Cancer Prevention Research

Effects of Message Framing on Cervical Cancer Screening Knowledge and Intentions Related to Primary HPV Testing

Abstract Numerous national guidelines now include primary human papillomavirus (HPV) testing as a recommended screening option for cervical cancer in the United States yet little is known regarding screening intentions for this specific screening strategy or interventions that may increase uptake. Gain- and loss-framed messaging can positively impact health behaviors; however, there is mixed evidence on which is more effective for cervical cancer screening, with no published evidence examining HPV testing. To help address this gap, this study compared the effects of message framing on screening knowledge and intentions related to primary HPV testing. We randomized females aged 21–65 (n = 365) to receive brief messaging about cervical cancer screening with either gain- or loss-framing. In January–February 2020, participants completed pretest and posttest measures evaluating cervical cancer knowledge, beliefs, and intentions to be screened using HPV testing. We used generalized estimating equations to model message and framing effects on screening outcomes, controlling for age, education, race, and baseline measures. In comparison to pretest, messaging significantly increased HPV-related screening intentions [adjusted OR (aOR): 2.4 (1–3.5)] and knowledge [aOR: 1.7 (1.2–2.4)], perceived effectiveness of HPV testing [aOR: 4.3 (2.8–6.5)], and preference for primary HPV screening [aOR: 3.2 (1.2–8.5)], regardless of message framing. For all outcomes, no significant interaction by message framing was observed. Brief public health messaging positively impacted HPV-related screening intentions, knowledge, and beliefs, independent of message framing. In conjunction with other strategies, these results suggest that messaging could be an effective tool to increase uptake of primary HPV testing. Prevention Relevance: Primary HPV tests are more sensitive and offer greater reassurance than Pap tests alone yet use for routine cervical cancer screening remains low. Brief public health messaging can positively impact awareness, knowledge, and screening intention regarding primary HPV testing. Messaging campaigns paired with other strategies can increase uptake across populations. See related Spotlight, p. 823

The Surge in Human Papillomavirus Vaccine Rejection in Nigeria

Abstract In October 2023, Nigeria integrated the single-dose human papillomavirus (HPV) vaccine into its routine immunization program, aiming to protect 7.7 million girls aged 9 to 14 years. This milestone in the fight against HPV-related cancers, especially cervical cancer, faces significant challenges due to high vaccine rejection rates driven by misinformation and cultural barriers. Despite the vaccine’s proven safety and efficacy, uptake remains low. This communication highlights the urgent need for a comprehensive public health education campaign to address these barriers. Proposed strategies include leveraging digital health technologies, integrating HPV education into school curricula, training community health workers, engaging religious and cultural leaders, and launching media campaigns featuring personal narratives. Implementing these evidence-based interventions is crucial for dispelling myths, misconceptions, and skepticism surrounding HPV vaccines. This will enhance acceptance and uptake, ultimately reducing cervical cancer mortality in Nigeria.

Risk Factors for Recurrence in Patients with Atypical Endometrial Hyperplasia and Endometrioid Adenocarcinoma after Fertility-Sparing Treatments

Abstract The aim of this work was to evaluate the risk factors for recurrence in young patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma after fertility-sparing treatments (FST). A retrospective case–control study was designed. Patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma who received FSTs from January 2010 to December 2017 were reviewed. All patients who met the inclusion criteria were divided into a recurrence group and a control group. Risk factors for recurrence- and disease-free survival were evaluated by logistic regression analysis and Cox regression analysis. A total of 127 patients were included, 53 patients in the recurrence group and 74 patients in the control group. No deaths occurred during the follow-up time. The rate of successful pregnancy was 62.5% in the control group and 20.5% in the recurrence group after complete remission (CR) of the primary disease. In a multivariate regression model, after adjusting for other factors, menstruation cycle, progestin type, and regular maintenance treatments after CR were the main risk factors for disease recurrence. Gonadotropin-releasing hormone agonist was mainly used to treat obese patients and was associated with longer progression-free survival (PFS) time compared with that in patients who received high-dose oral progestin such as megestrol acetate [risk ratio (RR), 2.158; 95% confidence interval (CI), 0.948–4.913]. Regular oral progestin also significantly prolonged the PFS time (RR, 4.726; 95% CI, 2.672–8.359). The progestin type used in treatment and regular maintenance treatment of young patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma after CR might be correlated with disease recurrence.

Progestin Significantly Inhibits Carcinogenesis in the Mogp-TAg Transgenic Mouse Model of Fallopian Tube Cancer

Abstract Recent studies suggest that the fallopian tube epithelium (FTE) harbors the precursor for high-grade ovarian cancer, creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE is not well characterized. The murine oviduct–specific glycoprotein promotor-driven simian virus 40 large T-Antigen (mogp-TAg) transgenic mouse model develops neoplastic lesions in the fallopian tube in a manner similar to that described in human fallopian tube and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin depo-medroxyprogesterone acetate (DMPA) on fallopian tube carcinogenesis following treatment for 3 and 7 weeks in 5-week-old mogp-TAg mice. Overall, compared with vehicle-treated mice, the fallopian tube of DMPA-treated mice was significantly smaller (P < 0.0005), accumulated fewer p53-positive cells, had normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and had a significantly lower proliferative index (P = 0.001). Accumulation of p53 signatures and serous tubal intraepithelial carcinomas (STIC) in the fallopian tube was significantly reduced in the DMPA (P < 0.0005) treatment group. Moreover, the fallopian tube of the DMPA-treated mice developed significantly less adenocarcinoma compared with vehicle (P < 0.005) at both treatment time points. DMPA treatment significantly induced cleaved caspase-3 (P < 0.0005) in the FTE compared with vehicle suggesting that apoptosis is involved in DMPA-related clearance of abnormal cells from the fallopian tube. These data demonstrate that DMPA targets early events in fallopian tube carcinogenesis by clearing genetically damaged cells, leading to marked reduction in adenocarcinoma, supporting progestins as chemopreventive agents for fallopian tube and ovarian cancers. Prevention Relevance: The fallopian tube is thought to harbor the cell of origin for most ovarian cancers. We show in a mouse model of fallopian tube cancer that progestin eradicates the earliest known precancerous lesions and markedly inhibits fallopian tube carcinogenesis, adding to growing preclinical evidence supporting progestins as potent ovarian cancer chemopreventive agents.

Multiyear Clinical Outcomes of Cancers Diagnosed Following Detection by a Blood-Based Multicancer Early Detection Test

Abstract In the US, <20% of cancers are diagnosed by standard-of-care (SoC) screening. Multicancer early detection (MCED) tests offer the opportunity to expand cancer screening. Understanding the characteristics and clinical outcomes of MCED-detected cancers is critical to clarifying MCED tests’ potential impact. DETECT-A is the first prospective interventional trial of an MCED blood test (CancerSEEK). CancerSEEK, coupled with diagnostic PET-CT, identified cancers including those not detected by SoC screening, the majority of which were localized or regional. We report multiyear outcomes in patients with cancers diagnosed following a positive CancerSEEK test. Nine cancer types were diagnosed in 26 participants whose cancers were first detected by CancerSEEK. Information on cancer diagnoses, treatments, and clinical outcomes was extracted from medical records through November 2022. Data collection occurred at a median of 4.4 years (IQR: 4.1–4.6) following study enrollment. Thirteen of 26 (50%) participants were alive and cancer-free [ovarian (4), thyroid (1), uterine (2), breast (1), colorectal (2), and lung (3)]; 7/13 (54%) had cancers without recommended SoC screening modalities. All eight treated stage I or II participants (8/8, 100%) and 12/14 (86%) surgically treated participants were alive and cancer-free. Eligibility for surgical treatment was associated with favorable multiyear outcomes (P = 0.0002). Half of participants with MCED-detected cancers were alive and cancer-free after 4.4 years median follow-up. Most were diagnosed with early-stage cancers and were treated surgically. These results suggest that early cancer detection by CancerSEEK may have facilitated curative-intent treatments and associated positive clinical outcomes in some DETECT-A participants. Prevention Relevance: This study provides preliminary evidence of the potential of multicancer early detection testing as an effective screening tool for detecting cancers without standard-of-care (SoC) screening modalities and complementing SoC cancer screening.

Assessment of and Interventions for Women at High Risk for Breast or Ovarian Cancer: A Survey of Primary Care Physicians

Abstract As clinical guidelines for cancer prevention refer individuals to primary care physicians (PCP) for risk assessment and clinical management, PCPs may be expected to play an increasing role in cancer prevention. It is crucial that PCPs are adequately supported to assess an individual’s cancer risk and make appropriate recommendations. The objective of this study is to assess use, familiarity, attitude, and behaviors of PCPs regarding breast and ovarian cancer risk and prevention, to better understand the factors that influence their prescribing behaviors. We conducted a cross-sectional, web-based survey of PCPs in the United States, recruited from an opt-in healthcare provider panel. Invitations were sent in batches until the target sample size of 750 respondents (250 each for obstetrics/gynecology, internal medicine, and family medicine) was met. Self-reported use of breast/ovarian cancer risk assessments was low (34.7%–59.2%) compared with discussion of cancer family history (96.9%), breast exams (87.1%), and mammograms (92.8%). Although most respondents (48.0%–66.8%) were familiar with cancer prevention interventions, respondents who reported to be less familiar were more likely to report cautious attitudes. When presented with hypothetical cases depicting patients at different breast/ovarian cancer risks, up to 34.0% of respondents did not select any of the clinically recommended course(s) of action. This survey suggests that PCP use of breast/ovarian cancer risk assessment tools and ability to translate the perceived risks to clinical actions is variable. Improving implementation of cancer risk assessment and clinical management guidelines within primary care may be necessary to improve the appropriate prescribing of cancer prevention interventions. Prevention Relevance: Primary care physicians are becoming more involved in cancer prevention management, so it is important that cancer risk assessment and medical society guideline recommendations for cancer prevention are better integrated into primary care to improve appropriate prescribing of cancer prevention interventions and help reduce cancer risk.

Quantifying the Effect of Physical Activity on Endometrial Cancer Risk

Abstract Endometrial cancer incidence is rising, with 435,000 global cases in 2019. An effective, low-cost primary prevention strategy is required to reduce disease burden. Obesity, insulin resistance, and inflammation contribute to endometrial carcinogenesis and physical activity targets these pathways. This study sought to quantify the amount of physical activity required to impact upon endometrial cancer risk. Physical activity data from 222,031 female participants with an intact uterus in the UK Biobank study were analyzed using a multivariable Cox proportional hazards model. A systematic review of the literature was performed, searching CENTRAL, Embase, and MEDLINE databases up to April 19, 2021. Studies including participants with and without endometrial cancer investigating the effect of physical activity measured in MET-hours/week (MET-h/week) on disease risk were included. Two reviewers independently selected studies, extracted data, and evaluated the risk of bias. Within the UK Biobank, each 1 MET-h/week increase in total physical activity was associated with a 0.2% [95% confidence interval (CI), 0.1–0.4; P = 0.020] reduction in endometrial cancer risk, equating to a 10.4% reduction if performing 50 MET-h/week or 7 hours of jogging per week. Eleven cohort and 12 case–control studies were identified in the systematic review, including 821,599 participants. One study reported a nonsignificant effect of 1 MET-h/week increases in physical activity on endometrial cancer risk (OR, 1.00; 95% CI, 0.99–1.00). Eight studies found significant reductions in disease risk of 15%–53%, but only in the most physically active individuals. Physical activity reduces endometrial cancer risk, but the effect size appears small. Regular vigorous activity should be encouraged to maximize the health benefit observed. Prevention Relevance: Effective, low-cost primary prevention strategies are urgently needed to tackle the rapid global increase in endometrial cancer. We sought to quantify the effect of physical activity on endometrial cancer risk, noting a linear inverse relationship influenced by body mass index. The most beneficial type and amount of activity remain unclear.

Comparison of Different HPV-based Strategies and Cytology in Routine Cervical Cancer Screening Programme in China: A Population-based Study

Abstract The study aimed to compare the performance of human papillomavirus (HPV)-based strategies to cytology for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in routine program in China. The study included 50,434 women ages 30–64 years from January 2015 to December 2019, to assess four strategies: cytology with HPV triage (strategy 1), primary HPV testing with reflex cytology (strategy 2), primary HPV testing with HPV-16/18 genotyping and reflex cytology for non-16–18 high-risk HPV genotypes (strategy 3), and co-testing (strategy 4). The main outcomes were sensitivity for CIN3+ and colposcopy referral rate. Overall, the rates of HPV positivity and cytologic abnormality were 7.0% [95% confidential interval (CI), 6.8–7.2] and 3.5% (95% CI, 3.3–3.6], respectively. The sensitivity for CIN3+ were 88.5% for strategy 4, 83.2% for strategy 3, 64.6% for strategy 1, and 60.1% for strategy 2. The relative sensitivity of strategy 4 and strategy 3 compared with strategy 1 for detecting CIN3+ were 1.38 (95% CI, 1.24–1.54) and 1.29 (95% CI, 1.14–1.46), respectively. The colposcopy referral rates of strategies 4 and 3 were significantly higher than that of strategy 1 (2.4% and 2.2% vs. 1.4%, P < 0.001). In conclusion, co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology improved the sensitivity for CIN3+ compared with cytology but increased the colposcopy referral rate. Long-term negative predicted value for HPV-negative women should be studied to determine the screening interval. Our study provides further evidence to the introduction of HPV-based strategies in China. Prevention Relevance: Both co-testing and primary HPV testing with HPV-16/18 genotyping and reflex cytology triage provided higher sensitivity for detecting CIN3+; however, the number of colposcopy referrals also increased compared with cytology in a routine program. It has great public health implications for the introduction of HPV-based screening strategies in China.

Catch-up HPV Vaccination and Subsequent Uptake of Papanicolaou Testing in A State-mandated Health System

Abstract The objective of this study was to evaluate the association between human papillomavirus (HPV) vaccination and uptake of initial Papanicolaou (Pap) testing in Israel among women not previously vaccinated through the national immunization program. In this retrospective cohort we used health provider records of vaccinations and cancer screening attendance among female members of a state-mandated health provider in Israel (Maccabi Healthcare Services, MHS). All eligible female members (N = 20,904) immunized with at least one dose of HPV vaccine from the date of its introduction in Israel (June 2007) until December 31, 2018 were individually matched with nonvaccinated MHS members on one to one ratio by year of birth, residential area socioeconomic level, and district of residence. Data on the uptake of Pap smears until December 2018 were extracted from MHS central datasets, and the number of Pap smears for each woman during the study period was counted. During the observed follow-up period (mean, 6.6 years; interquartile range, 3.9–8.7 year), the cumulative uptake rate of Pap testing in vaccinated women (26.8%) was significantly (P < 0.001) greater than among unvaccinated (22.4%) women. In a multivariable model, HPV vaccination was associated with an HR of 1.34 [95% confidence interval (CI), 1.29–1.41] to perform Pap testing. Our findings suggest that uptake of catch-up HPV vaccine was positively correlated to increased uptake of Pap testing. Prevention Relevance: We found that catch-up HPV vaccination was associated with increased attention to long-term cervical screening attendance. Whereas, those who are not vaccinated and unprotected from HPV, are more likely to abstain from secondary prevention screening tests too and further increase their cervical cancer risk.

Effect of Health Education on Cervical Cancer Screening Uptake and Knowledge among Target Women in Addis Ababa: A Randomized Controlled Trial

Abstract Health education can improve cervical cancer screening uptake; however, evidence from randomized controlled trials in the general population of Addis Ababa is limited. The aim of this study is to assess the effect of health education on screening uptake and knowledge among women aged 30 to 49 years in Addis Ababa, Ethiopia. A randomized controlled trial was conducted involving 1,300 women who had never been screened before. The intervention group received home-based health education about cervical cancer, supplemented by brochures. The χ2 test, independent sample t test, and paired t tests were used to assess pre- and pos-tintervention differences. The impact of the intervention was measured using the differences-in-differences approach. Three months after the intervention, 1,154 (88.8%) were interviewed. Screening uptake was significantly higher in the intervention group, with 241 (41.8%) of women screened compared with 93 (16.1%) in the control group. After the intervention, awareness increased by 42.2%, knowledge of symptoms increased by 23.1%, knowledge of risk factors increased by 15.2%, positive attitudes improved by 26.7%, and overall knowledge increased by 19.5% among the intervention group, indicating that the change is statistically significant. The differences-in-differences analysis indicated that 51% of the change in overall knowledge was due to the intervention. Age, occupation, and income were significantly associated with the uptake of screening, whereas the lack of time was a common barrier. Structured home-based education significantly increases cervical cancer knowledge and screening uptake. Scaling up home-based health education can significantly improve screening uptake. Prevention Relevance: Cervical cancer is the second leading cause of cancer-related morbidity and mortality among women in Ethiopia. Increasing awareness, improving access to screening, and promoting timely preventive interventions are critical to reducing the disease burden and increases life saving among women.

Contemporary Status and Frontiers of Cervical Cancer Screening in the United States

Abstract Cervical cancer screening and its implementation have evolved tremendously since the first method, cytology using the Papanicolaou stain, was introduced in the 1950s. New screening methods, such as human papillomavirus testing, have been discovered, and evidence-based changes have been made to official screening guidelines set forth by various US organizations. With the advent of a human papillomavirus vaccine in 2006 and with more recent research into populations carrying disparate burdens of cervical disease, the effectiveness of current cervical cancer screening programs is being called into question as the disease incidence has not decreased as expected in the past 20 years. This review highlights where cervical cancer screening in the United States started, the current clinical methods, and promising developments on the frontiers of screening research to introduce new screening options or improve current screening programs and outcomes. We also highlight certain population factors that hinder effective screening in high-risk groups, based on research aimed at ensuring that population-wide screening continues to be an effective strategy for reducing cervical cancer incidence and mortality.

The Role of Statins in the Prevention of Ovarian and Endometrial Cancers

Abstract Ovarian and endometrial cancers are the most common gynecologic malignancies and emerging evidence suggests that lipid metabolism and subsequent inflammation are important etiologic factors for both tumors. Statins (HMG-CoA reductase inhibitors) are the most widely prescribed lipid-lowering drugs in the United States and are used by 25% of adults aged 40+ years. In addition to their cardio-protective actions, statins have anti-inflammatory effects and have demonstrated antiproliferative and apoptotic properties in cancer cell lines, supporting a potential role in cancer prevention. To appropriately quantify potential public health impact of statin use for cancer prevention, there is a great need to understand the potential risk reduction among individuals at a higher risk of gynecologic cancers, the group that will likely need to be targeted to effectively balance risk/benefit of medications repurposed for cancer prevention. In this commentary, we focus on summarizing emerging evidence suggesting that the anti-inflammatory and lipid-lowering mechanisms of statins may provide important cancer-preventive benefits for gynecologic cancers as well as outline important unanswered questions and future research directions.

Determinants of Cervical Cancer Screening Acceptance among Women in Urban and Tribal Communities of Maharashtra, India: A Cross-sectional Study

Abstract Although screening, treatment, and human papillomavirus vaccination can prevent cervical cancer, 17.7% new Indian cases were still recorded in 2022. Illiteracy, undesirable attitudes, and ineffective screening services undermine the effectiveness of cervical cancer screening. We evaluated the knowledge (K), attitude (A), and practices (P) toward cervical cancer and their influence on screening acceptance among urban and tribal women of Maharashtra, India. A cross-sectional study was conducted among 500 urban and 500 tribal women, recruited to equally represent both populations. KAP data on cervical cancer were collected using a structured questionnaire. Participants received free cervical cancer screening. KAP scores were calculated, and their associations with sociodemographic factors and cervical cancer screening were assessed using logistic regression. A total of 939 participants were enrolled. Considering both populations, a total of 530 (56%) participants were unaware about cervical cancer, 296 (72%) about its symptoms, and 250 (61%) of risk factors. Common misconceptions were that only women with symptoms of cervical cancer (166, 18%) or a family history of cervical cancer (385, 41%) needed screening. Fear of pain, bad result, and embarrassment were major perceived barriers. Whereas 65 (6.85%) participants had previously undergone screening, 756 (81%) desired screening and 670 (71.40%) underwent screening. Although women had limited cervical cancer knowledge, their attitude for screening is favorable. Generating awareness and implementing socioculturally acceptable strategies are crucial for amplifying cervical cancer screening among vulnerable women. Prevention Relevance: Despite limited awareness and prevalent misconceptions about cervical cancer screening, the women expressed willingness to undergo screening following appropriate counseling. This highlights the potential for targeted educational interventions to enhance cervical cancer prevention through early detection and improving uptake of screening.

Feasibility and Acceptability of Pay-it-forward in Increasing Uptake of HPV Vaccination among 15- to 18-Year-Old Girls in China: Pilot RCT Results

Abstract China has a low human papillomavirus (HPV) vaccination rate due to limited public funding and mistrust in domestic vaccines. This pilot study aimed to evaluate the feasibility, acceptability, and preliminary effectiveness of an innovative pay-it-forward strategy to improve HPV vaccine uptake among adolescent girls. Conducted at a community health center in Western China (January 4–February 18, 2022), the study recruited 100 adolescent girls (ages 15–18 years) with no prior HPV vaccination. Participants were randomly assigned to either the standard-of-care arm (self-paid vaccines, n = 50) or the pay-it-forward arm (subsidized vaccines, handwritten postcards, and the opportunity to donate and/or write postcards, n = 50). Feasibility was assessed through recruitment, retention, and questionnaire completion rates. Acceptability and feasibility were measured using a standard scale. Preliminary effectiveness was evaluated by first-dose vaccination rate. Of 109 screened participants, 100 were eligible to participate (91.7%). The retention rate was 100% in both arms. The questionnaire completion rate was 98% (49/50) in the pay-it-forward arm and 82% (41/50) in the standard-of-care arm. Most participants self-reported that the strategy was feasible (97.6%, 41/42) and acceptable (90.5%, 38/42). Ninety-seven percent (97/100) of participants made vaccination appointments. The first-dose HPV vaccine uptake rate was 98% (49/50) in the pay-it-forward arm and 82% (41/50) in the standard-of-care arm (P < 0.05). No serious adverse events were identified. The pay-it-forward strategy was feasible and acceptable and showed preliminary effectiveness in increasing HPV vaccination uptake. Further refinement and population-based recruitment are needed to better reflect local contexts and enhance the generalizability of the formal trial. Prevention Relevance: The results of this pilot study demonstrate that the pay-it-forward strategy is both feasible and acceptable in increasing HPV vaccine uptake among 15- to 18-year-old girls. The future use of this strategy holds promise as an effective approach to enhance HPV vaccination rates that will eventually lead to a reduction in cervical cancer incidence.

Differences in Serum miRNA Profiles by Race, Ethnicity, and Socioeconomic Status: Implications for Developing an Equitable Ovarian Cancer Screening Test

Abstract Serum miRNAs are promising biomarkers for several clinical conditions, including ovarian cancer. To inform equitable implementation of these tests, we investigated the effects of race, ethnicity, and socioeconomic status on serum miRNA profiles. Serum samples from a large institutional biobank were analyzed using a custom panel of 179 miRNA species highly expressed in human serum, measured using the Abcam Fireplex assay via flow cytometry. Data were log-transformed prior to analysis. Differences in miRNA by race and ethnicity were assessed using logistic regression. Pairwise t tests analyzed racial and ethnic differences among eight miRNAs previously associated with ovarian cancer risk. Pearson correlations determined the relationship between mean miRNA expression and the social deprivation index (SDI) for Massachusetts residents. Of 1,586 patients (76.9% white, non-Hispanic), compared with white, non-Hispanic patients, those from other racial and ethnic groups were younger (41.9 years ± 13.2 vs. 51.3 ± 15.1, P < 0.01) and had fewer comorbidities (3.5 comorbidities ± 2.7 vs. 4.6 ± 2.8, P < 0.01). On logistic regression, miRNAs predicted race and ethnicity at an AUC of 0.69 (95% confidence interval, 0.66–0.72), which remained consistent when stratified by most comorbidities. Among eight miRNAs previously associated with ovarian cancer risk, seven significantly varied by race and ethnicity (all P < 0.01). There were no significant differences in SDI for any of these eight miRNAs. miRNA expression is significantly influenced by race and ethnicity, which remained consistent after controlling for confounders. Understanding baseline differences in biomarker test characteristics prior to clinical implementation is essential to ensure instruments perform comparably across diverse populations. Prevention Relevance: This study aimed to understand factors affecting miRNA expression, to ensure we create equitable screening tests for ovarian cancer that perform well in diverse populations. The goal is to ensure that we are detecting ovarian cancer cases earlier (secondary prevention) in women of all races, ethnic backgrounds, and socioeconomic means.

Knowledge Mediates the Effects of Game Changers for Cervical Cancer Prevention (GC-CCP) Intervention on Increased VIA Screening Advocacy in Uganda

Abstract Game Changers for Cervical Cancer Prevention (GC-CCP), a group advocacy training intervention, has been shown to increase cervical cancer prevention and screening advocacy. In this secondary analysis, we examined mediators and moderators of this effect. A randomized controlled trial of GC-CCP—a 7-session, peer led intervention designed to empower women to engage in cervical cancer prevention advocacy—was conducted with women who had recently been screened by visual inspection of the cervix with acetic acid for cervical cancer. Participants were assessed at baseline and month 6 follow-up. Cervical cancer–related constructs targeted by the intervention were examined as mediators using multivariate linear regression analysis. Individual and social network characteristics were examined as moderators. Change in cervical cancer knowledge fully mediated the intervention effect on increased cervical cancer prevention advocacy; change in cervical cancer risk management self-efficacy was a partial mediator. Moderators of the effect included no secondary education, having a main sex partner, and having trustworthy, supportive, non-stigmatizing peers. The effect of GC-CCP on cervical cancer prevention advocacy seems largely driven by its impact on cervical cancer knowledge, and the intervention may be most effective among women who are partnered, less educated, and have trusting, supportive social networks. Prevention Relevance: Enhancing cervical cancer knowledge among women who have screened for cervical cancer is key to empowering these women to engage in cervical cancer prevention advocacy and acting as change agents for encouraging other women to screen.

Uptake and Predictors of Opportunistic Salpingectomy for Ovarian Cancer Risk Reduction in the United States

Abstract Evidence suggesting that high-grade serous ovarian cancers originate in the fallopian tubes has led to the emergence of opportunistic salpingectomy (OS) as an approach to reduce ovarian-cancer risk. In the U.S., some national societies now recommend OS in place of tubal ligation for sterilization or during a benign hysterectomy in average-risk women. However, limited data exist on the dissemination of OS in clinical practice. We examined the uptake and predictors of OS in a nationwide sample of inpatient and outpatient claims (N = 48,231,235) from 2010 to 2017. Incidence rates of OS were calculated, and an interrupted time-series analysis was used to quantify changes in rates before (2010–2013) and after (2015–2017) national guideline release. Predictors of OS use were examined using Poisson regression. From 2010 to 2017, the age-adjusted incidence rate of OS for sterilization and OS during hysterectomy increased 17.8-fold [95% confidence interval (CI), 16.2–19.5] and 7.6-fold (95% CI, 5.5–10.4), respectively. The rapid increase (age-adjusted increase in quarterly rates of between 109% and 250%) coincided with the time of national guideline release. In multivariable-adjusted analyses, OS use was more common in young women and varied significantly by geographic region, rurality, family history/genetic susceptibility, surgical indication, inpatient/outpatient setting, and underlying comorbidities. Similar differences in OS uptake were noted in analyses limited to women with a family history/genetic susceptibility to breast/ovarian cancer. Our results highlight significant differences in OS uptake in both high- and average-risk women. Defining subsets of women who would benefit most from OS and identifying barriers to equitable OS uptake is needed. Prevention Relevance: Opportunistic salpingectomy for ovarian-cancer risk reduction has been rapidly adopted in the U.S., with significant variation in uptake by demographic and clinical factors. Studies examining barriers to opportunistic salpingectomy access and the long-term effectiveness and potential adverse effects of opportunistic salpingectomy are needed.

Common Analgesic Use for Menstrual Pain and Ovarian Cancer Risk

Abstract Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18–0.94 and OR, 0.43; 95% CI, 0.21–0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain (Pinteraction ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer. Prevention Relevance: This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.

Effect of Sequential Rounds of Cervical Cancer Screening on Management of HPV-positive Women: A 15-year Population-based Cohort Study from China

Abstract Women are anticipated to go through more than two rounds of cervical screening in their lifetime. Human papillomavirus (HPV) testing is increasingly used as the primary cervical cancer screening test. However, triage strategies for HPV-positive women were usually evaluated at baseline screening. We assessed the effect of sequential rounds of cervical screening on several algorithms for HPV triage. A total of 1,997 women ages 35–45 years were enrolled in 1999 in Shanxi, P.R. China and followed up three times at approximately 5-year intervals. Cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) prevalence by prior HPV results and performance of 12 triage algorithms with cytology, genotyping, and prior HPV were examined among 229 HPV-positive women at the fourth round. CIN2+ prevalence varied from 56.5% (95% confidence interval, 36.8%–74.4%) following 15 years HPV persistence to 3.5% (1.2%–9.9%) with an incident HPV within 15 years. Triage with cytology (with threshold of atypical squamous cells of undetermined significance) yielded positive predictive value (PPV) of 21.4% (13.8%–29.0%), entailing immediate colposcopic referral, and negative predictive value (NPV) of 97.4% (94.6%–100%), permitting retesting at short intervals. Triage with genotyping (16/18/31/33/45/52/58) or prior HPV results showed comparable performance with cytology. Among 11 triage algorithms with similar NPV to cytology, triage with prior HPV results and reflex genotyping (16/18) achieved highest PPV of 28.9% (18.8%–39.1%) and lowest colposcopy referral of 33.2% (27.4%–39.5%). HPV persistence across rounds is an effective risk stratifier in HPV-positive women. Mainstream cytology and genotyping, with or without consideration of prior HPV results, remain effective for HPV triage at fourth round. Prevention Relevance: The study highlights the sustained effectiveness of mainstream HPV triage methods, such as cytology and genotyping, after sequential rounds of cervical screening. It also suggests that use of HPV persistence across rounds can improve management of HPV-positive women in cervical cancer screening.

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy

Abstract Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Genetically Predicted Circulating Levels of Antioxidants and Risk of Breast and Ovarian Cancer

Abstract Evidence from observational studies for the effects of circulating antioxidants on the risk of breast and ovarian cancer was inconsistent. To elucidate the potential causal association of circulating antioxidants on the risk of breast and ovarian cancer, we carried out a two-sample Mendelian randomization (MR) study. The instrumental variables as proxies of genetic liability to circulating antioxidants were obtained from several published data. Summary-level data of breast and ovarian cancer were obtained from genome-wide association study (GWAS) conducted by the Breast (122,977 cases and 105,974 controls) and the Ovarian (25,509 cases and 40,941 controls) Cancer Association Consortiums. MR analyses were mainly performed using the inverse variance–weighted tests. Sensitivity analyses were further conducted to assess heterogeneity and horizontal pleiotropy. No evidence of causal association between genetically predicted circulating antioxidants and breast cancer and its histotypes was discovered as assessed by absolute levels [β-carotenoid: OR, 0.98; 95% confidence interval (CI), 0.92–1.05; P = 0.627; lycopene: OR, 0.99; 95% CI, 0.95–1.03; P = 0.532; retinol: OR, 0.87; 95% CI, 0.49–1.55; P = 0.645; ascorbate: OR, 1.00; 95% CI, 0.99–1.00; P = 0.123] and metabolites (α-tocopherol: OR, 0.88; 95% CI, 0.65–1.19; P = 0.394; γ-tocopherol: OR, 1.00; 95% CI, 0.87–1.16; P = 0.978; retinol: OR, 1.02; 95% CI, 1.00–1.04; P = 0.070; ascorbate: OR, 0.99; 95% CI, 0.91–1.06; P = 0.703). Similarly, no beneficial effect of genetic determinants of circulating antioxidants on ovarian cancer and its histotypes was found. Our study might not indicate a protective role of circulating antioxidants on the breast or ovarian cancer risk. Prevention Relevance: Although this study does not find that circulating antioxidants are protective against breast and ovarian cancer, it is still possible that a high intake of antioxidant-rich foods containing other potentially beneficial components could be cancer preventative.

Variant Identification in BARD1 , PRDM9 , RCC1 , and RECQL in Patients with Ovarian Cancer by Targeted Next-generation Sequencing of DNA Pools

Abstract Several ovarian cancer susceptibility genes have been discovered, but more are likely to exist. In this study, we aimed to analyze knowledge-based selected genes, that is, BARD1, PRDM9, RCC1, and RECQL, in which pathogenic germline variants have been reported in patients with breast and/or ovarian cancer. As deep sequencing of DNA samples remains costly, targeted next-generation sequencing of DNA pools was utilized to screen the exons of BARD1, PRDM9, RCC1, and RECQL in approximately 400 Polish ovarian cancer cases. A total of 25 pools of 16 samples (including several duplicated samples with known variants) were sequenced on the NovaSeq6000 and analyzed with SureCall (Agilent) application. The set of variants was filtrated to exclude spurious variants, and, subsequently, the identified rare genetic variants were validated using Sanger sequencing. No pathogenic mutation was found within the analyzed cohort of patients with ovarian cancer. Validation genotyping of filtered rare silent and missense variants revealed that the majority of them were true alterations, especially those with a higher mutation quality value. The high concordance (R2 = 0.95) of population allele frequency for 44 common SNPs in the European control population (gnomAD) and our experiment confirmed the reliability of pooled sequencing. Mutations in BARD1, PRDM9, RCC1, and RECQL do not contribute substantially to the risk of ovarian cancer. Pooled DNA sequencing is a cost-effective and reliable method for the initial screening of candidate genes; however, it still requires validation of identified rare variants. Prevention Relevance: BARD1, PRDM9, RCC1, and RECQL are not high/moderate-risk ovarian cancer susceptibility genes. Pooled sequencing is a reliable and cost-effective method to detect rare variants in candidate genes.

Effect of Antibiotics on Gut and Vaginal Microbiomes Associated with Cervical Cancer Development in Mice

Abstract Antibiotics affect microbial diversity in the gut, leading to dysbiosis and impaired immunity. However, the impact of antibiotics on microbial communities at other sites, such as vagina is less understood. It is also not clear whether changes induced by antibiotics in both microbiomes affect the development of cervical cancer. In this study, we utilized the murine model to evaluate these questions. We show that oral application of broad-spectrum antibiotics in mice changed not only diversity, but composition and sharing of gut and vaginal microbiomes in mice and influenced cervical cancer development in an orthotopic tumor model. Antibiotics decreased richness and diversity indexes in the gut but increased them in the vagina. Some beneficial taxa, such as Bacteroides, Ruminococcaceae, and Lachnospiraceae increased their abundance in the vagina while other pathogenic species, such as Proteobacteria, were decreased. As a result of the changes, mice with greater richness and diversity of the vaginal microbiome after antibiotics exposure were less likely developed tumors. No association between richness and diversity of the gut microbiome and tumor development was identified.

A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus–positive and -Negative Cervical Precancers

Abstract Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Reasons for Not Attending Cervical Cancer Screening and Associated Factors in Rural Ethiopia

Abstract Social, economic, and cultural factors have been associated with the level of participation in cervical cancer screening programs. This study identified factors associated with nonparticipation in cervical cancer screening, as well as reasons for not attending, in the context of a population-based, cluster-randomized trial in Ethiopia. A total of 2,356 women aged 30 to 49 years in 22 clusters were invited to receive one of two screening approaches, namely human papillomavirus (HPV) self-sampling or visual inspection with acetic acid (VIA). Participants and nonparticipants were analyzed according to their sociodemographic and economic characteristics. Reasons were determined for the refusal of women to participate in either screening method. More women in the VIA arm compared to the HPV arm declined participation in the screening [adjusted OR (AOR) 3.5; 95% confidence interval (CI), 2.6–4.8]. Women who declined attending screening were more often living in rural areas (AOR = 2.0; 95% CI, 1.1–3.5) and were engaged in informal occupations (AOR = 1.6; 95% CI, 1.1–2.4). The majority of nonattendants perceived themselves to be at no risk of cervical cancer (83.1%). The main reasons given for not attending screening for both screening approaches were lack of time to attend screening, self-assertion of being healthy, and fear of screening. We found that perceived time constraints and the perception of being at no risk of getting the disease were the most important barriers to screening. Living in rural settings and informal occupation were also associated with lower participation. Offering a swift and convenient screening service could increase the participation of women in cervical cancer screening at the community level.

Performance of HPV Genotyping Combined with p16/Ki-67 in Detection of Cervical Precancer and Cancer Among HPV-Positive Chinese Women

Abstract Women with positive high-risk human papillomavirus (hrHPV) need efficient triage testing to determine colposcopy referrals. Triage strategies of combining p16/Ki-67 with extended HPV genotyping were evaluated in this study. In total, 899 women attending cervical cancer screening program and 858 women referred to colposcopy from five hospitals were recruited. All the participants were tested by HPV assays and p16/Ki-67 dual staining. Colposcopy and biopsy were performed on women with any abnormal results. HPV genotypes were divided into four strata (HPV16/18, HPV31/33/58/52, HPV45/59/56/66, and HPV51/39/68/35) according to their risks for cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The positive rates of four genotype strata among CIN3+ women were 3.47% (HPV51/39/68/35), 7.73% (HPV45/59/56/66), 14.7% (HPV31/33/58/52), and 78.1% (HPV16/18), respectively (Ptrend < 0.001). The positive rates of p16/Ki-67 increased with the elevation of HPV risk hierarchical from 65.0% in HPV51/39/68/35-positive women to 88.0% in HPV16/18-positive women (Ptrend < 0.001). p16/Ki-67 was an effective method for risk stratification of CIN2+ among HPV31/33/58/52- and HPV45/59/56/66-positive women [HPV31/33/58/52: OR for dual stain+ (ORDS+) of 26.7 (16.8–42.4) and OR for dual stain− (ORDS−) of 3.87(1.89–7.91); HPV45/59/56/66: ORDS+ of 10.3(5.05–21.0) and ORDS− of 1.27(0.38–4.26)]. The combination of HPV16/18 genotyping and p16/Ki-67 triage of HPV31/33/58/52/45/59/56/66-positive women resulted in a lower referral rate (40.1% vs. 41.3%; P < 0.001) as compared with triage of 12 other HPV-positive women with p16/Ki-67, although sensitivity and specificity levels for these two strategies were identical. Combining HPV extended genotyping and p16/Ki-67 can be considered as a promising strategy for cervical cancer screening and triage.

A Multi-level Model to Understand Cervical Cancer Disparities in Appalachia

Abstract The Appalachian region experiences higher incidence and mortality due to cervical cancer compared with other regions of the United States. The goal of the Ohio State University Center for Population Health and Health Disparities (CPHHD), called the Community Awareness Resources and Education (CARE) project, was to understand reasons for this disparity. The first wave (2003–2008) of funding included three projects focusing on the known risk factors for cervical cancer, lack of screening, smoking, and infection with human papillomavirus (HPV). On the basis of the results of these projects, the second wave (2011–2017) included four projects, designed to address a multi-level model of factors contributing to cervical disparities in Appalachia. The results of these projects were then used to refine a multi-level model that explains cervical cancer disparities in Appalachia. Future funded projects will take these multi-level explanations for cervical disparities and focus on implementation science strategies to reduce the burden of cervical cancer morbidity and mortality in Appalachia. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention

Assessing Nurses' Adherence to the See-and-Treat Guidelines of Botswana's National Cervical Cancer Prevention Programme

Abstract The see-and-treat approach for cervical cancer screening [visual inspection with acetic acid (VIA) followed by immediate cryotherapy] was first pilot tested in Botswana in 2009. Botswana's Ministry of Health and the Botswana-UPenn Partnership collaborated to expand see-and-treat to five additional sites throughout the country in 2014. The purpose of this study was to evaluate whether nurses’ adherence to guideline-based screening was maintained during scale-up. Therefore, we compared nurses’ adherence between the pilot and scaled-up sites and determined main drivers of nonadherence across all sites. We conducted a retrospective review of 6,644 medical charts from Botswana's National Cervical Cancer Prevention Programme between February 2014 and October 2015. Using multivariable regression modeled with generalized estimating equations, we determined whether nurses’ adherence to the see-and-treat guideline differed between the pilot and scale-up sites after controlling for significant covariates. Overall, adherence to the guideline was high (88.4%). Although the scaled-up sites had higher adherence compared with the pilot site (90.9% vs. 80.2%, respectively), the difference between sites was not statistically significant in the multivariable model (P = 0.221). Of the nonadherent clinical encounters, the three most frequent visit types were VIA not performed (178, 23.3%), VIA negative: HIV unknown (163, 21.3%), and VIA negative: HIV negative (144, 18.9%). The most common reason for nonadherence was misspecification of follow-up times. Despite known challenges of scaling-up health innovations in resource-limited settings, our study shows that nurses maintained guideline-adherent care in Botswana's national see-and-treat program. The successful scale-up may have been attributable to the program's intensive quality assurance monitoring.

Vulvar Cancer Incidence in the United States and its Relationship to Human Papillomavirus Vaccinations, 2001–2018

Abstract The human papillomavirus (HPV) vaccine was indicated for the prevention of vulvovaginal cancers in 2008, but its impact on the incidence of vulvar cancers within the US is unknown. To determine this, we conducted a secondary analysis of 88,942 vulvar cancer cases among women 20+ years old using the US Cancer Statistics 2001–2018 databases. Data were stratified by tumor behavior (in situ or invasive), age (20–44, 45–64, 65+ years old), race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic), and US census region (Northeast, South, Midwest, West), and incidence rates and average annual percentage changes (AAPC) were calculated by group. Reversing previous trends, the incidence of vulvar carcinoma in situ significantly decreased between 2001 and 2018 among women from all age groups, races/ethnicities, and regions (combined AAPC,  −4.3; 95% confidence interval (CI), −4.7 to −3.8). The incidence of invasive vulvar squamous cell carcinoma decreased significantly among 20- to 44-year-old women (AAPC, −0.8; 95% CI, −1.3 to −0.3), but significantly increased among those 45 to 64 (AAPC, 2.3; 95% CI, 1.8–2.8) and 65+ years old (AAPC, 1.2; 95% CI, 1.1–1.4). Regardless of tumor behavior, incidence was highest among non-Hispanic Whites and the Midwest region. Overall, the significant declines in vulvar carcinoma in situ among all ages, as well as invasive vulvar cancer among younger women, are encouraging and complement other recent data suggesting HPV vaccinations are already reducing anal and cervical cancer incidence. Over time, further declines in vulvar carcinoma incidence are likely as uptake and completion rates of the HPV vaccine increase in the US. Prevention Relevance: We found evidence that HPV vaccinations likely contributed to a decrease in the incidences of vulvar carcinoma in situ and invasive vulvar carcinoma among 20- to 44-year-old women between 2001 and 2018. Our data add to the growing evidence that HPV vaccinations are reducing the incidence of HPV-related anogenital cancers.

High-burden Cancers in Middle-income Countries: A Review of Prevention and Early Detection Strategies Targeting At-risk Populations

AbstractCancer incidence is rising in low- and especially middle-income countries (MIC), driven primarily by four high-burden cancers (breast, cervix, lung, colorectal). By 2030, more than two-thirds of all cancer deaths will occur in MICs. Prevention and early detection are required alongside efforts to improve access to cancer treatment. Successful strategies for decreasing cancer mortality in high-income countries are not always effective, feasible or affordable in other countries. In this review, we evaluate strategies for prevention and early detection of breast, cervix, lung, and colorectal cancers, focusing on modifiable risk factors and high-risk subpopulations. Tobacco taxation, human papilloma virus vaccination, cervical cancer screen-and-treat strategies, and efforts to reduce patient and health system–related delays in the early detection of breast and colorectal cancer represent the highest yield strategies for advancing cancer control in many MICs. An initial focus on high-risk populations is appropriate, with increasing population coverage as resources allow. These strategies can deliver significant cancer mortality gains, and serve as a foundation from which countries can develop comprehensive cancer control programs. Investment in national cancer surveillance infrastructure is needed; the absence of national cancer data to identify at-risk groups remains a barrier to the development of context-specific cancer control strategies.

Increasing Cervical Cancer Prevention Through HPV Testing: Challenges in Developing Persuasive Messages

Abstract Decades of promotion of the Pap test have fallen short in persuading vulnerable women to get screened for cervical cancer. Human papillomavirus (HPV) testing provides an additional screening tool, and the task for cancer control is to promote understanding of the test and encourage its use. Ogden and colleagues investigated the effect of message framing on increasing knowledge and intention to receive HPV testing. Although both messages increased knowledge and intention, no differences were found between gain- and loss-framed messages. We explore implications of this finding and discuss needed research to expand upon and contextualize this important formative research. See related article, p. 839

A Digital Storytelling Intervention for Vietnamese American Mothers to Promote Their Children's HPV Vaccination

Abstract Despite higher rates of human papillomavirus (HPV)-associated cancer in Vietnamese Americans (VA), their vaccination rate remains low. Culturally grounded narratives incorporating culture-specific beliefs and practices may be a promising approach to promote HPV vaccination and potentially mitigate HPV-associated cancer disparities experienced by VAs. We codeveloped personal, audiovisual digital stories about HPV vaccination with VA mothers of vaccinated children, and examined the effects of the digital storytelling (DST) intervention on vaccination intention among VA mothers of unvaccinated children ages 11–14. The stories (3 minutes each) were produced in both English and Vietnamese through a 2-day workshop in collaboration with two VA first-generation immigrant mothers. A community sample of 114 VA mothers of unvaccinated children viewed the stories and filled out an anonymous survey before and after the intervention. Of these mothers (mean age = 41.5 years; SD = 5.4), 35.2% were immigrants, and about half (51%) reported having a child who received free or reduced-price lunch at school. After the intervention, changes in two items indicating mothers’ positive attitudes toward HPV vaccination were significant. Mothers’ intention to vaccinate their children increased from 53% to 74%; the difference was large (OR = 9.12; Cohen g = 0.40) and statistically significant, χ2(1, N = 114) = 17.63, P < 0.001. Mothers’ scores on the narrative quality assessment scale were high, suggesting high levels of identification and engagement with the stories. This brief intervention using digital stories was feasible and showed preliminary effects on promoting VA mothers’ intention to vaccinate their children against HPV. Prevention Relevance: HPV vaccination has effectively prevented its related cancers. A culturally and linguistically congruent DST intervention targeting HPV vaccination can increase mothers’ intention to vaccinate their children. See related Spotlight, p. 419

From Therapy to Cancer Prevention Using HRD Testing on Patients with High-grade Ovarian Cancer

Abstract Approximately half of high-grade ovarian cancers are characterized by genetic and epigenetic alterations in genes involved in homologous recombination repair (HRR), most commonly BRCA1 and BRCA2. HRR defects (HRD) identified by tests of genomic instability confer PARP inhibitor sensitivity in ovarian cancers. Commercial tests that combine tumor BRCA testing with a genomic instability score (HRD test) are available in clinical practice. We seek to determine the performance of three different HRD tests to improve therapy management and prevention of ovarian cancer. Tumor samples from 50 patients with high-grade ovarian cancers were investigated for tumoral BRCA status, genomic instability, and BRCA1 promoter methylation for treatment purposes. Patients with ovarian cancer that tested positive for BRCA variants and/or genomic instability defect were referred to the Cancer Genetics Service for germline testing. A positive HRD status was observed in 54% of cases, and pathogenic variants in BRCA genes were identified in 41% of cases presenting genomic instability. BRCA1 methylation assay revealed promoter hypermethylation in 20% of ovarian cancers that tested positive for HRD and negative for BRCA1/2 variants. Among 26 women referred to cancer genetic counseling, 10 carried germline variants in HRR genes. HRD status determined eligibility for PARP inhibitor treatment in all but two ovarian cancers. This study outlines that determining genomic instability helps identify inherited ovarian cancers. HRD testing, crucial for making high-grade ovarian cancer treatment choices, must be linked to an established path of cancer genetic counseling and management of individuals at high cancer risk. Prevention Relevance: Genomic instability status (HRD testing), which is essential for making therapy choices, is useful to identify inherited ovarian cancers. Identifying these families with high cancer risk is critical for implementing targeted cancer prevention strategies.

Calculating Future 10-Year Breast Cancer Risks in Risk-Adapted Surveillance: A Method Comparison and Application in Clinical Practice

Abstract The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has successfully implemented risk-adapted breast cancer surveillance for women at high breast cancer risk in Germany. Women with a family history of breast and ovarian cancer but without pathogenic germline variants in recognized breast cancer risk genes are recommended annual breast imaging if their predicted 10-year breast cancer risk is 5% or higher, using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk model, as outlined in the current GC-HBOC guideline. However, women who initially do not meet this risk threshold may do so later, even if there is no new cancer in their family. To determine when this threshold is crossed, one could annually repeat BOADICEA calculations using an aging pedigree: the “prediction by aging pedigree” (AP) approach. Alternatively, we propose a simplified and more practical “'conditional probability” (CP) approach, which calculates future risks based on the initial BOADICEA assessment. Using data from 6,661 women registered with GC-HBOC, both methods were compared. Initially, 74% of women, ages 30 to 48 years, had a 10-year breast cancer risk below 5%, but 53% exceeded this threshold at an older age based on the AP approach. Among the women with an initial risk below the threshold, the CP approach revealed that 99% of women exceeded the 5% threshold at the same or an earlier age compared with the AP approach (88% of cases were within the same year or 1 year earlier). The CP approach has been implemented as a user-friendly web application. Prevention Relevance: The German Consortium for Hereditary Breast Cancer recommends annual breast imaging for women if their 10-year breast cancer risk is 5% or higher. Women who initially do not meet this risk threshold may do so later. We propose a simple method to determine future risks based on initial risk assessments.

Avoiding Low-Value Care and Patient Financial Harm in Cervical Cancer Screening

Abstract The provision of low-value care remains a significant concern in healthcare. The negative impacts resulting from low-value cervical cancer screenings are extensive at the population level and can lead to harms and substantial out-of-pocket expenses for patients. Inattention to the financial implications of screening poses a serious threat to low-income populations that depend on affordable screening services, and it may exacerbate existing healthcare disparities and inequities. Identifying and implementing strategies that promote high-value care and reduce patient out-of-pocket expenses are important to ensure that all people, regardless of their socioeconomic status, have access to effective and affordable preventive care. See related article by Rockwell et al., p. 385

The Progesterone Challenge Test as a Functional Biomarker of Endometrial Cancer Risk: Results from a Prospective Feasibility Study

Abstract Endometrial cancer incidence continues to increase globally, driven mainly by obesity. Current diagnostic pathways rely on symptom presentation; no validated approach exists to identify asymptomatic individuals who may benefit from targeted prevention. The progesterone challenge test (PCT) is a physiologic assessment of endometrial hormonal responsiveness that could pragmatically guide endometrial cancer prevention interventions. The RESToRE study (NCT05651282) prospectively assessed the feasibility of the PCT as a community-based risk-stratification tool for endometrial cancer prevention in British Columbia, Canada, between 2023 and 2024. Asymptomatic postmenopausal participants, defined by the absence of vaginal bleeding, with body mass index ≥34.9 kg/m2 and an intact uterus, completed a 10-day course of oral medroxyprogesterone acetate (MPA) 10 mg daily. Feasibility, tolerability, and acceptability were evaluated. Of 96 eligible individuals, 68 enrolled, 53 initiated, and 51 completed the PCT. Sixteen participants experienced withdrawal bleeding (+PCT; 30.2% of those with evaluable results). All +PCT individuals were referred to a gynecologist for standard-of-care evaluation, including an endometrial biopsy. Among the 15 who underwent biopsy, two had a proliferative endometrium, and one had simple hyperplasia. Participants and providers found the test acceptable, citing its simplicity and low administrative burden. Side effects of the PCT were mild (median severity ≤three of 10), resulting in 3.8% (two of 53) of participants discontinuing the MPA. The PCT was feasible, well-tolerated, and acceptable among higher-risk postmenopausal individuals, supporting its use as a physiologic, functional biomarker of endometrial responsiveness. These findings provide early evidence for a scalable, low-cost strategy to identify individuals likely to benefit from targeted endometrial cancer prevention. Prevention Relevance: This study demonstrates that the PCT is feasible and acceptable as a functional biomarker associated with the risk of endometrial cancer in asymptomatic postmenopausal individuals with obesity. As a low-cost, scalable, community-deliverable approach, our findings support validation of this test in the context of endometrial cancer precision prevention.

Female Reproductive Traits and Late-Life Hormone-Sensitive Cancer Risk: A Mendelian Randomization Study

Abstract Ovarian reserve is a crucial component of female reproductive traits. However, the possible causal effects between ovarian reserve and hormone-sensitive cancers remain incompletely understood. In this study, two-sample Mendelian randomization (MR) analyses were performed to assess potential causal effects of reproductive traits on hormone-sensitive cancers. In addition, multivariable MR was applied to determine the potential mediation effects of reproductive traits on hormone-sensitive cancers. A 1-SD incremental increase in the anti-Müllerian hormone (AMH) level was associated with a higher risk of endometrial cancer [OR = 1.27; 95% confidence interval (CI), 1.05–1.54] but a lower risk of breast cancer (OR = 0.80; 95% CI, 0.69–0.94). Each 1-year incremental increase in age at natural menopause was associated with higher risks of breast (OR = 1.04; 95% CI, 1.02–1.05), ovarian (OR = 1.03; 95% CI, 1.01–1.05), and endometrial cancers (OR = 1.07; 95% CI, 1.04–1.09). Nulliparity increased the risk of breast cancer (OR = 1.07; 95% CI, 1.05–1.09). An elevated AMH level was indirectly associated with endometrial cancer risk with 2.67% of the effect attributed to later age at natural menopause (per 1-year increase). Each 1-year incremental increase in age at menarche was indirectly associated with endometrial cancer risk with 4.71% of the effect attributed to later age at natural menopause. The findings herein highlight AMH as a potential key biological marker for endometrial and breast cancer risk stratification. Identifying natural menopause as a key modulator may enhance our understanding of the mechanisms underlying the development of hormone-sensitive cancers. Prevention Relevance: This study identified the potential causal effects between reproductive traits and hormone-sensitive cancers. The results suggested that some reproductive traits seem to be potential risk factors for hormone-sensitive cancers, which could have utility for risk stratification and aid in understanding the mechanisms underlying the development of hormone-sensitive cancers in women.

Use Patterns of Levonorgestrel-Releasing Intrauterine System among American Women

Abstract Levonorgestrel-releasing intrauterine system (LNG-IUS) use is approved by the FDA for contraception and heavy menorrhagia. More importantly, it effectively treats endometrial hyperplasia, a precursor to endometrial cancer. Therefore, LNG-IUS use is associated with potential endometrial cancer risk reduction, but current use patterns in the United States are unknown. We analyzed LNG-IUS use prevalence among women ages 18 to 50 years using a weighted statistical analysis of the 2017 to 2019 National Survey of Family Growth. Summary statistics were stratified by race and ethnic group and known endometrial cancer sociodemographic and health risk factors and assessed statistically with bivariate Rao–Scott χ2 tests. A multivariable logistic regression model was developed to explore LNG-IUS use predictors. Current LNG-IUS use in the United States was 6.9% [95% confidence interval (CI), 5.9%–8.1%]. LNG-IUS use was lower in Hispanic women compared with White women [adjusted OR (AOR), 0.7; 95% CI, 0.5–1.0]. Compared with women with ≤high school education, LNG-IUS use was higher for women with ≥college degree (AOR, 2.0; 95% CI, 1.3–3.1). Parous (AOR, 2.6; 95% CI, 1.7–3.9) and insured (AOR, 1.7; 95% CI, 1.0–3.1) women had higher odds of LNG-IUS use, whereas women with diabetes (AOR, 0.3; 95% CI, 0.1–0.7) had lower odds of LNG-IUS use. No differences in LNG-IUS use were observed by endometrial cancer risk factors of women’s body mass index, age of menarche, hypertension, and personal history of cancer. More research is needed to establish the potential benefits of LNG-IUS use on endometrial cancer, which will further highlight potential opportunities for population-level primary prevention to address the growing incidence of endometrial cancer. Prevention Relevance: This study describes the characteristics of American women using the LNG-IUS. Reproductive-age women (especially Hispanic, with lower education, nulliparous, uninsured, and with diabetes) have lower LNG-IUS use odds. These groups may benefit from LNG-IUS use for endometrial cancer primary prevention, conditioned that LNG-IUS use is proven effective in reducing endometrial cancer incidence.

Weight Loss During Intrauterine Progestin Treatment for Obesity-associated Atypical Hyperplasia and Early-Stage Cancer of The Endometrium

Abstract Intrauterine progestin is a treatment option for women with atypical hyperplasia or low-risk endometrial cancer who wish to preserve their fertility, or whose poor surgical fitness precludes safe hysterectomy. We hypothesized that in such women with obesity, weight loss during progestin treatment may improve oncological outcomes. We conducted a prospective nonrandomized study of women with obesity and atypical hyperplasia or low-grade stage 1a endometrial cancer undergoing progestin treatment. Women with a body mass index (BMI) ≥ 35 kg/m2 were offered bariatric surgery; those who declined and those with a BMI of 30 to 34.9 kg/m2 were encouraged to lose weight by low-calorie diet. We assessed uptake of bariatric surgery; weight lost during progestin treatment; and the impact of more than 10% total body weight loss on progestin treatment response at 12 months. 71 women [median age 58 years (interquartile range; IQR 35–65); mean BMI 48 kg/m2 (SD 9.3)] completed the study. Twenty-three women (32%) had bariatric surgery, on average 5 months (IQR 3–8) after progestin treatment commenced. Weight change during progestin treatment was −33.4 kg [95% confidence interval (CI) −42.1, −24.7] and −4.6 kg (95% CI −7.8, −1.4) in women receiving bariatric surgery and low-calorie diet, respectively (P < 0.001). Forty-three women (61%) responded to progestin, while 23 (32%) showed stabilized and 5 (7%) progressive disease. Response at 12 months was not predicted by age or baseline BMI, but women who lost more than 10% of their total body weight were more likely to respond to progestin than those who did not (adjusted odds ratio 3.95; 95% CI 1.3, 12.5; P = 0.02). Thus weight loss may improve oncological outcomes in women with obesity-associated endometrial neoplastic abnormalities treated with progestin. Prevention Relevance: This study found that weight loss improves response rates in women with obesity and atypical hyperplasia or low-risk endometrial cancer undergoing conservative management with intrauterine progestin. Given the additional benefits of weight loss for fertility, cardiovascular health and quality of life, future research should focus on how best to accomplish it.

PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study

Abstract Obesity is the major etiologic driver for endometrial cancer. The levonorgestrel intrauterine system (LNG-IUS) reduces the risk of endometrial cancer and its precursor, atypical hyperplasia. We assessed feasibility and uptake of the LNG-IUS for primary prevention of endometrial cancer in high-risk women and its impact on endometrial tissue biomarkers. Women with class-III obesity [body mass index (BMI) > 40 kg/m2] and histologically normal endometrium were invited to participate in a clinical trial of the LNG-IUS for endometrial protection. Recruitment, successful LNG-IUS insertion, and adherence to trial procedures were recorded. We measured impact of the LNG-IUS on circulating biomarkers of endometrial cancer risk, endometrial proliferation (Ki-67, pAKT, PTEN), endometrial hormone receptor status [estrogen receptor and progesterone receptor (PR)], mental wellbeing, and menstrual function. At 6 months, women chose to keep their LNG-IUS or have it removed. In total, 103 women were approached, 54 were offered a participant information sheet, 35 agreed to participate, and 25 received a LNG-IUS. Their median age and BMI were 54 years [interquartile range (IQR) 52–57] and 47 kg/m2 (IQR 44–51), respectively. Three women (3/35, 9%) were ineligible due to atypical hyperplasia/endometrial cancer on their baseline biopsy. The LNG-IUS was well tolerated and had a positive overall effect on bleeding patterns and mental wellbeing. The LNG-IUS was associated with endometrial morphologic change, reduced Ki-67, and PR expression, but circulating biomarkers of endometrial cancer risk were unchanged. All but one woman (96%) kept her LNG-IUS. The LNG-IUS appears to be acceptable to some women with class-III obesity for primary prevention of endometrial cancer, which could provide a strategy for a prevention trial. Prevention Relevance: Novel strategies are urgently needed to prevent the rise in endometrial cancer diagnoses predicted by escalating obesity rates. Here, we show that women with class III obesity are willing to engage in risk reduction with a levonorgestrel intrauterine system, which could provide a strategy for an endometrial cancer prevention trial.

Intercepting Endometrial Cancer: Opportunities to Expand Access Using New Technology

AbstractAlthough endometrial cancer is often diagnosed at an early curable stage, the incidence and mortality from endometrial cancer is rising and minority women are particularly at risk. We hypothesize that delays in clinical presentation contribute to racial disparities in endometrial cancer mortality and treatment-related morbidity. Improved methods for endometrial cancer risk assessment and distinguishing abnormal uterine bleeding and postmenopausal bleeding from physiologic variation are needed. Accordingly, we propose a multipronged strategy that combines innovative patient education with novel early detection strategies to reduce health impacts of endometrial cancer and its precursors, especially among Black women. Futuristic approaches using gamification, smartphone apps, artificial intelligence, and health promotion outside of the physical clinic hold promise in preventing endometrial cancer and reducing morbidity and mortality related to the disease, but they also raise a number of questions that will need to be addressed by future research.

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata

Abstract Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. Prevention Relevance: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

CervicalMethDx: A Precision DNA Methylation Test to Identify Risk of High-Grade Intraepithelial Lesions in Cervical Cancer Screening Algorithms

Abstract Cervical cancer is one of the most common cancers in women. Despite progress in prevention and success in early detection through cytologic screening and human papillomavirus (HPV) detection, there remains a challenge in triaging women appropriately to colposcopy and biopsy. We sought to validate the CervicalMethDx test, a precision DNA methylation classifier for cervical cancer detection, as a reflex test in women with HPV-positive samples. A blinded retrospective study was performed on well-characterized samples in PreservCyt media from a large referral clinical laboratory in the United States. DNA methylation was assessed in three gene promoters (ZNF516, FKBP6, and INTS1) and a control gene (β-actin) by quantitative real-time methylation-specific PCR (qMSP) analysis, using machine learning algorithms. We compared DNA methylation levels in HPV-positive patients presenting with lesions in the Pap test and cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3 histologic diagnosis with DNA methylation levels in HPV-positive patients with lesions in the Pap test but no intraepithelial lesion or malignancy. The CervicalMethDx test correctly classified 95% of the CIN2 samples (n = 210), with 91% sensitivity, 100% specificity, and an area under the ROC curve (AUC) of 0.96, and 94% of CIN3 samples (n = 141), with 90% sensitivity, 100% specificity, and an AUC of 0.96. Moreover, the CervicalMethDx test correctly classified 94% of combined CIN2/CIN3 samples (n = 351), with 93% sensitivity, 97% specificity, and an AUC of 0.96. CervicalMethDx demonstrated strong discriminatory power for identifying CIN2/CIN3 risk and may complement current triage strategies for colposcopy referral. Prospective, population-based studies, including those in low-resource settings, are needed for further evaluation. Prevention Relevance: The CervicalMethDx test integrates DNA methylation analysis and machine learning to improve early detection of high-grade cervical lesions (high-grade squamous intraepithelial lesions), offering a noninvasive, cost-effective screening tool. Enhanced risk stratification and overtreatment reduction expand equitable access to precision prevention programs. Further validation will clarify CervicalMethDx’s alignment with global cervical cancer prevention strategies.

Viewing Native American Cervical Cancer Disparities through the Lens of the Vaginal Microbiome: A Pilot Study

Abstract Vaginal dysbiosis is implicated in persistent human papillomavirus (HPV) infection and cervical cancer. Yet, there is a paucity of data on the vaginal microbiome in Native American communities. Here, we aimed to elucidate the relationships between microbiome, HPV, sociodemographic, and behavioral risk factors to better understand an increased cervical cancer risk in Native American women. In this pilot study, we recruited 31 participants (16 Native American and 15 non-Native women) in Northern Arizona and examined vaginal microbiota composition, HPV status, and immune mediators. We also assessed individuals’ sociodemographic information and physical, mental, sexual, and reproductive health. Overall, microbiota profiles were dominated by common Lactobacillus species (associated with vaginal health) or a mixture of bacterial vaginosis–associated bacteria. Only 44% of Native women exhibited Lactobacillus dominance, compared with 58% of non-Native women. Women with vaginal dysbiosis also had elevated vaginal pH and were more frequently infected with high-risk HPV. Furthermore, we observed associations of multiple people in a household, lower level of education, and high parity with vaginal dysbiosis and abundance of specific bacterial species. Finally, women with dysbiotic microbiota presented with elevated vaginal levels of proinflammatory cytokines. Altogether, these findings indicate an interplay between HPV, vaginal microbiota, and host defense, which may play a role in the cervical cancer disparity among Native American women. Future longitudinal studies are needed to determine the mechanistic role of vaginal microbiota in HPV persistence in the context of social determinants of health toward the long-term goal of reducing health disparities between non-Hispanic White and Native American populations. Prevention Relevance: Cervical cancer disproportionally affects Native American women. Sociodemographic and behavioral factors might contribute to this disparity via alteration of vaginal microbiota. Here, we show the association between these factors and vaginal dysbiosis and immune activation, which can be implicated in high-risk HPV infection among Native American and other racial/ethnic populations.

Treatment of Cervical Precancers is the Major Remaining Challenge in Cervical Screening Research

AbstractDeepening understanding of cervical cancer pathogenesis has yielded one-dose prophylactic human papillomavirus (HPV) vaccines and accurate HPV-based cervical screening tests. Knowing the heterogeneous carcinogenic potential of the individual high-risk HPV types permits prioritization of vaccination and screening strategies. However, “correct” (i.e., safe and effective) treatment of women found to have precancer is still undefined, forcing reliance on one or more rounds of untargeted destructive/excisional treatment. Both over-treatment and under-treatment are common results. Until safe and effective anti-HPV therapies are invented, defining optimal destructive/excisional treatment of precancer remains a fundamental and under-researched challenge, especially in resource-constrained settings.See related article by King et al., p. 681

Clinical Performance of hrHPV Primary Screening Using Vaginal versus Cervical Samples to Detect High-grade Intraepithelial Lesions

Abstract High-risk human papillomavirus (hrHPV) testing is now the most recommended primary method for cervical cancer screening worldwide. Clinician-collected cervical sampling continues to be the main sampling method, but hrHPV vaginal self-sampling is an appealing alternative because of its greater acceptability and potentially higher cost-effectiveness. This study aimed to determine whether hrHPV vaginal self-sampling is comparable with clinician-collected cervical sampling for detecting histologically confirmed high-grade cervical intraepithelial neoplasia (CIN2/3) as part of a cervical cancer screening program in Mexico. We analyzed data from 5,856 women screened during a hrHPV-based screening study. Clinical performance and diagnostic efficiency metrics were estimated for the two sampling methods for the CIN3 and CIN2+ endpoints, using three triage strategies: HPV16/18 genotyping, HPV16/18/33/58 extended genotyping, and HPV16/18/31/33/58 extended genotyping. hrHPV-positivity was found in 801 (13.7%) cervical and 897 (15.3%) vaginal samples. All women with hrHPV-positive samples were referred to colposcopy, which detected 17 total CIN3 cases before considering retrospective triage strategies. Using the HPV16/18/31/33/58 extended genotyping strategy, 245 women had hrHPV-positive cervical samples and 269 had hrHPV-positive vaginal samples. Ten CIN3 cases were detected each among women with hrHPV-positive cervical samples and among those with hrHPV-positive vaginal samples when using this strategy, with no significant differences in sensitivity and specificity observed. We observe that self- and clinician-collected sampling methods are comparable for detecting CIN3 and CIN2+ regardless of the triage strategy used. These findings can help public health officials to develop more cost-effective cervical cancer screening programs that maximize participation. Prevention Relevance: We found that hrHPV vaginal self-sampling is comparable with hrHPV clinician cervical sampling when using any triage strategy to refer women to colposcopy, so self-sampling is a viable cervical screening method. Therefore, policymakers should consider incorporating self-sampling into cervical screening programs to increase screening coverage and reduce cervical cancer burden. See related Spotlight, p. 649

Bilateral Salpingo-oophorectomy and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Assessing the Evidence

Abstract Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Polymorphisms in the Nonhomologous End-joining DNA Repair Pathway are Associated with HPV Integration in Cervical Dysplasia

Abstract Previous evidence indicates that human papillomavirus (HPV) integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process is understudied. The aim of this study was to examine the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Women enrolled in two large trials of optical technologies for cervical cancer detection and positive for HPV16 or HPV18 were selected for HPV integration analysis and genotyping. Associations between SNPs and cytology (normal, low-grade, or high-grade lesions) were evaluated. Among women with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each SNP on viral integration status. Of the 710 women evaluated [149 high-grade squamous intraepithelial lesion (HSIL), 251; low-grade squamous intraepithelial lesion (LSIL, 310 normal)], 395 (55.6%) were positive for HPV16 and 192 (27%) were positive for HPV18. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC4, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV16 integration status. Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression. Prevention Relevance: HPV integration in premalignant lesions and is thought to be an important driver of carcinogenesis. However, it is unclear what factors promote integration. The use of targeted genotyping among women presenting with cervical dysplasia has the potential to be an effective tool in assessing the likelihood of progression to cancer.

Cost Effectiveness of Whole Population BRCA Genetic Screening for Cancer Prevention in Israel

Abstract With the growing technical ease and reduction in genetic screening costs, whole population BRCA screening may be a feasible option. Our objective was to investigate the cost effectiveness of whole population screening for BRCA mutations in Israel, for varying degrees of BRCA carrier state. Lifetime costs of whole female population screening for BRCA mutation carrier state versus nonscreening were compared using a Markovian process decision analysis model. Model parameters including ovarian and breast cancer risks were obtained from previously published data. Screening and other treatment-related costs were received from the Israeli Ministry of Health pricing list according to specified codes. Quality-adjusted life years were used for cost-effectiveness analysis. Sensitivity analysis was conducted to evaluate model uncertainties, specifically varying degrees of BRCA prevalence. Results show that whole population BRCA screening in Israel is cost effective across a wide range of BRCA prevalence rates with an incremental cost-effectiveness ratio of 81,493 new Israeli Shekels for a BRCA prevalence of 2.5%, increasing to 250,000 new Israeli Shekels for a 0.75% prevalence rate, per quality-adjusted life year gained. Discount rate and population BRCA prevalence and rate of risk reduction salpingo-oophorectomy are the most influential parameters in the model. Whole population screening for BRCA mutations should be offered as part of general health screening strategies by national medical insurance providers, even for non-Ashkenazi Jews. Our algorithm can be applied for other countries, adjusting local costs of screening and treatment. Prevention Relevance: Whole population BRCA mutation screening in Israel is cost effective across a wide prevalence rate and should be offered as part of general health screening strategies by national medical insurance providers for cancer prevention.

Sleep Characteristics and Risk of Ovarian Cancer Among Postmenopausal Women

Abstract Several studies have assessed the relationship between sleep duration and ovarian cancer risk, but the results are conflicting. Importantly, no studies addressed the relationship between sleep disturbance or sleep quality and ovarian cancer incidence. Moreover, few studies have examined the relationships between sleep measures and subtypes of ovarian cancer. This study included 109,024 postmenopausal women ages 50–79 from the Women's Health Initiative during 1993–1998 and followed through 2018. The Cox proportional hazards model was used to estimate adjusted HRs for the associations between sleep habits and the incidence of ovarian cancer and its subtypes. No association was observed between sleep duration, sleep quality, sleep disturbance, or insomnia and risk of overall ovarian cancer, serous/nonserous, or type I/type II ovarian cancer subtype. However, compared with women with average sleep quality, women with restful or very restful sleep quality had a significantly lower risk of invasive serous subtype [HR: 0.73, 95% confidence interval (CI): 0.60–0.90] while insomnia was associated with a higher risk of invasive serous subtype (HR: 1.36, 95% CI: 1.12–1.66). Associations with insomnia differed significantly by serous and nonserous subtypes, and type I and type II subtypes (Pheterogeneity = 0.001 and Pheterogeneity <0.001, respectively). This study provides no evidence on association between sleep habits and overall ovarian cancer risk among postmenopausal women. However, restful or very restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer. Associations with insomnia differed by subtypes. Prevention Relevance: This study shows no association between sleep duration, sleep quality, or insomnia with the risk of overall ovarian cancer among postmenopausal women. However, restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer.

HIST1H2BB and MAGI2 Methylation and Somatic Mutations as Precision Medicine Biomarkers for Diagnosis and Prognosis of High-grade Serous Ovarian Cancer

Abstract Molecular alterations that contribute to long-term (LT) and short-term (ST) survival in ovarian high-grade serous carcinoma (HGSC) may be used as precision medicine biomarkers. DNA promoter methylation is an early event in tumorigenesis, which can be detected in blood and urine, making it a feasible companion biomarker to somatic mutations for early detection and targeted treatment workflows. We compared the methylation profile in 12 HGSC tissue samples to 30 fallopian tube epithelium samples, using the Infinium Human Methylation 450K Array. We also used 450K methylation arrays to compare methylation among HGSCs long-term survivors (more than 5 years) and short-term survivors (less than 3 years). We verified the array results using bisulfite sequencing and methylation-specific PCR (qMSP). in another cohort of HGSC patient samples (n = 35). Immunoblot and clonogenic assays after pharmacologic unmasking show that HIST1H2BB and MAGI2 promoter methylation downregulates mRNA expression levels in ovarian cancer cells. We then used qMSP in paired tissue, ascites, plasma/serum, vaginal swabs, and urine from a third cohort of patients with HGSC cancer (n = 85) to test the clinical potential of HIST1H2BB and MAGI2 in precision medicine workflows. We also performed next-generation exome sequencing of 50 frequently mutated in human cancer genes, using the Ion AmpliSeqCancer Hotspot Panel, to show that the somatic mutation profile found in tissue and plasma can be quantified in paired urine samples from patients with HGSC. Our results suggest that HIST1H2BB and MAGI2 have growth-suppressing roles and can be used as HGSC precision medicine biomarkers.

Population-based Genetic Testing for Precision Prevention

Abstract Global interest in genetic testing for cancer susceptibility genes (CSG) has surged with falling costs, increasing awareness, and celebrity endorsement. Current access to genetic testing is based on clinical criteria/risk model assessment which uses family history as a surrogate. However, this approach is fraught with inequality, massive underutilization, and misses 50% CSG carriers. This reflects huge missed opportunities for precision prevention. Early CSG identification enables uptake of risk-reducing strategies in unaffected individuals to reduce cancer risk. Population-based genetic testing (PGT) can overcome limitations of clinical criteria/family history–based testing. Jewish population studies show population-based BRCA testing is feasible, acceptable, has high satisfaction, does not harm psychologic well-being/quality of life, and is extremely cost-effective, arguing for changing paradigm to PGT in the Jewish population. Innovative approaches for delivering pretest information/education are needed to facilitate informed decision-making for PGT. Different health systems will need context-specific implementation strategies and management pathways, while maintaining principles of population screening. Data on general population PGT are beginning to emerge, prompting evaluation of wider implementation. Sophisticated risk prediction models incorporating genetic and nongenetic data are being used to stratify populations for ovarian cancer and breast cancer risk and risk-adapted screening/prevention. PGT is potentially cost-effective for panel testing of breast and ovarian CSGs and for risk-adapted breast cancer screening. Further research/implementation studies evaluating the impact, clinical efficacy, psychologic and socio–ethical consequences, and cost-effectiveness of PGT are needed.

Dietary Advanced Glycation End-products (AGE) and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

Abstract Advanced glycation end-products (AGEs) are implicated in the pathogenesis of several chronic diseases including cancer. AGEs are produced endogenously but can also be consumed from foods. AGE formation in food is accelerated during cooking at high temperatures. Certain high fat or highly processed foods have high AGE values. The objective of the study was to assign and quantify Nε-carboxymethyl-lysine (CML)-AGE content in food and investigate the association between dietary AGE intake and breast cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The study included women enrolled in the intervention arm who were cancer-free at baseline and completed a baseline questionnaire and food frequency questionnaire (DQX). CML-AGE values were assigned and quantified to foods in the DQX using a published AGE database. Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer among all women, and stratified by race/ethnicity, invasiveness of disease, and hormone receptor status. After a median 11.5 years of follow-up, 1,592 women were diagnosed with breast cancer. Higher CML-AGE intake was associated with increased risk of breast cancer among all women (HRQ5VSQ1, 1.30; 95% CI, 1.04–1.62; Ptrend = 0.04) and in non-Hispanic white women (HRT3VST1, 1.21; 95% CI, 1.02–1.44). Increased CML-AGE intake was associated with increased risk of in situ (HRT3VST1, 1.49; 95% CI, 1.11–2.01) and hormone receptor–positive (HRT3VST1, 1.24; 95% CI, 1.01–1.53) breast cancers. In conclusion, high intake of dietary AGE may contribute to increased breast cancer.

Reducing Ovarian Cancer Mortality Through Early Detection: Approaches Using Circulating Biomarkers

Abstract More than two-thirds of all women diagnosed with epithelial ovarian cancer (EOC) will die from the disease (>14,000 deaths annually), a fact that has not changed considerably in the last three decades. Although the 5-year survival rates for most other solid tumors have improved steadily, ovarian cancer remains an exception, making it the deadliest of all gynecologic cancers and five times deadlier than breast cancer. When diagnosed early, treatment is more effective, with a 5-year survival rate of up to 90%. Unfortunately, most cases are not detected until after the cancer has spread, resulting in a dismal 5-year survival rate of less than 30%. Current screening methods for ovarian cancer typically use a combination of a pelvic examination, transvaginal ultrasonography, and serum cancer antigen 125 (CA125), but these have made minimal impact on improving mortality. Thus, there is a compelling unmet need to develop new molecular tools that can be used to diagnose early-stage EOC and/or assist in the clinical management of the disease after a diagnosis, given that more than 220,000 women are living with ovarian cancer in the United States and are at risk of recurrence. Here, we discuss the state of advancing liquid-based approaches for improving the early detection of ovarian cancer. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention

Clinical Evaluation of DNA Ploidy for the Triage of HPV-Positive Chinese Women During Cervical Cancer Screening

Abstract Quantification of DNA aneuploidy has great potential as a prognostic marker of cervical precancerous lesions. We aim to evaluate the performance of DNA ploidy analysis for the triage of HPV-positive women. 523 HPV-positive women ages 25–64 undergoing HPV and pap cytology testing with valid cervical biopsies in Renji Hospital were enrolled in a prospective observational study from June 2018 to June 2019. The clinical performances of DNA ploidy, with or without HPV16/18 genotyping, were evaluated for all HPV-positive women to detect histologic high-grade squamous intraepithelial lesion or worse (HSIL+). For HSIL+ detection, DNA ploidy had statistically higher specificity (83.89%) than Pap cytology (75.50%, P = 0.002) and HPV16/18 genotyping (77.92%, P = 0.023). Although the sensitivity of DNA ploidy (58.57%) remained similar with pap cytology (65.71%, P = 0.461) and HPV16/18 genotyping (55.71%, P = 0.734). A comparable sensitivity (84.29% vs. 84.29%, P = 1.000) and a higher specificity (66.00% vs. 58.94%, P < 0.001) compared with combination with Pap cytology. DNA ploidy triage strategy required fewer colposcopies per detection of HSIL+ compared with pap cytologic testing, with a 13.1% (34 of 258) reduction of colposcopies compared with routine triage strategy of HPV screening with Pap cytologic testing. HPV16/18-negative women with negative DNA ploidy results had the lowest risk of HSIL+ among HPV-positive women (3.55%). Automated DNA ploidy analysis, alone or in combination with HPV16/18 genotyping, shows the potential as a triage strategy of cervical cancer screening for HPV-positive women. Prevention Relevance: Results from this study indicate that DNA ploidy analysis has good performance in early detection of high-grade precancerous and cancerous lesions of the cervix. This strategy could be used in the triage of HPV-positive women in cervical cancer screening.

The Quality of Pap Smears from the Brazilian Cervical Cancer Screening Program According to the Human Development Index

Abstract Brazil is a country with strong socioeconomic disparities, which may explain the different rates of cervical cancer incidence and mortality and influence the quality of cervical cancer screening tests. The aim of this study was to perform a trend analysis of some quality indicators of Pap smears according to the Municipal Human Development Index (MHDI). Information about cytopathological exams (approximately 65,000,000) performed from 2006 to 2014 in women ages 25 to 64 years was obtained from the Cervical Cancer Information System (SISCOLO). The average annual percentage change (AAPC) for each indicator was calculated using the Joinpoint Regression Program, according to MHDI levels. Very low frequencies of unsatisfactory cases (<5%) were observed at different MHDI levels. Although the positivity index in the low- and medium-MHDI groups has increased, the values remained below international recommendations (3%–10%). The HSIL (high-grade squamous intraepithelial lesion) percentage remained stationary at all levels of the MHDI. In the low- and medium-MHDI groups, most quality indicators were below the recommendations by Brazilian National Cancer Institute INCA, with no improvement trend; in the high-MHDI group, the majority of the indicators also presented no improvement, although they show slightly better quality indicators. The MHDI should be considered in the definition of the policies of the screening program for cervical cancer in Brazil, and the current program may require adjustments to achieve improved efficiency.

Preventing Cervical Cancer Globally: Are We Making Progress?

Abstract An unacceptable number of women continue to die from cervical cancer around the world each year. Despite established primary and secondary prevention measures, and a natural history of disease which provides a long latent phase in which to intervene, there are still more than 500,000 women diagnosed with cervical cancer globally each year, and 300,000 related deaths. Approximately 90% of these cervical cancer cases and deaths occur in low- and middle-income countries (LMIC). The World Health Organization (WHO) recently launched a Global Strategy to Accelerate the Elimination of Cervical Cancer that outlines 3 key steps: (i) vaccination against human papillomavirus (HPV); (ii) cervical screening; and (iii) treatment of precancerous lesions and management of invasive cancer. Successful implementation of all 3 steps could reduce more than 40% of new cervical cancer cases and 5 million related deaths by 2050. However, this initiative requires high level commitment to HPV immunization programs, innovative approaches to screening, and strengthening of health systems to provide treatment for both precancerous lesions as well as invasive cervical cancer.