more strongly inversely associated with risk of dominant than nondominant ovarian cancer (Pheterogeneity = 0.004). Ever use of oral contraceptives (OC) was associated with lower risk of dominant tumors, but was not associated with nondominant tumors (Pheterogeneity = 0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or nondominant tumors (Pheterogeneity = 0.08). Conclusions: These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin. Impact: Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.

Weight Gain and the Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

Abstract Background: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with BRCA mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers. Methods: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer. Results: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13–3.54; P = 0.02). Current BMI of 26.5 kg/m2 or greater was associated with an increased risk of ovarian cancer in BRCA1 mutation carriers, compared with those with a BMI less than 20.8 kg/m2 (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04–4.36; P = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer. Conclusions: Adult weight gain is a risk factor for ovarian cancer in women with a BRCA1 or BRCA2 mutation. Impact: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.

Ovarian Cancer Risk in Relation to Blood Cholesterol and Triglycerides

Abstract Background: The association between circulating cholesterol and triglyceride levels and ovarian cancer risk remains unclear. Methods: We prospectively evaluated the association between cholesterol [total, low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C)] and triglycerides and ovarian cancer incidence in a case–control study nested in the Nurses' Health Study (NHS) and NHSII cohorts and a longitudinal analysis in the UK Biobank. Results: A total of 290 epithelial ovarian cancer cases in the NHS/NHSII and 551 cases in UK Biobank were diagnosed after blood collection. We observed a reduced ovarian cancer risk comparing the top to bottom quartile of total cholesterol [meta-analysis relative risk (95% confidence interval): 0.81 (0.65–1.01), Ptrend 0.06], with no heterogeneity across studies (Pheterogeneity = 0.74). Overall, no clear patterns were observed for HDL-C, LDL-C, or triglycerides and ovarian cancer risk. Comparing triglyceride levels at clinically relevant cut-off points (&gt;200 vs. ≤200 mg/dL) for cases diagnosed more than 2 years after blood draw saw a positive relationship with risk [1.57 (1.03–2.42); Pheterogeneity = 0.003]. Results were similar by serous/non-serous histotype, menopausal status/hormone use, and body mass index. Conclusions: Data from two large cohorts in the United States and United Kingdom suggest that total cholesterol levels may be inversely associated with ovarian cancer risk, while triglycerides may be positively associated with risk when assessed at least 2 years before diagnosis, albeit both associations were modest. Impact: This analysis of two large prospective studies suggests that circulating lipid levels are not strongly associated with ovarian cancer risk. The positive triglyceride–ovarian cancer association warrants further evaluation.

High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival

Abstract Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

Prolactin and Risk of Epithelial Ovarian Cancer

Abstract Background: Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ovarian cancer. Methods: We conducted a pooled case–control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype. Results: Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (Ptrend = 0.045; OR, quartile 4 vs. 1 = 1.34; 95% CI = 0.97–1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR = 1.38; 95% CI = 0.74–2.58; Ptrend = 0.32 and OR = 1.41; 95% CI = 0.93–2.13; Ptrend = 0.08, respectively; Pheterogeneity = 0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI ≥ 25 kg/m2, but not BMI &lt; 25 kg/m2 (corresponding OR = 2.68; 95% CI = 1.56–4.59; Ptrend &lt; 0.01 and OR = 0.90; 95% CI = 0.58–1.40; Ptrend = 0.98, respectively; Pheterogeneity &lt; 0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis. Conclusions: We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI ≥ 25 kg/m2. Impact: This work supports a previous study linking higher prolactin with ovarian carcinogenesis in a high adiposity setting. Future work is needed to understand the mechanism underlying this association.

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

Abstract 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.

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

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

Association of Oophorectomy and Fat and Lean Body Mass: Evidence from a Population-Based Sample of U.S. Women

Abstract Background: Bilateral oophorectomy during a nonmalignant hysterectomy is frequently performed for ovarian cancer prevention in premenopausal women. Oophorectomy before menopause leads to an abrupt decline in ovarian hormones that could adversely affect body composition. We examined the relationship between oophorectomy and whole-body composition. Methods: Our study population included cancer-free women 35 to 70 years old from the 1999–2006 National Health and Nutrition Examination Survey, a representative sample of the U.S. population. A total of 4,209 women with dual-energy x-ray absorptiometry scans were identified, including 445 with hysterectomy, 552 with hysterectomy and oophorectomy, and 3,212 with no surgery. Linear regression was used to estimate the difference in total and regional (trunk, arms, and legs) fat and lean body mass by surgery status. Results: In multivariable models, hysterectomy with and without oophorectomy was associated with higher total fat mass [mean percent difference (β); βoophorectomy: 1.61%; 95% confidence interval (CI), 1.00–2.28; βhysterectomy: 0.88%; 95% CI, 0.12–1.58] and lower total lean mass [βoophorectomy: −1.48%; 95% CI, −2.67, −1.15; βhysterectomy: −0.87%; 95% CI, −1.50, −0.24) compared with no surgery. Results were stronger in women with a normal body mass index (BMI) and those &lt;45 years at surgery. All body regions were significantly affected for women with oophorectomy, whereas only the trunk was affected for women with hysterectomy alone. Conclusions: Hysterectomy with oophorectomy, particularly in young women, may be associated with systemic changes in fat and lean body mass irrespective of BMI. Impact: Our results support prospective evaluation of body composition in women undergoing hysterectomy with oophorectomy at a young age.

Prospective Analyses of Lifestyle Factors Related to Energy Balance and Ovarian Cancer Risk by Infiltration of Tumor-Associated Macrophages

Abstract Background: Lifestyle factors related to energy balance have been associated with ovarian cancer risk and influence the tumor immune microenvironment, including tumor-associated macrophages (TAM). However, no studies have assessed whether these factors differentially impact ovarian cancer risk by TAM densities. Methods: We conducted a prospective analysis in the Nurses' Health Studies to examine the associations of physical activity, sitting time, and a food-based empirical dietary inflammatory pattern (EDIP) score with invasive epithelial ovarian cancer risk by TAM density assessed by immunohistochemistry. We considered density of CD68 (marker of total TAMs) and CD163 (marker of pro-carcinogenic M2-type TAMs), and their ratios. We used multivariable Cox proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) of exposures with risk of ovarian tumors with high versus low TAMs, including analyses stratified by body mass index. Results: Analyses included 312 incident ovarian cancer cases with TAM measurements. Physical activity, sitting time, and EDIP score were not differentially associated with ovarian cancer risk by TAM densities (Pheterogeneity &gt; 0.05). Among overweight and obese women, higher EDIP score was associated with increased risk of CD163 low-density tumors (HR comparing extreme tertiles, 1.57; 95% CI, 0.88–2.80; Ptrend = 0.01), but not CD163 high-density tumors (comparable HR, 1.16; 95% CI, 0.73–1.86; Ptrend = 0.24), though this difference was not statistically significant (Pheterogeneity = 0.22). Conclusions: We did not observe differential associations between lifestyle factors and ovarian cancer risk by TAM densities. Impact: Future investigations examining the interplay between other ovarian cancer risk factors and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.

Circulating Biomarkers of Inflammation and Ovarian Cancer Risk in the Nurses' Health Studies

AbstractBackground:Chronic inflammation is a well-established mechanism of ovarian carcinogenesis; however, the specific immunogenic processes influencing ovarian tumor development remain unclear. In a case–control study nested within the Nurses' Health Study (NHS) and the NHSII, we examined the association between six inflammatory chemokines and cytokines [B-cell activating factor (BAFF), C-X-C motif chemokine ligand 13 (CXCL13), IL8, soluble(s)IL2-receptor-α(Rα), sIL6Rα] and epithelial ovarian cancer risk.Methods:Among 299 epithelial ovarian cancer cases and 334 matched controls, six inflammatory biomarkers were measured in plasma collected 1–24 years before diagnosis or index date using two custom multiplex Luminex panels. ORs and 95% confidence intervals (CI) were estimated for the association between each biomarker and risk using multivariable conditional logistic regression with adjustment for relevant confounders. We additionally assessed heterogeneity in the risk associations by histotype [high-grade serous carcinoma (HGSC) vs. non-HGSC], body mass index, smoking status, menopausal status, and aspirin use.Results:Women with the highest versus lowest quartile (Q) levels of CXCL13 had a 72% increased ovarian cancer risk (OR = 1.72; 95% CI = 1.04–2.83; Ptrend = 0.007). The positive association with CXCL13 was stronger in magnitude for non-HGSC, overweight or obese women, and postmenopausal women, although only menopausal status demonstrated statistically significant heterogeneity (Pinteraction = 0.04). The remaining biomarkers were not associated with risk.Conclusions:This first evidence that prediagnostic CXCL13, a B-cell chemoattractant, is associated with an increased risk of epithelial ovarian cancer expands current understanding of the role of inflammation in ovarian carcinogenesis.Impact:CXCL13 may represent a novel biomarker for ovarian cancer.

Tobacco Smoking and Survival Following a Diagnosis with Ovarian Cancer

Abstract Background: Little is known about the influence of smoking on ovarian cancer survival. We investigated this relationship in a hospital-based study. Methods: Analyses included 519 women with ovarian cancer. We used multivariable adjusted Cox proportional hazards regression models to estimate HRs and 95% confidence intervals (CI). Results: Risk of all-cause mortality was increased for current smokers (HR = 1.70; 95% CI: 1.09–2.63) versus never smokers, especially for those with ≥15 cigarettes per day (HR = 1.92; 95% CI: 1.15–3.20). Results were largely similar after additional adjustment for debulking status (current vs. never smokers, HR = 2.96; 95% CI: 1.07–8.21) or neoadjuvant chemotherapy (comparable HR = 2.87; 95% CI: 1.02–8.06). Compared with never smokers, smoking duration ≥20 years (HR = 1.38; 95% CI: 0.94–2.03) and ≥20 pack-years (HR = 1.35; 95% CI: 0.92–1.99) were suggestively associated with worse outcomes. Current smoking was also positively associated with the risk of mortality among patients with ovarian cancer recurrence (current vs. never/past smokers, HR = 2.79; 95% CI: 1.44–5.41), despite the null association between smoking and recurrence (HR = 1.46; 95% CI: 0.86–2.48). Furthermore, no association was observed for smoking initiation before age 18 (HR = 1.22; 95% CI: 0.80–1.85), or either environmental smoke exposure at home (HR = 1.16; 95% CI: 0.76–1.78) or at work (HR = 1.10; 95% CI: 0.75–1.60). Conclusions: Our results suggest active tobacco smoking is associated with worse ovarian cancer outcomes, particularly after a recurrence. Impact: Our findings support structured smoking cessation programs for patients with ovarian cancer, especially in recurrent settings. Further research to confirm these findings and examine the interplay between smoking and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.

The Intervention Probability Curve: Modeling the Practical Application of Threshold-Guided Decision-Making, Evaluated in Lung, Prostate, and Ovarian Cancers

Abstract Background: Diagnostic prediction models are useful guides when considering lesions suspicious for cancer, as they provide a quantitative estimate of the probability that a lesion is malignant. However, the decision to intervene ultimately rests on patient and physician preferences. The appropriate intervention in many clinical situations is typically defined by clinically relevant, actionable subgroups based upon the probability of malignancy. However, the “all-or-nothing” approach of threshold-based decisions is in practice incorrect. Methods: Here, we present a novel approach to understanding clinical decision-making, the intervention probability curve (IPC). The IPC models the likelihood that an intervention will be chosen as a continuous function of the probability of disease. We propose the cumulative distribution function as a suitable model. The IPC is explored using the National Lung Screening Trial and the Prostate Lung Colorectal and Ovarian Screening Trial datasets. Results: Fitting the IPC results in a continuous curve as a function of pretest probability of cancer with high correlation (R2 &gt; 0.97 for each) with fitted parameters closely aligned with professional society guidelines. Conclusions: The IPC allows analysis of intervention decisions in a continuous, rather than threshold-based, approach to further understand the role of biomarkers and risk models in clinical practice. Impact: We propose that consideration of IPCs will yield significant insights into the practical relevance of threshold-based management strategies and could provide a novel method to estimate the actual clinical utility of novel biomarkers.

Associations of Healthcare Affordability, Availability, and Accessibility with Quality Treatment Metrics in Patients with Ovarian Cancer

Abstract Background: Differential access to quality care is associated with racial disparities in ovarian cancer survival. Few studies have examined the association of multiple healthcare access (HCA) dimensions with racial disparities in quality treatment metrics, that is, primary debulking surgery performed by a gynecologic oncologist and initiation of guideline-recommended systemic therapy. Methods: We analyzed data for patients with ovarian cancer diagnosed from 2008 to 2015 in the Surveillance, Epidemiology, and End Results–Medicare database. We defined HCA dimensions as affordability, availability, and accessibility. Modified Poisson regressions with sandwich error estimation were used to estimate the relative risk (RR) for quality treatment. Results: The study cohort was 7% NH-Black, 6% Hispanic, and 87% NH-White. Overall, 29% of patients received surgery and 68% initiated systemic therapy. After adjusting for clinical variables, NH-Black patients were less likely to receive surgery [RR, 0.83; 95% confidence interval (CI), 0.70–0.98]; the observed association was attenuated after adjusting for healthcare affordability, accessibility, and availability (RR, 0.91; 95% CI, 0.77–1.08). Dual enrollment in Medicaid and Medicare compared with Medicare only was associated with lower likelihood of receiving surgery (RR, 0.86; 95% CI, 0.76–0.97) and systemic therapy (RR, 0.94; 95% CI, 0.92–0.97). Receiving treatment at a facility in the highest quartile of ovarian cancer surgical volume was associated with higher likelihood of surgery (RR, 1.12; 95% CI, 1.04–1.21). Conclusions: Racial differences were observed in ovarian cancer treatment quality and were partly explained by multiple HCA dimensions. Impact: Strategies to mitigate racial disparities in ovarian cancer treatment quality must focus on multiple HCA dimensions. Additional dimensions, acceptability and accommodation, may also be key to addressing disparities.

Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: A Reappraisal

Abstract Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case–control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34–0.55; P &lt; 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87–1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

Could HPV Testing on Self-collected Samples Be Routinely Used in an Organized Cervical Screening Program? A Modeled Analysis

Abstract Background: Cervical screening on self-collected samples has mainly been considered for targeted use in underscreened women. Updated evidence supports equivalent sensitivity of PCR-based human papillomavirus (HPV) testing on self-collected and clinician-collected samples. Methods: Using a well-established model, we compared the lifetime impact on cancer diagnoses and deaths resulting from cervical screening using self-collected samples only, with and without the existing restriction in Australia to women aged 30+ years and ≥2 years overdue, compared with the mainstream program of 5-yearly HPV screening on clinician-collected samples starting at 25 years of age. We conservatively assumed sensitivity of HPV testing on self-collected relative to clinician-collected samples was 0.98. Outcomes were estimated either in the context of HPV vaccination (“routinely vaccinated cohorts;” uptake as in Australia) or in the absence of HPV vaccination (“unvaccinated cohorts”). Results: In unvaccinated cohorts, the health benefits of increased participation from self-collection outweighed the worst case (2%) loss of relative test sensitivity even if only 15% of women, who would not otherwise attend, used it (“additional uptake”). In routinely vaccinated cohorts, population-wide self-collection could be marginally (0.2%–1.0%) less effective at 15% additional uptake but 6.2% to 12.4% more effective at 50% additional uptake. Most (56.6%–65.0%) of the loss in effectiveness in the restricted self-collection pathway in Australia results from the requirement to be 2 or more years overdue. Conclusions: Even under pessimistic assumptions, any potential loss in test sensitivity from self-collection is likely outweighed by improved program effectiveness resulting from feasible levels of increased uptake. Impact: Consideration could be given to offering self-collection more widely, potentially as an equal choice for women. See related commentary by Lim, p. 245

Racial Differences in the Tumor Immune Landscape and Survival of Women with High-Grade Serous Ovarian Carcinoma

Abstract Background: Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts. Methods: The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race. Results: Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant. Conclusions: Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC. Impact: This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.

Reproductive Factors Do Not Influence Survival with Ovarian Cancer

Abstract Background: Previous studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes. Methods: Using data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype. Results: During the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype. Conclusions: This study found no association between reproductive factors and survival after an ovarian cancer diagnosis. Impact: Reproductive factors are well-established risk factors for ovarian cancer, but they are not associated with survival after a diagnosis of ovarian cancer.

Assessing Impact of HPV Vaccination on Cervical Cancer Incidence among Women Aged 15–29 Years in the United States, 1999–2017: An Ecologic Study

Abstract Background: To date, the impact of the human papillomavirus (HPV) vaccine on invasive cervical cancers in the United States has not been documented due, in part, to the time needed for cancer to develop and to recent changes to cervical cancer screening guidelines and recommendations, which complicate data interpretation. Methods: We examined incidence rates of cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) among women aged 15–29 years diagnosed during 1999–2017 using population-based cancer registry data covering 97.8% of the U.S. population. Trends were stratified by age and histology. The annual percent change in cervical cancer incidence per year was calculated using joinpoint regression. Results: During 1999–2017, SCC rates decreased 12.7% per year among women aged 15–20 years, 5.5% among women aged 21–24 years, and 2.3% among women aged 25–29 years. The declines in SCC rates were largest among women aged 15–20 years during 2010–2017, with a decrease of 22.5% per year. Overall, AC rates decreased 4.1% per year among women aged 15–20 years, 3.6% per year among women aged 21–24 years, and 1.6% per year among women aged 25–29 years. AC rates declined the most among women aged 15–20 years during 2006–2017, decreasing 9.4% per year. Conclusions: Since HPV vaccine introduction, both SCC and AC incidence rates declined among women aged 15–20 years, a group not typically screened for cervical cancer, which may suggest HPV vaccine impact. Impact: Timely vaccination and improved screening and follow-up among recommended age groups could result in further reductions in invasive cervical cancer.

Risk of Injuries around Diagnosis of Cervical Cancer and Its Precursor Lesions: A Nationwide Cohort Study in Sweden

Abstract Background: Highly increased risk of injuries has been noted around the time of cancer diagnosis. Whether there is a similar increase in risk around the diagnosis of cervical cancer and its precursor lesions was unknown. Methods: We performed a cohort study including 3,016,307 Swedish women that participated in cervical screening during 2001 to 2012. We calculated the incidence rates (IR) of hospitalized iatrogenic or noniatrogenic injuries during the diagnostic workup, and the time interval from smear or punch biopsy until surgical treatment or 2 months after the last smear or biopsy, among women with invasive cervical cancer (ICC) or its precursor lesions. We calculated the IRs of injuries during the 2 months after a normal smear among the other women as reference. IR ratios (IRR) and 95% confidence intervals (CI) were calculated using Poisson regression. Results: Compared with other women, there was an increased rate of iatrogenic injuries during the diagnostic workup of women with ICC (IR, 0.58 per 1,000 person-months; IRR, 8.55; 95% CI, 3.69–19.80) as well as of women with cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ (IR, 0.09 per 1,000 person-months; IRR, 3.04; 95% CI, 1.73–5.34). We also found an increased rate of noniatrogenic injuries during the diagnostic workup of women with invasive cancer (IR, 0.65 per 1,000 person-months; IRR, 2.48; 95% CI, 1.30–4.47). Conclusions: Although rare, there was an increased risk of inpatient care for iatrogenic and noniatrogenic injuries during the diagnostic workup of women with ICC. Impact: Women experienced burden of medical complications and psychologic distress around diagnosis of a potential cervical cancer.

Assessing 10-Year Safety of a Single Negative HPV Test for Cervical Cancer Screening: Evidence from FOCAL-DECADE Cohort

Abstract Background: Long-term safety of a single negative human papillomavirus (HPV) test for cervical cancer screening is unclear. The HPV FOr cerviCAL Cancer Trial (FOCAL) was a randomized trial comparing HPV testing with cytology. The FOCAL-DECADE cohort tracked women who received one HPV test during FOCAL, and were HPV negative, for up to 10 years to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) detected through a provincial screening program. Methods: FOCAL participants who received one HPV test, were negative, and had at least one post-FOCAL cervix screen were included (N = 5,537). We constructed cumulative incidence curves of CIN2+/CIN3+ detection, analyzed cumulative risk of detection at intervals post-HPV test, calculated average incidence rates for detection, and compared hazard across ages. Results: Ten years after one negative HPV test, the probability of CIN2+ detection was lower than 1%, with most lesions detected 7 years or later. Average incidence rates of CIN2+/CIN3+ lesions over follow-up were 0.50 [95% confidence interval (CI), 0.31–0.78] and 0.18 (95% CI, 0.07–0.36) per 1,000 person-years, respectively. Hazards were higher for younger ages (nonsignificant trend). Conclusions: Among women with a single negative HPV test, long-term risk of CIN2+ detection was low, particularly through 7 years of follow-up; thus, one negative HPV test appears to confer long-term protection from precancerous lesions. Even 10-year risk is sufficiently low to support extended testing intervals in average-risk populations. Impact: Our findings support the safety of screening policies using HPV testing alone at 5-year or longer intervals.

HPV Types in Cervical Precancer by HIV Status and Birth Region: A Population-Based Register Study

Abstract Background: Data are lacking regarding which human papillomavirus (HPV) types cause high-grade cervical neoplasia (CIN2+) in people with HIV in Europe. We assessed which HPV types are associated with CIN2+ in women living in Sweden by HIV status. Methods: The Swedish National HIV Registry, the Swedish Population Registry, and the Swedish National Cervical Screening Registry were linked. CIN2+ tissue blocks of 130 women living with HIV (WLWH) and 234 HIV-negative women, matched for country of birth (1:2), were retrieved from bio-banks and HPV genotyped. Adjusted ORs (adjOR), stratified by country of birth, were calculated using conditional logistic regression. Matching was broken for cross-group comparisons. Results: WLWH with CIN2 were less likely to have HPV16 [14% vs. 40%; adjOR 0.1; 95% confidence interval (CI), 0.04–0.56] than HIV-negative women, but among women with CIN3, there was no difference in HPV16 prevalence by HIV status (adjOR 0.9; 95% CI, 0.51–1.70). WLWH were six times more likely to have HPV35 in CIN3 than HIV-negative women (adjOR 6.2; 95% CI, 1.3–30.4). WLWH from sub-Saharan Africa (SSA) had less 9-valent vaccine types, compared with both HIV-negative women born in Sweden (adjOR 0.1; 95% CI, 0.02–0.44) and WLWH born in Sweden (adjOR 0.1; 95% CI, 0.01–0.73), mostly because of decreased HPV16 and increased HPV35. Conclusions: WLWH from SSA were less likely to be covered by the 9-valent vaccine, mostly due to less HPV16 and more HPV35. Impact: This could have implications for HPV vaccines, currently not including HPV35, and for HPV-screening algorithms in women with origin from SSA.

Variation in Cervical Cancer Screening Preferences among Medically Underserved Individuals in the United States: A Systematic Review

AbstractUnderutilization of effective screening is one driver of disparities in cervical cancer incidence and mortality. Consideration of patient preferences could help to improve screening rates in populations facing substantial barriers to preventive care. We conducted a systematic review of the literature on cervical cancer screening preferences among medically underserved patients in the United States. We searched six electronic databases (PubMed, Web of Science, EMBASE, Scopus, CINAHL, and PsycINFO) for articles published through February 2019 (Prospero ID: CRD42019125431). Among the 43 articles included, 23 reported screening modality preferences, 11 reported preferences related to provider demographics and attributes, six reported screening scheduling and results delivery preferences, and nine reported preferences related to health education and communication. This review demonstrates the wide variety of medically underserved patient preferences related to cervical cancer screening. It also draws attention to two key preference trends that emerged despite heterogeneity in study design, populations, and preference assessment. Consistent preferences for human papillomavirus self-testing over traditional Pap testing highlight a key potential mechanism for increasing cervical cancer screening uptake among medically underserved populations. In addition, preferences for gender- and language-concordant providers underscore the need for continued efforts toward expanding diversity among medical professionals.

Hazard of Cervical, Oropharyngeal, and Anal Cancers in HIV-Infected and HIV-Uninfected Medicaid Beneficiaries

AbstractBackground:Human immunodeficiency virus–infected (HIV+) individuals are disproportionately at risk for human papillomavirus (HPV)-associated cancers, but the magnitude of risk estimates varies widely. We conducted a retrospective study using a large U.S.-based cohort to describe the relationship between HIV infection and incident cervical, oropharyngeal, and anal cancers.Methods:Using 2001–2012 U.S. Medicaid data from 14 states, we matched one HIV+ to three HIV-uninfected (HIV−) enrollees on sex, race, state, age, and year, and followed persons for up to 10 years. We developed Cox proportional hazards models comparing HIV+ to HIV− for time to cancer diagnosis adjusted for demographic and comorbidity attributes.Results:Our cohorts included 443,592 women for the cervical cancer analysis, and 907,348 and 906,616 persons for the oropharyngeal and anal cancer analyses. The cervical cancer cohort had a mean age of 39 years and was 55% Black. The oropharyngeal and anal cancer cohorts were 50% male, had a mean age of 41 years, and were 51% Black. We estimated the following HRs: cervical cancer, 3.27 [95% confidence interval (CI), 2.82–3.80]; oropharyngeal cancer, 1.90 (95% CI, 1.62–2.23; both sexes), 1.69 (95% CI, 1.39–2.04; males), and 2.55 (95% CI, 1.86–3.50; females); and anal cancer, 18.42 (95% CI, 14.65–23.16; both sexes), 20.73 (95% CI, 15.60–27.56; males), and 12.88 (95% CI, 8.69–19.07; females).Conclusions:HIV+ persons were at an elevated risk for HPV-associated cancers, especially anal cancer.Impact:Medicaid claims data corroborate previous estimates based on registries and clinical cohorts.

Modeling the Balance of Benefits and Harms of Cervical Cancer Screening with Cytology and Human Papillomavirus Testing

Abstract Background: Benefits of screening should outweigh its potential harms. We compared various metrics to assess the balance of benefits and harms of cervical cancer screening. Methods: We used a cervical cancer natural history Markov model calibrated to the Canadian context to simulate 100,000 unvaccinated women over a lifetime of screening with either cytology every 3 years or human papillomavirus (HPV) testing every 5 years. We estimated the balance of benefits and harms attributable to screening using various metrics, including colposcopies/life-year gained, and net lifetime quality-adjusted life-years (QALY) gained, a measure integrating women's health preferences. We present the average (minimum–maximum) model predictions. Results: Cytology-based screening led to 1,319,854 screening tests, 30,395 colposcopies, 13,504 life-years gained over a lifetime, 98 screening tests/life-year gained, 2.3 (1.6–3.3) colposcopies/life-year gained, and a net lifetime gain of 10,735 QALY (5,040–17,797). HPV-based screening with cytology triage in the same population would lead to 698,250 screening tests, 73,296 colposcopies, 15,066 life-years gained over a lifetime, 46 screening tests/life-year gained, 4.9 colposcopies/life-year gained (2.9–11.1), and a net lifetime gain of 11,690 QALY (4,409–18,742). HPV-based screening was predicted to prevent more cancers, but also incur more screening harms than cytology-based screening. Conclusions: Metrics using colposcopies as the main harm outcome favored cytology-based screening, whereas metrics based on screening tests and health preferences tended to favor HPV-based screening strategies. Impact: Whether HPV-based screening will improve the balance between benefits and harms of cervical cancer screening depends on how the balance between benefits and harms is assessed.

The Improving Risk Informed HPV Screening (IRIS) Study: Design and Baseline Characteristics

Abstract Background: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed. Endometrial and ovarian cancers could be amenable to similar testing. Methods: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. Results: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. Conclusions: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. Impact: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

Risk of Gynecologic Cancer after Atypical Glandular Cells Found on Cervical Cytology: A Population-Based Cohort Study

Abstract Background: Atypical glandular cells (AGC) are rare abnormalities found on cervical cytology associated with a range of lesions of the female reproductive system. We compared the risk of cervical and other gynecologic cancers following AGC on cervical cytology with the risk following squamous cell abnormalities of comparable severity. Methods: We used data from the Dutch Pathology Archive (PALGA) from 2000 to 2015 to categorize cervical cytology tests into groups based on most severe cytologic abnormality and correlated follow-up advice (normal cytology and “no follow-up” advice, squamous-cell–based, AGC-based, and combined AGC/squamous-cell based each with either repeat testing or referral advice). Cancer data were linked from the Netherlands Cancer Registry. Cox proportional hazard models were calculated stratified by age [younger (&lt;50 years) and older (50+ years)], adjusted for number of previous primary cytology tests. Results: 8,537,385 cytology smears and 9,061 cancers were included. When repeat cytology testing was advised, HRs of cervical cancer (younger women: HR, 6.91; 95% CI, 5.48–8.71; older women: HR, 3.98; 95% CI, 2.38–6.66) or other gynecologic cancer diagnosis in younger women (HR, 2.82; 95% CI, 1.39–5.74) were significantly higher after an AGC-based abnormality compared with squamous-based abnormalities. Hazards were also significantly higher for “referral” advice cytology, except for cervical cancer among older women (HR, 0.88; 95% CI, 0.63–1.21). Conclusions: AGC indicates an increased risk of gynecologic cancer compared with squamous-based abnormalities of comparable severity. Impact: Gynecologists should be alert for cervical and endometrial cancers when examining women referred following AGC.

A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study

Background: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women. Methods: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). Results: 324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia. Conclusions: Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer. Impact: These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Association between Gene Promoter Methylation and Cervical Cancer Development: Global Distribution and A Meta-analysis

Abstract DNA methylation is the main epigenetic event for gene silencing and is associated with carcinogenesis. In this meta-analysis, we evaluated the association between the methylation of the promoter regions of APC, CADM1, CCNA1, CDH1, DAPK, FHIT, HIC1, MAL, MGMT, hMLH1, P16, PAX1, RAR-β, and RASSF1 genes and the risk of cervical cancer development and progression. Overall, 194 eligible studies were identified assessing the associations of promoter methylation status of aforementioned genes with low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) and cervical cancer development. The majority of studies were conducted on Caucasian and Asian populations, whereas rare studies were available on the African population. Promoter methylation frequencies were shown to be significantly higher in LSIL and HSIL cervical cancer cases as compared to control specimens for CADM1, CCNA1, CDH1, DAPK1, FHIT, MAL, P16, PAX1, RAR-β, and RASSF1 genes. A moderate association was found between HIC promoter methylation, whereas APC, MGMT, and hMLH1 promoter methylation was not correlated with cervical cancer development. Promoter methylation could be considered as a noninvasive biomarker for early cervical lesions, making them highly promising targets for a personalized therapeutic approach.

The Differential Risk of Cervical Cancer in HPV-Vaccinated and -Unvaccinated Women: A Mathematical Modeling Study

Abstract Background: With increased uptake of vaccination against human papillomavirus (HPV), protection against cervical cancer will also increase for unvaccinated women, due to herd immunity. Still, the differential risk between vaccinated and unvaccinated women might warrant a vaccination-status–screening approach. To understand the potential value of stratified screening protocols, we estimated the risk differentials in HPV and cervical cancer between vaccinated and unvaccinated women. Methods: We used STDSIM, an individual-based model of HPV transmission and control, to estimate the HPV prevalence reduction over time, after introduction of HPV vaccination. We simulated scenarios of bivalent or nonavalent vaccination in females-only or females and males, at 20% coverage increments. We estimated relative HPV-type–specific prevalence reduction compared with a no-vaccination counterfactual and then estimated the age-specific cervical cancer risk by vaccination status. Results: The relative cervical cancer risk for unvaccinated compared with vaccinated women ranged from 1.7 (bivalent vaccine for females and males; 80% coverage) to 10.8 (nonavalent vaccine for females-only; 20% coverage). Under 60% vaccination coverage, which is a representative coverage for several western countries, including the United States, the relative risk (RR) varies between 2.2 (bivalent vaccine for females and males) and 9.2 (nonavalent vaccine for females). Conclusions: We found large cervical cancer risk differences between vaccinated and unvaccinated women. In general, our model shows that the RR is higher in lower vaccine coverages, using the nonavalent vaccine, and when vaccinating females only. Impact: To avoid a disbalance in harms and benefits between vaccinated and unvaccinated women, vaccination-based screening needs serious consideration.

An Evaluation of Dose-Related HPV Vaccine Effectiveness Using Central Registries in Michigan

Abstract Background: Human papillomavirus (HPV) vaccine effectiveness (VE) evaluations provide important information for vaccination programs. We established a linkage between statewide central registries in Michigan to estimate HPV VE against in situ and invasive cervical lesions (CIN3+). Methods: We linked females in Michigan's immunization and cancer registries using birth records to establish a cohort of 773,193 women with known vaccination history, of whom 3,838 were diagnosed with CIN3+. Residential address histories from a stratified random sample were used to establish a subcohort of 1,374 women without CIN3+ and 2,900 with CIN3+ among continuous Michigan residents. VE and 95% confidence intervals (CI) were estimated using cohort and case–cohort methods for up-to-date (UTD) vaccination and incomplete vaccination with 1 and 2 doses, and stratified by age at vaccination. Results: Both analytic approaches demonstrated lower CIN3+ risk with UTD and non-UTD vaccination vs. no vaccination. The cohort analysis yielded VE estimates of 66% (95% CI, 60%–71%) for UTD, 33% (95% CI, 18%–46%) for 2 doses-not UTD, and 40% (95% CI, 27%–50%) for 1 dose. The case–cohort analysis yielded VE estimates of 72% (95% CI, 64%–79%) for UTD, 39% (95% CI, 10%–58%) for 2 doses-not UTD, and 48% (95% CI, 25%–63%) for 1 dose. VE was higher for vaccination at age &lt;20 than ≥20 years. Conclusions: The statewide registry linkage found significant VE against CIN3+ with incomplete HPV vaccination, and an even higher VE with UTD vaccination. Impact: Future VE evaluations by number of doses for women vaccinated at younger ages may further clarify dose-related effectiveness.

Reducing Poverty-Related Disparities in Cervical Cancer: The Role of HPV Vaccination

AbstractBackground:Near elimination of cervical cancer in the United States is possible in coming decades, yet inequities will delay this achievement for some populations. We sought to explore the effects of human papillomavirus (HPV) vaccination on disparities in cervical cancer incidence between high- and low-poverty U.S. counties.Methods:We calibrated a dynamic simulation model of HPV infection to reflect average counties in the highest and lowest quartile of poverty (percent of population below federal poverty level), incorporating data on HPV prevalence, cervical cancer screening, and HPV vaccination. We projected cervical cancer incidence through 2070, estimated absolute and relative disparities in incident cervical cancer for high- versus low-poverty counties, and compared incidence with the near-elimination target (4 cases/100,000 women annually).Results:We estimated that, on average, low-poverty counties will achieve near-elimination targets 14 years earlier than high-poverty counties (2029 vs. 2043). Absolute disparities by county poverty will decrease, but relative differences are estimated to increase. We estimate 21,604 cumulative excess cervical cancer cases in high-poverty counties over the next 50 years. Increasing HPV vaccine coverage nationally to the Healthy People 2020 goal (80%) would reduce excess cancer cases, but not alter estimated time to reach the near-elimination threshold.Conclusions:High-poverty U.S. counties will likely be delayed in achieving near-elimination targets for cervical cancer and as a result will experience thousands of potentially preventable cancers.Impact:Alongside vaccination efforts, it is important to address the role of social determinants and health care access in driving persistent inequities by area poverty.

A Randomized Comparison of Different Vaginal Self-sampling Devices and Urine for Human Papillomavirus Testing—Predictors 5.1

Abstract Background: Human papillomavirus (HPV)-based screening is rapidly replacing cytology as the cervical screening modality of choice. In addition to being more sensitive than cytology, it can be done on self-collected vaginal or urine samples. This study will compare the high-risk HPV positivity rates and sensitivity of self-collected vaginal samples using four different collection devices and a urine sample. Methods: A total of 620 women referred for colposcopy were invited to provide an initial stream urine sample collected with the Colli-Pee device and take two vaginal self-samples, using either a dry flocked swab (DF) and a wet dacron swab (WD), or a HerSwab (HS) and Qvintip (QT) device. HPV testing was performed by the BD Onclarity HPV Assay. Results: A total of 600 vaginal sample pairs were suitable for analysis, and 505 were accompanied by a urine sample. Similar positivity rates and sensitivities for CIN2+ and CIN3+ were seen for DF, WD, and urine, but lower values were seen for QT and HS. No clear user preferences were seen between devices, but women found urine easiest to collect, and were more confident they had taken the sample correctly. The lowest confidence in collection was reported for HS. Conclusions: Urine, a DF swab, and WD swab all performed well and were well received by the women, whereas the Qvintip and HerSwab devices were less satisfactory. Impact: This is the first study to compare five self-sampling methods in the same women taken at the same time. It supports wider use of urine or vaginal self-sampling for cervical screening.

Validation of BD Onclarity HPV Assay on Vaginal Self-Samples versus Cervical Samples Using the VALHUDES Protocol

Abstract Background: In this study, we evaluated accuracy of HPV testing on self-samples versus clinician-taken samples through the VALHUDES protocol. VALHUDES was designed as a diagnostic test accuracy study, where women referred to colposcopy collected self-samples followed by clinician-taken cervical samples. Methods: Four hundred eighty-five women recruited in five colposcopy clinics (median age = 40 years; IQR, 31–49) with valid results for all specimens were included in the main analysis: 230 vaginal self-samples were collected with Evalyn Brush and 255 with Qvintip. Cervical samples were taken by the gynecologist with the Cervex-Brush. HPV testing was performed with BD Onclarity HPV assay (Onclarity). Colposcopy and histology were used as the reference standard for accuracy estimation. Results: The sensitivity for CIN2+ on vaginal self-samples overall was not different from cervical samples (ratio = 0.96; 95% CI, 0.90–1.03), whereas specificity was significantly higher (ratio = 1.09; 95% CI, 1.02–1.16). However, the relative accuracy (self- vs. clinician sampling) differed by vaginal collection device: relative sensitivity and specificity ratios of 1.00 (95% CI, 0.94–1.06) and 1.15 (95% CI, 1.05–1.25), respectively for Evalyn-Brush; 0.91 (95% CI, 0.79–1.04) and 1.03 (95% CI, 0.95–1.13), respectively for Qvintip. Conclusions: Clinical accuracy of BD Onclarity HPV assay on vaginal self-samples was not different from cervical samples. Impact: VALHUDES study showed that HPV testing with Onclarity HPV on vaginal self-samples is similarly sensitive compared with cervical specimens. However, differences in accuracy by self-sampling devices, although not significant, were noted. Onclarity HPV testing on vaginal self-samples following validated collection and handling procedures may be used in primary cervical cancer screening.

Extended Human Papillomavirus Genotyping to Predict Progression to High-Grade Cervical Precancer: A Prospective Cohort Study in the Southeastern United States

Abstract Background: High-risk human papillomavirus (hrHPV) testing is utilized in primary cervical cancer screening, generally along with cytology, to triage abnormalities to colposcopy. Most screening-based hrHPV testing involves pooled detection of any hrHPV or of HPV16/18. Cervical neoplasia progression risks based on extended hrHPV genotyping—particularly non-16/18 hrHPV types—are not well characterized. HPV genotype-specific incidence of high-grade cervical intraepithelial neoplasia or more severe (CIN2+) following an abnormal screening result was examined. Methods: We assessed a US-based prospective, multiracial, clinical cohort of 343 colposcopy patients with normal histology (n = 226) or CIN1 (n = 117). Baseline cervical samples underwent HPV DNA genotyping, and participants were followed up to 5 years. Genotype-specific CIN2+ incidence rates (IR) were estimated with accelerated failure time models. Five-year CIN2+ risks were estimated nonparametrically for hierarchical hrHPV risk groups (HPV16; else HPV18/45; else HPV31/33/35/52/58; else HPV39/51/56/59/68). Results: At enrollment, median participant age was 30.1 years; most (63%) were hrHPV-positive. Over follow-up, 24 participants progressed to CIN2+ (7.0%). CIN2+ IR among hrHPV-positive participants was 3.4/1,000 person-months. CIN2+ IRs were highest for HPV16 (8.3), HPV33 (7.8), and HPV58 (4.9). Five-year CIN2+ risk was higher for HPV16 (0.34) compared with HPV18/45 (0.12), HPV31/33/35/52/58 (0.12), and HPV39/51/56/59/68 (0.16) (P = 0.05). Conclusions: Non-16/18 hrHPV types are associated with differential CIN2+ progression rates. HPV16, 33, and 58 exhibited the highest rates over 5 years. HPV risk groups warrant further investigation in diverse US populations. Impact: These novel data assessing extended HPV genotyping in a diverse clinical cohort can inform future directions to improve screening practices in the general population.

Clinical Performance of Triage Strategies for Hr-HPV–Positive Women; A Longitudinal Evaluation of Cytology, p16/K-67 Dual Stain Cytology, and HPV16/18 Genotyping

Abstract Background: We evaluated the longitudinal performance of three options: HPV16/18 genotyping (HPV16/18), cytology (LBC), and p16/Ki-67 dual stain cytology (DS) for the triage of high-risk Human Papillomavirus–positive (Hr-HPV+) women within the cervical screening program in Scotland. Methods: Data were derived from a cohort of Hr-HPV+ women (n = 385) who participated in PaVDaG (Papillomavirus Dumfries and Galloway) study. Performance of triage strategies for detecting high-grade disease was assessed at 3 (in women &lt;50 years) or 5 years (in women &gt;50 years). Sensitivity, specificity, PPV, and cNPV of each triage test were calculated for CIN2+ and CIN3+ when used singly or sequentially. Results: The sensitivity of LBC (≥ borderline), DS, and HPV 16/18 genotyping for the detection of CIN2+ was 62.7% (50.7–73.3), 77.7% (63.1–83.7), and 62.7% (50.7–73.3) with corresponding cNPVs of 10.9%, 8.4%, and 11.9%. The option with the highest sensitivity and lowest cNPV was HPV 16/18 genotyping followed by LBC of Hr-HPV other+ and then DS of the LBC negatives. This yielded sensitivity of 94.7% (86.2–98.3) and cNPV 2.7% for CIN2+. Triage performance was similar if women had tested Hr-HPV+ positive by vaginal self-sampling. Conclusions: Two-step triage with HPV 16/18 genotyping before LBC (or DS) for Hr-HPV other+ women was associated with a lower risk of significant disease at follow-up compared with single triage approaches. Impact: This study provides longitudinal performance data on triage strategies in Hr-HPV+ women and will be informative for the evolution of cervical screening programs that increasingly rely on molecular technologies.

Causal Association between Chronic Kidney Disease and Risk of 19 Site-Specific Cancers: A Mendelian Randomization Study

Abstract Background: Results of previous observational studies examining the risk of cancer among patients with chronic kidney disease (CKD) are conflicting. We here explore the causal relationship between estimated glomerular filtration rate (eGFR) and albuminuria, two principal measurements of CKD, and 19 site-specific cancers using Mendelian randomization (MR) analysis. Methods: Single-nucleotide polymorphisms reported to be strongly correlated with eGFR and albuminuria in recent large genome-wide association studies were used as instrumental variables to investigate the causal relationship with cancer using summary-level statistics from several cancer-specific consortia, as well as data of 347,408 participants in the UK Biobank and 260,405 participants in the FinnGen. Results: Our data showed that impaired kidney function was associated with higher odds of leukemia [OR = 1.23; 95% confidence interval (CI), 1.06–1.43; P = 0.007], cervical cancer (OR = 1.22; 95% CI, 1.04–1.43; P = 0.017), and female renal cell carcinoma (OR = 1.4; 95% CI, 1.12–1.77; P = 0.004), per 10% decrease in eGFR. The ORs were 1.21 (95% CI, 1.07–1.36; P = 0.002) for colorectal cancer and 0.76 (95% CI, 0.62–0.92; P = 0.006) for non–Hodgkin lymphoma, per doubling odds of albuminuria. In multivariable MR, effect sizes of eGFR–cervical cancer remained strong after adjusting for confounders. Conclusions: The current study indicates that progression of CKD contributes to carcinogenesis of renal cell carcinoma, leukemia, cervical, and colorectal cancer. Impact: The potential association of kidney function and albuminuria with certain cancers warrants further investigation in order to provide appropriate recommendations regarding cancer screening among patients with CKD.

Temporal Trends and Projection of Cancer Attributable to Human Papillomavirus Infection in China, 2007–2030

Abstract Background: Information on temporal trends of cancer attributable to human papillomavirus (HPV) in China is limited. Methods: Cancer incidence and mortality during 2007 to 2015 were extracted from the Chinese Cancer Registry Annual Report and the national population from the National Bureau of Statistics. HPV-attributable cancer burden and the average annual percentage change during 2007 to 2015 were estimated and cancer burden during 2016 to 2030 was projected. Results: HPV-attributable cancer cases have increased by 3.8% [95% confidence interval (CI), 2.9%–4.8%] annually from 85,125 to 113,558 and age-standardized incidence rate (ASIR) rose by 3.0% (95% CI, 2.5%–3.5%) from 4.67 to 5.83 per 100,000 persons during 2007 to 2015. Cervical, female anal, and vulva cancer cases have increased by 3.8% (95% CI, 2.8%–4.7%), 6.5% (95% CI, 1.2%–12.2%), and 3.7% (95% CI, 1.6%–5.8%) per year. Male anal and oropharyngeal cancer cases have elevated by 7.5% (95% CI, 2.8%–12.5%) and 4.4% (95% CI, 2.4%–6.3%) annually. The increases of cervical and anal cancer were most rapid among those aged 50 and older. HPV-attributable cancer deaths and mortality rate have risen by 4.7% (95% CI, 2.9%–6.7%) and 3.3% (95% CI, 0.9%–5.8%) respectively. HPV-attributable cancer cases and ASIR are projected to reach 214,077 and 9.35 of 100,000 persons by 2030 respectively, with 87.7% being cervical cancer, and anal cancer cases are expected to triple. Conclusions: HPV-attributable cancer burden has largely increased in the past and will keep rising for the next decade. Cervical cancer control should be the priority and anal cancer prevention should be addressed. Impact: This study supplies fundamental evidence for policy-making on HPV-attributable cancer control.

A Review of Ethical and Legal Aspects of Gender-Neutral Human Papillomavirus Vaccination

Abstract While launching a campaign to eliminate cervical cancer, the World Health Organization called to halt human papillomavirus (HPV) gender-neutral vaccination (GNV) because of limited vaccine supply, raising ethical and legal questions about female-only vaccination versus GNV. We identified ethical and legal aspects of HPV GNV by searching MEDLINE for records up to February 19, 2021. We also provided an overview of HPV vaccines, the evolution of HPV vaccine recommendations in North America, and a timeline of male HPV vaccination introduction by searching PubMed, Google, and government websites. Four HPV vaccines are available: Cervarix, Gardasil, Gardasil9, and Cecolin. Vaccine recommendations in North America evolved from female only to eventually include males. Following the FDA's approval of the first HPV vaccine for males (2009), 35 countries began vaccinating males (2011–2020). On the basis of 59 eligible records out of 652, we identified the following constructs: lower male awareness of HPV and vaccination (n = 13), limited economic resources (n = 5), shared social responsibility (n = 18), unprotected groups from female-only HPV vaccination (n = 10), limited screening for HPV-associated noncervical cancers (n = 6), consideration of ethical principles (n = 17), and HPV vaccine mandates (n = 5). Ethical and legal aspects must be considered when recommending vaccination for females only or GNV.

Cancer Statistics over Time in Northwestern São Paulo State, Brazil: Incidence and Mortality

Abstract Background: Population studies can serve as an essential source of information on cancer's etiology, and assessments of cancer trends over time can detect changes. This study aimed to provide statistics over time on cancer incidence and mortality in the Barretos Region, Brazil. Methods: Cancer incidence data were obtained from the population-based cancer registry of the Barretos Region, and mortality data were obtained from the Official Federal Database from 2002 to 2016. Age-standardized rates for incidence and mortality were calculated. Joinpoint Regression software was used to estimate the average annual percentage changes (AAPC). Results: Age-standardized rates of incidence increased significantly for colon cancer (AAPC: 2.2), rectum and rectosigmoid (AAPC: 2.4), liver (AAPC: 4.7), female breast (AAPC: 2.2), and thyroid cancer (AAPC: 3.8) but decreased for esophageal (AAPC: −3.2), stomach (AAPC: −4.2), lung (AAPC: −2.0), and ovarian cancer (AAPC: −5.6). The mortality increased for liver cancer (AAPC: 2.3) and decreased for pharyngeal cancer (AAPC: −5.8), stomach cancer (AAPC: −6.6), cervical uterine cancer (AAPC: −5.9), prostate cancer (AAPC: −2.4), and ovarian cancer (AAPC: −3.3). Conclusions: We observed decreases in some cancers related to tobacco smoking and cervical and stomach cancers related to infectious agents, showing strong regional and national prevention programs' successes. But, we also observed rises in many cancer sites linked to lifestyle factors, such as breast or colorectal cancer, without a sign of declining mortality. Impact: These results can impact and support cancer control program implementation and improvement at the community level and extrapolate to the state level and/or the whole country.

Clinical Performance of the BD Onclarity Extended Genotyping Assay for the Management of Women Positive for Human Papillomavirus in Cervical Cancer Screening

Abstract Background: Among women whose cervical specimens tested positive for high-risk human papillomaviruses (hrHPV) via the Hybrid Capture 2 assay in the Canadian Cervical Cancer Screening Trial (CCCaST), we assessed hrHPV genotype concordance between BD Onclarity HPV Assay and Roche's Linear Array, overall and stratified by hrHPV viral load. We also evaluated the performance of cytology, cytology combined with hrHPV genotyping (Onclarity assay) for HPV16/18 and non-HPV16/18 types, and hrHPV genotyping triage strategies for the detection of cervical intraepithelial neoplasia grade 2 or 3 and worse (CIN2+/CIN3+). Methods: Standard measures (expected agreement, agreement, and κ values) were used to compare Onclarity to the reference test, Linear Array. Twenty-four triage strategies were evaluated by calculating their sensitivities, specificities, and positive and negative predictive values for CIN2+ and CIN3+ detection. Results: Among 734 hrHPV+ samples tested, there was near perfect concordance irrespective of viral load between the Onclarity and Linear Array assays for the individual genotypes [human papillomaviruses (HPV) 16, 18, 31, 45, 51, 52] by Onclarity (κ values ranged from 0.92–0.98). Strategies with adequate specificity (&gt;75%) and the highest sensitivities to detect CIN3+ among 617 women positive for hrHPV, were positivity to HPV16 and/or 31 (Sensitivity: 65.2%, Specificity: 76.9%) and HPV16 and/or 18 (Sensitivity: 58.7%, Specificity: 81.6%). Conclusions: While confirming the importance of HPV16, we found that HPV31 was comparable with HPV18 for the detection of CIN2/3+ in the triage of women positive for hrHPV. Impact: HPV31 may be an important genotype in the triage of women positive for hrHPV.

Impact of a Human Papillomavirus Vaccination Program within Organized Cervical Cancer Screening: Cohort Study

Abstract Background: We assessed the effectiveness of an HPV (human papillomavirus) vaccination program in lowering cervical abnormality risk, and conferring herd protection. Methods: Retrospective cohort study using linked screening and vaccination administrative health data of the general population of Ancona Province, Italy. We included all female residents born in 1990–1993, eligible for catch-up HPV vaccination up to age 25 years, and adhering to organized screening in 2015–2020 (n = 4,665). Cervical abnormalities rates were compared between: Vaccinated and unvaccinated women, and cohorts with high and low vaccination uptake. Analyses were adjusted for age, country of birth, screening tests number, laboratory, and municipality average income. Main outcomes were ASC-US+ or LSIL+ Pap smears, and CIN1+ or CIN2+ histology. Results: Mean screening age was 26.6±1.5 years, and 1,118 screened women (24.0%) were vaccinated (mean vaccination age 19.2±1.5 years). The diagnosed cervical abnormalities were: 107 LSIL+ (2.3%), 70 CIN1+ (1.5%), and 35 CIN2+ (0.8%). The adjusted odds ratios of LSIL+, CIN1+, and CIN2+ among vaccinated versus unvaccinated women were, respectively: 0.55 [(95% confidence interval (CI), 0.33–0.91)], 0.43 (95% CI, 0.22–0.86), and 0.31 (95% CI, 0.11–0.91). Among the unvaccinated, those in the highest-uptake (45.3%) 1993 cohort, versus the last pre-vaccination 1990 cohort, showed AORs of LSIL+ and CIN1+ of 0.23 (95% CI, 0.10–0.50), and 0.22 (95% CI, 0.07–0.69), respectively. Conclusions: In the first evaluation from Central Italy, catch-up HPV vaccination considerably reduced the risk of all cervical abnormalities diagnosed within organized screening, and conferred an elevated degree of herd protection among unvaccinated women. Impact: The high protection conferred by HPV vaccination suggests the need to update cervical screening.

Cancer-Specific Mortality in Asian American Women Diagnosed with Gynecologic Cancer: A Nationwide Population-Based Analysis

Abstract Background: Cancer is the leading cause of death in Asian Americans (AA), the fastest-growing U.S. population group. Despite heterogeneity in socioeconomic status and health behaviors by ethnicity, few studies have assessed cancer outcomes across AA ethnic groups. We examined differences in gynecologic cancer mortality between AA ethnic groups and non-Hispanic Whites (NHW). Methods: Using the Surveillance, Epidemiology, and End Results database, we identified ovarian (n = 69,113), uterine (n = 157,340), and cervical cancer cases (n = 41,460) diagnosed from 1991–2016. Competing risk regression was used to compare cancer-specific mortality for AAs by ethnicity, using NHW as the reference population. Results: In adjusted analyses, AAs had a lower risk of ovarian [HR, 0.90; 95% confidence interval (CI), 0.86–0.94] and cervical cancer death (HR, 0.80; 95% CI, 0.75–0.87) than NHWs, with stronger associations among those ≥50 years at diagnosis [(HRovary, 0.87; 95% CI, 0.82–0.92); (HRcervix, 0.74; 95% CI, 0.67–0.81)]. No overall difference was noted for uterine cancer death (HR, 1.03; 95% CI, 0.97–1.10); however, AAs &lt;50 years at diagnosis had a higher risk of uterine cancer death than NHWs (HR, 1.26; 95% CI, 1.08–1.46). Patterns of cancer mortality were heterogeneous, with Filipino and Chinese women at the highest risk of uterine cancer death and Indian/Pakistani women at the lowest risk of ovarian and cervical cancer death. Conclusions: There are significant differences in gynecologic cancer mortality between AAs and NHWs, with heterogeneity by AA ethnicity. Impact: Disaggregated analysis of AA is needed to better understand the burden of gynecologic cancer and identify high-risk groups for cancer prevention efforts.

Metabolic Syndrome and the Risk of Breast, Endometrial, and Ovarian Cancer among Postmenopausal Women in the UK Biobank

Abstract Background: There is some evidence that metabolic syndrome (MetS) is associated with postmenopausal breast and gynecologic cancer. However, results from previous studies have been inconsistent and varied by the definition of MetS used. Methods: Using data from the UK Biobank, the association between MetS, according to three definitions, and the risk of breast, endometrial, and ovarian cancer was assessed among postmenopausal women with serologic biomarker data. Cox proportional hazards regression was used to calculate HRs with 95% confidence intervals (CI), adjusting for a range of confounders. Results: In total, 4,791 breast cancers, 820 endometrial cancers, and 582 ovarian cancers were diagnosed. For all definitions, MetS was associated with a higher risk of breast cancer (harmonized definition; HR, 1.11; 95% CI, 1.04–1.19) and endometrial cancer (harmonized definition; HR, 2.18; 95% CI, 1.86–2.55) but not ovarian cancer (harmonized definition; HR, 1.08; 95% CI, 0.88–1.31). Assessment of the individual MetS components revealed that only abdominal obesity was consistently associated with breast cancer, whereas all components were associated with a higher risk of endometrial cancer. Conclusions: In this cohort, MetS and all MetS components were individually associated with a higher risk of endometrial cancer, but only abdominal obesity was consistently associated with an increased risk of breast cancer. No associations were observed between MetS and ovarian cancer risk. Impact: These findings underline the need for further mechanistic research to clarify potential causal relationships and to better inform public health strategies to address the increasing obesity-related cancer burden, particularly endometrial cancer in postmenopausal women.

Personalizing CA125 Levels Using Tumor Marker Variants: A Case–Control Analysis of Diagnostic Performance for Pancreatic Cancer

Abstract Background: Cancer antigen 125 (CA125) is widely recognized as a useful biomarker for the surveillance of patients with ovarian and other cancers. Prior genome-wide association studies have identified variants that influence CA125 levels. We evaluated the utility of stratifying CA125 levels by such variants and evaluated diagnostic performance in control subjects and patients with pancreatic ductal adenocarcinoma (PDAC). Methods: We measured CA125 levels in 807 control subjects and 450 patients with PDAC and genotyped 10 variants involving four genes (GAL3ST2, MSLN, D2HGDH, and MUC16). We compared CA125 levels in controls by variant and generated variant-defined CA125 cutoffs and then classified cases and controls into functional groups based on their variant profile. We used this variant classification to evaluate the diagnostic performance of CA125 in patients with PDAC. Results: Six variants associated with CA125 levels were used to group controls into one of four groups. Mean CA125 levels in the highest variant group were approximately fourfold higher than in the lowest group. African Americans were more likely to have a variant group associated with low CA125 levels. After setting diagnostic cutoffs by variant group, the diagnostic sensitivity of CA125 for PDAC was 20.2% at 98% specificity (areas under the ROC curve, 0.702), not significantly different from a uniform CA125 diagnostic cutoff (areas under the ROC curve, 0.700). Conclusions: Gene variants can be used to generate personalized CA125 reference ranges. This approach did not significantly improve CA125’s diagnostic performance for pancreatic cancer, but it merits evaluation in other diagnostic settings, such as detecting ovarian cancer. Impact: Gene variants can be used to personalize CA125 levels.

Regular Physical Inactivity and Ovarian Cancer Risk in the Ovarian Cancer in Women of African Ancestry Consortium

Abstract Background: Regular physical inactivity may increase ovarian cancer risk, but few studies have investigated whether this association is similar among Black and White women. Methods: In a pooled nested case–control study within the Ovarian Cancer in Women of African Ancestry consortium, logistic regression models evaluated regular recreational physical inactivity with risk of epithelial ovarian cancer among Black (223 cases; 1,472 controls) and White women (985 cases; 6,212 controls) enrolled in four cohort studies. Models were further stratified by histologic type. Results: Regular physical inactivity was not associated with the risk of overall ovarian cancer among Black [OR = 1.16; 95% confidence interval (CI), 0.83–1.61] or White women (OR = 1.03; 95% CI, 0.87–1.23). We did not detect associations according to histologic type. Conclusions: Physical inactivity was not associated with ovarian cancer among Black or White women in a consortium of cohort studies. Impact: These results are counter to case–control-based studies and emphasize the complexity of investigating physical activity prospectively.

Estimating the Opportunity for Early Detection of Ovarian Cancer Using Individual-Patient Data from a Large Randomized Controlled Trial

Abstract Background: The UK Collaborative Trial of Ovarian Cancer Screening did not detect a reduction in ovarian cancer mortality with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) compared with no screening. The trial data provide an invaluable resource to quantify the opportunity for interception in ovarian cancer. Methods: We used Bayesian inference to estimate ovarian cancer natural history based on individual screening and cancer diagnosis records from the UK Collaborative Trial of Ovarian Cancer Screening, a randomized controlled ovarian cancer screening trial conducted in England, Wales, and Northern Ireland. The trial included 202,638 women ages 50 to 74 years with no family history of ovarian cancer, randomized in a 1:1:2 ratio to annual MMS (serum CA125 interpreted using the risk of ovarian cancer algorithm), annual USS, or no screening. The current analysis included 199,499 women, with 674,806 screens and 2,025 cancer diagnoses. Results: Among high-grade serous cancers (HGSC), the estimated preclinical detectable phase was 1.7 years (95% credible interval, 1.3–2.2), compared with 7.8 years (95% credible interval, 5.7–10.6) for non-HGSCs. The preclinical detectable phase depended on screening modality: for HGSCs, it was longer in the MMS arm (2.2 years) compared with the USS arm (0.8 years), whereas for non-HGSCs, it was shorter in the MMS arm (2.7 years) compared with the USS arm (8.2 years). Conclusions: The interception opportunity for ovarian cancer strongly depends on histologic subtype and screening modality. Impact: Achieving a clinically significant benefit of ovarian cancer early detection will require prolonging the interception window through judicious combination of first- and second-line tests.

Occupational-Related Exposure to Benzene and Risk of Cervical, Ovarian, and Endometrial Cancers: Systematic Review and Meta - analysis

Abstract Benzene is a known cause of leukemia and other blood cancers, but its link to female genital cancers (ovarian, endometrial, and cervical) remains unclear. This meta-analysis evaluated the association between occupational benzene exposure and the risk of these cancers. A systematic search of PubMed, SCOPUS, and EMBASE identified 7,221 publications, with nine cohort studies meeting inclusion criteria. Summary risk ratios (RR) were calculated using Preferred Reporting Items for Systematic Reviews and Meta-Analyses; Meta-analysis of Observational Studies in Epidemiology; and Participants, Exposition, Comparators, Outcomes, and Study Design guidelines. Study quality was assessed with a modified Newcastle–Ottawa scale, and publication bias was evaluated via the Egger test and funnel plots. The overall summary RR for benzene exposure was 1.22 [95% confidence interval (CI), 1.03–1.44], primarily driven by mortality (RR = 1.69; 95% CI, 1.18–2.41) rather than incidence (RR = 1.08; 95% CI, 0.91–1.29). Cancer-specific RRs were 1.24 for cervical, 1.21 for endometrial, and 1.28 for ovarian cancers, none reaching statistical significance. No significant heterogeneity was found by cancer type, region, exposure duration, industry, or study quality. No publication bias was detected (P = 0.43). This analysis suggests a potential association between occupational benzene exposure and increased risk of female genital cancers, particularly in mortality data. However, the evidence remains inconclusive due to potential confounding factors and limitations in the available studies.

An Analytic Pipeline to Obtain Reliable Genetic Ancestry Estimates from Tumor-Derived RNA Sequencing Data

Abstract Background: Germline genetics may influence tumor molecular characteristics and ultimately cancer survival. Studies of tumor characteristics, including our epithelial ovarian cancer (EOC) studies of Black women in the United States, may have RNA sequencing (RNA-seq) data from archival tumor tissue but lack germline DNA for at least some individuals. Incomplete germline DNA measurements impede analyses of important measures such as global genetic ancestry, often used in downstream analyses, by reducing sample sizes. Methods: The study population consists of 184 women who participated in two population-based studies of EOC with both germline and formalin-fixed, paraffin-embedded (FFPE) tumor samples and an additional 58 women diagnosed with EOC from the same two studies with only FFPE tumor tissue. We used tumor RNA-seq data to calculate proportions of African, European, and Asian genetic ancestry using a pipeline built on the packages SeqKit, HISAT2, SAMtools, BCFtools, PLINK, and ADMIXTURE. Women from the 1000 Genomes Project were used as the reference populations, and germline genetic ancestry estimates from blood or saliva were used as the baseline comparison. We evaluated multiple quality control strategies to improve genetic ancestry estimation. Results: Correlations between tumor RNA-seq–derived estimates of genetic ancestry from our pipeline and germline-derived African and European genetic ancestry ranged between 0.76 and 0.94. Conclusions: RNA-seq data from archival FFPE tumor tissue can be confidently and efficiently used to approximate global genetic ancestry in an admixed population when germline DNA is unavailable. Impact: This approach supports analyses of genetic ancestry and cancer when germline samples are not available.

Pubertal Timing and Incident Ovarian Cancer in the Sister Study Cohort

Abstract Background: Pubertal milestones such as menarche (first period) and thelarche (onset of breast development) are markers of hormonal changes that may be relevant to the hormonal etiology of ovarian cancer. Prior studies of the association between age at menarche and ovarian cancer risk have been inconsistent, whereas age at thelarche has not been examined in relation to ovarian cancer incidence. Methods: With data from 40,809 women in the Sister Study, we used multivariable-adjusted Cox proportional hazards regression to estimate HRs and 95% confidence intervals (CI) for associations of self-reported ages at thelarche and menarche with incident ovarian cancer, both overall and by histotype. Results: During a median follow-up of 13.3 years, 291 women reported a diagnosis of ovarian cancer. Ages at thelarche (HR = 0.94; 95% CI, 0.87–1.02 per 1-year older) and menarche (HR = 0.99; 95% CI, 0.91–1.07 per 1-year older) were not associated with ovarian cancer overall. Although imprecise, HRs suggested a possible inverse association of ages at thelarche (HR = 0.71; 95% CI, 0.48–1.04) and menarche (HR = 0.79; 95% CI, 0.59–1.04) with the incidence of clear-cell tumors. Conclusions: Ages at thelarche and menarche were not associated with ovarian cancer incidence overall. Impact: Though our results do not provide clear evidence of associations of pubertal timing with ovarian cancer incidence, possible associations of earlier thelarche and menarche with increased incidence of ovarian clear-cell carcinoma may warrant further investigation, especially considering secular trends toward earlier thelarche.

Patterns of Subsequent Cancer Incidence Over Time in Patients with Breast Cancer

Abstract Background: Breast cancer survivors face a higher risk of subsequent primary cancers. This study investigated the patterns of subsequent cancer risk according to time since breast cancer diagnosis. Methods: Using data from the Surveillance, Epidemiology, and End Results Program (2000–2018), we identified a cohort of 771,681 breast cancer survivors. Standard incidence ratios (SIR) were calculated by comparing the observed with the expected number of subsequent cancers over different follow-up periods since breast cancer diagnosis. Analyses were conducted for multiple cancer types, stratified by hormone receptor status, treatment of the first breast cancer, age, and race/ethnicity. Results: Survivors experienced a 16% increased risk of subsequent cancer with the SIR continuing to increase with longer follow-up (SIR = 1.04, 1.22, and 1.31 for 12–59, 60–119, and ≥120 months). This trend was driven primarily by a subsequent breast cancer, particularly among women &lt;50 years of age, those with initial hormone receptor–negative cancer, and racial/ethnic minorities. The patterns of subsequent non-breast cancer risk varied by type. An early-onset and sustained increased risk was observed for subsequent leukemia, thyroid cancer, soft-tissue sarcoma, melanoma, pancreatic cancer, and uterine cancer. A delayed increased risk was observed for subsequent esophageal, ovarian, oral cavity/pharyngeal, and lung cancers, whereas for small intestine, stomach, kidney, and colorectal cancers, there was a decrease after an initial increased risk. Conclusions: Patterns in subsequent cancer risk since breast cancer diagnosis differ by cancer type and characteristics of the first breast cancer. Impact: These findings can inform etiology and tailored approaches to screening and prevention of subsequent cancers.

Molecular Subtypes of High-Grade Serous Ovarian Cancer across Racial Groups and Gene Expression Platforms

Abstract Background: High-grade serous carcinoma (HGSC) gene expression subtypes are associated with differential survival. We characterized HGSC gene expression in Black individuals and considered whether gene expression differences by self-identified race may contribute to poorer HGSC survival among Black versus White individuals. Methods: We included newly generated RNA sequencing data from Black and White individuals and array-based genotyping data from four existing studies of White and Japanese individuals. We used K-means clustering, a method with no predefined number of clusters or dataset-specific features, to assign subtypes. Cluster- and dataset-specific gene expression patterns were summarized by moderated t-scores. We compared cluster-specific gene expression patterns across datasets by calculating the correlation between the summarized vectors of moderated t-scores. After mapping to The Cancer Genome Atlas–derived HGSC subtypes, we used Cox proportional hazards models to estimate subtype-specific survival by dataset. Results: Cluster-specific gene expression was similar across gene expression platforms and racial groups. Comparing the Black population with the White and Japanese populations, the immunoreactive subtype was more common (39% vs. 23%–28%) and the differentiated subtype was less common (7% vs. 22%–31%). Patterns of subtype-specific survival were similar between the Black and White populations with RNA sequencing data; compared with mesenchymal cases, the risk of death was similar for proliferative and differentiated cases and suggestively lower for immunoreactive cases [Black population HR = 0.79 (0.55, 1.13); White population HR = 0.86 (0.62, 1.19)]. Conclusions: Although the prevalence of HGSC subtypes varied by race, subtype-specific survival was similar. Impact: HGSC subtypes can be consistently assigned across platforms and self-identified racial groups.

Comparison of Human Papillomavirus Genotyping by Research vs. Clinical Assay for Two Self-Collection Devices

Abstract Background: Human papillomavirus (HPV) assays and self-collection devices for HPV detection have evolved. We aim to compare two self-sampling devices against speculum-based testing for HPV genotype agreement and their accuracy for cervical intraepithelial neoplasia grade 2 (CIN2+) disease. Secondarily, we aim to compare two HPV assays for different HPV genotype detection agreement and their accuracy for CIN2+ disease. Methods: Women from colposcopy (N = 97) and primary care (N = 96) were block-randomized to two different self-sampling device groups. Self-sampling and speculum-collected pairs of HPV specimens were analyzed with the research assay. A second speculum-collected specimen provided clinical results using the clinical HPV assay. Agreement (prevalence-based κ) and accuracy (sensitivity/specificity ratios) provided the statistical comparison. Results: The two devices did not differ in their κ agreement scores for overall HPV detection compared with the speculum-collected sample [κ = 0.83 (0.72–0.94) and κ = 0.90 (0.81–0.98), respectively, nonsignificant exact McNemar test results]. The two devices did not differ in accuracy as measured by the relative sensitivity/specificity for overall HPV at the CIN2+ disease threshold [1.0 (0.15–6.77) and 1.19 (0.56–2.54), respectively]. The two assays did not differ in HPV agreement nor assay accuracy for CIN2+ (n = 10). Conclusions: HPV self-sampling devices robustly detected high-risk HPV types for cervical cancer screening when using the research assay to compare them. Both research and clinical HPV assays provide equivalent HPV detection for specific and aggregated HPV types. Impact: This study provides a US-based population to show that self-collection for primary HPV testing is accurate for CIN2+ detection with multiple devices using a validated HPV assay.

Lifetime Exposure to Cigarette Smoke, B-Cell Tumor Immune Infiltration, and Immunoglobulin Abundance in Ovarian Tumors

Abstract Background: Cigarette smoke exposure has been linked to systemic immune dysfunction, including for B-cell and immunoglobulin (Ig) production, and poor outcomes in patients with ovarian cancer. No study has evaluated the impact of smoke exposure across the life-course on B-cell infiltration and Ig abundance in ovarian tumors. Methods: We measured markers of B and plasma cells and Ig isotypes using multiplex immunofluorescence on 395 ovarian cancer tumors in the Nurses’ Health Study (NHS)/NHSII. We conducted beta-binomial analyses evaluating odds ratios (OR) and 95% confidence intervals (CI) for positivity of immune markers by cigarette exposure among cases and Cox proportional hazards models to evaluate hazard ratios (HR) and 95% CI for developing tumors with low (&lt;median) or high (≥median) immune cell/Ig percentage. Results: There were no associations between smoke exposure and B-cell or IgM infiltration in ovarian tumors. Among cases, we observed higher odds of IgA+ among ever smokers (OR, 1.54; 95% CI, 1.14–2.07) and ever smokers with no parental smoke exposure (OR, 2.03; 95% CI, 1.18–3.49) versus never smokers. Women with parental cigarette smoke exposure versus not had higher risk of developing ovarian cancer with low IgG+ (HR, 1.51; 95% CI, 1.10–2.09), whereas ever versus never smokers had a lower risk (HR, 0.74; 95% CI, 0.56–0.99). Conclusions: Ever smoking was associated with increased odds of IgA in ovarian tumors. Impact: IgA has been associated with improved ovarian cancer outcomes, suggesting that although smoking is associated with poor outcomes in patients with ovarian cancer, it may lead to improved tumor immunogenicity.

Association between Dietary Anthocyanidins and Biliary Cancer Risk in 98,458 Participants: Results from a Prospective Study

Abstract Background: Previous studies have suggested anthocyanidins or anthocyanidin-rich foods and extracts exhibit protective effects against various cancers. However, the relationship between dietary anthocyanidins and the risk of biliary cancer remains uncertain. Methods: This study used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to investigate the relationship between total anthocyanidins intake and biliary cancer incidence. Cox regression analysis was conducted to estimate HRs and corresponding 95% confidence intervals (CI) for the incidence of biliary cancer, with adjustments made for confounding factors. A restricted cubic spline model was employed to examine the dose–response relationship. In addition, subgroup and sensitivity analyses were conducted to evaluate potential interactions and test the model's robustness. Results: During 8.9 years and 872,645.3 person-years of follow-up, 95 cases of biliary cancer were observed. The incidence rate of biliary cancer in this study was 11 cases per 100,000 person-years. Using the fully adjusted Cox regression model, the inverse association was observed between total anthocyanidins intake and the risk of biliary cancer (HR Q4 vs..Q1: 0.52; 95% CI: 0.29–0.91; Ptrend = 0.043). This association remained significant in sensitivity analyses. A linear dose–response relationship (Pnonlinearity = 0.118) and potential interaction with drinking status (Pinteraction = 0.033) were identified. Conclusions: This study provides evidence of an inverse association between total anthocyanidins intake and biliary cancer incidence. Impact: Our study found a total anthocyanidin-rich diet was associated with a reduced risk of biliary cancer in Americans ages 55 to 74 years.

Fine Particulate Matter, Noise Pollution, and Greenspace and Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Cohort

Abstract Background: Greenspace is hypothesized as being protective against cancer, whereas noise pollution and fine particulate matter (&lt;2.5 μm in diameter, PM2.5) are both potential risk factors. Findings from recent studies of greenspace and PM2.5 with prostate cancer are not conclusive and the association between noise exposure and cancer has not been evaluated in a U.S. study. Methods: We assessed PM2.5, noise, and greenspace exposure using spatiotemporal models and satellite-based estimates at enrollment addresses for N = 43,184 male participants of the prospective Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial cohort (enrolled 1994–2001). We used Cox regression models adjusted for age, race and ethnicity, study center, family history of prostate cancer, and Area Deprivation Index to estimate associations between ambient PM2.5 (μg/m3), greenspace (index range from –1 to 1), and noise pollution (loudest 10% of total existing sound, decibels) and incident prostate cancer risk through December 2017. Results: A total of 6,327 cases of prostate cancer were diagnosed among male participants during follow-up. PM2.5 and noise exposures were moderately positively correlated (Spearman ρ = 0.46), and PM2.5 and greenspace were not correlated (ρ = 0.10); greenspace and noise were inversely correlated (ρ = −0.32). In single-pollutant and multipollutant models mutually adjusted for coexposures, we found no associations with prostate cancer risk. Conclusions: We did not find evidence that PM2.5, greenspace, and noise pollution were associated with prostate cancer risk in this large, geographically spread cohort. Impact: This study contributes to a small body of existing literature investigating these biologically plausible associations.

Inequities in the Impacts of Hurricanes and Other Extreme Weather Events for Cancer Survivors

Abstract In this minireview, we examine the impacts of hurricanes and other extreme weather events on cancer survivors, focusing on structural and social determinants of health. We briefly explore influences on biological, psychosocial, and behavioral outcomes and discuss risk and resilience factors in cancer survivorship during and after hurricanes. Our goal is to inform future directions for research that can identify areas in which we can most efficiently improve cancer outcomes and inform changes in health systems, clinical practice, and public health policies. This timely minireview provides researchers and clinicians with an overview of challenges and opportunities for improving disaster preparedness and response for cancer survivors.

Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis

Abstract Background: Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers. Methods: We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable. Results: IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00–1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07–1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status. Conclusions: Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers. Impact: Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.

Impact of Changes in Obesity and Abdominal Obesity on Endometrial Cancer Risk in Young Korean Women: A Nationwide Cohort Study

Abstract Background: The increasing incidence of endometrial cancer in young women parallels the increasing prevalence of obesity, a well-established risk factor. However, the impact of longitudinal changes in obesity and abdominal obesity on early-onset endometrial cancer remains insufficiently understood. Methods: This nationwide cohort study utilized data from the Korean National Health Insurance Service. Women, ages 20 to 39 years, who underwent two health examinations at a 3-year interval between 2009 and 2015, with no history of cancer, were included. Participants were categorized based on changes in obesity (body mass index ≥25 kg/m2) or abdominal obesity (waist circumference ≥85 cm) into four groups: stable non-obese, non-obese to obese, obese to non-obese, and stable obese. The risk of endometrial cancer was assessed using Cox proportional hazards models. Results: Among 935,600 women, 798 developed endometrial cancer. Compared with the stable non-obese group, adjusted HRs for endometrial cancer were 1.940 (1.468–2.563), 2.083 (1.447–3.001), and 2.083 (1.447–3.001) in the non-obese to obese, obese to non-obese, and stable obese groups, respectively. With regard to abdominal obesity, the adjusted HRs were 2.048 (1.581–2.651), 2.302 (1.684–3.146), and 4.394 (3.557–5.427), respectively. The risk of cancer was higher in the obese to non-obese group than in the non-obese to obese group. Conclusions: Changes in obesity and abdominal obesity statuses were associated with early-onset endometrial cancer, with persistent abdominal obesity showing the highest risk. Impact: These findings support the need for early, sustained obesity interventions to reduce endometrial cancer risk in young women.

The Role of Rurality, Travel Time, and Neighborhood Socioeconomics on Patterns of Adjuvant Therapy Receipt among Patients with Endometrial Cancer

Abstract Background: Rural patients with endometrial cancer are more likely to receive lower-quality treatment compared with their urban peers. We evaluated the role of contextual factors [rurality, distance to care, and community socioeconomics (SES)] on the receipt of adjuvant therapy (AT): vaginal brachytherapy (VBT), external beam radiation, and chemotherapy. Methods: We analyzed Surveillance Epidemiology and End Results–Medicare and included stages IB grade 3 and stages II to IV. We used county-level rural–urban continuum codes to define rurality, the Yost index to measure community SES, and measure of average driving time to gynecologic oncology care. Multivariable logistic regression was used to estimate adjusted ORs (aOR) and 95% confidence intervals (CI) evaluating AT receipt, adjusting for patient-level clinical and demographic characteristics. Results: A total of 7,572 individuals met inclusion criteria; 15% were rural residing. Rurality was only associated with lower odds of any AT receipt among patients with stage IB endometrial cancer (aOR = 0.62; 95% CI, 0.46–0.83). Increasing travel time was associated with lower odds of VBT (aOR = 0.89; 95% CI, 0.84–0.95). Residence in a low-SES neighborhood was associated with lower odds of chemotherapy (aOR = 0.79; 95% CI, 0.67–0.92) and VBT (aOR = 0.81; 95% CI, 0.69–0.95); however, associations were no longer significant after adjusting for individual SES. Conclusions: Travel time to gynecologic oncology care negatively affects the receipt of treatment regardless of rural or urban residence. Travel time may be a proxy for access to brachytherapy services and may explain the associations between travel and receipt of VBT. Impact: Factors characterizing the place of residence beyond rural/urban residence are important for predicting inequitable access to AT.

State-Specific Incidence of Endometrial Cancer in the United States by Histologic Subtype Corrected for Hysterectomy Prevalence from 2010 to 2019

Abstract Background: Accurate reporting of state-specific endometrial cancer incidence is important for informing cancer control efforts and may lead to new hypotheses about environmental and/or geographic risk factors. Previous studies have demonstrated the importance of accounting for hysterectomy prevalence when estimating state-level endometrial cancer incidence rates as hysterectomy prevalence varies by geographic region. Methods: We used the Cancer in North America Public Use Dataset produced by the North American Association of Central Cancer Registries to identify incident endometrial cancer cases among women ≥20 years of age diagnosed from 2010 to 2019. We estimated state-specific hysterectomy-corrected, age-adjusted incidence rates overall and by histology. State-specific hysterectomy prevalence data were obtained from the Behavioral Risk Factor Surveillance System. Results: Hysterectomy prevalence was highest in Southern and Midwestern states and lowest in the Northeast. Although uncorrected endometrial cancer incidence rates were highest in the Northeast, hysterectomy-corrected rates were highest in states within the Midwest and Appalachia. Geographic patterns of the hysterectomy-corrected incidence of endometrioid cancer resembled those of endometrial cancer overall. In contrast, corrected rates of non-endometrioid cancer were highest in the South and in certain states within the Northeast and Midwest. There was no overlap in the top 10 states with the highest rates of endometrioid and non-endometrioid cancers, respectively. Conclusions: State-specific, hysterectomy-corrected incidence rates of endometrial cancer vary by histology, suggesting potential differences in behavioral, sociodemographic, and/or environmental exposures at the state level. Impact: This study presents an accurate assessment of US endometrial cancer rates and emphasizes the importance of hysterectomy correction for geographic comparisons.

Agreement between Surveillance, Epidemiology, and End Results– and Medicare Claims–Derived Uterine Cancer Treatment Data

Abstract Background: Despite the prevalent use of Surveillance, Epidemiology, and End Results (SEER)–Medicare data to study uterine cancer treatment patterns and survival, concordance between SEER and Medicare claims has not been a focus of prior research. We assessed the agreement between SEER and Medicare claims, predictors of disagreement between sources, and associations between treatment (identified in SEER vs. Medicare) and survival. Methods: Patients diagnosed with uterine cancer between 2000 and 2019 were identified using the SEER–Medicare linked database. We calculated kappa statistics to assess the agreement between the two data sources for receipt of hysterectomy with or without bilateral salpingo-oophorectomy (BSO), hysterectomy with BSO, lymphadenectomy, external beam radiotherapy (EBRT), vaginal brachytherapy (VBT), and chemotherapy. For each treatment type, we examined temporal trends in the kappa and used multivariable-adjusted logistic regression to examine predictors of disagreement. Treatment hazard ratios in Cox proportional hazards regression models using treatment information from SEER versus Medicare were compared. Results: For each treatment, we excluded patients with unknown SEER information, resulting in variable sample sizes. Agreement was lowest for hysterectomy with BSO (kappa = 0.71) and highest for lymphadenectomy and chemotherapy (kappas = 0.85). Temporal variation was evident, with lymphadenectomy, EBRT, and VBT agreement dropping in recent years. Black race, younger age at diagnosis, high-risk histology, and advanced stage were associated with higher odds of disagreement for certain treatments. Associations between treatment identified in SEER versus Medicare and survival outcomes were similar. Conclusions: Treatment agreement between SEER and Medicare was high. Impact: Our results support the use of both data sources for uterine cancer treatment–survival analyses.

Risk of Epithelial Ovarian Tumors among Women Diagnosed with Hypothyroidism and Hyperthyroidism: Findings from a Large Nationwide Cohort Study

Abstract Background: Prior research on the association between thyroid disease, ovarian cancer, and borderline ovarian tumors has been inconsistent. This nationwide cohort study investigated the risk of epithelial ovarian cancer and borderline ovarian tumors among 1,058,745 Danish women born between January 1, 1960, and December 31, 1997, and were followed until December 31, 2022, in relation to hypothyroidism and hyperthyroidism. Methods: Data on thyroid diagnoses, ovarian tumors, covariates, migration, and vital status were retrieved from Danish national registers. Hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer and borderline ovarian tumors overall and for histologic subtypes were estimated using adjusted Cox proportional hazard models. A landmark analysis assessed ovarian tumor risk at age 60 years by thyroid disease status before age 40 years. Results: Over a median of 18.4 years of follow-up, 49,015 women developed hypothyroidism, 26,950 hyperthyroidism, 905 ovarian cancer, and 1,111 borderline ovarian tumors. No association was found between hypothyroidism and ovarian cancer (HR, 1.10; CI, 0.78–1.55) or borderline tumors (HR, 0.88; CI, 0.60–1.29). Hyperthyroidism was associated with increased rates of serous ovarian cancer (HR, 1.62; CI, 1–2.63) and borderline ovarian tumors (HR, 1.78; CI, 1.26–2.52), especially in postmenopausal and premenopausal women, respectively. However, absolute risk differences at age 60 years were small and not statistically significant. Conclusions: Hyperthyroidism may increase the rate of epithelial ovarian tumors, though clinical significance remains unclear, warranting further research. Impact: These findings indicate that hyperthyroidism may modestly influence epithelial ovarian tumor risk, underscoring the need to clarify shared biological mechanisms between thyroid and ovarian function.

Establishing a Cervical Cytology Biorepository: A Protocol for Advancing Translational Cervical Cancer Research through Biobanking

Abstract Background: Cervical cancer remains a major global health concern, with disparities in screening access and outcomes, particularly among younger women in the United States. Although high-risk human papillomavirus infection is the primary etiologic factor, nongenetic and environmental contributors remain underexplored. We established the Sacred Womb Cervical Cytology Biorepository to support research on cervical cancer risk, molecular biomarkers, and gynecologic health disparities. Methods: We implemented standardized protocols for the recovery, processing, and long-term storage of residual ThinPrep Papanicolaou (Pap) specimens from women aged 21 to 65 receiving routine gynecologic care across VCU Health outpatient clinics. Core elements included an opt-out consent model, an Institutional Review Board–approved waiver for discarded cytology material, electronic health record linkage for longitudinal clinical data, and workflows for specimen recovery, aliquoting, and processing of pellet and supernatant fractions. Specimens are cryostored at −80°C with quality control checks and secure data governance. Results: The biorepository supports standardized recovery and processing of residual Pap specimens, yielding sufficient postdiagnostic volume and enabling high-quality genomic DNA extraction and metabolomic profiling. Pilot genomic and metabolomic data demonstrate that residual cervical cytology material provides adequate input for multiomic analyses, confirming feasibility and scalability. Conclusions: This protocol outlines a framework for establishing a cervical cytology biobank using residual clinical specimens. The integration of biospecimens with linked clinical and demographic data enables multidimensional research into cervical cancer etiologies and other gynecologic conditions. Impact: This resource supports molecular epidemiology studies aimed at identifying biomarkers, understanding cervical cancer progression, and addressing reproductive health disparities in diverse populations.

A Comparison of Neighborhood Socioeconomic Deprivation Measures and the Association with Survival among Black and White Women with Endometrial Cancer

Abstract Background: Black women with endometrial cancer have twice the mortality compared with White. Survival disparities remain after accounting for individual-level socioeconomic and cancer-related factors. We investigated associations between area-based deprivation and survival and explored whether area-based deprivation attenuates the association between race and survival, among a cohort of Black and White women. Methods: Data from endometrial cancers diagnosed between 2013 and 2022 were collected from a comprehensive cancer registry covering Metropolitan Detroit. Addresses at diagnosis were linked to the area deprivation (ADI) and social vulnerability (SVI) indices. Adjusted Fine and Gray models and Cox proportional hazard models were run investigating associations between area-based deprivation measures and survival; analyses were conducted estimating the proportion of the association between race and survival that was attenuated by area-based measures. Results: Higher deprivation was associated with poorer survival, adjusted for race, insurance status, and tumor characteristics. Compared with the least disadvantaged quartile, the quartile with the highest disadvantage using ADI and SVI had 1.18 [95% confidence interval (CI), 0.99–1.43] and 1.40 (1.14–1.71) times the hazard of endometrial cancer–specific mortality, respectively. ADI and SVI attenuated 18% (3%–38%) and 27% (10%–48%) of associations between race and mortality overall and 24% (95% CI, 3%–61%) and 40% (95% CI, 16%–78%) among those with high-grade histology. Conclusions: This study demonstrates a clear association between neighborhood-level disadvantage and survival among women with endometrial cancer living in Metropolitan Detroit. Neighborhood disadvantage attenuates the relationship between race and survival, particularly among those with high-grade histology. Impact: These findings serve as motivation to understand how neighborhood affects cancer outcomes.

The Potential Impact of Histamine-2 Receptor Antagonists on Gynecologic Cancer Risk: A Population-Based Study of 23 Million Individuals

Abstract Background: Gynecologic cancers, including cervical, endometrial, and ovarian cancers, remain a major global health burden. Although histamine-2 receptor antagonists (H2RA) are inexpensive and widely accessible agents with reported anticancer properties, their associations with gynecologic cancer risk remain unclear. This study evaluated the potential of H2RAs for repurposing in chemoprevention. Methods: A nationwide, population-based case–control study was conducted using Taiwan’s National Health Insurance claims and Cancer Registry data from 2002 to 2016. A total of 97,736 women with newly diagnosed gynecologic cancer were matched 1:4 with controls by sex, age (±5 years), and month and year of diagnosis. H2RA exposure was defined as &gt;60 days of use within two years before the index date. Adjusted odds ratios (aOR) and 95% confidence intervals were estimated using conditional logistic regression, adjusting for age, Charlson comorbidity index, and use of metformin, aspirin, and statins. Results: H2RA use was associated with reduced risks of cervical (aOR 0.80), endometrial (0.68), and ovarian cancers (0.78). Age-stratified analyses showed lower risks of cervical and endometrial cancers across all age groups, whereas the reduced ovarian cancer risk was most evident in women aged 40 to 64. Individual H2RA agents showed protective effects in the overall population, with cimetidine demonstrating the broadest reduction. Conclusions: Long-term H2RA use was associated with lower risks of major gynecologic cancers, with notable age- and agent-specific differences. Prospective studies are warranted to confirm causality and inform clinical application. Impact: Findings support repurposing H2RAs as accessible chemopreventive candidates for further translational application in women.

Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility

Abstract Background: Predicting protein levels from genotypes for proteome-wide association studies (PWAS) may provide insight into the mechanisms underlying cancer susceptibility. Methods: We performed PWAS of breast, endometrial, ovarian, and prostate cancers and their subtypes in several large European-ancestry discovery consortia (effective sample size: 237,483 cases/317,006 controls) and tested the results for replication in an independent European-ancestry GWAS (31,969 cases/410,350 controls). We performed PWAS using the cancer GWAS summary statistics and two sets of plasma protein prediction models, followed by colocalization analysis. Results: Using Atherosclerosis Risk in Communities (ARIC) models, we identified 93 protein–cancer associations [false discovery rate (FDR) &lt; 0.05]. We then performed a meta-analysis of the discovery and replication PWAS, resulting in 61 significant protein–cancer associations (FDR &lt; 0.05). Ten of 15 protein–cancer pairs that could be tested using Trans-Omics for Precision Medicine (TOPMed) protein prediction models replicated with the same directions of effect in both cancer GWAS (P &lt; 0.05). To further support our results, we applied Bayesian colocalization analysis and found colocalized SNPs for SERPINA3 protein levels and prostate cancer (posterior probability, PP = 0.65) and SNUPN protein levels and breast cancer (PP = 0.62). Conclusions: We used PWAS to identify potential biomarkers of hormone-related cancer risk. SNPs in SERPINA3 and SNUPN did not reach genome-wide significance for cancer in the original GWAS, highlighting the power of PWAS for novel locus discovery, with the added advantage of providing directions of protein effect. Impact: PWAS and colocalization are promising methods to identify potential molecular mechanisms underlying complex traits.

Prospective Cohort of Pre- and Post-Diagnosis Diet with Survival Outcomes: an Alberta Endometrial Cancer Cohort Study

Abstract Background: The prognostic relationship between diet and endometrial cancer survival remains largely unknown. We sought to determine pre- and post-diagnosis dietary composition, glycemic load (GL), inflammatory potential (dietary inflammatory index) and quality [Canadian Healthy Eating Index (C-HEI) 2005] associations with disease-free (DFS) and overall survival (OS) among endometrial cancer survivors. In addition, we assessed associations between dietary changes with OS and explored obesity/physical activity effect modification. Methods: Survivors, diagnosed in Alberta, Canada between 2002 and 2006, completed past-year, food-frequency questionnaires at-diagnosis (n = 503) and 3-year follow-up (n = 395). Participants were followed to death or January 2022. Cox proportional regression estimated HR [95% confidence intervals (CI)] for dietary survival associations. Results: During 16.9 median years of follow-up, 138 participants had a DFS event and 120 died. Lower pre-diagnosis GL (HRT1vsT3, 0.49; 95% CI, 0.25–0.97) and greater post-diagnosis energy intakes (EI) from total- and monounsaturated-fat (HRT3vsT1, 0.48; 95% CI, 0.26–0.87) were associated with better OS. Higher pre-diagnosis C-HEI, less inflammatory diets and lower added sugar intakes were nonlinearly associated with better DFS. Consistently low pre- to post-diagnosis EI from carbohydrates and total-fats were associated with better (HR, 0.36; 95% CI, 0.18–0.72) and worse (HR, 2.26; 95% CI, 1.21–4.20) OS, respectively. Decreased pre- to post-diagnosis C-HEI was associated with worse OS. In stratified analysis, healthy diets were most beneficial for survivors with obesity and physical inactivity. Conclusions: Adherence to higher quality dietary patterns were associated with better survival. Impact: Our study provides novel evidence that both pre- and post-diagnosis diet are important prognostic factors for endometrial cancer survivors. Post-diagnosis survival associations with diet composition and quality highlight the potential for future interventions.

Mortality Patterns of Synchronous Uterine and Ovarian Cancers: A SEER Registry Analysis

Abstract Background: The degree to which uterine cancer metastatic to the ovary is misdiagnosed as synchronous stage I uterine and ovarian cancers is unclear. We sought to determine whether patients with synchronous cancers had mortality patterns similar to either stage IIIA uterine, stage I uterine, or stage I ovarian cancers alone. Methods: The Surveillance, Epidemiology, and End Results database was used to compare mortality of patients with synchronous stage I uterine and stage I ovarian cancers versus those with stage IIIA uterine, stage I uterine, or stage I ovarian cancers alone. We calculated age-adjusted mortality hazard ratios (HR) and 95% confidence intervals (CI) accounting for calendar year and grade, adjuvant treatment, grade 1 endometrioid cancers, grade 3 endometrioid cancers, and stage IA cancers. Results: Among the 9,321 patients, we observed lower age-adjusted mortality in patients with stage I synchronous cancers (n = 937) compared to those with stage IIIA uterine (n = 531; HR, 0.45 95% CI, 0.35–0.58), stage I uterine (n = 6,919; HR, 0.74; 95% CI, 0.60–0.91), and stage I ovarian cancers (n = 934; HR, 0.52; 95% CI, 0.41–0.67). Results were similar after taking into account diagnosis year and grade, and limiting to those receiving adjuvant therapy, grade 1 or grade 3 endometrioid cancers, or stage IA cancers. Conclusions: We observed lower mortality for synchronous stage I uterine and ovarian cancers, which was not explained by younger age, earlier stage, lower grade, histology type, or adjuvant therapy. Impact: The possible misdiagnosis associated with clinicopathologic of synchronous uterine and ovarian cancers does not appear to worsen survival on a population level.

Adverse Urinary System Diagnoses among Older Women with Endometrial Cancer

Abstract Background: Endometrial cancer and its treatment may impact urinary system function, but few large-scale studies have examined urinary diagnoses among endometrial cancer survivors. We investigated the risk of several urinary outcomes among older women with endometrial cancer compared with similar women without a cancer history. Methods: Women aged 66+ years with an endometrial cancer diagnosis during 2004–2017 (N = 44,386) and women without a cancer history (N = 221,219) matched 1:5 on exact age, race/ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to define urinary outcomes in the Medicare claims. HRs for urinary outcomes were estimated using multivariable Cox proportional hazards regression models. Results: Relative to women without cancer, endometrial cancer survivors were at an increased risk of several urinary system diagnoses, including lower urinary tract infection [HR, 2.36; 95% confidence interval (CI), 2.32–2.40], urinary calculus (HR, 2.22; 95% CI, 2.13–2.31), renal failure (HR, 2.28; 95% CI, 2.23–2.33), and chronic kidney disease (HR, 1.85; 95% CI, 1.81–1.90). Similar associations were observed in sensitivity analyses limited to 1+ and 5+ years after endometrial cancer diagnosis. Black race, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often significant predictors of urinary outcomes among endometrial cancer survivors. Conclusions: Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer. Impact: Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history.

Association of Endogenous Pregnenolone, Progesterone, and Related Metabolites with Risk of Endometrial and Ovarian Cancers in Postmenopausal Women: The B∼FIT Cohort

AbstractBackground:Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism.Methods:Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992–1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk.Results:Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85–4.11); Ptrend = 0.17] or ovarian cancer risk [1.16 (0.58–2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09–0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18–0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39–6.93); 0.01].Conclusions:Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer.Impact:While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

Long-term Patterns of Excess Mortality among Endometrial Cancer Survivors

Abstract Background: We investigated excess mortality after endometrial cancer using conditional relative survival estimates and standardized mortality ratios (SMR). Methods: Women diagnosed with endometrial cancer during 2000–2017 (N = 183,153) were identified in the Surveillance Epidemiology and End Results database. SMRs were calculated as observed deaths among endometrial cancer survivors over expected deaths among demographically similar women in the general U.S. population. Five-year relative survival was estimated at diagnosis and each additional year survived up to 12 years post-diagnosis, conditional on survival up to that year. Results: For the full cohort, 5-year relative survival was 87.7%, 96.2%, and 97.1% at 1, 5, and 10 years post-diagnosis, respectively. Conditional 5-year relative survival first exceeded 95%, reflecting minimal excess mortality compared with the general population, at 4 years post-diagnosis overall. However, in subgroup analyses, conditional relative survival remained lower for Black women (vs. White) and for those with regional/distant stage disease (vs. localized) throughout the study period. The overall SMR for all-cause mortality decreased from 5.90 [95% confidence interval (CI), 5.81–5.99] in the first year after diagnosis to 1.16 (95% CI, 1.13–1.19) at 10+ years; SMRs were consistently higher for non-White women and for those with higher stage or grade disease. Conclusions: Overall, endometrial cancer survivors had only a small survival deficit beyond 4 years post-diagnosis. However, excess mortality was greater in magnitude and persisted longer into survivorship for Black women and for those with more advanced disease. Impact: Strategies to mitigate disparities in mortality after endometrial cancer will be needed as the number of survivors continues to increase.

Trends in Cervical Cytology Test Reports and Cervical Dysplasia Severity according to Social Deprivation in Mexico (2013–2019): An Analysis of a National Database

Abstract Background: Cervical cancer is a leading cause of cancer-related mortality in women living in low- and middle-income countries such as Mexico. Preventive and screening programs are often inaccessible to socially deprived populations, whose limited access to timely diagnosis and treatment reduces the chance of detecting premalignant lesions early. Methods: Cervical malignant and premalignant lesion positivity rates were analyzed from 2013 to 2016 using the Bethesda system, whereas human papillomavirus (HPV) positivity rates were analyzed from 2017 to 2019. Both were stratified according to state-level Social Deprivation Indices in Mexico, published by the National Council for the Evaluation of Social Development Policy. The data originated from the four main healthcare providers in Mexico. Data processing and statistical analyses were performed using Joinpoint Regression Software and SPSS version 25. Results: Positivity rates for dysplasia and atypia varied across social deprivation levels. A downward trend in premalignant lesion positivity rates was observed. This varied across social deprivation groups, with differing annual percentage changes (APC). The greatest decrease occurred in high-grade cervical intraepithelial dysplasia (CIN 2–3) in states with very high social deprivation, with an estimated APC of −22.1% (−30% to −14.7%; P = 0.001). HPV positivity by PCR ranged from 11% to 24% between 2017 and 2019. The estimated APC for invasive cervical carcinoma was −22.3% [95% confidence interval (CI); −54.4% to 19.8%], which was not statistically significant (P = 0.223). Conclusions: Our study highlights a decline in cervical dysplasia positivity rates. These declines were uneven across social deprivation levels. Impact: Reducing health inequities is essential to prevent, detect, and treat cervical cancer and its precursors.

Dietary Intake of Acrylamide and Risk of Breast, Endometrial, and Ovarian Cancers: A Systematic Review and Dose–Response Meta-analysis

Abstract Acrylamide is a probable human carcinogen. Aside from occupational exposures and smoking, diet is the main source of exposure in humans. We performed a systematic review of the association between estimated dietary intake of acrylamide and risk of female breast, endometrial, and ovarian cancers in nonexperimental studies published through February 25, 2020, and conducted a dose–response meta-analysis. We identified 18 papers covering 10 different study populations: 16 cohort and two case–control studies. Acrylamide intake was associated with a slightly increased risk of ovarian cancer, particularly among never smokers. For endometrial cancer, risk was highest at intermediate levels of exposure, whereas the association was more linear and positive among never smokers. For breast cancer, we found evidence of a null or inverse relation between exposure and risk, particularly among never smokers and postmenopausal women. In a subgroup analysis limited to premenopausal women, breast cancer risk increased linearly with acrylamide intake starting at 20 μg/day of intake. High acrylamide intake was associated with increased risks of ovarian and endometrial cancers in a relatively linear manner, especially among never smokers. Conversely, little association was observed between acrylamide intake and breast cancer risk, with the exception of premenopausal women.

Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium

Abstract Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. Results: Most associations did not vary by tumor site (Phet ≥ 0.05). Associations between first pregnancy (Phet = 0.04), tubal ligation (Phet = 0.01), and early-adult (age 18–21 years) body mass index (BMI; Phet = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (Phet = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.

Accuracy of HPV Self-Collection Compared with Clinician-Collected HPV Testing and Cytology: A Meta-analysis

Abstract Meta-analyses show comparable clinical accuracy of PCR-based human papillomavirus (HPV) assays on self- compared with clinician-collected specimens. We extended these meta-analyses by comparing HPV testing on both samples with cytology from clinician-collected specimens. Studies published in PubMed, Embase, and Cochrane Library up to September 2024 were reviewed for inclusion. Studies had to report paired HPV self-collection, clinician-collected HPV testing, and cytology. Performance measures included sensitivity and specificity of atypical squamous cells of undetermined significance or worse and high-risk HPV positivity in self- and clinician-collected samples for cervical intraepithelial neoplasia 2 or worse. Accuracy data were pooled using the bivariate normal model for logit transforms of sensitivity and specificity. Sixteen full-text articles met inclusion criteria. Studies were heterogeneous and included referral populations, which may overestimate cytology sensitivity. Cytology was less sensitive in detecting cervical intraepithelial neoplasia 2 or worse (pooled sensitivity 87%; 95% confidence interval, 76–93) compared with HPV testing on self- (90%) and clinician-collected samples (93%) when restricting to PCR-based HPV assays. Overall, HPV self-collection sensitivity surpassed clinician-collected cytology testing, demonstrating that 3-year screening intervals, which are recommended for negative cytology results, are safe to use for negative HPV results from self-collected specimens. Longitudinal data of HPV testing on self- versus clinician-collected samples are lacking.

Potential Protective Effect of Statins against High-Grade Squamous Intraepithelial Lesions in Women with Metabolic Comorbidities

Abstract Background: Although human papillomavirus vaccination and Papanicolaou screening have advanced cervical cancer prevention, high-grade squamous intraepithelial lesions (HSIL) remain common, particularly among individuals with metabolic comorbidities such as diabetes and hypercholesterolemia. Statins, commonly used for lipid control, possess anti-inflammatory and antiproliferative properties that may offer protective effects against cervical dysplasia. We explored the association between statin use and lesion grade in a population of patients with dysplasia and whether effects vary by comorbidity and race. Methods: Cross-sectional, observational retrospective analysis of electronic health records and billing data for 2,378 non-Latina/e (nL) Black (nLB) and nL White patients diagnosed with low-grade squamous intraepithelial lesions or HSIL between 2014 and 2021 at a large academic medical center. Logistic regression assessed associations between statin use, comorbidity profiles (diabetes, hypercholesterolemia), race, and HSIL versus low-grade squamous intraepithelial lesions, adjusting for potential confounders. Interaction terms were tested to evaluate effect modification. Results: Statin users had significantly lower odds of HSIL than nonusers (adjusted OR = 0.48, P &lt; 0.0001), despite being older, and having higher comorbidity rates. Predicted HSIL probabilities ranged from 4% to 20% in statin users versus 13% to 29% in nonusers. The lowest risk was observed among patients with diabetes on statins, particularly among nLB patients, suggesting a possible synergistic protective effect in metabolically vulnerable populations. Only 35% of patients with a hypercholesterolemia diagnosis listed were on statins. Conclusions: Statin use was associated with substantially lower HSIL risk, particularly among nLB patients with diabetes. Impact: These findings support further investigation of statins as a potential low-cost chemopreventive tool for cervical dysplasia, especially in populations with metabolic dysfunction.

Evaluating Efficacy of Cervical HPV-HR DNA Testing as Alternative to PET/CT Imaging for Posttreatment Cancer Surveillance: Retrospective Proof-of-Concept Study

Abstract Background: High-risk human papillomaviruses (HPV-HR) are implicated in more than 99% of cervical/vaginal malignancies. Despite this strong association, current guidelines recommend PET/CT imaging over HPV-HR DNA testing as the standard prognostic tool following definitive therapy. This retrospective, single-institution, proof-of-concept study evaluated HPV-HR DNA testing as a potential alternative to PET/CT imaging for posttreatment surveillance in cervical and vaginal cancers. Methods: Female patients with cervical or vaginal cancer treated between 2010 and 2023 at our institution were retrospectively analyzed. Eligible patients had complete documentation of pre- and posttreatment PET/CT imaging and HPV-HR DNA testing. Of more than 100 patients identified, only 53 met the inclusion criteria, and both radical hysterectomy and chemoradiation patients were included. Statistical analyses, including sensitivity, specificity, and predictive values, were conducted using Stata, with significance set at 0.05. Results: Posttreatment HPV-HR DNA testing demonstrated a superior sensitivity (92.31%) and negative predictive value (97.44% NPV) compared with PET/CT imaging (76.92% sensitivity and 92.31% NPV). Although PET/CT imaging maintained higher specificity over HPV-HR DNA testing (100% vs. 95%) and positive predictive value (100% vs. 85.71%), HPV-HR DNA testing offers a more sensitive and cost-effective method for identifying patients requiring further evaluation. Conclusions: HPV-HR DNA testing is a promising, cost-effective surveillance tool with higher sensitivity and NPV than PET/CT. Its clinical use may reduce PET/CT need, improve safety, and lower costs and require further validation. Impact: HPV-HR DNA testing offers a cost-effective alternative to PET/CT, reducing costs, unnecessary imaging, and improving accessibility.

A Randomized Control Trial of Two Interventions Compared with Usual Care for Increasing Cervical Cancer Screening among Women Living in the Rural Midwest

Abstract Background: Lower cervical cancer screening rates are associated with higher cervical cancer mortality among women living in rural compared with urban areas (defined by rural–urban community codes). The study purpose was to examine the effectiveness of a mailed digital video disc (DVD) versus DVD plus patient navigation (PN) versus usual care (UC) on increasing the percentage of rural women up to date (UTD) with cervical cancer screening guidelines. Methods: Rural women (ages 50–74 years) who were not UTD for cervical cancer screening (n = 553) were consented and randomized 2:2:1 (DVD, DVD + PN, and UC, respectively). Baseline and 12-month surveys included sociodemographic characteristics, history of previous cervical cancer screening, and cervical cancer screening knowledge and beliefs. Screening status was assessed by medical record review at baseline and 12 months after randomization. Results: The mean age of participants was 59.8 years. After controlling for covariates, women randomized to the DVD + PN group had greater odds [OR = 5.01; 95% confidence interval (CI), 2.38–11.50] of being UTD with cervical cancer screening compared with UC at 12 months after randomization. Other significant covariates in the model included having a college versus high school or lower education (OR = 2.36; 95% CI, 1.08–5.63), private (OR = 4.16; 95% CI, 1.28–19.1) or no insurance (OR = 8.74; 95% CI, 1.77–51.9) versus public insurance, normal (OR = 3.25; 95% CI, 1.46–7.24) or overweight (OR = 2.15; 95% CI, 1.05–4.42) versus obese body mass index, and positive screening intention in the next six months (OR = 2.59; 95% CI, 1.48–4.52). Conclusions: A DVD + PN intervention increased the percentage of rural women UTD with cervical cancer screening compared with UC or DVD only. Impact: Women who have a high school or lower education, were on public insurance, obese, and not planning to be screened need increased attention to become UTD with cervical cancer screening.

Cervical Cancer Screening Uptake and Sociocultural Barriers among Women in Addis Ababa, Ethiopia: Population-Based Study

Abstract Background: Cervical cancer is the second leading cause of cancer death among women in Addis Ababa and other parts of Ethiopia. Yet, there are limited age-eligible city-wide data on cervical cancer screening prevalence in Addis Ababa to inform public policy. Methods: A population-based cross-sectional study was conducted among 1881 screening eligible women aged 30 to 49 years, who were selected from 63 enumeration areas in Addis Ababa based on multistage sampling and proportional sample size allocation. Logistic regression was used to identify barriers to screening. All statistical tests were two-sided, P &lt; 0.05. Results: Overall, 30.8% [95% confidence interval (CI), 28.8%–33.0%] of study participants reported receipt of screening in the past 5 years. Less than half (45.7%) of women reported that they received healthcare provider recommendation for screening, and only 15% of married women reported that they had spousal support for it. In the multivariable adjusted model, the odd of being screened was considerably higher in women with healthcare provider recommendation, with spousal support, and with good cervical cancer screening awareness and knowledge of risk factors for the disease. Factors associated with not seeking screening service included feeling healthy and perception of low risk for cervical cancer. Conclusions: Cervical cancer screening uptake is low in Addis Ababa, and less than half received healthcare provider recommendation. Future studies should identify barriers to provider recommendations. Impact: The findings underscore the need for a coordinated effort to enhance healthcare provider recommendations for cervical cancer screening and to raise awareness about the benefits of screening in the general population.

The Paradox of Poor Cervical Cancer Screening Uptake for Kidney Transplant Recipients

Abstract Kidney transplant recipients have an increased risk for developing and dying from cervical cancer compared with the general population due to their immunosuppressed state. As one of the cancers most amenable to an effective screening program, encouraging eligible women after transplantation to adhere to screening is critically important. Therefore, the observation that kidney transplant recipients may have a lower uptake of cervical cancer screening compared with the general population is concerning. The reasons for this should be studied so that any barriers can be identified and overcome. Kidney transplant recipients and recipients of other solid organ allografts must be encouraged and supported to adhere to recommended screening programs to mitigate the morbidity and mortality of posttransplantation cancer. See related article by Hsu et al., p. 1678

A Mail-Based HPV Self-Collection Program to Increase Cervical Cancer Screening in Appalachia: Results of a Group Randomized Trial

Abstract Background: Despite the promise of mail-based human papillomavirus (HPV) self-collection programs for increasing cervical cancer screening, few have been evaluated in the United States. We report the results of a mail-based HPV self-collection program for underscreened women living in Appalachia. Methods: We conducted a group randomized trial from 2021 to 2022 in the Appalachian regions of Kentucky, Ohio, Virginia, and West Virgnia. Participants were women of ages 30 to 64 years who were underscreened for cervical cancer and from a participating health system. Participants in the intervention group (n = 464) were mailed an HPV self-collection kit followed by telephone-based patient navigation (if needed), and participants in the usual care group (n = 338) were mailed a reminder letter to get a clinic-based cervical cancer screening test. Generalized linear mixed models compared cervical cancer screening between the study groups. Results: Overall, 14.9% of participants in the intervention group and 5.0% of participants in the usual care group were screened for cervical cancer. The mail-based HPV self-collection intervention increased cervical cancer screening compared with the usual care group (OR, 3.30; 95% confidence interval, 1.90–5.72; P = 0.005). One or more high-risk HPV types were detected in 10.5% of the returned HPV self-collection kits. Among the participants in the intervention group whom patient navigators attempted to contact, 44.2% were successfully reached. Conclusions: HPV self-collection increased cervical cancer screening, and future efforts are needed to determine how to optimize such programs, including the delivery of patient navigation services. Impact: Mail-based HPV self-collection programs are a viable strategy for increasing cervical cancer screening among underscreened women living in Appalachia.

Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Abstract Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17–3.81; P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66–2.95; P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.

HPV Extended Genotyping to Triage Abnormal Cervical Cancer Screens—Balancing the Harms and Benefits of an Additional Triage Test before Direct Colposcopy Referral

Abstract The Netherlands’ cervical cancer screening program transitioned to primary human papillomavirus (HPV) screening in 2017. After the introduction of HPV-based screening, the country saw increases in colposcopy referral rates and detections of low-grade lesions. In July 2022, genotyping was introduced, and those with borderline or mild dyskaryotic (BMD) cytologic abnormalities were only referred to colposcopy if positive for HPV type 16 or 18, and repeat screening otherwise. In this article, various strategies using extended genotyping (HPV16/18/31/33/45/52/58) as a triage test after an abnormal screen were explored using data from HPV-positive participants with normal or BMD cytology in the Population-Based Screening Study Amsterdam (POBASCAM) trial. The authors assessed positive and negative predictive values and colposcopy referral rates for each strategy using extended genotyping to triage women to either direct referral to colposcopy or repeat screening. Direct referral did not meet positive and negative predictive value thresholds for efficiency for any strategies. However, the authors note that direct referral may nonetheless be useful among those with BMD due to minimal increases in colposcopy referrals and concerns of loss to follow-up at repeat screening. These findings demonstrate the potential utility of extended genotyping as a triage test in primary HPV screening programs. The results should be considered alongside the fact that referral to repeat screening may result in loss of engagement of women who need treatment to prevent invasive cancer. See related article by Kroon et al., p. 1037

Cervical Cancer Screening Utilization among Kidney Transplant Recipients, 2001 to 2018

Abstract Background: Kidney transplant recipients (KTR) have elevated risks of cervical precancers and cancers and guidelines recommend more frequent cervical cancer screening exams. However, little is known about current trends in cervical cancer screening in this unique population. We described patterns in the uptake of cervical cancer screening exams among female KTRs and identified factors associated with screening utilization. Methods: This retrospective cohort study included female KTRs between 20 and 65 years old, with Texas Medicare fee-for-service coverage, who received a transplant between January 1, 2001, and December 31, 2017. We determined the cumulative incidence of receiving cervical cancer screening post-transplant using ICD-9, ICD-10, and CPT codes and assessed factors associated with screening utilization, using the Fine and Gray model to account for competing events. Subdistribution hazard models were used to assess factors associated with screening uptake. Results: Among 2,653 KTRs meeting the inclusion and exclusion criteria, the 1-, 2-, and 3-year cumulative incidences of initiating a cervical cancer screening exam post-transplant were 31.7% [95% confidence interval (CI), 30.0%–33.6%], 48.0% (95% CI, 46.2%–49.9%), and 58.5% (95% CI, 56.7%–60.3%), respectively. KTRs who were 55 to 64 years old (vs. &lt;45 years old) and those with a higher Charlson Comorbidity Score post-transplant were less likely to receive cervical cancer screening post-transplant. Conclusions: Cervical cancer screening uptake is low in the years immediately following a kidney transplant. Impact: Our findings highlight a need for interventions to improve cervical cancer screening utilization among kidney transplant recipients. See related In the Spotlight, p. 1554

The Association of Kidney Function and Inflammatory Biomarkers with Epithelial Ovarian Cancer Risk

Abstract Background: One of the mechanisms of ovarian tumorigenesis is through inflammation. Kidney dysfunction is associated with increased inflammation; thus, we assessed its relationship with ovarian cancer risk. Methods: In prospectively collected samples, we evaluated the association of kidney function markers and C-reactive protein (CRP) with ovarian cancer risk in the UK Biobank. We used multivariable-adjusted Cox proportional hazards models to evaluate quartiles of serum and urine markers with ovarian cancer risk overall and by histology. We assessed effect modification by CRP (≤3.0, &gt;3.0 mg/L). Results: Among 232,908 women (1,110 ovarian cancer cases diagnosed from 2006–2020), we observed no association between estimated glomerular filtration rate and ovarian cancer risk (Q4 vs. Q1: HR, 1.00; 95% confidence intervals, 0.83–1.22). Potassium was associated with endometrioid (Q4 vs. Q1: 0.33, 0.11–0.98) and clear cell (4.74, 1.39–16.16) tumors. Poor kidney function was associated with a nonsignificant increase in ovarian cancer risk among women with CRP&gt;3.0 mg/L (e.g., uric acid Q4 vs. Q1; 1.23, 0.81–1.86), but not CRP≤3.0 mg/L (0.83, 0.66–1.05). Other associations did not vary across CRP categories. Conclusions: Kidney function was not clearly associated with ovarian cancer risk. Larger studies are needed to evaluate possible histology specific associations. Given the suggestive trend for increased ovarian cancer risk in women with poor kidney function and high CRP, future work is needed, particularly in populations with a high prevalence of inflammatory conditions. Impact: This study provided the first evaluation of markers of kidney function in relation to ovarian cancer risk.

Assessing Management of Abnormal Cervical Cancer Screening Results and Concordance with Guideline Recommendations in Three US Healthcare Settings

Abstract Background: Follow-up of abnormal results is essential to cervical cancer screening, but data on adherence to follow-up are limited. We describe patterns of follow-up after screening abnormalities and identify predictors of guideline-concordant follow-up. Methods: We identified the index screening abnormality (positive human papillomavirus test or atypical squamous cells of undetermined significance or more severe cytology) among women of ages 25 to 65 years at three US healthcare systems during 2010 to 2019. We estimated the cumulative incidence of surveillance testing, colposcopy, or treatment after the index abnormality and initial colposcopy. Logistic regressions were fit to identify predictors of guideline-concordant follow-up according to contemporaneous guidelines. Results: Among 43,007 patients with an index abnormality, the cumulative incidence of any follow-up was 49.6% by 4 years for those with atypical squamous cells of undetermined significance/human papillomavirus–negative and higher for abnormalities warranting immediate colposcopy. The 1-year cumulative incidence of any follow-up after colposcopy was 70% for patients with normal results or cervical intraepithelial neoplasia I and 90% for patients with cervical intraepithelial neoplasia II+. Rates of concordant follow-up after screening and colposcopy were 52% and 47%, respectively. Discordant follow-up was associated with factors including age, race/ethnicity, overweight/obese body mass index, and specific types of public payor coverage or being uninsured. Conclusions: Adherence to the recommended follow-up of cytologic and histopathologic abnormalities is inconsistent in clinical practice. Concordance was poor for mild abnormalities and improved, although suboptimal, for more severe abnormalities. Impact: There remain gaps in the cervical cancer screening process in clinical practice. Further study is needed to understand the barriers to the appropriate management of cervical abnormalities.

Germline Mutations in 12 Genes and Risk of Ovarian Cancer in Three Population-Based Cohorts

Abstract Background: With the widespread use of multigene panel genetic testing, population-based studies are necessary to accurately assess penetrance in unselected individuals. We evaluated the prevalence of germline pathogenic or likely pathogenic variants (mutations) in 12 cancer-predisposition genes and associations with ovarian cancer risk in three population-based prospective studies [Nurses’ Health Study (NHS), NHSII, Cancer Prevention Study II]. Methods: We included women with epithelial ovarian or peritoneal cancer (n = 776) and controls who were alive and had at least one intact ovary at the time of the matched case diagnosis (n = 1,509). Germline DNA was sequenced for mutations in 12 genes. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer risk by mutation status. Results: The mutation frequency across all 12 genes was 11.2% in cases and 3.3% in controls (P &lt; 0.0001). BRCA1 and BRCA2 were the most frequently mutated (3.5% and 3.8% of cases and 0.3% and 0.5% of controls, respectively) and were associated with increased ovarian cancer risk [OR, BRCA1 = 12.38; 95% confidence interval (CI) = 4.72–32.45; OR, BRCA2 = 9.18; 95% CI = 3.98–21.15]. Mutation frequencies for the other genes were ≤1.0% and only PALB2 was significantly associated with risk (OR = 5.79; 95% CI = 1.09–30.83). There was no difference in survival for women with a BRCA germline mutation versus no mutation. Conclusions: Further research is needed to better understand the role of other mutations in ovarian cancer among unselected populations. Impact: Our data support guidelines for germline genetic testing for BRCA1 and BRCA2 among women diagnosed with epithelial ovarian cancer; testing for PALB2 may be warranted.

Colposcopy Referral and CIN3+ Risk of Human Papillomavirus Genotyping Strategies in Cervical Cancer Screening

Abstract Background: High-risk human papillomavirus (hrHPV)-based cervical cancer screening in the Netherlands led to a substantial increase in number of colposcopy referrals and low-grade lesions detected. Genotyping strategies may be employed to lower the screening-related burden. Methods: We evaluated 14 triage strategies with genotyping (HPV16/18 or HPV16/18/31/33/45/52/58) for hrHPV-positive borderlineormilddyskaryosis (BMD)ornormal cytology,usingdata from a population-based hrHPV-based screening trial with 5-year interval (POBASCAM). We considered colposcopy referral at baseline, after 6-month repeat cytology and after 5-year hrHPV testing. Performance was evaluated by one-round positive and negative predictive value (PPVandNPV) for CIN3+ and by two-roundcolposcopy referral rate. To identify efficient strategies, they were ordered by the one-round colposcopy referral rate. Adjacent strategies were compared by the marginal PPV for detecting one additional CIN3+ (mPPV). Results: The most conservative strategy (repeat cytology after BMD and HPV16/18/31/33/45/52/58-positive normal cytology, next round otherwise) yielded an mPPV of 28%, NPV of 98.2%, and two-round colposcopy referral rate of 47.2%. Adding direct referral after BMD or genotype-positive BMD yielded an mPPV ≤ 8.2%, NPV ≥ 98.5% and an increase in colposcopy referral rate of 1.9% to 6.5%. Adding direct referral after HPV16/18-positive normal cytology yielded an mPPV ≤ 3.5%, NPV ≥ 99.5% and an increase in colposcopy referral rate of 13.9%. Conclusions: Direct colposcopy referral of women with BMD or normal cytology is unlikely to be efficient, but genotype-guided direct referral after BMD may be considered because the increase in colposcopies is limited. Impact: hrHPV screening programs can become very efficient when immediate colposcopy referral is limited to women at highest CIN3+ risk. See related In the Spotlight, p. 979

Associations of Dietary Patterns with Colorectal Adenomas in the Prostate, Lung, Colorectal, and Ovarian Cancer Cohort

Abstract Background: Most colorectal cancers arise from adenomas, and although insulinemic and inflammatory dietary patterns have been associated with colorectal cancer risk, these dietary patterns have not been studied in relation to adenoma risk. Methods: Using data from 21,192 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer screening cohort, we calculated the Empirical Dietary Index for Hyperinsulinemia (EDIH), Empirical Dietary Inflammatory Pattern (EDIP), and overall dietary quality measured via the Healthy Eating Index (HEI-2015), from food frequency questionnaires (FFQ). In multivariable-adjusted logistic regression, we investigated associations of these dietary indices with adenoma (any adenoma, advanced adenoma, n = 19,493) and recurrent adenoma (n = 1,699). Results: EDIH was not associated with adenoma or advanced adenoma but was marginally associated with recurrent adenoma. The OR (95% CI) comparing highest (lowest insulinemic) versus lowest (most hyperinsulinemic) quintiles was 0.76 (0.55–1.05) after multivariable adjustment including BMI. EDIP and HEI-2015 were not associated with any of the three outcomes. Conclusions: In the PLCO cohort, we did not observe substantial associations between dietary patterns and risk of colorectal adenomas. Impact: Pending confirmation in larger prospective studies, our findings suggest that these dietary patterns may not substantially affect colorectal cancer risk via the adenoma–carcinoma sequence.

Folate Intake and Ovarian Cancer Risk among Women with Endometriosis: A Case–Control Study from the Ovarian Cancer Association Consortium

Abstract Background: Although folate intake has not been associated with an increased risk of ovarian cancer overall, studies of other cancer types have suggested that high folate intake may promote carcinogenesis in precancerous lesions. Women with endometriosis (a potential precancerous lesion) have an increased risk of developing ovarian cancer; however, whether high folate intake increases risk in this group is unknown. Methods: We conducted a pooled analysis of six case–control studies from the Ovarian Cancer Association Consortium to investigate the association between folate intake and risk of ovarian cancer among women with and without self-reported endometriosis. We included 570 cases/558 controls with and 5,171/7,559 without endometriosis. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals for the association between folate intake (dietary, supplemental, and total) and ovarian cancer risk. Finally, we used Mendelian randomization (MR) to evaluate our results using genetic markers as a proxy for folate status. Results: Higher dietary folate intake was associated with an increased risk of ovarian cancer for women with endometriosis [OR, 1.37 (1.01–1.86)] but not for women without endometriosis. There was no association between supplemental folate intake and ovarian cancer risk for women with or without endometriosis. A similar pattern was seen using MR. Conclusions: High dietary folate intake may be associated with an increased risk of ovarian cancer among women with endometriosis. Impact: Women with endometriosis with high folate diets may be at increased risk of ovarian cancer. Further research is needed on the potential cancer-promoting effects of folate in this group.

Short-term Endpoints for Cancer Screening Trials: Does Tumor Subtype Matter?

Abstract Multicancer early detection tests are precipitating a reexamination of potential short-term endpoints for cancer screening trials. A reduction in advanced stage incidence is a prime candidate, and stage-shift models that substitute early-stage for late-stage survival have been used to predict mortality reduction due to screening. However, standard stage-shift models often ignore prognostic subtypes, effectively implying that cancers detected early also have an associated subtype shift. To illustrate the differences between mortality predictions from stage-shift models that ignore versus preserve prognostic subtype, we use ovarian cancer partitioned by histologic subtype and prostate cancer partitioned by grade. We infer general conditions under which stage-shift models that preserve prognostic subtype are likely to predict mortality reductions that differ from those that ignore subtype and examine the implications for short-term endpoints based on stage in cancer screening trials.

Measurement of Ovarian Tumor Immune Profiles by Multiplex Immunohistochemistry: Implications for Epidemiologic Studies

Abstract Background: Despite the immunogenic nature of many ovarian tumors, treatment with immune checkpoint therapies has not led to substantial improvements in ovarian cancer survival. To advance population-level research on the ovarian tumor immune microenvironment, it is critical to understand methodologic issues related to measurement of immune cells on tissue microarrays (TMA) using multiplex immunofluorescence (mIF) assays. Methods: In two prospective cohorts, we collected formalin-fixed, paraffin-embedded ovarian tumors from 486 cases and created seven TMAs. We measured T cells, including several sub-populations, and immune checkpoint markers on the TMAs using two mIF panels. We used Spearman correlations, Fisher exact tests, and multivariable-adjusted beta-binomial models to evaluate factors related to immune cell measurements in TMA tumor cores. Results: Between-core correlations of intratumoral immune markers ranged from 0.52 to 0.72, with more common markers (e.g., CD3+, CD3+CD8+) having higher correlations. Correlations of immune cell markers between the whole core, tumor area, and stromal area were high (range 0.69–0.97). In multivariable-adjusted models, odds of T-cell positivity were lower in clear cell and mucinous versus type II tumors (ORs, 0.13–0.48) and, for several sub-populations, were lower in older tissue (sample age &gt; 30 versus ≤ 10 years; OR, 0.11–0.32). Conclusions: Overall, high correlations between cores for immune markers measured via mIF support the use of TMAs in studying ovarian tumor immune infiltration, although very old samples may have reduced antigenicity. Impact: Future epidemiologic studies should evaluate differences in the tumor immune response by histotype and identify modifiable factors that may alter the tumor immune microenvironment.

Racial/Ethnic Differences in Ovarian Cancer Risk: Results from the Multiethnic Cohort Study

Abstract Background: Incidence rates of epithelial ovarian cancer (EOC) vary across racial/ethnic groups, yet little is known about the impact of hormone-related EOC risk factors in non-Whites. Methods: Among 91,625 female Multiethnic Cohort Study participants, 155 incident EOC cases were diagnosed in Whites, 93 in African Americans, 57 in Native Hawaiians, 161 in Japanese Americans, and 141 in Latinas. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between race/ethnicity and EOC risk and between hormone-related factors and EOC risk across racial/ethnic groups. Results: Compared with Whites, African Americans and Japanese Americans had a lower multivariable-adjusted EOC risk; Native Hawaiians had a suggestive higher risk. Parity and oral contraceptive (OC) use were inversely associated with EOC risk (Pint race/ethnicity ≥ 0.43); associations were strongest among Japanese Americans (e.g., ≥4 vs. 0 children; HR = 0.45; CI, 0.26–0.79). Age at natural menopause and postmenopausal hormone (PMH) use were not associated with EOC risk in the overall population, but were positively associated with risk in Latinas (e.g., ≥5 years vs. never PMH use; HR = 2.13; CI, 1.30–3.49). Conclusions: We observed strong associations with EOC risk for parity and OC use in Japanese Americans and PMH use and age at natural menopause in Latinas. However, differences in EOC risk among racial/ethnic groups were not fully explained by established hormone-related risk factors. Impact: Our study indicates there are racial/ethnic differences in EOC risk and risk factors, and could help improve prevention strategies for non-White women.

Ecologic Analysis of Correlates of Cervical Cancer Morbidity and Mortality in Sub-Saharan Africa

Abstract Background: Cervical cancer is the fourth leading cause of death among women worldwide, with 85% of the burden falling on low- to middle- income countries. We studied the correlates of cervical cancer incidence and mortality, and case-fatality in Sub-Saharan Africa. Methods: Country-level data on 16 putative cervical cancer correlates for 37 Sub-Saharan African countries were collected from publicly available data sources. We performed univariate and multiple (stepwise) linear regression analyses to identify correlates of cervical cancer incidence and mortality, and case-fatality. Results: In univariate analyses, incidence and mortality rates were significantly correlated with contraceptive use, penile cancer incidence, and human immunodeficiency virus prevalence. Incidence rates were also correlated with literacy rates, whereas mortality rates were correlated with the proportion of rural population and screening coverage. Multiple regression analyses showed contraceptive use (P = 0.009) and penile cancer incidence (P = 0.004) as associated with cervical cancer incidence. Penile cancer incidence (P = 9.77 × 10–5) and number of medical doctors (P = 0.0433) were associated with mortality. The goodness of fit of the incidence and mortality models was moderate at best, explaining 49% and 37% of variability in the data, respectively. However, the case-fatality model had the best fit explaining most of the variation (adjusted R2 = 0.948; P = 6.822 × 10–16). Conclusions: To reduce the burden of cervical cancer in Sub-Saharan Africa, it would be important to design multimodal interventions that not only target screening and HPV vaccination, but also focus on cervical cancer correlates. Impact: Identifying contextual factors associated with cervical cancer in this region could inform targeted interventions.

Randomized Implementation of a Primary Human Papillomavirus Testing–based Cervical Cancer Screening Protocol for Women 34 to 69 Years in Norway

Abstract Background: Cervical cancer screening programs are facing a programmatic shift where screening protocol based on human papillomavirus testing (HPV-Screening protocol) is replacing the liquid-based cytology (LBC-Screening protocol). For safe technology transfer within the nationwide screening programme in Norway, HPV-Screening protocol was implemented randomized to compare the real-world effectiveness of HPV-Screening protocol and LBC-Screening protocol at the first screening round. Methods: Among 302,295 women ages 34 to 69 years scheduled to attend screening from February 2015 to June 2017, 157,447 attended. A total of 77,207 were randomly allocated to the HPV-Screening protocol and 80,240 were allocated to the LBC-Screening protocol. All women were followed up for 18 months. Results: The HPV-Screening protocol resulted in a relative increase of 60% in the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse [risk ratio (RR) = 1.6, 95% confidence interval (CI) = 1.5–1.7], 40% in CIN grade 3 or worse (RR = 1.4, 95% CI = 1.3–1.6), 40% in cancer (RR = 1.4, 95% CI = 1.0–2.1), and 60% in colposcopy referrals (RR = 1.6, 95% CI = 1.5–1.6) compared with LBC-Screening. The performance of both protocols was age dependent, being more effective in women ages under 50 years. Conclusions: The HPV-Screening protocol was well accepted by women in Norway and detected more CIN2, CIN3, and cancers compared with the LBC-Screening protocol. Impact: A randomized implementation of the HPV-Screening protocol with real-world assessment enabled a gradual, quality assured, and safe technology transition. HPV-based screening protocol may further be improved by using HPV genotyping and age-specific referral algorithms.

Prospective Analysis of Circulating Biomarkers and Ovarian Cancer Risk in the UK Biobank

Abstract Background: Risk factors have a limited ability to predict individuals at high risk of developing ovarian cancer among average-risk women, highlighting the need for discovery of novel biomarkers. In the UK Biobank, we investigated serum biomarkers commonly measured in clinical laboratory tests and ovarian cancer risk. Methods: We conducted a prospective analysis of 20 serum biomarkers and ovarian cancer risk in 232,037 female UK Biobank participants (including 1,122 incident ovarian cancer cases diagnosed from 2006 to 2020). Multivariable adjusted Cox proportional hazards models were used to examine associations between biomarkers and ovarian cancer risk overall and by histotype. FDR was used to account for multiple testing. Results: Overall, higher levels of insulin-like growth factor (IGF)-1 [RRquartile 4 vs. 1 = 0.73; 95% confidence interval (CI), 0.60–0.87; P-trend = 0.002/FDR = 0.04], HbA1c (RRquartile 4 vs. 1 = 0.74; 95% CI, 0.62–0.89; P-trend = 0.002/FDR = 0.04), and alanine aminotransferase (RRquartile 4 vs. 1 = 0.76; 95% CI, 0.63–0.91; P-trend = 0.002/FDR = 0.04) were significantly associated with lower ovarian cancer risk. When stratified by histotype, higher IGF1 levels were associated with lower risk of serous (RRquartile 4 vs. 1 = 0.73; 95% CI, 0.58–0.91; P-trend = 0.01/FDR = 0.20) and clear cell tumors (RRquartile 4 vs. 1 = 0.18; 95% CI, 0.07–0.49; P-trend = 0.001/FDR = 0.02), and higher HbA1c levels were associated with lower risk of serous tumors (RRquartile 4 vs. 1 = 0.73; 95% CI, 0.59–0.90; P-trend = 0.004/FDR = 0.08). Conclusions: We observed that higher levels of circulating IGF1, HbA1c, and alanine aminotransferase were associated with lower ovarian cancer risk. Impact: These results suggest metabolism of glucose/amino acid and insulin/IGF1 signaling pathway may be contributing to ovarian carcinogenesis. Further research is needed to replicate our findings and elucidate how systemic changes in metabolism impact ovarian carcinogenesis.

Identifying Neighborhoods with Cervical Cancer Disparities for Targeted Community Outreach and Engagement by an NCI-Designated Cancer Center: A Geospatial Approach

Abstract Background: Cervical cancer disparities exist in the United States with the highest incidence in Hispanic women and the highest mortality in Black women. Effective control of cervical cancer in the population requires targeted interventions tailored to community composition in terms of race, ethnicity, and social determinants of health (SDOH). Methods: Using cancer registry and SDOH data, geospatial hot spot analyses were carried out to identify statistically significant neighborhood clusters with high numbers of cervical cancer cases within the catchment area of an NCI-Designated Cancer Center. The locations, racial and ethnic composition, and SDOH resources of these hot spots were used by the center's community outreach and engagement office to deploy mobile screening units (MSU) for intervention in communities with women facing heightened risk for cervical cancer. Results: Neighborhood hot spots with high numbers of cervical cancer cases in south Florida largely overlap with locations of poverty. Cervical cancer hot spots are associated with a high percentage of Hispanic cases and low SDOH status, including low income, housing tenure, and education attainment. Conclusions: A geospatially referenced cancer surveillance platform integrating cancer registry, SDOH, and cervical screening data can effectively identify targets for cervical cancer intervention in neighborhoods experiencing disparities. Impact: Guided with a data-driven surveillance system, MSUs proactively bringing prevention education and cervical screening to communities with more unscreened, at-risk women are an effective means for addressing disparities associated with cervical cancer control.

DNA Methylation Profiles of Ovarian Clear Cell Carcinoma

Abstract Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P &lt; 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P &lt; 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P &lt; 10−4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P &lt; 10−6). Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Cost-effectiveness of Human Papillomavirus Self-collection Intervention on Cervical Cancer Screening Uptake among Underscreened U.S. Persons with a Cervix

Abstract Background: We evaluate the cost-effectiveness of human papillomavirus (HPV) self-collection (followed by scheduling assistance for those who were HPV+ or inconclusive) compared with scheduling assistance only and usual care among underscreened persons with a cervix (PWAC). Methods: A decision tree analysis was used to estimate the incremental cost-effectiveness ratios (ICER), or the cost per additional PWAC screened, from the Medicaid/state and clinic perspectives. A hypothetical cohort represented 90,807 low-income, underscreened individuals. Costs and health outcomes were derived from the MyBodyMyTest-3 randomized trial except the usual care health outcomes were derived from literature. We performed probabilistic sensitivity analyses (PSA) to evaluate model uncertainty. Results: Screening uptake was highest in the self-collection alternative (n = 65,721), followed by the scheduling assistance alternative (n = 34,003) and usual care (n = 18,161). The self-collection alternative costs less and was more effective than the scheduling assistance alternative from the Medicaid/state perspective. Comparing the self-collection alternative with usual care, the ICERs were $284 per additional PWAC screened from the Medicaid/state perspective and $298 per additional PWAC screened from the clinic perspective. PSAs demonstrated that the self-collection alternative was cost-effective compared with usual care at a willingness-to-pay threshold of $300 per additional PWAC screened in 66% of simulations from the Medicaid/state perspective and 58% of simulations from the clinic perspective. Conclusions: Compared with usual care and scheduling assistance, mailing HPV self-collection kits to underscreened individuals appears to be cost-effective in increasing screening uptake. Impact: This is the first analysis to demonstrate the cost-effectiveness of mailed self-collection in the United States.

CanRisk Tool—A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants

Abstract Background: The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. Methods: The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. Results: This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. Conclusions: The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. Impact: There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.

Pre- and Post-Diagnosis Diet Quality and Ovarian Cancer Survival

Abstract Background: Prior studies evaluating diet quality in relation to ovarian cancer survival are sparse, and to date none have assessed diet quality or diet-quality change after diagnosis. Methods: In the prospective Ovarian cancer Prognosis And Lifestyle (OPAL) study, diet-quality scores were calculated using data from food frequency questionnaires completed pre-diagnosis (n = 650) and 12 months' post-diagnosis (n = 503). We used Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between diet quality and survival. Results: During the median follow-up of 4.4 years, 278 women died from ovarian cancer. There was no evidence of an association between diet quality pre- or post-diagnosis and progression-free, overall, or ovarian cancer–specific survival. No survival advantage was observed for women who had either improved their diet quality or who consumed a high-quality diet both before and 12 months after diagnosis. Conclusions: Higher pre- and post-diagnosis diet quality was not associated with better survival outcomes in this cohort of women with ovarian cancer. Impact: Diet quality is important for a range of health outcomes but may not improve survival after a diagnosis of ovarian cancer.

Biomarkers and Strategies for Early Detection of Ovarian Cancer

Abstract Early detection of ovarian cancer remains an important unmet medical need. Effective screening could reduce mortality by 10%–30%. Used individually, neither serum CA125 nor transvaginal sonography (TVS) is sufficiently sensitive or specific. Two-stage strategies have proven more effective, where a significant rise above a woman's baseline CA125 prompts TVS and an abnormal sonogram prompts surgery. Two major screening trials have documented that this strategy has adequate specificity, but sensitivity for early-stage (I–II) disease must improve to have a greater impact on mortality. To improve the first stage, different panels of protein biomarkers have detected cases missed by CA125. Autoantibodies against TP53 have detected 20% of early-stage ovarian cancers 8 months before elevation of CA125 and 22 months before clinical diagnosis. Panels of autoantibodies and antigen–autoantibody complexes are being evaluated with the goal of detecting &gt;90% of early-stage ovarian cancers, alone or in combination with CA125, while maintaining 98% specificity in control subjects. Other biomarkers, including micro-RNAs, ctDNA, methylated DNA, and combinations of ctDNA alterations, are being tested to provide an optimal first-stage test. New technologies are also being developed with greater sensitivity than TVS to image small volumes of tumor. See all articles in this CEBP Focus section, “NCI Early Detection Research Network: Making Cancer Detection Possible.”

Risks of Second Primary Gynecologic Cancers following Ovarian Cancer Treatment in Asian Ethnic Subgroups in the United States, 2000–2016

Abstract Background: The differential occurrence of second primary cancers by race following ovarian cancer is poorly understood. Our objective was to determine the incidence of second primary gynecologic cancers (SPGC) following definitive therapy for ovarian cancer. Specifically, we aimed to determine differences in SPGC incidence by Asian ethnic subgroups. Methods: We identified 27,602 women ages 20 years and older and diagnosed with first primary epithelial ovarian cancer between 2000 and 2016 who received surgery and chemotherapy in 18 population-based Surveillance, Epidemiology and End Results Program registries. We compared the incidence of SPGC with expected incidence rates in the general population of women using estimated standardized incidence ratios (SIR) and 95% confidence intervals (CI). Results: The incidence of SPGC was lower among White women (SIR = 0.73; 95% CI, 0.59–0.89), and higher among Black (SIR = 1.80; 95% CI, 0.96–3.08) and Asian/Pacific Islander (API) women (SIR = 1.83; 95% CI, 1.07–2.93). Increased risk of vaginal cancers was observed among all women, although risk estimates were highest among API women (SIR = 26.76; 95% CI, 5.52–78.2) and were also significant for risk of uterine cancers (SIR = 2.53; 95% CI, 1.35–4.33). Among API women, only Filipinas had significantly increased incidence of SPGC overall including both uterine and vaginal cancers. Conclusions: Risk of SPGC following treatment of ovarian cancer differs by race and ethnicity, with Filipina women having the highest rates of second gynecologic cancers among Asian women. Impact: Ensuring access and adherence to surveillance may mitigate ethnic differences in the early detection and incidence of second gynecologic cancers.

Estrogen Receptor-β Expression of Ovarian Tumors and Its Association with Ovarian Cancer Risk Factors

Abstract Background: Differential associations between ovarian cancer risk factors and estrogen receptor-α (ERα) ovarian tumor expression have been noted; however, no research has assessed estrogen receptor-β (ERβ) expression. Thus, in exploratory analyses, we assessed the association of several factors with ovarian cancer risk by ERβ tumor status. Methods: We conducted a nested case–control study within the prospective Nurses' Health Study cohorts (NHS/NHSII), with exposures collected through biennial questionnaires. Paraffin-embedded tumor blocks were requested for cases diagnosed from 1976 to 2006 (NHS) and 1989 to 2005 (NHSII) and tissue microarrays were stained for nuclear ERβ (ERβ-nuc) and cytoplasmic ERβ (ERβ-cyto), with any staining considered positive (+). We obtained odds ratios (OR) and 95% confidence intervals (CI) using multivariate polytomous logistic regression. Results: We included 245 cases [43% ERβ-cyto (+) and 71% ERβ-nuc (+)] and 1,050 matched controls. An inverse association was observed between parity and risk of ERβ-nuc (+) (OR, parous vs. nulliparous: 0.46; 95% CI, 0.26–0.81), but not ERβ-nuc (–) tumors (OR, parous vs. nulliparous: 1.51; 95% CI, 0.45–5.04; Pheterogeneity = 0.04). Conversely, parity was inversely associated with ERβ-cyto (–) tumors (OR, parous vs. nulliparous: 0.42; 95% CI, 0.23–0.78), but was not associated with ERβ-cyto (+) tumors (OR, parous vs. nulliparous: 1.08; 95% CI, 0.45–2.63; Pheterogeneity = 0.05). Associations for other exposures, including hormone therapy, did not differ by ERβ-nuc or ERβ-cyto status. Conclusions: Our results suggest that parity may influence ovarian cancer risk, in part, through alterations in ERβ localization within tumor cells. Impact: Alterations in ERβ expression and localization appear to be important for ovarian cancer etiology. Future research should confirm our results and assess potential biologic mechanisms for the observed associations.

Dietary and Circulating Fatty Acids and Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition

AbstractBackground:Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer.Methods:Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case–control analysis.Results:A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 = 1.29; 95% confidence interval (CI) = 1.03–1.62; Ptrend = 0.02, q-value = 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 = 1.10; 95% CI = 1.01–1.21; Ptrend = 0.03) and n-3 α-linolenic acid (HRQ5-Q1 = 1.18; 95% CI = 1.05–1.34; Ptrend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 = 1.39; 95% CI = 0.99–1.94; Ptrend = 0.06) and α-linolenic acids (ORT3-T1 = 1.30; 95% CI = 0.98–1.72; Ptrend = 0.06).Conclusions:Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer.Impact:If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.

Scratching Below the Ovarian Cancer GWAS Surface

Abstract Despite recent notable treatment advancements, ovarian cancer survival rates remain poor, with about half of women surviving five years after diagnosis. Uncovering novel prognostic factors is critical to better understand and reduce mortality from this deadly disease. While genome-wide association studies have identified numerous loci associated with risk of epithelial ovarian cancer, the investigation of genetic factors associated with outcomes among women with ovarian cancer has been limited due to several challenges summarized in the present commentary. Using data from the Ovarian Cancer Association Consortium, Quinn and colleagues conducted a genome-wide association study of patients with ovarian cancer receiving debulking surgery and standard chemotherapy as first-line treatment, revealing a locus at 12q24.33 associated with progression-free survival. Experimental evidence suggests that ULK1, a gene coding for a serine/threonine kinase implicated in autophagy, is the target of the association. We discuss the novelty of these findings, unanswered questions, and next steps for the road ahead in translating the work of Quinn and colleagues into clinical practice. See related article by Quinn et al., p. 1669

Association of Anti-Mullerian Hormone, Follicle-Stimulating Hormone, and Inhibin B with Risk of Ovarian Cancer in the Janus Serum Bank

Abstract Background: Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk. Methods: Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II). Results: Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14–3.39; Ptrend = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04–9.23; Ptrend = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05–7.38). AMH was not associated with ovarian cancer risk. Conclusions: FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes. Impact: Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.

The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer

Abstract Background: Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures. Methods: Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing gene-expression profiles of paired microdissected ovarian tumor and stroma. Results: Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11–1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content. Conclusions: Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important. Impact: Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.

Process Mapping to Compare and Improve Management of Abnormal Cervical Cancer Screening Results in Two US Healthcare Systems within the PROSPR Consortium

Abstract Background: Guidelines for management of abnormal cervical cancer screening results have increased in complexity over the past two decades. Little is known about how patient-, clinician-, and organization-level factors influence implementation when guidelines change. Process mapping may offer insights into organizational processes and facilitate visualization for potential intervention opportunities. Methods: We conducted an iterative multimodal qualitative assessment to compare abnormal cervical cancer screening management between two health systems: a safety-net institution and an integrated health system. We interviewed clinicians and staff to generate (phase I, May 2019–March 2021) and validate (phase II, July–Oct 2022) process maps at both systems. We conducted a rapid and thematic content analysis and engaged clinical and nonclinical stakeholders during interpretation. Results: At both health systems, process maps informed by phase I participants (n = 31) identified a gap in care during patients’ transition back to primary care following resolution of abnormal tests by gynecologists. In phase II, participants (n = 21) validated and revised maps, noting guideline updates and quality improvement initiatives. Although each system deployed unique strategies to address gaps in care, strategies in common included creating electronic health record–based clinical decision support tools, enabling gynecologists to provide real-time e-consults to primary care clinicians, and engaging patients via the portal. Conclusions: The complexity of cervical cancer screening management guidelines elevates the importance of identifying system-level tools to support clinician decision-making and coordinate between primary and specialty care teams. Impact: Process maps are valuable in generating cross-system comparisons by documenting clinical workflows, identifying care gaps, and engaging participants in formulating potential interventions.

Associations between Parity, History of Breastfeeding, and T-cell Profile of Ovarian Tumors

Abstract Background: Parity and breastfeeding are associated with systemic changes in maternal inflammation and reduced risk of ovarian cancer, but little is known about their impact on the ovarian tumor immune microenvironment. Methods: We evaluated the associations of self-reported parity and history of breastfeeding with tumor-infiltrating T cells among 1,706 ovarian carcinoma cases with tumor tissue collected across four studies. The abundance of tumor-infiltrating T cells was measured by multiplex immunofluorescence in tumor tissue microarrays. ORs and 95% confidence intervals (CI) for the positivity of tumor immune cells were calculated using beta-binomial models and stratified by histotype. Results: Compared with ovarian tumors in nulliparous women, there was no association between parity and ovarian tumor T-cell abundance among all histotypes combined but suggestion of increased cytotoxic T cells and T-cell exhaustion among parous women with clear-cell tumors. When restricted to parous women, history of breastfeeding was associated with increased odds for all T-cell types [i.e., total T, cytotoxic T, helper T (Th), regulatory T, and exhausted T cells], with ORs ranging from 1.11 to 1.42. For every 6 months of breastfeeding, we observed increased odds of activated Th-cell infiltration (CD3+CD4+CD69+; OR, 1.13, 95% CI, 0.99–1.29), with a similar association for high-grade serous tumors, but lower odds in clear-cell tumors (OR, 0.43, 95% CI, 0.21–0.87). Conclusions: History of breastfeeding may alter the ovarian tumor immune microenvironment by modulating the abundance of tumor-infiltrating T cells. Impact: Although replication is required, history of breastfeeding may play a role in the activation of the ovarian tumor immune response.

Extended HPV Genotyping to Compare HPV Type Distribution in Self- and Provider-Collected Samples for Cervical Cancer Screening

Abstract Background: Primary high-risk human papillomavirus (hr-HPV) testing of self-collected cervico-vaginal swabs could increase cervical cancer screening coverage, although triage strategies are needed to reduce unnecessary colposcopies. We evaluated the use of extended hr-HPV genotyping of self-collected samples for cervical cancer screening. Methods: We recruited women ages 25–65 years at two colposcopy clinics in North Carolina between November 2016 and January 2019, and obtained self-collected cervico-vaginal samples, provider-collected cervical samples, and cervical biopsies from all enrolled women. Self- and provider-collected samples were tested for 14 hr-HPV genotypes using the Onclarity Assay (Becton Dickinson). We calculated hr-HPV genotype–specific prevalence and assessed agreement between results in self- and provider-collected samples. We ranked the hr-HPV genotypes according to their positive predictive value (PPV) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+). Results: A total of 314 women participated (median age, 36 years); 85 women (27%) had CIN2+. More women tested positive for any hr-HPV on self-collected (76%) than on provider-collected samples (70%; P = 0.009) with type-specific agreement ranging from substantial to almost perfect. HPV-16 was the most common genotype in self-collected (27%) and provider-collected samples (20%), and HPV-16 prevalence was higher in self- than provider-collected samples (P &lt; 0.001). In self- and provider-collected samples, HPV-16 had the highest PPV for CIN2+ detection. Conclusions: Overall sensitivity for CIN2+ detection was similar for both sample types, but the higher HPV-16 prevalence in self-collected samples could result in increased colposcopy referral rates. Impact: Additional molecular markers might be helpful to improve the triage of women who are hr-HPV positive on self-collected samples.

Impact and Cost-Effectiveness of Human Papillomavirus Vaccination Campaigns

Abstract Background: Data to inform evidence-based policy of human papillomavirus (HPV) vaccine delivery strategies in low- and middle-income countries are limited. We examined the cost-effectiveness of campaign compared with routine delivery strategies of adolescent female HPV vaccination in Uganda. Methods: We used a multiple modeling approach that captured HPV transmission, cervical carcinogenesis, and population demographics to project health and economic outcomes associated with HPV vaccination. Costs included vaccination and operational costs and cervical cancer costs over the lifetimes of the current female population in Uganda. Health outcomes included number of cervical cancer cases and disability-adjusted life years (DALY). Incremental cost-effectiveness ratios (i.e., cost per DALY averted) were calculated and compared against gross domestic product (GDP) per capita. Results: Compared with routine HPV vaccination of 9-year-old girls at 70% coverage, campaign vaccination yielded greater health benefits if campaigns occurred frequently and targeted a wide age range. Campaign delivery strategies were both less costly and more effective than routine HPV vaccination. Campaign vaccination of 9- to 30-year-old girls/women at a 3-year frequency (40% coverage) was considered cost-effective compared with the GDP per capita threshold for Uganda ($674 in U.S. 2015 dollars). Conclusions: We projected that campaign HPV vaccination would provide substantial population health benefits compared with routine vaccination. Expanding the target age range of campaign vaccination up to age 30 years may be an efficient strategy, depending on the achievable coverage level and campaign frequency. Impact: In settings where routine health systems infrastructure may be limited, reaching adolescent populations with a campaign delivery strategy may be an efficient use of resources.

Exposure Definition in Case–Control Studies of Cervical Cancer Screening: A Systematic Literature Review

Abstract The first step in evaluating the effectiveness of cervical screening is defining exposure to screening. Our aim was to describe the spectrum of screening exposure definitions used in studies of the effectiveness of cervical screening. This systematic review included case-control studies in a population-based screening setting. Outcome was incidence of cervical cancer. Three electronic databases were searched from January 1, 2012 to December 6, 2018. Articles prior to 2012 were identified from a previous review. The qualitative synthesis focused on describing screening exposure definitions reported in the literature and the methodologic differences that could have an impact on the association between screening and cervical cancer. Forty-one case–control studies were included. Six screening exposure definitions were identified. Cervical cancer risk on average decreased by 66% when screening exposure was defined as ever tested, by 77% by time since last negative test, and by 79% after two or more previous tests. Methodologic differences included composition of the reference group and whether diagnostic and/or symptomatic tests were excluded from the analysis. Consensus guidelines to standardize exposure definitions are needed to ensure evaluations of cervical cancer screening can accurately measure the impact of transitioning from cytology to human papillomavirus–based screening and to allow comparisons between programs.

Cancer Incidence in Migrants in Australia: Patterns of Three Infection-Related Cancers

Abstract Background: Australia provides an ideal population-base for cancer migration studies because of its multicultural society and high-quality cancer registrations. Among migrant groups there is considerable variability in the incidence of infection-related cancers; thus, the patterns of three such cancers were examined among migrant groups relative to Australian-born residents. Methods: Using national incidence data for cancers of the stomach, liver, and cervix diagnosed during 2005 to 2014, incidence rates were compared for selected migrant groups with the Australian-born population using incidence rate ratios (IRR), from a negative binomial regression model. Results: Wide variations in incidence between countries/regions of birth were observed for all three cancers (P &lt; 0.0001). The patterns were similar for cancers of the stomach and liver, in that migrants from countries/regions with higher incidence rates maintained an increased risk in Australia, with the highest being among South American migrants (IRR = 2.35) for stomach cancer and among Vietnamese migrants (5.44) for liver cancer. In contrast, incidence rates of cervical cancer were lower for many migrant groups, with women from Southern Asia (0.39) and North Africa (0.42) having the lowest rates. The rate of cervical cancer was higher in migrants from New Zealand, Philippines, and Polynesia. Conclusions: Several Australian migrant groups were found to experience a disproportionate burden of infection-related cancers; further studies of associated risk factors may inform the design of effective interventions to mediate these disparities. Impact: By identifying these migrant groups, it is hoped that these results will motivate and inform prevention or early detection activities for these migrant groups. See related commentary Dee and Gomez, p. 1251

Adverse Urinary System Outcomes among Older Women with Endometrial Cancer

Purpose of the study: Endometrial cancer and its treatment may cause damage to the urinary system, but few large-scale studies have examined the incidence of urinary-related outcomes among endometrial cancer survivors. We investigated the risk of several urinary disease diagnoses among older women with endometrial cancer compared to women without a cancer history. Methods: Women ages 66 years and older with an endometrial cancer diagnosis during 2004-2017 (N=44,386) and women without a cancer history (N=221,219) matched 5:1 on age, race/ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to identify urinary outcomes in the Medicare claims data. Cumulative incidences (IP) of urinary outcomes were estimated among women with and without endometrial cancer. Multivariable Cox proportional hazards regression models were used to estimate hazards ratios (HR) for urinary outcomes comparing women with and without endometrial cancer. HRs were also used to identify characteristics associated with urinary outcomes among endometrial cancer survivors. Results: Relative to women without cancer, endometrial cancer survivors had an increased risk of urinary system diagnoses, including renal failure (5-year IP: 25% vs 14%; HR=1.50; 95% CI: 1.47-1.53), chronic kidney disease (5-year IP: 20% vs 14%; HR=1.25; 95% CI: 1.22-1.28), calculus of the urinary tract (5-year IP: 7% vs 4%; HR=1.55; 95% CI: 1.50-1.61), lower urinary tract infection (5-year IP: 55% vs 33%; HR=1.75; 95% CI: 1.72, 1.78), and bladder diseases (5-year IP: 10% vs 6%; HR=1.57; 95% CI: 1.52, 1.62). These associations persisted in analyses limited to 1+ and 5+ years after endometrial cancer diagnosis. Non-Hispanic Black or Hispanic race/ethnicity, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often predictors of urinary outcomes among women with endometrial cancer. Conclusions: Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer. Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history.

Breast Density Changes after Risk-Reducing Salpingo-oophorectomy in Women with a Pathogenic Germline Variant in BRCA1 or BRCA2

Abstract Background: We studied changes in mammographic density (MD) among premenopausal women with a pathogenic germline variant (PGV) in the BRCA1 or BRCA2 gene, comparing those who did and did not undergo risk-reducing salpingo-oophorectomy (RRSO) in the interval between mammograms, accounting for changes in exogenous oral contraceptive or hormone replacement therapy (HRT) use. Methods: From five studies of the International BRCA1/2 Carrier Cohort Study consortium, we included 691 participants who had two or more screening mammograms available, were less than 47 years at the time of RRSO (N = 208), or premenopausal at all mammograms without RRSO (N = 483). MD metrics [percent density (PD), dense area (DA), and non-DA] were quantified using STRATUS. Multivariable linear mixed models assessed changes in MD metrics between groups, adjusting for confounders. Results: The mean PD at first mammogram was 26.8% ± 15.3 (RRSO) and 31.3% ± 18.1 (no RRSO). In a median 1.1 years between mammograms, PD decreased on average by 0.9% [95% confidence interval (CI), −1.6 to −0.2] among women who did not undergo RRSO in the interval between mammograms compared with 5.9% (95% CI, −7.4 to −4.5) among women who underwent RRSO in the interval (adjusted difference, −5.9%; 95% CI, −9.5 to −2.2; P = 0.002). Results were driven primarily by MD changes among BRCA2 PGV carriers. The use of HRT after RRSO attenuated the decline in PD. Conclusions: On average, PD and DA decrease following RRSO in premenopausal carriers, particularly among BRCA2 PGV carriers. HRT formulation affects MD changes. Impact: A decrease in MD may inform the potential protective effect of RRSO against breast cancer.

Causal Effects of Breast Cancer Risk Factors across Hormone Receptor Breast Cancer Subtypes: A Two-Sample Mendelian Randomization Study

Abstract Background: It is unclear if established breast cancer risk factors exert similar causal effects across hormone receptor breast cancer subtypes. We estimated and compared causal estimates of height, body mass index (BMI), type 2 diabetes, age at menarche, age at menopause, breast density, alcohol consumption, regular smoking, and physical activity across these subtypes. Methods: We used a two-sample Mendelian randomization approach and selected genetic instrumental variables from large-scale genome-wide association studies. Publicly available summary-level Breast Cancer Association Consortium data (n = 247,173; 133,384 cases, 113,789 controls) for the following subtypes were included: luminal A–like (45,253 cases), luminal B–/HER2-negative–like (6,350 cases), luminal B–like (6,427 cases), HER2-enriched (2,884 cases), and triple-negative (8,602 cases). We employed multiple Mendelian randomization methods to evaluate the strength of causal evidence for each risk factor–subtype association. Results: Collectively, our analyses indicated that increased height and decreased BMI are probable causal risk factors for all five subtypes. For the other risk factors, the strength of evidence for causal effects differed across subtypes. Heterogeneity in the magnitude of causal effect estimates for age at menopause and breast density was explained by null findings for triple-negative tumors. Regular smoking was the sole risk factor for which there was no evidence of a causal effect on any subtype. Conclusions: This study suggests that established breast cancer risk factors differ across hormone receptor subtypes. Impact: Our results are valuable for the development of primary prevention strategies, improvement of breast cancer risk stratification in the general population, and identification of novel breast cancer risk factors.

Cancer Epidemiology, Biomarkers & Prevention

Papers (140)

Publisher

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Cancer Epidemiology, Biomarkers &amp; Prevention

Papers (140)

Publisher

ISSN

Cancer Epidemiology, Biomarkers & Prevention