Jiangrong Wang

The WID‐EC test for the detection and risk prediction of endometrial cancer

AbstractThe incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID‐EC (Women's cancer risk IDentification‐Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid‐based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID‐EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID‐EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88‐0.97) in the external set and of 0.82 (95% CI: 0.74‐0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID‐EC test can identify women with or at risk of endometrial cancer.

Mental disorders and socioeconomic outcomes in women with cervical cancer, and their children and co-parents

Abstract Background Cervical cancer often affects women who are in the middle of life and may carry substantial mental and socioeconomic impact also on families. We performed a generation-spanning study to elucidate this burden. Methods We used nationwide registers during 1991-2018 in Sweden to perform 2 matched cohort studies based on a source population of more than 5 million women. The individual sub-study included 6060 cases of cervical cancer diagnosed during 2006-2018 and 5 population comparators individually matched to each case by age, birth year, and region (n = 30 300). The family sub-study included 9332 cases of cervical cancer diagnosed during 1991-2016 and 45 674 matched population comparators and all their children and co-parents. Results We found an increased risk for mental disorders in cases compared with comparators, particularly during the first 2 years postdiagnosis (HR = 3.74, 95% CI = 3.45 to 4.06). Socioeconomic status changed negatively in cases after their diagnosis: a decreased income and increased need for financial aid appeared within 2 years, whereas unemployment escalated from 2 years after cancer diagnosis. We further found an increased risk of mental disorders in both children and co-parents of the cases, compared with the children and co-parents of the comparators. Furthermore, we observed negative socioeconomic trajectories in the co-parents and lower educational attainment in the children of the cases, especially if the case had died. Conclusions Women with cervical cancer, and their close family members, display increased risk of negative mental health and socioeconomic outcomes after diagnosis. The lower educational attainment in children appears particularly worrying.

Population-Based Age-Period-Cohort Analysis of Declining Human Papillomavirus Prevalence

Abstract Background Most countries in the world have launched human papillomavirus (HPV) vaccination programs, and declining HPV prevalences are reported. We aimed to disentangle the influences of calendar time, birth cohort, and age by analyzing HPV prevalences in the population-based cervical screening program using age-period-cohort modeling. Methods All 813 882 primary HPV-based cervical screening tests from women aged 23–64 years between 2014 and 2023 in the capital region of Sweden were identified in the Swedish National Cervical Screening Registry. The odds ratio (OR) of HPV-16/18 infection was estimated comparing birth cohorts to the unvaccinated 1984-born using an age-period-cohort model. The impact of changing HPV prevalences on the number needed to screen (NNS) to detect and prevent 1 cervical cancer case was calculated. Results HPV vaccination coverage was 82%–83% among women born in 1999–2000. Before 2019, the HPV-16/18 prevalence was highest among the youngest women. During 2020–2023 the prevalence consistently decreased among the birth cohorts offered organized school-based vaccination. There was a 98% decline in HPV-16 prevalence (OR, 0.02 [95% confidence interval {CI}, .01–.04]) and a 99% decline in HPV-18 prevalence (OR, 0.01 [95% CI, .00–.04]) among the 2000-born compared to the 1984-born. The declining HPV-16/18 prevalences resulted in major increases in the NNS to detect and to prevent 1 case of cervical cancer. Conclusions The declines of HPV-16/18 were considerably larger than the vaccination coverage, suggesting herd immunity. The changing epidemiology of HPV types impacts screening needs, necessitating updated screening programs.

Evaluation of primary HPV-based cervical screening among older women: Long-term follow-up of a randomized healthcare policy trial in Sweden

Background Evidence on invasive cervical cancer prevention among older women is limited, especially with the introduction of human papillomavirus (HPV)-based screening and longer interval. We conducted a long-term follow-up of the first phase of a randomized healthcare policy trial in cervical screening, targeting women aged 56 to 61 years old, to investigate the effectiveness of primary HPV-based screening in preventing invasive cervical cancer (ICC) and the safety of extending screening interval. Methods and findings The randomized healthcare policy trial of primary HPV-based cervical screening targeted women residing in Stockholm-Gotland region during 2012 to 2016, aged 30 to 64 years. The trial aimed to investigate the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) within 24 months and long-term protection against invasive cervical cancer, comparing primary HPV-based screening to primary cytology-based screening. The initial phase of the trial, which was the focus of this study, targeted women aged 56 to 61 years old in 2012 to 2014 who were randomized to primary cytology arm (n = 7,401) or primary HPV arm (n = 7,318). We used national registries to identify the subsequent cervical tests and all histopathological diagnoses including ICC before December 31, 2022. We calculated cumulative incidence, incidence rate (IR) and IR ratio (IRR) of ICC, by baseline test result. Furthermore, we calculated longitudinal sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by receipt of primary cytology or primary HPV test for the recommended screening intervals in this age group. We found that the IR of ICC among women in the primary HPV arm was 7.2/100,000 person-years (py) and 3.0 for women who tested HPV negative, compared to 18.4/100,000 py among women in the primary cytology arm and 18.8 for women who tested cytology negative. We further found that the overall point estimate for the risk of ICC over 10 years of follow-up among women in the primary HPV arm was 0.39 compared to women in the primary cytology arm, but this was not statistically significant (IRR: 0.39; 95% confidence interval, CI [0.14, 1.09]; p = 0.0726). However, among women with a negative test result at baseline, women in the primary HPV arm had an 84% lower risk of ICC compared to women in the primary cytology arm (IRR: 0.16; 95% CI [0.04, 0.72]; p = 0.0163). Moreover, primary HPV testing had a higher sensitivity for detecting CIN2+ within a 7-year interval than primary cytology testing within a 5-year interval (89.6% versus 50.9%, p < 0.0001). We were limited by a partial imbalance of invitations during the follow-up between the 2 arms which may have led to an underestimation of the effectiveness of primary HPV-based screening. Conclusions In this study, we observed that women over 55 years of age who received a primary negative HPV test result had substantially lower risk of CIN2+, and ICC, compared to women who received a primary negative cytology result. This should apply even if the screening interval were prolonged to 7 years. Trial Registration NCT01511328.

Nationwide registry‐based trial of risk‐stratified cervical screening

AbstractIn well‐screened populations, most cervical cancers arise from small groups of women with inadequate screening. The present study aims to assess whether registry‐based cancer risk assessment could be used to increase screening intensity among high‐risk women. The National Cervical Screening Registry identified the 28,689 women residents in Sweden who had either no previous cervical screening or a screening history indicating high risk. We invited these women by SMS and/or physical letter to order a free human papillomavirus (HPV) self‐sampling kit. The Swedish national HPV reference laboratory performed extended HPV genotyping and referred high‐risk HPV‐positive women to their regional gynecologist. A total of 3691/28,689 (12.9%) women ordered a self‐sampling kit and 10.0% (2853/28,689) returned a sample for testing. Participation among women who had never attended screening was low, albeit improved. Up to 22.5% of women in other high‐risk groups attended. High‐risk HPV types were detected in 8.3% of samples. High‐risk HPV‐positive women (238/2853) were referred without further triaging and severe cervical precancer or cancer (HSIL+) in histopathology were detected in 36/158 (23%) of biopsied women. Repeat invitations gave modest additional participation. Nationwide contacting of women with high risk for cervical cancer with personal invitations to order HPV self‐sampling kits resulted in high yield of detected CIN2+. Further efforts to improve risk‐stratified screening strategies should be directed to improving (i) the precision of the risk‐stratification algorithm, (ii) the convenience for the women to participate and, (iii) ensuring that screen‐positive women are followed‐up.

Incidence of oncogenic HPV infection in women with and without mental illness: A population-based cohort study in Sweden

Background Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. Methods and findings Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. Conclusions Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide.

Increase of cervical cancer incidence in Sweden in relation to screening history: population cohort study

Cervical cancer case–control audit: Results from routine evaluation of a nationwide cervical screening program

Our study used a refined case–control cervical cancer Audit framework to investigate effectiveness of cervical screening, with measures of three screening failures: irregular‐participation, cervical cancer developed after cytological abnormalities and after normal screening results. The register‐based study included 4,254 cervical cancer cases diagnosed in Sweden during 2002–2011, and 30 population‐based controls per case. We used conditional logistic regression models to examine relative risks of cervical cancer in relation to screening participation and screening results in the past two screening rounds from 6 months before cancer diagnosis. We found that women unscreened in past two screening rounds showed four times increased risk of cervical cancer compared to women screened in time (OR = 4.1, 95% CI = 3.8–4.5), and women unscreened in the previous round but screened in the most recent round also showed a statistically significantly elevated risk (OR = 1.6, 95% CI = 1.5–1.8). Women having abnormality in previous two rounds exhibited higher risk of cervical cancer compared to women screened with normal results, while having normal results in the subsequent round after the abnormality also yielded an increased risk (OR = 4.0, 95% CI = 3.2–5.1). Being screened with only normal results was associated with 89% risk reduction for squamous cell cancer, compared to women unscreened, but only 60% reduction for adenocarcinoma. Our findings emphasize the importance of routine participation in cervical screening and suggest that management of abnormalities, as well as sensitivity of the test, warrants improvement especially for preventing cervical adenocarcinoma. The Audit framework serves as routine evaluation model and the findings benchmark for future evaluation of changes in screening practice.

Impact of cervical screening by human papillomavirus genotype: Population-based estimations

Background Cervical screening programs use testing for human papillomavirus (HPV) genotypes. Different HPV types differ greatly in prevalence and oncogenicity. We estimated the impact of cervical screening and follow-up for each HPV type. Methods and findings For each type of HPV, we calculated the number of women needed to screen (NNS) and number of women needing follow-up (NNF) to detect or prevent one cervical cancer case, using the following individual level input data (i) screening and cancer data for all women aged 25 to 80 years, resident in Sweden during 2004 to 2011 (N = 3,568,938); (ii) HPV type-specific prevalences and screening histories among women with cervical cancer in Sweden in 2002 to 2011(N = 4,254); (iii) HPV 16/18/other HPV prevalences in the population-based HPV screening program (N = 656,607); and (iv) exact HPV genotyping in a population-based cohort (n = 12,527). Historical screening attendance was associated with a 72% reduction of cervical cancer incidence caused by HPV16 (71.6%, 95% confidence interval (CI) [69.1%, 73.9%]) and a 54% reduction of cancer caused by HPV18 (53.8%, 95% CI [40.6%, 63.1%]). One case of HPV16-caused cervical cancer could be prevented for every 5,527 women attending screening (number needed to screen, NNS). Prevention of one case of HPV16-caused cervical cancer required follow-up of 147 HPV16–positive women (number needed to follow-up, NNF). The NNS and NNF were up to 40 to 500 times higher for HPV types commonly screened for with lower oncogenic potential (HPV35,39,51,56,59,66,68). For women below 30 years of age, NNS and NNF for HPV16 were 4,747 and 289, respectively, but >220,000 and >16,000 for HPV35,39,51,56,59,66,68. All estimates were either age-standarized or age-stratified. The primary limitation of our study is that NNS is dependent on the HPV prevalence that can differ between populations and over time. However, it can readily be recalculated in other settings and monitored when HPV type-specific prevalence changes. Other limitations include that in some age groups, there was little data and extrapolations had to be made. Finally, there were very few cervical cancer cases associated with certain HPV types in young age group. Conclusions In this study, we observed that the impact of cervical cancer screening varies depending on the HPV type screened for. Estimating and monitoring the impact of screening by HPV type can facilitate the design of effective and efficient HPV-based cervical screening programs. Trial registration ClinicalTrials.gov with numbers NCT00479375, NCT01511328.

Long‐term follow‐up of cervical cancer incidence after normal cytological findings

AbstractAn increase in cervical cancer incidence in Sweden from 2014 to 2015 has been attributed to an increase in false‐negative cytological findings before cancer diagnoses. Years later, we performed a long‐term follow‐up to investigate whether the problem persisted. At each calendar year from 2016 to 2020, we identified women with prior normal cervical screening results through linkage to the Swedish National Cervical Screening Registry. We reported their incidence rates (IRs) of invasive cervical cancer in consecutive years and compared the IRs over time. For the years 2016 to 2020, there was no overall change in cervical cancer incidence after two normal cytology in the last two screening intervals. However, there was a further 62% increase among women 50 to 60 years of age with normal cytology in the past two screening intervals. The incidence rate of cervical cancer was high among nonscreened women and low among HPV‐screened women with negative results, with no trends over time. Our results imply that the previously reported decrease in sensitivity of cervical cytology is persisting. Although primary cytology screening is no longer used, cytology is used in triaging among HPV‐positive women. Our findings suggest that improved triaging is needed, for example, improved quality assurance and/or use of alternative triage tests.

Clinical Studies of Endometrial Cytology and Cervical Methylation Assays in Endometrial Cancer Screening and Fertility-Preservation Evaluation

The current study aims to assess high-risk patients using both liquid-based cytology and cervical methylation testing. The results will be compared with the traditional hysteroscopic pathological findings to determine the sensitivity and specificity of these methods for early detection of endometrial cancer, thereby evaluating their potential application in early screening. Primary Objectives： 1. To evaluate the sensitivity, specificity, and accuracy of endometrial cytology for screening endometrial cancer. 2. To assess the sensitivity, specificity, and accuracy of methylation testing for screening endometrial cancer. 3. To perform further molecular testing on tissue samples obtained from endometrial cytology and cervical methylation tests, aiming to explore early screening-sensitive indicators. Secondary Objectives： 1. To determine the value of endometrial cytology in evaluating the efficacy of fertility-sparing treatments for endometrial cancer. 2. To assess the value of methylation testing in evaluating the efficacy of fertility-sparing treatments for endometrial cancer.

Screening for Early Cervical Cancer Detection

This study is to audit results and adherence to Cervical Screening program before and after the implementing awareness of the WHO guidelines of screening among the multidisciplinary healthcare workers and patients.

Research Project on Reminders and Self-Sampling Can Increase Participation in Gynecology Cell Sampling - Preventive Examination Against Cervical Cancer.

Prevention of cervical cancer with cervical screening is one of the most successful screening activities in medicine. In Sweden, screening was implemented in the 1960s and has since prevented tens of thousands of women from having cervical cancer. Individual invitations to screening result in increased attendance therefore evaluating strategies for reaching women through invitations is particularly valuable. Women who regularly attend screening following an invitation reduce their risk of cervical cancer by as much as 90%. Of the women who are diagnosed with cervical cancer (about 550 women per year in Sweden), as many as 38% did not participate in the screening. Invitations for screening are sent to the entire population in Sweden aged 23-70. The current coverage of screening is 82.9%, which represents the proportion of women ages 23-70 who attend according to recommendations. In addition, many women are sporadic attenders who reduce their risk for cancer somewhat. The highest cancer risk is seen among those women who have never participated as well as women who have had a history of precancerous lesions or HPV infection but have not been followed-up. Cervical cancer is the first form of cancer for which there are approved molecular screening tests (HPV test). Unlike the older screening method (cytology), self-collected samples can be analyzed for HPV (the analysis method is so sensitive that it does not matter if the sample is not optimally taken). Invitations and reminders about cervical screening are sent by letter to the woman's home address (about 3 million letters per year in Sweden). This strategy results in a waste of resources and has a negative environmental impact. Regarding reminders, we have seen in previous research that the effect is not optimal. When sending a physical reminder letter to women who have not participated in more than 10 years (current routine), only 2% of the women invited came for sampling. Reminders with SMS are now standard for many businesses in society, such as car testing or dental appointments. It is inexpensive, saves the environment and there are studies that suggest it is more effective than sending physical letters. In this study, we intend to investigate whether SMS reminders, electronic letters, and physical letters for screening lead to increased participation and thus to a higher proportion of detected, treatable precursors of cervical cancer compared to before.

Randomized Implementation of Primary HPV Testing in the Organized Screening for Cervical Cancer in Stockholm

The purpose is to evaluate whether implementation of primary human papillomavirus (HPV) screening in the screening programme for cervical cancer improves the programme in terms of better cancer protection and better cost efficiency.

Randomized Controlled Trial of Human Papillomavirus Testing in Primary Cervical Cancer Screening

Human papillomavirus (HPV)-based cervical screening is known to increase sensitivity for detection of high-grade cervical intraepithelial neoplasia (CIN). Randomized trials of longitudinal efficacy are required to assess whether these gains represent overdiagnosis or a protective effect. Methods: A total of 12527 women, aged 32-38, attending population-based invitational screening in Sweden were randomized 1:1 to HPV test and cytology (intervention arm) or cytology only (control arm). HPV-positive women were invited for a second HPV test at least one year later and women with type-specific persistent infections were then invited to colposcopy. A similar number of random double-blinded procedures are performed in the control arm. Women are followed with comprehensive registry-based follow-up. Primary outcome is the relative rates of CIN grade 2 or worse (CIN2/CIN3+) found in subsequent screening. Secondary outcomes are the relative rates of CIN2/CIN3+ found in the aseline screening and outcomes stratified by grade of CIN (CIN 2 or CIN3+).