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Background Long-term follow-up of large cohorts is needed to determine the effects of HPV and screening on CIN3 (grade 3 cervical intraepithelial neoplasia) and ICC (invasive cervical cancer). Methods Women were recruited when attending for routine cervical screening in Greater Manchester, UK: 1987–93 for the Manchester Cohort (MC: 47,625 women) and 2001–03 for the ARTISTIC Cohort (AC: 24,496 women). Both were followed through national registration for cancer incidence and mortality to 2020. Results Risk patterns following HPV infection differed for CIN3 and ICC. Risk of ICC in the MC rises for 30 years following a single positive HPV test, reaching 2.5% (95% CI: 1.3–4.5%). A similar pattern was seen in the AC, but the risks of cancer were approximately halved. CIN3 was diagnosed much sooner in the AC due to more efficient cytology. More sensitive HPV testing was able to better predict future risk. Conclusion The sensitivity of HPV testing and cytology influences the CIN3 detection rate. Sensitive HPV testing enables effective risk stratification. Increased risk of ICC is observed 15–30 years after HPV infection. Women testing HPV + should be followed until their infection clears. Discharging women from screening programmes whilst they remain HPV + may not be safe, even if cytology and colposcopy tests are normal.

Background Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants. Methods We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods. Results DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS. Conclusions Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.

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.

The 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 1,086 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 three 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. This article is protected by copyright. All rights reserved.

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, PAn endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

The frequency of lung cancer detection in the Manchester Lung Health Checks (MLHCs), a community-based screening service, was higher than in the National Lung Screening Trial (NLST) over two screening rounds. We aimed to identify the potential reasons for this difference.We analyzed individual-level data from NLST and MLHCs, restricting to MLHCs participants who met NLST eligibility criteria. We calculated 'detection ratios' comparing the frequency of lung cancer detection in MLHCs vs NLST, first after excluding NLST participants ineligible by MLHC eligibility criteria (6-year lung cancer risk ≥ 1.51 %), and then after standardization to remove the influence of different distributions of baseline lung cancer risk.Among the 1,079 MLHCs participants who met NLST eligibility criteria, 4.7% were diagnosed with lung cancer over two screening rounds compared with 1.7% in NLST, giving an initial detection ratio of 2.6 (95%CI 2.2-3.0). This was reduced to 2.2 (95%CI 1.3-2.3) after imposing the MLHCs eligibility criterion on NLST, and further to 1.6 (95%CI 1.2-2.1) after removing the influence of different risk distributions. In stratified analyses, the standardized detection ratio was particularly elevated in individuals who were older, living in areas of high socioeconomic disadvantage, or had an FEV/FVC ratio less than 60.The 2.6-fold higher lung cancer detection in the community-based MLHCs vs NLST is partly explained by differences in eligibility criteria and baseline risk distributions. The residual 60% increase may relate to higher detection in certain risk groups, including older participants, those with more obstructive lung disease, and those living in areas of socioeconomic disadvantage.

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.

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

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.

Supplementary Data from Quantifying the Effect of Physical Activity on Endometrial Cancer Risk

Immunohistochemical antibodies and protocols

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.

Immunohistochemistry staining protocols

Supplementary methods

Purpose:Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin in vivo using a robust window study design.Patients and Methods: A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K–Akt–mTOR and insulin signaling pathways and obesity.Results:Eighty-eight women received metformin (n = 45) or placebo (n = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference −0.57%; 95% CI, −7.57%–6.42%; P = 0.87). Metformin did not affect expression of markers of the PI3K–Akt–mTOR or insulin signaling pathways, and did not result in weight loss.Conclusions:Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.

Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type.Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships.Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction = 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P = 0.34) or histologic type (P = 0.26).Conclusions: HRT use modifies the BMI-endometrial cancer risk association.Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30. ©2010 AACR.

Abigail E Derbyshire,1 Michelle L MacKintosh,1 Christina M Pritchard,1 Arya Pontula,2 Basil J Ammori,3,4 Akheel A Syed,4,5 Rebecca J Beeken,6 Emma J Crosbie1,2 1Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester, UK; 2Division of Cancer Sciences, University of Manchester, Manchester, UK; 3Department of Surgery, Salford Royal NHS Foundation Trust, Salford, UK; 4Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK; 5Department of Obesity Medicine, Diabetes & Endocrinology, Salford Royal NHS Foundation Trust, Salford, UK; 6Leeds Institute of Health Sciences, University of Leeds, Leeds, UKCorrespondence: Emma J CrosbieDivision of Cancer Sciences, University of Manchester, Manchester, UK, Tel +44 161 701 6942, Email emma.crosbie@manchester.ac.ukIntroduction: Endometrial cancer rates are rising in parallel with the global obesity epidemic. Our aim was to assess the willingness of women at greatest risk of obesity-related endometrial cancer to engage with risk-reducing strategies and establish perceived barriers that may preclude their participation in a randomized controlled trial of primary endometrial cancer prevention.Materials and Methods: Women attending gynecology, obesity and sleep apnea clinics in Manchester Academic Health Sciences Centre-affiliated hospitals with obesity classes II (BMI 35– 39.9kg/m2) and III (BMI ≥ 40kg/m2) were invited to participate in a cross-sectional survey. We asked women about their perceived risk, knowledge of risk factors and willingness to engage with endometrial cancer risk-reducing interventions.Results: Seventy-four women with a median age of 51 years (range 22– 73) and BMI of 47kg/m2 (range 34– 81) took part in the study. Two-thirds (65.6%) knew that obesity was a risk factor for endometrial cancer but few were able to recall other major risk factors. Just over half (53.5%) perceived their risk of developing endometrial cancer to be higher than average. Women were prepared to lose weight (94%), eat healthily (91%), exercise more (87%), take a pill every day (74%) or receive an intra-uterine device (49%) for primary endometrial cancer prevention. Perceived barriers included cost, forgetting, willpower, finding time, physical fitness, social anxiety, possible side effects and previous bad experiences.Conclusion: Women at highest risk of obesity-related endometrial cancer may not always appreciate their susceptibility. However, willingness to engage in risk-reducing strategies suggests recruitment to a randomized controlled trial for primary endometrial cancer prevention could be feasible.Keywords: endometrial cancer, obesity, risk reducing interventions, weight loss, exercise, chemoprevention, levonorgestrel-releasing intrauterine system, metformin

Background Global annual cancer incidence is forecast to rise to 27.5M by 2040, a 62% rise from 2018. For most cancers, prevention and early detection are the most effective ways of reducing mortality. This study maps trials in cancer screening, prevention and early diagnosis (SPED) to identify areas of unmet need and highlight research priorities. Methods A systematic mapping review was conducted to evaluate all clinical trials focused on cancer SPED, irrespective of tumour type. The National Cancer Research Institute (NCRI) portfolio, EMBASE, PubMed and Medline were searched for relevant papers published between 01/01/2007 and 01/04/2020. References were exported into Covidence software and double-screened. Data were extracted and mapped according to tumour site, geographical location, and intervention type. Results 117,701 abstracts were screened, 5157 full texts reviewed, and 2888 studies included. 1184 (52%) trials focussed on screening, 554 (24%) prevention, 442 (20%) early diagnosis and 85 (4%) a combination. Colorectal, breast and cervical cancer comprised 61% of all studies compared with 6.4% in lung and 1.8% in liver cancer. The latter two are responsible for 26.3% of global cancer deaths compared with 19.3% for the former three. Number of studies varied markedly according to geographical location; 88% were based in North America, Europe or Asia. Conclusions This study shows clear disparities in the volume of research conducted across different tumour types and according to geographical location. These findings will help drive future research effort so that resources can be directed towards major challenges in cancer SPED.

BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case-control study of 3,767 cases and 2,043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3-444.2; P=0.0001). The risk was highest for women with EOC (OR=140.8; 95% CI 23.5-1723.0; PT was associated with smaller risks for BC/EOC (OR=5.4; 95%CI 2.4-12.7; P=0.0003), EOC (OR=5.9; 95% CI 1.3-23.0; p=0.0550), and BC (OR=5.3; 95%CI 2.3-12.9; P=0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant-negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant-negative missense variants may confer higher risks than their loss-of-function counterparts.

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.

ObjectiveTo compare the cost and effects of three sampling strategies for human papillomavirus (HPV) primary screening.DesignCost-consequence analysis using a decision tree in Excel.SettingEngland.ParticipantsA cohort of 10,000 women age 25 to 65 eligible for the NHS Cervical Screening Programme (NHSCSP) (Box 1).MethodsThe model was informed by the NHSCSP HPV primary screening pathway and adapted for self-sampling. It used a 3-year recall cycle with routine screening in year 1 and recall screening in years 2/3. Parameters were obtained from published studies, manufacturers, NHSCSP reports, and input from experts.InterventionsThree sampling strategies were: 1) routine clinician-collected cervical sample, 2) self-collected first-void (FV) urine; 3) self-collected vaginal swab. The hypothetical self-sampling strategies involved women being mailed a sampling kit at home.Main outcome measuresPrimary 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.ResultsIn 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 (DSA), 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.ConclusionSelf-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.Strengths and limitations of the studyThis is the first study to assess the cost of screening for cervical cancer using self-collected first-void urine or vaginal swab compared to the current strategy of clinician-collected cervical sampling within the context of England’s NHS Cervical Screening Programme (NHSCSP).The cost per screen was used to calculate the total cost of the NHSSCP in England, allowing a comparison of different uptake scenarios if self-sampling was offered to non-attenders only or to all eligible women.Limited published data were available to inform the cost of self-sampling devices and HPV laboratory testing of self-collected samples.One pathway for self-sampling was examined. However, there are alternative pathways which could be explored, some of which are dependent on new technologies, such as DNA methylation testing, being validated and costed.

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.

Increased adiposity is a known risk factor for endometrial cancer (EC). This study aimed to disentangle the separate causal roles of child and adult adiposity on EC risk in adults, including endometrioid and non-endometrioid histological subtypes using multivariable Mendelian randomisation. These analyses employed genetic associations derived from UK Biobank as proxies for child and adult body size in 12,906 cases and 108,979 controls that participated in the Endometrial Cancer Association Consortium. In multivariable analyses, adult body size increased overall EC (OR 2.30, 95% CI 1.73-3.06) and endometrioid EC risk (OR 2.28, 95% CI 1.65-3.16), while child body size had minimal effect. In contrast, child body size (OR 2.26, 95% CI 1.03-4.99) but not adult body size increased non-endometrioid EC risk. As such, child adiposity has an indirect effect on endometrioid EC risk that is mediated by adult adiposity but has a direct effect on non-endometrioid EC risk that is independent of adult adiposity. These novel findings indicate that interventions targeting adiposity during distinct periods in life have a critical role in preventing subtype-specific EC.

BackgroundWomen testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers.MethodsWomen were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk.ResultsIn total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01–24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO–10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%.ConclusionOver a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.

Key content Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk-reducing strategies.Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is now recommended by the National Institute for Health and Care Excellence; thus, gynaecologists must become familiar with testing strategies and their results.Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing. Learning objectives To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk-reducing strategies to enable informed decision-making. Ethical issues Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk-reducing hysterectomy.Genetic testing may yield variants of unknown significance with ill-defined clinical implications, which can lead to confusion and anxiety.Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial.

Risk-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

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

Endometrial cancer (EC) is the most common gynaecological malignancy, and its incidence is rising alongside the growing prevalence of obesity. Effective risk-reducing interventions hijacking the key mechanisms driving endometrial carcinogenesis may affect EC diagnoses if aimed at those at greatest risk. An understanding of the key risk factors and their role in tumourigenesis is critical in developing such prevention strategies. In this review, we summarise the major risk factors for EC and the evidence for available risk-reducing interventions in high-risk women. We suggest potential prevention strategies and make a case for the need for risk prediction models that identify specific groups of women at a particularly high risk of EC for whom risk-reducing interventions are likely to have a significant impact.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: We aim to assess population‐level effects of human papillomavirus (HPV) vaccination programmes on HPV‐related disease and harms from vaccination.

Clinical guidelines recommend testing both germline and tumour DNA forAn observational study that included all tumourOne hundred and thirteen tumourWe predict the likelihood of a tumour

PURPOSE: Epithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and/or mismatch repair genes. We aimed to review the testing of women with familial EOC at our center.METHODS: Women with familial EOC (≥2 EOC in family, including index case) referred to our center between 1993 and 2021 were included. Genetic testing (BRCA/Lynch syndrome screening, exome sequencing, panel testing, 100,000 Genome Project, and NIHR BioResource genome sequencing) and clinical demographic, diagnosis, and survival data were reviewed.RESULTS: Of 277, 128 (46.2%) women were BRCA heterozygotes (BRCA1: 89, BRCA2: 39). The detection rate in BRCA-negative women was 21.8%; the most commonly affected gene was BRIP1 (5.9%). The non-BRCA detection rate was significantly higher in families with 2 affected members with EOC only (22.4%) than the families with ≥3 (11.1%) affected members (odds ratio = 9.9, 95% CI = 1.6-105.2, P = .0075). Overall, 112 different PVs in 12 homologous recombination/mismatch repair genes were detected in 150 of 277 (54.2%) unrelated women.CONCLUSION: This is the largest report of women with familial EOC undergoing wider testing to date. One-fifth of BRCA-negative women were heterozygous for a PV in a potentially actionable gene. Wider genetic testing of women with familial EOC is essential to optimize their treatment and prevention of disease in family members.

To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer. ispartof: ISCIENCE vol:26 issue:5 ispartof: location:United States status: published

ObjectivesTo evaluate incident cardiovascular outcomes and imaging phenotypes in UK Biobank participants with previous cancer.MethodsCancer and cardiovascular disease (CVD) diagnoses were ascertained using health record linkage. Participants with cancer history (breast, lung, prostate, colorectal, uterus, haematological) were propensity matched on vascular risk factors to non-cancer controls. Competing risk regression was used to calculate subdistribution HRs (SHRs) for associations of cancer history with incident CVD (ischaemic heart disease (IHD), non-ischaemic cardiomyopathy (NICM), heart failure (HF), atrial fibrillation/flutter, stroke, pericarditis, venous thromboembolism (VTE)) and mortality outcomes (any CVD, IHD, HF/NICM, stroke, hypertensive disease) over 11.8±1.7 years of prospective follow-up. Linear regression was used to assess associations of cancer history with left ventricular (LV) and left atrial metrics.ResultsWe studied 18 714 participants (67% women, age: 62 (IQR: 57–66) years, 97% white ethnicities) with cancer history, including 1354 individuals with cardiovascular magnetic resonance. Participants with cancer had high burden of vascular risk factors and prevalent CVDs. Haematological cancer was associated with increased risk of all incident CVDs considered (SHRs: 1.92–3.56), larger chamber volumes, lower ejection fractions, and poorer LV strain. Breast cancer was associated with increased risk of selected CVDs (NICM, HF, pericarditis and VTE; SHRs: 1.34–2.03), HF/NICM death, hypertensive disease death, lower LV ejection fraction, and lower LV global function index. Lung cancer was associated with increased risk of pericarditis, HF, and CVD death. Prostate cancer was linked to increased VTE risk.ConclusionsCancer history is linked to increased risk of incident CVDs and adverse cardiac remodelling independent of shared vascular risk factors.

Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour BRCA1/2 variants. The value of germline BRCA1/2 testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour BRCA1/2 testing by the North West of England Genomic Laboratory Hub. A subgroup of women also underwent germline testing using a panel of homologous recombination repair (HRR) genes and/or tumour testing for homologous recombination deficiency (HRD) using Myriad’s myChoice® companion diagnostic. Seven-hundred-two patients successfully underwent both germline and tumour BRCA1/2 testing. Of these, 48 were diagnosed with non-mucinous high-grade EOC aged ≥80. In this age group, somatic BRCA1/2 pathogenic/likely pathogenic variants (PV/LPVs) were detected nine times more often than germline BRCA1/2 PV/LPVs. The only germline PV reported in a patient aged ≥80 was detected in germline and tumour DNA (BRCA2 c.4478_4481del). No patient aged ≥80 had a germline PV/LPVs in a non-BRCA1/2 HRR gene. Thirty-eight percent of patients aged ≥80 had a tumour positive for HRD. Our data suggest that tumour BRCA1/2 and HRD testing is adequate for patients diagnosed with non-mucinous high-grade EOC aged ≥80, with germline BRCA1/2 testing reserved for women with a tumour BRCA1/2 PV/LPVs.

In England, a risk-based approach is used to determine eligibility for lung cancer screening. Ensuring effective communication and counselling of risk is therefore increasingly important. In this study, we explore the perception of lung cancer risk in attendees of a community-based screening service, located in socio-economically deprived areas of Manchester. We analyse responses based on demographic variables, calculated risk score and screening eligibility.The Manchester Lung Health Check (LHC) programme invited ever smokers, age 55-80, to a lung cancer risk assessment in which their 6-year risk was calculated (using the PLCO371 participants completed the questionnaire; 66% (n = 243) had linked clinical data. Perceived absolute risk was markedly higher than calculated risk (median: 20% vs. 1%; p 0.001) and higher in women than men (25% vs. 15%; p = 0.001). There was no correlation between perceived absolute and calculated risk. Overall, 30% classified themselves at higher, and 21% at lower, lung cancer risk compared to others their age. Median PLCOEmploying comparative rather than absolute risk may assist risk counselling. Further research is required to determine the optimal approach to risk communication in this setting.

Objectives Rates of vulvar cancer are increasing globally. Early detection reduces surgical morbidity and prolongs survival. Although population screening has no role, vulvar self-examination may prompt early diagnosis in high-risk women. UK guidance promotes self-examination in women with high-risk vulvar conditions, but there is a lack of evidence about current practice, acceptability and barriers to vulvar self-examination. Methods Clinician questionnaires were completed at a UK vulvar conference. Patient questionnaires (incorporating vulvar self-examination and cancer awareness) were distributed through patient networks and clinics. Results All ninety-eight clinicians agreed that self-examination plays an important role in detecting sinister vulvar changes in high-risk women. 87% recommended monthly self-examination and 81% provided one-to-one teaching despite believing that few patients practised self-examination. 455 patients (median age 58 years) with lichen sclerosus(69%), lichen planus(13%), vulvar cancer(14%) and VIN(13%) participated. Clinic respondents(n=197) were older(median 65 vs 52 years, p Conclusions Patients and clinicians recognise that vulvar self-examination is important in early detection of cancer, but a lack of formal teaching impairs confidence in the identification of abnormalities. Visual aids may facilitate self-examination but should be reinforced by education and support.

Novel diagnostics for uterine cancer are urgently needed to reduce the burden of invasive testing for the majority of healthy women with postmenopausal bleeding. We have previously shown that uterine cancer cells can be detected by cytology in urine and vaginal samples with high diagnostic accuracy. Here, we demonstrate its potential to distinguish malignant cells of different aetiologies in the same urogenital biofluid sample according to their distinctive morphology and immunoprofiles. Synchronous tumours of the urogenital tract are uncommon but can cause diagnostic confusion, delays and poor outcomes. A 79-year-old woman presented to accident and emergency with postmenopausal bleeding. Voided urine and Delphi screener-collected vaginal samples were assessed by cytology and immunocytochemistry. Two malignant cell populations with distinct morphology and immunophenotypes consistent with synchronous uterine and urothelial tumours were identified. Subsequent routine diagnostics confirmed concurrent uterine carcinosarcoma and high-grade urothelial carcinoma of the bladder. This case demonstrates that cytology and adjunctive immunocytochemistry can simultaneously identify and phenotype cancers of different aetiologies from a single urogenital biofluid sample. This can help rationalise diagnostic pathways in complex, unusual cases of dual urogenital primaries.

Introduction/Background* The TransPORTEC Consortium was established in 2013 by the PIs and translational science representatives of the PORTEC-3 trial groups from the Netherlands, United Kingdom, Australia, Canada and France. Purpose of the collaboration is to improve treatment of endometrial cancer (EC) patients. Here, we evaluate our experience with international collaboration to identify challenges and strengths. Methodology Result(s)*: Since its establishment, TransPORTEC had a strong scientific team of chief investigators, translational leads and core members from participating groups. Twice-yearly TransPORTEC-meetings were organised to build and maintain friendships, share results and discuss new proposals. Over time, the TransPORTEC-biobank has expanded with PORTEC-trial tumour tissues and other cohorts, and is now the world’s largest set of molecularly classified ECs. The research focus has expanded to include molecular cancer immunology and digital pathology. The group’s output include 10 scientific papers and numerous posters and presentations on (inter)national meetings. Their analysis of PORTEC-3 showing differences in chemotherapy effect by molecular group led to initiating an international program with 4 clinical trials on Refining Adjuvant treatment IN endometrial cancer Based On molecular features (RAINBO) to compare personalised to standard treatment in terms of efficacy, toxicity, quality of life and cost-utility (figure 1). Tumour material of all participants will be collected for translational research. To achieve this, the consortium evolved: new talented members were attracted and trial-specific and expertise teams were installed (figure 2). Despite this impacting on group equilibrium, the collaboration is continuously productive. Keys to success were frequent meetings, sharing of draft protocols and experiences with contacting (inter)national research organisations and potential funders. The first of the RAINBO trials is expected to open by the end of 2021 and the program will probably fuel translational research for years to come. Conclusion* International research collaborations are dynamic and demanding. Challenges include: balancing between a stable organisational structure and flexibility to adapt to opportunities; providing all members with a satisfying share; and acquisition of funding for academic-sponsored international trials. Strengths are the profound interaction and trust between members with different expertise and backgrounds and shared ambitions and successes, resulting in unique and innovative academic research projects with leverage.

Introduction/Background* The molecular endometrial cancer (EC) classification has proven prognostic value and can direct adjuvant treatment decisions. Despite this, a relatively large group of EC is still molecularly unclassified (NSMP-EC). In this study we aimed to identify biomarkers among high-risk NSMP-EC patients with prognostic and/or predictive relevance. Methodology Paraffin-embedded tumour material (n=423) from the PORTEC-3 HREC trial were available for analysis. All patients with NSMP-EC were selected, hence those without pathogenic POLE mutations, mismatch repair deficiency and p53-abnormal immunohistochemistry (IHC). Protein expression of L1CAM, ER and PR (ongoing) were analysed by IHC using a 10% threshold for positivity. Tumour DNA was analysed for pathogenic somatic mutations using a next generation sequencing (NGS) cancer hotspot panel. Time to recurrence was analysed using the Kaplan-Meier method, log-rank tests and Cox’s proportional hazard models. Result(s)* In total, 126 NSMP-EC were identified in PORTEC-3, the majority were hormone receptor positive (ER n=106/121, 87.6%, PR will be presented at ESGO2021). L1CAM overexpression was observed in 11.2% (n=14/125) and mutations in CTNNB1-exon-3 were identified in 34.3% (n=36/105). Clustering showed that ER-positive NSMP-EC were predominantly endometrioid EC (n=99, 93.4%), low grade (n=88, 83.0%) and L1CAM-negative (n=102, 97.1%) (figure 1). PIK3CA and KRAS mutations were present in 27.3% (n=24) and 19.3% (n=17), respectively. ER-negative NSMP-EC were frequently non-endometrioid (n=11, 73.3%), L1CAM-positive (n=11, 73.3%) and rarely harboured PTEN and CTNNB1 mutations (n=1, 7.1% and 0%, respectively). ER-positivity was associated with lower risk of recurrence (HR 0.32 [95%CI 0.14-0.70]; figure 2A), while L1CAM-overexpression and CTNNB1-exon-3 mutations were not (HR 2.25 [95%CI 0.93-5.43] and HR 1.20 [95%CI 0.57-2.54], respectively). Multivariable analysis confirmed independent favourable prognostic impact of ER-positivity and LVSI. Figure 2B shows impact of LVSI on time to recurrence among patients with ER-positive NSMP-EC. Conclusion* The vast majority of NSMP-HREC are ER-positive (87.6%) and are likely sensitive to hormonal therapy. Other treatment targets might be found in this subgroup too as 27.3% had PIK3CA and 19.3% had KRAS mutations. NSMP-EC with loss of ER-expression were often of non-endometrioid histology and had a high risk of recurrence. Future studies should investigate whether this subgroup would benefit from other systemic therapies.

Introduction/Background* Ovarian cancer is the leading cause of mortality from gynaecological malignancy. Survival improves with early diagnosis, however, early detection in primary care is challenging. The current blood test, cancer antigen 125 (CA125), has limited sensitivity and specificity for early disease. Human Epididymis 4 (HE4) is a promising diagnostic biomarker. We aimed to investigate the diagnostic accuracy and clinical utility of serum HE4 in a symptomatic primary care population. Methodology We conducted a prospective observational study testing HE4 on primary care serum CA125 samples from women with suspected ovarian cancer in Manchester, UK, between April 2018 and April 2019. Serum HE4 was measured using chemiluminescent enzyme immunoassays following routine CA125 testing for clinical care. HE4 thresholds of 77pmol/L and 150pmol/L were used. The primary outcome was final diagnosis within 12 months of testing. Clinical outcomes were collected from hospital electronic patient records. Receiver operator characteristic (ROC) curves with area under the curve (AUC), sensitivity and specificity were calculated for CA125 and HE4 both alone and in combination. Age adjusted HE4 thresholds were calculated with linear regression models. Result(s)* 1247 patients were included, with a mean age of 50 years (SD 15.7). 100 women had epithelial ovarian cancer; including 82 invasive and 18 borderline ovarian tumours. There was little difference in overall performance of CA125 and HE4 (AUC 0.932 vs 0.914 respectively). At a threshold of 77pmol/L, HE4 alone had a better sensitivity than CA125 [89% (95%CI 81.2-94.4) vs 81% (95% CI 71.9-88.2)] but a worse specificity [75.6% (95%CI 73-78) vs 92.2% (95%CI 90.4-93.6)]. HE4 and CA125 combined had improved sensitivity compared with CA125 alone (93%, 95%CI 86.1-97.1), but at a significant cost to specificity (70%, 95%CI 67.3-72.6). Serum HE4 levels were correlated with increasing age (p Conclusion* HE4 adds little to current diagnostic pathways in primary care. Age-adjusted thresholds may improve accuracy, but not sufficiently to recommend routine use at present.