Emma J Crosbie

Measuring HE4 alongside CA125 for ovarian cancer diagnosis: A pilot clinical study

Gynaecological cancer surveillance for women with Lynch syndrome: systematic review and cost-effectiveness evaluation

Background Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome. Methods We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost–utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing. Results We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery. Limitations Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered. Conclusions There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit. Study registration This study is registered as PROSPERO CRD42020171098. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer

Abstract Background Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort. Methods After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided. Results Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for “other” vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, “other,” and MLH1-hypermethylated MMRd-EC groups, respectively. Conclusions The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.

Diagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples

AbstractPostmenopausal bleeding triggers urgent investigation by sequential invasive tests that are avoidable for the 90–95% of women who do not have endometrial cancer. A simple, non-invasive tool that accurately identifies cancer and safely reassures healthy women could transform patient care. Here we report, in a cross-sectional diagnostic accuracy study of 103 women with known cancer and 113 with unexplained postmenopausal bleeding, that urine and vaginal cytology has a combined sensitivity of 91.7% (95% CI 85.0%, 96.1%) and specificity of 88.8% (81.2%, 94.1%) for gynecological cancer detection. Cytology identifies 91 endometrial, two fallopian tube and one cervical cancer from 103 known cancer cases. In women with unexplained postmenopausal bleeding, cytology identifies all four endometrial cancers and three others (cervical, ovarian and bladder), for a 12/107 (11.2%) false positive rate. We show proof-of-principle that endometrial cancer can be detected in urine and vaginal fluid. Prospective validation of these findings will support incorporation of this non-invasive test into clinical practice.

Predicting risk of endometrial cancer in asymptomatic women (PRECISION): Model development and external validation

AbstractObjectivesDevelop an endometrial cancer risk prediction model and externally validate it for UK primary care use.DesignCohort study.SettingThe UK Biobank was used for model development and a linked primary (Clinical Practice Research Datalink, CPRD) and secondary care (HES), mortality (ONS) and cancer register (NRCAS) dataset was used for external validation.PopulationWomen aged 45–60 years with no history of endometrial cancer or hysterectomy.MethodsModel development was performed using a flexible parametric survival model and stepwise backward selection aiming to minimise the Akaike information criterion. Model performance on external validation was assessed through flexible calibration plots, calculation of the expected to observed ratio and C‐statistic and decision curve analysis.Main outcome measuresEndometrial cancer diagnosis within 1–10 years of the index date.ResultsModel development included 222 031 women (902 incident endometrial cancer cases) and external validation 3 094 371 women (8585 endometrial cancer cases). The final model (with equation provided) incorporated age, body mass index, waist circumference, age at menarche, menopause and last birth, hormone replacement, tamoxifen and oral contraceptive pill use, type 2 diabetes, smoking and family history of bowel cancer. It was well calibrated on external validation (calibration slope 1.14, 95% confidence interval [CI] 1.11–1.17, E/O 1.03, 95% CI 1.01–1.05), with moderate/good discrimination (C‐statistic 0.70, 95% CI 0.69–0.70) and had improved net benefit compared with previously developed models.ConclusionsThe Predicting risk of endometrial cancer in asymptomatic women model (PRECISION), using easily measurable anthropometric, reproductive, personal and family history, accurately quantifies a woman's 10‐year risk of endometrial cancer. Its use could determine eligibility for primary endometrial cancer prevention trials and for targeted resource allocation in UK general practices.

Leading causes of death after a diagnosis of endometrial cancer: a systematic review and meta-analysis

Despite curative treatment, an endometrial cancer (EC) diagnosis is associated with an elevated risk of death compared with age-matched women in the general population. This study aimed to quantify their risk of death from EC, cardiovascular disease, and other causes. A systematic review of Medline, Embase, and CENTRAL databases was performed to February 2024. Studies reporting cause of death after a diagnosis of EC were included. Mortality rates and 95% CIs were calculated using a random-effects model. Heterogeneity was assessed through visual inspection of forest plots and the I In total, 22 studies including 323,551 participants were analyzed and 102,711 (31.7%) died within 20 years of diagnosis, 62.6% (n = 64,155) from non-EC causes. In the 12 studies that reported cardiovascular death, 24.6% of participants (n = 24,309) died from cardiovascular disease. Those with local disease at presentation were more likely to die from non-EC causes than those with advanced disease at presentation (48.9% vs 13.5%). A total of 2 studies reported cause of death by ethnicity; overall, Black individuals were more likely to die than individuals of White or Other ethnicities (40.8% vs 27.9% vs 18.9%). Deaths related to non-EC causes, including cardiovascular disease, overtook EC-specific deaths >5 years after diagnosis. Significant heterogeneity was noted, despite sub-group analyses, and the findings were based on very low certainty evidence. Individuals with a history of EC are at increased risk of death from other causes. Oncology follow-up appointments provide the ideal opportunity to optimize cardiovascular risk factors to reduce preventable deaths. Future research needs to reflect the global majority.

Lay and general practitioner attitudes towards endometrial cancer prevention: a cross-sectional study

Abstract Background Effective and targeted endometrial cancer prevention strategies could reduce diagnoses by 60%. Whether this approach is acceptable to individuals and general practitioners (GPs) is currently unknown. This study sought to determine attitudes towards the provision of personalised endometrial cancer risk assessments and the acceptability of potential prevention strategies. Methods Specific online questionnaires were developed for individuals aged 45–60 years with a uterus and UK-practising GPs, with social media, charity websites, and email used to advertise the study. Individuals completed the questionnaires between February and April 2022. Results Of 660 lay questionnaire respondents, 90.3% (n = 596) thought that undergoing an endometrial cancer risk assessment was a good or very good idea and 95.6% (n = 631) would be willing to undergo such an assessment. The commonest reasons for wanting to participate were “to try and reduce my risk” (n = 442, 67.0%), “to be informed” (n = 354, 53.6%), and “it could save my life’ (n = 315, 47.7%). Over 80% of respondents would make lifestyle changes to reduce their endometrial cancer risk (n = 550), with half accepting a pill, Mirena, or hysterectomy for primary prevention. GPs were similarly engaged, with 93.0% (n = 106) willing to offer an endometrial cancer risk assessment if a tool were available, potentially during a Well Woman screen. Conclusion Personalised endometrial cancer risk assessments are acceptable to potentially eligible individuals and GPs and could be accommodated within routine practice. Clinical trials to determine the effectiveness of lifestyle modification and Mirena for endometrial protection are urgently required and should be targeted at those at greatest disease risk.

Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers

Background Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million. Methods Tumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate. Results In total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%, p<0.0001). Overall, 65/134 (48.5%) patients with MLH1 loss and no MLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss. Conclusions Reflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.

Quantitative SWATH-based proteomic profiling of urine for the identification of endometrial cancer biomarkers in symptomatic women

Abstract Background A non-invasive endometrial cancer detection tool that can accurately triage symptomatic women for definitive testing would improve patient care. Urine is an attractive biofluid for cancer detection due to its simplicity and ease of collection. The aim of this study was to identify urine-based proteomic signatures that can discriminate endometrial cancer patients from symptomatic controls. Methods This was a prospective case–control study of symptomatic post-menopausal women (50 cancers, 54 controls). Voided self-collected urine samples were processed for mass spectrometry and run using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning techniques were used to identify important discriminatory proteins, which were subsequently combined in multi-marker panels using logistic regression. Results The top discriminatory proteins individually showed moderate accuracy (AUC > 0.70) for endometrial cancer detection. However, algorithms combining the most discriminatory proteins performed well with AUCs > 0.90. The best performing diagnostic model was a 10-marker panel combining SPRR1B, CRNN, CALML3, TXN, FABP5, C1RL, MMP9, ECM1, S100A7 and CFI and predicted endometrial cancer with an AUC of 0.92 (0.96–0.97). Urine-based protein signatures showed good accuracy for the detection of early-stage cancers (AUC 0.92 (0.86–0.9)). Conclusion A patient-friendly, urine-based test could offer a non-invasive endometrial cancer detection tool in symptomatic women. Validation in a larger independent cohort is warranted.

Serum HE4 predicts progestin treatment response in endometrial cancer and atypical hyperplasia: A prognostic study

AbstractObjectiveTo investigate serum human epididymis‐4 (HE4) as a predictive biomarker of intrauterine progestin response in endometrial cancer and atypical endometrial hyperplasia (AEH).DesignProspective prognostic factor study.SettingConsecutive sample of women attending a tertiary gynaecological oncology centre in northwest England.PopulationWomen with AEH or early‐stage, low‐grade endometrial cancer who were unfit for or declined primary surgical management.MethodsA total of 76 women, 32 with AEH and 44 with endometrial cancer, were treated with a levonorgestrel intrauterine system (LNG‐IUS) for 12 months. Endometrial biopsies and imaging were performed to assess treatment response. Pretreatment serum HE4 was analysed by chemiluminescence immunoassay and diagnostic accuracy and logistic regression analyses were performed.Main Outcome MeasuresProgestin response at 12 months defined by histology and imaging.ResultsThe median age and body mass index (BMI) of the final cohort were 52 years (interquartile range [IQR] 33–62 years) and 46 kg/m2 (IQR 38–54 kg/m2), respectively. Baseline serum HE4 was significantly higher in non‐responders than responders (119.2 pmol/L, IQR 94.0–208.4 pmol/L versus 71.8 pmol/L, IQR 56.1–84.2 pmol/L, p < 0.001). Older age (odds ratio [OR] 0.96, 95% CI 0.93–0.99, p = 0.02), baseline serum HE4 (OR 0.97, 95% CI 0.96–0.99, p = 0.001) and endometrial cancer histology (OR 0.22, 95% CI 0.72–0.68, p = 0.009) were associated with a lower likelihood of progestin treatment response. Serum HE4 remained independently associated with progestin treatment failure when adjusted for age and histology (adjusted hazard ratio 0.97, 95% CI 0.96–0.99, p = 0.008).ConclusionSerum HE4 shows promise as a predictive biomarker of progestin treatment response in endometrial cancer and AEH.

Prognostic refinement of NSMP high-risk endometrial cancers using oestrogen receptor immunohistochemistry

Abstract Background Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. Methods Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial ( n  = 424), and a Dutch prospective clinical cohort called MST ( n  = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan–Meier method, log-rank tests and Cox’s proportional hazard models were used for survival analysis. Results In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15–0.75). Conclusions We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.

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.

Impact of socio‐economic deprivation on endometrial cancer survival in the North West of England: a prospective database analysis

ObjectiveTo assess the impact of socio‐economic deprivation on endometrial cancer survival.DesignSingle‐centre prospective database study.SettingNorth West England.PopulationWomen with endometrial cancer treated between 2010 and 2015.MethodsAreal‐level socio‐economic status, using the English indices of multiple deprivation from residential postcodes, was analysed in relation to survival using Kaplan–Meier estimation and multivariable Cox regression.Main outcome measuresOverall survival, cancer‐specific survival and patterns and rates of recurrence.ResultsA total of 539 women, with a median age of 66 years (interquartile range, IQR 56–73 years) and a body mass index (BMI) of 32 kg/m2 (IQR 26–39 kg/m2), were included in the analysis. Women in the most deprived social group were younger (median 64 years, IQR 55–72 years) and more obese (median 34 kg/m2, IQR 28–42 kg/m2) than women in the least deprived group (median age 68 years, IQR 60–74 years; BMI 29 kg/m2, IQR 25–36 kg/m2; P = 0.002 and <0.001, respectively). There were no differences in endometrial cancer type, stage or grade between social groups. There was no difference in recurrence rates, however, women in the middle and most deprived social groups were more likely to present with distant/metastatic recurrence (80.6 and 79.2%, respectively) than women in the least deprived group (43.5%, P < 0.001). Women in the middle and most deprived groups had a two‐fold (adjusted hazard ratio, HR = 2.00, 95% CI 1.07–3.73, P = 0.030) and 53% (adjusted HR = 1.53, 95% CI 0.77–3.04, P = 0.221) increase in cancer‐specific mortality compared with women in the least deprived group. There were no differences in overall survival.ConclusionsWe found that socio‐economically deprived women with endometrial cancer were more likely to develop fatal recurrence. Larger studies are needed to confirm these findings and to identify modifiable contributing factors.Tweetable abstractSocio‐economic deprivation is linked to an increased risk of death from endometrial cancer in the North West of England.

A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control Sets

PURPOSE Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival. METHODS We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86). RESULTS We describe the Women's cancer risk IDentification – quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology. CONCLUSION The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits.

Development and evaluation of polygenic risk scores for prediction of endometrial cancer risk in European women

Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention. We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB). Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, P An endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

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.

Discordant prognosis of mismatch repair deficiency in colorectal and endometrial cancer reflects variation in antitumour immune response and immune escape

AbstractDefective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T‐cell infiltrate and favourable outcome; however, this association has not been reliably detected in other tumour types, including endometrial cancer (EC). We sought to confirm this and explore the underpinning mechanisms. We first meta‐analysed CRC and EC trials that have examined the prognostic value of dMMR/MSI and confirmed that dMMR/MSI predicts better prognosis in CRC, but not EC, with statistically significant variation between cancers (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.54–0.73 versus HR = 1.15, 95% CI = 0.72–1.58; PINT = 0.02). Next, we studied intratumoural immune infiltrate in CRCs and ECs of defined MMR status and found that while dMMR was associated with increased density of tumour‐infiltrating CD3+ and CD8+ T‐cells in both cancer types, the increases were substantially greater in CRC and significant only in this group (PINT = 4.3e‐04 and 7.3e‐03, respectively). Analysis of CRC and EC from the independent Cancer Genome Atlas (TCGA) series revealed similar variation and significant interactions in proportions of tumour‐infiltrating lymphocytes, CD8+, CD4+, NK cells and immune checkpoint expression, confirming a more vigorous immune response to dMMR/MSI in CRC than EC. Agnostic analysis identified the IFNγ pathway activity as strongly upregulated by dMMR/MSI in CRC, but downregulated in EC by frequent JAK1 mutations, the impact of which on IFNγ response was confirmed by functional analyses. Collectively, our results confirm the discordant prognosis of dMMR/MSI in CRC and EC and suggest that this relates to differences in intratumoural immune infiltrate and tumour genome. Our study underscores the need for tissue‐specific analysis of cancer biomarkers and may help inform immunotherapy use. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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.

DEveloping Tests for Endometrial Cancer deTection (DETECT): protocol for a diagnostic accuracy study of urine and vaginal samples for the detection of endometrial cancer by cytology in women with postmenopausal bleeding

Introduction Postmenopausal bleeding (PMB), the red flag symptom for endometrial cancer, triggers urgent investigation by transvaginal ultrasound scan, hysteroscopy and/or endometrial biopsy. These investigations are costly, invasive and often painful or distressing for women. In a pilot study, we found that voided urine and non-invasive vaginal samples from women with endometrial cancer contain malignant cells that can be identified by cytology. The aim of the DE veloping T ests for E ndometrial C ancer de T ection (DETECT) Study is to determine the diagnostic test accuracy of urine and vaginal cytology for endometrial cancer detection in women with PMB. Methods and analysis This is a multicentre diagnostic accuracy study of women referred to secondary care with PMB. Eligible women will be asked to provide a self-collected voided urine sample and a vaginal sample collected with a Delphi screener before routine clinical procedures. Pairs of specialist cytologists, blinded to participant cancer status, will assess and classify samples independently, with differences settled by consensus review or involving a third cytologist. Results will be compared with clinical outcomes from standard diagnostic tests. A sample size of 2000 women will have 80% power to establish a sensitivity of vaginal samples for endometrial cancer detection by cytology of ≥85%±7%, assuming 5% endometrial cancer prevalence. The primary objective is to determine the diagnostic accuracy of urogenital samples for endometrial cancer detection by cytology. Secondary objectives include the acceptability of urine and vaginal sampling to women. Ethics and dissemination This study has been approved by the North West–Greater Manchester West Research Ethics Committee (16/NW/0660) and the Health Research Authority. Results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and via charity websites. Trial registration number ISRCTN58863784 .

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.

Polygenic risk score opportunities for early detection and prevention strategies in endometrial cancer

SummaryRecent large-scale genetic studies, particularly genome-wide association studies (GWAS), have emphasised the importance of common genetic variation in endometrial cancer susceptibility. Although each of these variants only confer modest effects on endometrial cancer risk, together they are likely to explain a substantial amount of the familial relative risk of the disease. Therefore, methods to combine genetic risk variants, such as polygenic risk scores (PRS) have gained traction as an attractive method for individualised risk prediction and management. Here, we discuss the benefits of a PRS for endometrial cancer and considerations required for clinical implementation.

Authors' reply re: Mirena Coil is a suitable treatment of early‐stage endometrial cancer in obese women: FOR or AGAINST?

Response to Benusiglio et al.

The Mirena coil is a suitable treatment of early‐stage endometrial cancer in obese women

Association between genetic polymorphisms and endometrial cancer risk: a systematic review

Introduction Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case–control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk. Methods We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion. Results We found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature. Conclusion Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.

Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin

AbstractBackgroundHigh expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin’s anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin.MethodsEndometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed.ResultsIn women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response.ConclusionsUnderstanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.

Detection of endometrial cancer in cervico-vaginal fluid and blood plasma: leveraging proteomics and machine learning for biomarker discovery

The anatomical continuity between the uterine cavity and the lower genital tract allows for the exploitation of uterine-derived biomaterial in cervico-vaginal fluid for endometrial cancer detection based on non-invasive sampling methodologies. Plasma is an attractive biofluid for cancer detection due to its simplicity and ease of collection. In this biomarker discovery study, we aimed to identify proteomic signatures that accurately discriminate endometrial cancer from controls in cervico-vaginal fluid and blood plasma. Blood plasma and Delphi Screener-collected cervico-vaginal fluid samples were acquired from symptomatic post-menopausal women with (n = 53) and without (n = 65) endometrial cancer. Digitised proteomic maps were derived for each sample using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning was employed to identify the most discriminatory proteins. The best diagnostic model was determined based on accuracy and model parsimony. A protein signature derived from cervico-vaginal fluid more accurately discriminated cancer from control samples than one derived from plasma. A 5-biomarker panel of cervico-vaginal fluid derived proteins (HPT, LG3BP, FGA, LY6D and IGHM) predicted endometrial cancer with an AUC of 0.95 (0.91-0.98), sensitivity of 91% (83%-98%), and specificity of 86% (78%-95%). By contrast, a 3-marker panel of plasma proteins (APOD, PSMA7 and HPT) predicted endometrial cancer with an AUC of 0.87 (0.81-0.93), sensitivity of 75% (64%-86%), and specificity of 84% (75%-93%). The parsimonious model AUC values for detection of stage I endometrial cancer in cervico-vaginal fluid and blood plasma were 0.92 (0.87-0.97) and 0.88 (0.82-0.95) respectively. Here, we leveraged the natural shed of endometrial tumours to potentially develop an innovative approach to endometrial cancer detection. We show proof of principle that endometrial cancers secrete unique protein signatures that can enable cancer detection via cervico-vaginal fluid assays. Confirmation in a larger independent cohort is warranted. Cancer Research UK, Blood Cancer UK, National Institute for Health Research.

Understanding preferences for self-sampling in a national cervical screening programme: a protocol for a discrete choice experiment

Introduction The National Health Service Cervical Screening Programme (NHSCSP) currently involves a healthcare professional collecting a cervical sample in a healthcare setting. This method of screening has barriers associated with access to screening appointments and the poor acceptability of the speculum examination. Primary screening through HPV testing has led to the development of self-sampling screening methods including vaginal and urine self-sampling, with many UK studies comparing these screening methods with the current NHSCSP. It is not known what features of self-sampling influence individuals’ preferences and cervical screening uptake. To understand these preferences, we plan to undertake a discrete choice experiment (DCE). This protocol aims to describe the steps taken to design the DCE and the proposed approach to fielding the DCE to identify preferences for different sampling approaches in cervical screening. Methods and analysis An online survey comprising a DCE was designed to understand preferences of individuals for self-sampling methods within the NHSCSP. Attributes and levels for the DCE were generated through an iterative process including a literature review of qualitative studies about self-sampling cervical screening methods, input from cervical screening clinical experts and a patient and public involvement group (n=6). A D-efficient design was used to create choice sets for the DCE survey. Regression-based analysis will be used to estimate the impact of each attribute and level on individual choices. Ethics and dissemination This study has been approved by The University of Manchester Proportionate Research Ethics Committee (2024-20767-37669). The results of the DCE will be submitted for publication in a relevant peer review journal and the results will be presented at national and international conferences. Data statement There are no data associated with this protocol. The data produced by this study and analysis scripts will be made available in a public repository following publication of the study.

Acceptability of Self‐Sampling for Cervical Screening in Ethnically Diverse Groups in Northwest England: A Focus Group Study

ABSTRACT Introduction Research indicates disproportionately low cervical screening uptake by diverse ethnic groups in England. If acceptable, self‐sampling might address population‐specific barriers and improve screening uptake. The Alternative CErvical Screening (ACES) Diversity study aimed to explore the prospective acceptability of self‐sampling (urine sampling and self‐swabbing), as an alternative to current cervical screening, among women from diverse ethnic groups. Methods A qualitative study design was employed using focus groups. Forty‐eight women from diverse ethnic groups were recruited via community partners in Northwest England and a cross‐sectional survey. Eight focus groups were conducted (one online and seven in‐person; four with interpreters for Mandarin, Cantonese, Polish and Urdu). Data were transcribed, translated and analysed in English using thematic framework analysis guided by the Theoretical Framework of Acceptability. Results Three themes were identified. ‘Cultural considerations’ explored how aspects of culture and faith influenced perceptions of self‐sampling. ‘Desire for comfort and control’ reflected views of how self‐sampling increases autonomy by maintaining privacy, potentially reducing both pain and tension associated with screening. ‘Confidence in testing’ illustrates beliefs about self‐sampling, around ease of use, practical challenges and accuracy concerns. Conclusions Self‐sampling for cervical screening was considered highly acceptable. If introduced, self‐sampling could increase cervical screening uptake amongst women from diverse ethnic groups. Having a choice in how to interact with the screening programme and continuing to raise awareness of cervical screening were considered important. Future research should explore the concurrent or retrospective acceptability of urine self‐sampling for cervical screening. Patient or Public Contribution Multiple public involvement discussion sessions in Northwest England‐based community centres were arranged with women to explore and build understanding about cervical screening and speak about the ACES Diversity study. A further session was held, with an interpreter, to discuss the focus group topic guide and study design with women and create an opportunity for any feedback. Written feedback was provided for the recruitment poster from seven women (two East Asian, two Central and Eastern European, two African‐Caribbean and one South Asian).

Investigating the acceptability of cervical screening, using conventional clinician-taken cervical samples or urine self-sampling, at 6 weeks postnatal: A cross-sectional questionnaire

Objectives United Kingdom (UK) guidelines recommend delaying cervical screening due during pregnancy to 12 weeks postnatal, despite a lack of supporting evidence. This questionnaire-based study aimed to determine the feasibility of a clinical study of cervical screening and urine self-sampling for human papillomavirus (HPV) at 6 weeks postnatal, as pilot work suggested this would improve uptake, if offered at the routine postnatal check-up. Methods Females who were pregnant/recently pregnant were invited to participate in a web-based questionnaire. Questions assessed acceptability of postnatal cervical screening at 6 weeks postnatal, analysed with chi-square, Fisher's exact and Mann–Whitney tests. Free-text responses were coded using the Theoretical Framework of Acceptability (TFA) to conduct a qualitative content analysis. Results Among the 454 participants, 266 (58.6%) would be more likely to undergo cervical screening if offered at 6 weeks postnatal, and an even higher proportion expressed increased willingness if urine self-sampling were offered ( n  = 338; 74.4%). Two-thirds (308/454; 67.8%) would be willing to be screened at 6 weeks postnatal for a research study and 356/454 (78.4%) if it would be limited only to urine self-sampling. When considering screening modality, over half (245/454; 54%) would prefer urine self-sampling to cervical screening, although a fifth (93/454; 21%) preferred conventional sampling. Free-text responses were provided by 279 participants, and these highlighted that affective attitude and burden TFA constructs underpinned prospective acceptability of having screening at 6 weeks postnatal. Conclusions Offering cervical screening at the 6-week postnatal check-up has potential to increase cervical screening participation. Most participants would be interested in taking part in the research. The feasibility of screening at 6 weeks postnatal and concurrent acceptability should be tested in pilot clinical studies.

Postnatal instead of normally-timed cervical screening (PINCS-1): a protocol for a feasibility study of paired-sample cervical screening and urine self-sampling at 6 weeks and 12 weeks postnatal in the UK

Introduction Cervical screening rates in the UK are falling, limiting our ability to prevent cervical cancer. Peak incidence of cervical cancer coincides with average age of childbirth, and women with young children are less likely to be screened. Current UK guidelines advise waiting 12 weeks after delivery to perform cervical screening, but this recommendation is not based on evidence from the era of liquid-based cytology or high-risk human papillomavirus (HPV) testing. New mums suggested offering cervical screening at 6 weeks postdelivery, in conjunction with the postnatal check-up with the general practice team in primary care. This study aims to assess the feasibility and acceptability of a paired-sample study design for cervical screening at 6 weeks and 12 weeks postnatal. Methods and analysis A study of 100 participants will be performed to assess feasibility and acceptability of cervical screening at both 6 weeks and 12 weeks postnatal, with urine self-sampling using a Colli-pee collection device at each time point. This will inform whether women are prepared to undergo cervical screening at 6 weeks postnatal and the feasibility of a future pair-wise diagnostic test accuracy (of HPV and abnormal cervical cytology) study or whether alternative study designs are needed. Participants must be aged 24.5–64 years old and eligible for the National Health Service Cervical Screening Programme (NHS CSP). At each appointment, participants will complete a questionnaire about their experience and thoughts regarding screening. Substudies ask participants who withdraw or decline to participate their reasons, to identify barriers. The study will be closed for recruitment once 100 participants have completed the 6-week screen in Postnatal Instead of Normally-Timed Cervical Screening (PINCS-1) or if recruitment is poor and 50% not recruited by 6 months, indicating that a paired-sample design is not feasible. Ethics and dissemination Ethical approval for PINCS-1 was given by the Stanmore Research Ethics Committee. The results, including participant feedback at each stage, built into the trial design, will inform the design of large studies to determine accuracy and clinical impact of cervical screening at 6 weeks postnatal, identifying whether giving choice (eg, from timing of appointments and/or offering self-sampling) will improve screening uptake. Data will inform the sample size needed for future studies to have adequate power. Results will also inform future NHS CSP management. Results will be shared via scientific publication and via conventional and social media channels accessed by young women. Trial registration number ISRCTN10071810 .

Urine high‐risk human papillomavirus testing as an alternative to routine cervical screening: A comparative diagnostic accuracy study of two urine collection devices using a randomised study design trial

AbstractObjectiveTo evaluate the sensitivity of human papillomavirus (HPV) tested urine to detect high‐grade cervical precancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) using two urine collection devices.DesignRandomised controlled trial.SettingSt Mary's Hospital, Manchester, UK.PopulationColposcopy attendees with abnormal cervical screening; a total of 480 participants were randomised. Matched urine and cervical samples were available for 235 and 230 participants using a first‐void urine (FVU)‐collection device and standard pot, respectively.MethodsUrine was self‐collected and mixed with preservative – randomised 1:1 to FVU‐collection device (Novosanis Colli‐pee® 10 mL with urine conservation medium [UCM]) or standard pot. Matched clinician‐collected cervical samples were taken before colposcopy. HPV testing used Roche cobas® 8800. A questionnaire evaluated urine self‐sampling acceptability.Main outcome measuresThe primary outcome measured sensitivity of HPV‐tested urine (FVU‐collection device and standard pot) for CIN2+ detection. Secondary outcomes compared HPV‐tested cervical and urine samples for CIN2+ and evaluated the acceptability of urine self‐sampling.ResultsUrine HPV test sensitivity for CIN2+ was higher with the FVU‐collection device (90.3%, 95% CI 83.7%–94.9%, 112/124) than the standard pot (73.4%, 95% CI 64.7%–80.9%, 91/124, p = 0.0005). The relative sensitivity of FVU‐device‐collected urine was 0.92 (95% CI 0.87–0.97, pMcN = 0.004) compared with cervical, considering that all women were referred after a positive cervical HPV test. Urine‐based sampling was acceptable to colposcopy attendees.ConclusionsTesting of FVU‐device‐collected urine for HPV was superior to standard‐pot‐collected urine in colposcopy attendees and has promising sensitivity for CIN2+ detection. General population HPV testing of FVU‐device‐collected urine will establish its clinical performance and acceptability as an alternative to routine cervical screening.

MSH2 is the very young onset ovarian cancer predisposition gene, not BRCA1

Specialist oncological surgery for removal of the ovaries and fallopian tubes in BRCA1 and BRCA2 pathogenic variant carriers may reduce primary peritoneal cancer risk to very low levels

AbstractRisk‐reducing bilateral salpingo‐oophorectomy (RRBSO) is highly effective for the prevention of high‐grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow‐up before 35/45 years was “risk free” and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow‐up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow‐up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty‐one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013‐0.14), with combined Kaplan‐Meier analysis HR = 0.029 (95% CI = 0.009‐0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001‐0.13) compared to non‐specialist centres (HR = 0.11; 95% CI = 0.02‐0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95‐1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.

The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: A population-based cohort study

The serum biomarker cancer antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers. We studied women in the United Kingdom Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011-31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorized by age: <50 years and ≥50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity, and positive predictive value, were calculated for the standard CA125 cut-off (≥35 U/ml). The probability of a woman having cancer at each CA125 level between 1-1,000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the "risk threshold" at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation. A total of 50,780 women underwent CA125 testing; 456 (0.9%) were diagnosed with ovarian cancer and 1,321 (2.6%) with non-ovarian cancer. Of women with a CA125 level ≥35 U/ml, 3.4% aged <50 years and 15.2% aged ≥50 years had ovarian cancer. Of women with a CA125 level ≥35 U/ml who were aged ≥50 years and who did not have ovarian cancer, 20.4% were diagnosed with a non-ovarian cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall. This varied by age, with a value of 104 U/ml in 40-year-old women and 32 U/ml in 70-year-old women equating to a 3% probability. The main limitations of our study were that we were unable to determine why CA125 tests were performed and that our findings are based solely on UK primary care data, so caution is need in extrapolating them to other healthcare settings. CA125 is a useful test for ovarian cancer detection in primary care, particularly in women ≥50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral.

Assessment of mismatch repair deficiency in ovarian cancer

Background Hereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years. Methods Women with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated, MLH1 promoter methylation testing followed by constitutional testing for Lynch syndrome. Results In total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed MLH1 promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33–59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype. Conclusions Tumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.

The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta‐analysis

AbstractOvarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five‐year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd. The aim of our study was to conduct a systematic review of the literature and meta‐analysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed‐effects meta‐analysis models.I2score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8‐65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high‐quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed.

BRCA1/2 in non-mucinous epithelial ovarian cancer: tumour with or without germline testing?

National guidelines recommend testing all cases of non-mucinous epithelial ovarian cancer (NMEOC) for germline (blood) and somatic (tumour) BRCA1/2 pathogenic variants (PVs). We performed paired germline and somatic BRCA1/2 testing in consecutive cases of NMEOC (n = 388) to validate guidelines. Thirty-four somatic BRCA1/2 (sBRCA) PVs (9.7%) were detected in 350 cases with germline BRCA1/2 (gBRCA) wild-type. All sBRCA PVs were detected in non-familial cases. By analysing our regional germline BRCA1/2 database there were 92/1114 (8.3%) gBRCA PVs detected in non-familial cases (only 3% ≥70 years old) and 245/641 (38.2%) in familial cases. Germline non-familial cases were dominated by BRCA2 in older women (8/271 ≥ 70 years old, all BRCA2). The ratio of sBRCA-to-gBRCA was ≤1.0 in women aged <70 years old, compared to 5.2 in women aged ≥70 years old (P = 0.005). The likelihood of missed germline BRCA1/2 PVs (copy-number variants missed on most somatic assays) by testing only tumour DNA was 0.4% in women aged ≥70 years old. We recommend reflex tumour BRCA1/2 testing in all NMEOC cases, and that gBRCA testing is not required for women aged ≥70 years old with no identifiable tumour BRCA1/2 PV and/or family history of breast, ovarian, prostate and/or pancreatic cancer.

Eliminating Cervical Cancer: Progress and Challenges for High-income Countries

In 2020, the World Health Organization launched a major initiative to eliminate cervical cancer globally. The initiative is built around the three key pillars of human papillomavirus (HPV) vaccination, cervical screening and treatment, with associated intervention targets for the year 2030. The '90-70-90' targets specify that 90% of adolescent girls receive prophylactic HPV vaccination, 70% of adult women receive a minimum twice-in-a-lifetime cervical HPV test and 90% receive appropriate treatment for preinvasive or invasive disease. Modelling has shown that if these targets are met, the elimination of cervical cancer, defined as fewer than four cases per 100 000 women per annum, will be achieved within a century. Many high-income countries are well positioned to eliminate cervical cancer within the coming decades, but few have achieved '90-70-90' and many challenges must still be addressed to deliver these critical interventions effectively. This review considers the current status of cervical cancer control in relation to each of the three elimination pillars in high-income countries and discusses some of the developments that will assist countries in reaching these ambitious targets by 2030.

Does the vaginal microbiome drive cervical carcinogenesis?

A comparison of the carbon footprint of alternative sampling approaches for cervical screening in the UK: A descriptive study

AbstractObjectiveTo understand whether self‐sampling can reduce carbon emissions (CO2e) from the NHS cervical screening programme (NHSCSP) by comparing the carbon footprint of three sampling strategies: routine cervical sampling, vaginal self‐sampling and first‐void (FV) urine collection.DesignDescriptive study.SettingNational Health Service (NHS), United Kingdom (UK).Population or SamplePatients aged 25–64 years eligible for cervical screening in the UK.MethodsA carbon footprint analysis was undertaken for three cervical screening sampling approaches, from point of invitation to screening through to preparation for transport to the laboratory for HPV testing. A combination of primary and secondary data were used, with a bottom‐up approach applied to collection of primary data.Main Outcome MeasuresWe report CO2e per sampling approach, which is the unit used to express carbon footprint and harmonise the contributions of greenhouse gases with different global warming potentials.ResultsThe total carbon footprint of routine cervical sampling is 3670 g CO2e. By comparison, vaginal self‐sampling had a total carbon footprint of 423 g CO2e, and FV urine sampling 570 g CO2e. The largest share of emissions for routine sampling was attributable to the carbon footprint associated with an appointment in a primary care setting, which totalled 2768 g CO2e.ConclusionsRoutine cervical sampling is up to 8.7‐fold more carbon‐intensive than self‐sampling approaches with equivalent effectiveness. We found negligible differences in the carbon footprint of alternative self‐sampling methods, supporting the need for an informed choice of screening options for participants, which includes sharing information on their environmental impacts.

Two self-sampling strategies for HPV primary cervical cancer screening compared with clinician-collected sampling: an economic evaluation

Objective To compare the costs and effects of three sampling strategies for human papillomavirus (HPV) primary screening. Design Cost-consequence analysis from a health system perspective using a deterministic decision tree model. Setting England. Participants A cohort of 10 000 women aged 25–65 years eligible for the National Health Service Cervical Screening Programme (NHSCSP). Methods The model was based on the NHSCSP HPV primary screening pathway and adapted for self-sampling. It used a 3-year cycle: routine screening (year 1) and recall screening (years 2/3). Parameter inputs were informed using published studies, NHSCSP reports and input from experts and manufacturers. Costs were from 2020/2021, British pound sterling (£). Interventions Three sampling strategies were implemented: (1) routine clinician-collected cervical sample, (2) self-collected first-void (FV) urine, (3) self-collected vaginal swab. The hypothetical self-sampling strategies involved mailing women a sampling kit. Main outcome measures Primary outcomes: overall costs (for all screening steps to colposcopy), number of complete screens and cost per complete screen. Secondary outcomes: number of women screened, number of women lost to follow-up, cost per colposcopy and total screening costs for a plausible range of uptake scenarios. Results In the base case, the average cost per complete screen was £56.81 for clinician-collected cervical sampling, £38.57 for FV urine self-sampling and £40.37 for vaginal self-sampling. In deterministic sensitivity analysis, the variables most affecting the average cost per screen were the cost of sample collection for clinician-collected sampling and the cost of laboratory HPV testing for the self-sampling strategies. Scaled to consider routine screening in England, if uptake in non-attenders increased by 15% and 50% of current screeners converted to self-sampling, the NHSCSP would save £19.2 million (FV urine) or £16.5 million (vaginal) per year. Conclusion Self-sampling could provide a less costly alternative to clinician-collected sampling for routine HPV primary screening and offers opportunities to expand the reach of cervical screening to under-screened women.

Investigating the Acceptability of Cervical Screening and Self‐Sampling in Postnatal Women at the 6‐Week Postnatal Check‐Up: A Qualitative Study

ABSTRACT Introduction There is a lack of evidence to support UK and international clinical recommendations to delay cervical screening to 12‐weeks postnatal. In previous studies, half of women were out of date for screening by the end of pregnancy and the majority would be more likely to take up cervical screening, if offered at the 6‐week postnatal check‐up. We explored views about postnatal cervical screening the acceptability of offering cervical screening, using conventional and urine self‐sampling, earlier within the postnatal period. Methods A cross‐sectional qualitative design was used with recruitment from a larger questionnaire‐based study. Twenty‐six online semi‐structured interviews were conducted with 26 pregnant or recently pregnant participants. Interviews were transcribed and pseudonymised. A topic guide was developed, and data analysed using inductive reflexive thematic analysis. Results Three themes were generated from qualitative analysis of verbatim interview transcripts: 1) A window of opportunity; 2) Am I ready yet? Postpartum recovery; and 3) Neglect of women's health in and around pregnancy. Overall, there was a perception that women's health was not a priority in the postnatal period compared with their babies. Conclusion This is the first study to use qualitative interview methods to explore women's views about the offer of cervical screening alongside the postnatal check‐up. Results support the feasibility of a clinical trial to test the accuracy and effect on uptake of offering cervical screening at the postnatal check‐up, although recognised it might be too soon for some. This should be considered in future feasibility research that includes assessment of concurrent acceptability. Patient or Public Contribution This study was performed following focus groups in a quality improvement project, designed to increase uptake of cervical screening in women and people who were pregnant or recently pregnant. The suggestion for combining cervical screening with the routine 6‐week postnatal follow up was an idea generated by new parents and GP practice staff. The Somerset Maternity Voices group provided feedback on study materials, including the consent form and posters. The semi‐structured interview topic guide was designed following free‐text comments in the pre‐PINCS web‐based survey, results of which are published separately. Female pregnant and recently pregnant people, regardless of current gender identity, were included in this study. In line with the Royal College of Obstetricians and Gynaecologists language guide, we will use ‘women’ to describe participants. Clinical Trial Registration Trial was registered with the National Institute for Health and Care Research Central Portfolio Management System (CPMS ID: 55489) and https://bepartofresearch.nihr.ac.uk/ .

The Use of First‐Void Urine to Screen Women Aged 60–79 for HPV in the UK: The Catch‐Up Screen Study

ABSTRACT Objective Almost half the deaths from cervical cancer in the UK are among women aged over 65 who were already above the upper age of screening when primary HPV screening was introduced in the UK in 2019. Our aim is to test the feasibility of a national catch‐up HPV testing programme. Design This first phase of the Catch‐Up Screen study involved randomizing over 3000 invited participants to receive a urine HPV test and a follow‐up telephone call or text message. Setting GP practices in Hull and Manchester, UK. Population Women aged 60–79 who have not undergone primary HPV screening. Methods Eligible women were selected from GP practice records, and 3074 were invited to provide an at‐home first‐void urine sample for HPV testing. Main Outcome Measures Uptake of at‐home urine screening according to screening history, area‐level index of deprivation, and randomised follow‐up method. Results Overall, 59% (1816) of invited women returned a urine sample for HPV testing. Response varied by screening history and index of area‐level deprivation, but 39% of those who declined their last invited NHS screen responded favorably and took part in Catch‐Up Screen. Telephone reminders yielded a 5% absolute increase in response compared to the text message arm ( p  = 0.007). Conclusions An at‐home first‐void urine sample is a viable method for a national catch‐up HPV test and has the potential to address decreasing national coverage among older women being invited for their last screen.

CA125 and age-based models for ovarian cancer detection in primary care: a population-based external validation study

Abstract Background Cancer antigen-125 (CA125) is widely used to investigate symptoms of possible ovarian cancer (OC) in primary care. However, OC risk varies with age and CA125 level. We externally validated the Ovatools models, which provide CA125- and age-specific OC risk. Methods The performance of Ovatools in predicting OC diagnosis within 12 months of primary care CA125 was examined using English healthcare data for women &lt;50 and ≥50 years. Discrimination and calibration were examined, accuracy was calculated at varying risk thresholds and compared to CA125 ≥ 35U/ml. We estimated OCs missed/detected by Ovatools in hypothetical diagnostic pathways, including a two-threshold pathway where moderate risk (1–2.9%) triggered primary care ultrasound, and higher risk (≥3%) triggered urgent cancer referral. Results 342,278 women were included, 0.63% had OC. The AUC was 0.95 in women ≥50 and 0.89 in women &lt;50. When sensitivity/specificity were matched to CA125 ≥ 35U/ml, Ovatools showed marginally improved performance across other accuracy metrics in women ≥50 years. In a two-threshold pathway (≥50 years), 18.3% identified for urgent referral and 1% identified for ultrasound had OC. Discussion Ovatools performed well on external validation. Ovatools could be used to support informed decision-making and to triage women for further investigation based on cancer risk.

Urine human papillomavirus testing for cervical screening in a UK general screening population: a diagnostic test accuracy study

Background Cervical screening uptake is decreasing in the UK, with only 67.5% of those eligible under 50 years old attending in 2022. Barriers include restricted access to screening appointments and poor acceptability of the speculum examination. Urine self-sampling is an alternative cervical screening method that has the potential to improve uptake. Aim To determine the clinical performance and acceptability of human papillomavirus (HPV)-tested urine for cervical screening in a UK general screening population. Design and setting Prospective, cross-sectional diagnostic test accuracy study in North-West England. Method Urine was self-collected using a first-void urine (FVU) collection device (DNA Genotek Colli-Pee® 10 ml with urine conservation medium) before obtaining matched routine cervical screening samples. HPV testing used Roche Cobas® 8800 at cervical sample thresholds. A questionnaire evaluated urine self-sampling acceptability. HPV-positive cervical samples underwent reflex cytology, managed under standard NHS protocols, and clinical outcomes were collected. Results In total, 1517 participants provided matched urine and cervical samples. There were 207 of 1517 (13.6%) cervical and 245 of 1517 (16.2%) urine samples that were HPV positive with a 1.6% ( n = 25/1517) incidence of cervical intraepithelial neoplasia (CIN)2+ following colposcopic assessment ( n = 80). The specificity of urine was non-inferior ( P = 0.0004) to the specificity of cervical samples at 85.19% (95% confidence interval [CI] = 83.28 to 86.95) versus 87.80% (95% CI = 86.03 to 89.42), giving a relative specificity of 0.97 (95% CI = 0.95 to 0.99). Urine detected 24 of 25 (96.0%) participants with CIN2+. In the future, 41.6% ( n = 575/1382) of participants would prefer current cervical screening, compared with 30.0% ( n = 414/1382) with no preference and 28.4% ( n = 393/1382) preferring urine self-sampling. Conclusion HPV-tested urine showed non-inferior specificity to cervical samples in a general screening population. Urine self-sampling was acceptable to current attenders but some prefer traditional screening, making choice an important consideration for policymakers.

Utilizing Serum-Derived Lipidomics with Protein Biomarkers and Machine Learning for Early Detection of Ovarian Cancer in the Symptomatic Population

Abstract Ovarian cancer is the fifth leading cause of cancer-related deaths among women. Most patients are diagnosed at late stage (III/IV), resulting in a 5-year survival rate below 30%. This is driven by the presentation of vague abdominal symptoms that confound diagnosis at early stages (I/II) and a shortage of robust biomarkers. We are taking a novel approach for earlier ovarian cancer detection, leveraging lipids as biomarkers. We utilized untargeted ultrahigh pressure liquid chromatography–mass spectrometry to analyze sera from two large, independent cohorts (N = 433 and N = 399) designed to reflect the symptomatic population, including individuals with benign adnexal masses, early- and late-stage ovarian cancer, gastrointestinal disorders, and otherwise healthy women seeking care for symptoms. We identified a significantly altered lipid profile in ovarian cancer and early-stage ovarian cancer specifically across both cohorts compared with controls. We also profiled select protein biomarkers (cancer antigen 125, human epididymis protein 4, β-2 folate receptor α, and mucin 1) and, utilizing machine learning–based modeling, identified a proof-of-concept multiomic model consisting of less than 20 top-performing lipid and protein features. This model was trained on cohort 1 and tested on cohort 2, achieving AUCs of 92% (95% confidence interval, 87%–95%) for distinguishing ovarian cancer from controls and 88% (95% confidence interval, 83%–93%) for distinguishing early-stage ovarian cancer from controls. These findings demonstrate the clinical utility and robustness of lipids as proof-of-concept diagnostic biomarkers for early ovarian cancer within the clinically complex symptomatic population, particularly when applied in a multiomic approach. Significance: Patients with ovarian cancer endure delayed diagnosis and poor outcomes. We profiled lipids in two cohorts and integrated them with proteins in machine learning. This enabled early-stage detection in a complex range of controls.

Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene

The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. Panel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Evaluation of DNA Methylation Markers for Endometrial Cancer Risk-stratification Using Patient-collected Urine and Vaginal Samples and Clinician-collected Cervical Samples From Women With Postmenopausal Bleeding

The goal of this observational study is to investigate the clinical utility of DNA-methylation testing in urine and vaginal samples collected by patients and cervical samples collected by clinicians, to determine the risk of endometrial cancer in symptomatic women with postmenopausal bleeding. The study aims to answer the following research questions: * What is the diagnostic accuracy of DNA methylation testing in urine, vaginal and cervical samples compared to traditional TVUS for endometrial cancer detection? * What is the 2-year risk of EC among women testing negative on TVUS and/or DNA methylation tests or those testing positive on methylation only? Researchers will compare DNA methylation testing in patient-collected urine and vaginal samples as well as in clinician-collected cervical samples, with the traditional diagnostic pathway for women with PMB, which includes TVUS evaluation, and when indicated by abnormal TVUS findings, endometrial biopsy according to clinical guidelines. Participants will * take a urine and vaginal sample * have a cervical sample collected by a clinician * undergo TVUS evaluation according to clinical guidelines * If TVUS shows thickened endometrium (≥ 5 mm) and/or irregularity, an endometrial biopsy will be collected according to clinical guidelines * fill out a questionnaire regarding acceptability and preferences of sampling methods and complete a lifestyle questionnaire.

Human Papillomavirus (HPV) Self-Sampling Options to Promote Equity

This study is testing a new way to help people who are unhoused get screened for cervical cancer. Cervical cancer can often be prevented if it is found early. Many people who lack stable housing usually do not receive regular screenings. Through this project, the investigators will bring screening to community locations in Tucson, Arizona, using a mobile health unit (MHU) from the University of Arizona (UA) and El Rio Health. At these sites, participants will receive easy-to-understand education about cervical cancer, learn how to collect their own sample for human papillomavirus (HPV) testing, and get follow-up care if needed. The study has two goals: * First, the investigators will see if this community-based approach helps more people complete cervical cancer screening. * Second, the investigators will ask participants, clinicians, and outreach staff for their opinions about the program and its practicality and acceptability. By testing this approach, the investigators hope to find a way to make cervical cancer screening more accessible and effective for unhoused individuals.

The Clinical Utility of DNA Methylation Testing in Patient-collected Urine and Vaginal Samples to Detect Endometrial Cancer: a Case-control Study

The goal of this observational case-control study is to investigate the use of DNA-methylation testing in patient-collected urine and vaginal samples to detect endometrial cancer. The study aims to answer the following questions: * Can DNA methylation testing in vaginal and full-void urine samples distinguish endometrial cancer cases from healthy controls? Researchers will compare patient-collected urine and vaginal samples from patients with diagnosed endometrial cancer (cases) to gynaecologically and oncologically healthy controls (controls). Participants will * take a urine and vaginal sample at the hospital. * answer a questionnaire regarding acceptability and preferences of self-sampling methods. * answer a lifestyle questionnaire.

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.

Clinical and Pathological Characteristics of Women With Ovarian Cancers in Syria

the goal of this observational study is to describe ovarian cancer epidemiology and characteristics in Syrian women, especially during the war to do more research in the future about the risk factors of ovarian cancer.

Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer

RATIONALE: Drugs used in chemotherapy, such as cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving chemotherapy together with radiation therapy is more effective than giving radiation therapy alone in treating endometrial cancer. PURPOSE: This randomized phase III trial is studying chemotherapy and radiation therapy to see how well they work compared with radiation therapy alone in treating patients with high-risk, stage I, stage II, or stage III endometrial cancer.