British Journal of Cancer

ObjectiveDiagnosing ovarian cancer in premenopausal women is challenging due to the rarity of cancer and the ubiquity of symptoms, ovarian cysts on ultrasound, and raised serum CA125 tumour marker levels. We investigated the accuracy of risk prediction models and scores for diagnosing ovarian cancer in premenopausal women presenting to secondary care with symptoms and abnormal tests. MethodsA cohort of premenopausal women presenting with non-specific symptoms, and raised CA125 or abnormal imaging, were prospectively recruited in 23 hospitals in the UK between June 2015 and March 2023, predominantly referred through the NHS urgent suspected cancer pathway from primary to secondary care. A head-to-head comparison of the accuracy of the six risk prediction models and scores was conducted using donated blood and ultrasound scans performed by NHS staff trained in the use of IOTA imaging terminology. Index tests (at pre-stated thresholds) were: RMI1 (200, 250); ROMA (7.4%, 11.4%, 12.5%, 13.1%); IOTA ADNEX (3%, 10%); IOTA SRRisk (3%, 10%); IOTA simple rules; and CA125 (87 IU/ml). Participants were classified as having primary invasive ovarian cancer versus having benign or normal pathology according to the reference standard determined from surgical specimens, biopsies or cytology, by histology if undertaken, or else by 12-month follow-up. After June 2018, because of COVID restrictions and concerns about sample size, ongoing recruitment was restricted to only women undergoing surgery within 3 months of presentation (a selected group in whom ovarian cancer was more likely). ResultsOf 1,211 premenopausal recruited women 88 were diagnosed with primary OC, 857 in the pre-June 2018 cohort (prevalence of 5.7% (49/857)) and 354 in the post-June 2018 cohort 11.0% (39/354). For the diagnosis of primary ovarian cancer, (n=799 women after exclusion of n=58 other diagnoses), RMI1 at the 250 threshold had a sensitivity of 42.6%, 95% confidence interval 28.3 to 57.8, and specificity of 96.5%, 94.7 to 97.8. Compared to RMI1/250, CA125 and all other models had higher sensitivity (CA125: 55.1%, 40.2 to 69.3, p=0.06; ROMA/11.4%: 79.2%, 65.0 to 89.5, p<0.0001; IOTA ADNEX/10%: 89.1%, 76.4 to 96.4, p<0.0001; IOTA SRRisk/10%: 83.0%, 69.2 to 92.4, p<0.0001; IOTA simple rules: 75.0%, 56.6 to 88.5, p=0.01) and lower specificity (CA125: 89.0%, 86.5 to 91.2, p<0.0001; ROMA/11.4%: 73.1%, 69.6 to 76.3, p<0.0001; IOTA ADNEX/10%: 75.1%, 71.4 to 78.6, p<0.0001; IOTA SRRisk/10%: 76.0%, 72.4 to 79.3, p<0.0001; IOTA simple rules 95.2%, 93.0 to 96.9, p=0.06). IOTA simple rules have inconclusive results in 120/799 of the participants. Analysis of the complete cohort (n=1,211) including the 354 premenopausal women with a higher likelihood of ovarian cancer, yielded similar results. ConclusionsCompared to RMI 250, the current test used in NHS secondary care to triage women to tertiary care, most tests improve sensitivity but reduce specificity. Ultrasound triage with the IOTA ADNEX model at 10% in secondary care demonstrated the highest sensitivity gain with a comparable decline in specificity to other comparator tests. Ultrasound with the IOTA ADNEX model at 10% should be considered the new standard of care triage test for premenopausal women in secondary care; implementation in practice should incorporate staff training and quality assurance. Trial registration - ROCkeTS is registered ISRCTN17160843

BackgroundMesonephric-like adenocarcinoma has been recently classified as a rare type of ovarian carcinoma. Description of these tumours have been rare and mostly covered in case reports. In some cases, molecular characterization by sequencing has been employed for guided therapy recommendations, however, functional chemosensitivity testing of targetable pathways using advanced in vitro cellular models such as organoids has not been reported so far. Here, we report on a case of ovarian cancer that was later identified as mesonephric-like adenocarcinoma at an advanced stage. MethodsThe tumour was characterized by molecular techniques including immunohistochemistry and whole-exome sequencing. At the same time, ovarian cancer organoids were established by adapting existing protocols for high-grade serous ovarian carcinoma. The organoids were subsequently used for functional in vitro chemosensitivity testing by treatment with standard-of-care chemotherapeutics cisplatin, paclitaxel, and the Poly (ADP-Ribose) Polymerase 1-inhibitor olaparib. Based on molecular characteristics, we also applied the inhibitor binimetinib, to target Mitogen-Activated Protein Kinase downstream of the KRAS Proto-Oncogene. Additionally, chemotoxicity testing with healthy fallopian tube organoids and high-grade ovarian cancer organoids was applied to determine the therapeutic window. ResultsImmunohistochemical analysis showed characteristic PAX8+, GATA3+, TFF1+, ER-, PR-, WT1- staining while the sequencing revealed mutations in 31 genes of which KRAS G12V and DYNC1H1 G4072S were annotated as (likely) pathogenic. The tumour was mismatch-repair proficient. Tumour-derived organoids proved to be highly resistant to standard-of-care chemotherapeutics cisplatin, paclitaxel, and olaparib, but sensitive to inhibition by binimetinib, which aligned well with the molecular characteristics. Direct comparison to healthy fallopian tube organoids and high-grade ovarian cancer organoids confirmed low cytotoxic potential underlining a feasible therapeutic window for binimetinib. ConclusionsFor the first time, we show that existing protocols for high-grade serous ovarian carcinoma can be used for the generation of organoids derived from mesonephric-like adenocarcinoma. These organoids could be used as an essential tool for functional precision medicine purposes. This functional data could be applied as an additional layer for molecular tumour boards diagnostics by supporting molecular datasets and even identify targetable pathways beyond genetic variations, thus offering novel therapeutic options particularly for rare and aggressive tumours.

BackgroundProstate cancer (PCa) is one of the most common cancers globally. The potential for polygenic risk scores (PRSs) to improve risk stratification for early detection of PCA in screening interventions is of considerable interest. We evaluated the cost- effectiveness of PRS-guided screening strategies. MethodsThe Prostata microsimulation model, calibrated to UK-specific epidemiological and clinical data, simulated individual life histories, including disease onset and progression, tumour characteristics by Gleason score, and metastatic status. The model incorporated both measured and unmeasured components of polygenic risk for incident PCa, and included ancestry-specific strata. Screening strategies were compared against a no-screening baseline. We modelled one-off, age-based prostate specific antigen screening at 50, 60, or 70 years, as well as repeated uniform screening every 4 or 2 years from age 50 to 69 with and without PRS stratification. ResultsQuality-adjusted life years were similar across all screening strategies, while differences in costs were more pronounced. A "no screening" strategy had the lowest lifetime cost of all strategies and (very marginally) the shortest life expectancy. Realistic PRS implementations were dominated (less effective and more expensive) in all scenarios, and may not provide greater cost-effectiveness than a single PSA screen at age 50 or compared to no screening at all. ConclusionOur study found little evidence that PRSs would be cost-effective in pragmatic PCa screening settings.

BackgroundMutations in UGT1A gene have been associated with the development and prognosis of urinary bladder cancer (UBC). UGT1A proteins are involved in a spectrum of detoxification processes, hence the biological mechanism between UGT1A and UBC is difficult to elucidate. Concurrently, mild hyperbilirubinemia, caused by alterations in UGT1A, has been associated with multiple health outcomes. We have investigated the potential effect of mild hyperbilirubinemia on UBC risk and prognosis, using a Mendelian Randomization (MR) approach in the UK Biobank. MethodsData on 1,281 UBC patients and 4,071 controls was available for a two-stage least squares MR estimation with rs6742078 as an instrumental variable. First, linear regression was fitted to establish the relationship between the rs6742078 and bilirubin levels (total and unconjugated). Secondly, bilirubin values were used to predict tested outcomes under a logistic model. Both stages were adjusted for participant sex, smoking status, and age. ResultsMR analysis showed no significant effects of bilirubin levels on UBC risk (total bilirubin: OR=1.02, 95% CI: 0.99-1.04; unconjugated bilirubin: OR=1.02, 95% CI: 0.99-1.05). No effects were observed for events of UBC recurrence, progression, or survival. ConclusionOur study suggests mild hyperbilirubinemia is not associated with urinary bladder cancer risk and prognosis.

Abstract Background: High-grade serous ovarian cancer (HGSC) is characterized by extensive genomic heterogeneity and frequent alterations that promote replication stress (RS). Although RS has emerged as a promising therapeutic vulnerability, it remains unclear whether distinct RS-associated genomic alterations generate similar tumour states or drive unique biological programs and therapeutic dependencies. Methods: We developed and characterized a panel of syngeneic HGSC models representing recurrent RS-associated alterations, including overexpression of Ccne1, Brd4, Myc, Ndrg1, Pik3ca, and Brca1 heterozygosity, alongside previously established Pten/Nf1-deficient and Myc overexpressing models. Tumour fitness, transcriptomic programs, histopathology, extracellular matrix composition, immune organization, and therapeutic vulnerabilities were assessed using subcutaneous (s.c.) and intraperitoneal (i.p.) allografts, RNA sequencing (RNAseq), mass spectrometry (MS), cyclic-immunofluorescence (Cyc-IF), and preclinical therapeutic studies. Results: RS-associated genotypes exhibited marked differences in tumour fitness and generated distinct tumour ecosystem states despite sharing a common genetic background. Tumours harbouring BRCA1 heterozygosity displayed reduced tumour fitness, mesenchymal features, extracellular matrix remodelling, stromal expansion, and immune-excluded phenotypes. In contrast, tumours co-expressing Ccne1 and Brd4 exhibited the highest RS level together with strong activation of DNA damage response pathways and limited immune infiltration. Immune characterization identified immune-desert, immune-suppressed, and immune-excluded states across models, demonstrating substantial genotype-dependent immune heterogeneity. Elevated CD47 expression emerged as a defining feature of the Ccne1/Brd4 tumour state and was confirmed in human HGSC specimens with high CCNE1 and BRD4 protein expression. Therapeutic targeting of ATR and CD47 in intraperitoneal Ccne1/Brd4 allografts reduced tumour burden and induced histopathological responses compared with either monotherapy alone, supporting the translational relevance of this RS-high tumour state. Conclusions: Distinct RS-associated alterations do not converge on a common HGSC phenotype but instead generate diverse tumour ecosystem states with unique effects on tumour fitness, stromal remodelling, immune organization, and therapeutic vulnerabilities. These findings highlight the importance of considering the genetic origin of RS when developing therapeutic strategies and establish a framework for investigating genotype-specific vulnerabilities in HGSC.

BackgroundPreclinical studies support targeting PI3K/AKT/mTOR signalling in platinum-resistant ovarian cancer (PROC). A phase I study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel (wP) showed activity. We report the results of Arm 1 of OCTOPUS, the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer. MethodsPatients with platinum-resistant or refractory high grade serous carcinoma were randomised (1:1) to wP (80mg/m2 D1,8,15 of 28 day cycle) plus oral vistusertib (50mg BD) or placebo (P). The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results140 patients (median age 63, range: 36-86; 18% platinum-refractory; 54% [&ge;]3 prior therapies) were randomised. There was no difference in PFS (median 4.5 vs 4.1m (HR 0.84; 80% CI (0.67, 1.07); 1-sided p=0.18), OS (median 9.7 vs 11.1m (HR 1.21; 80% CI (0.91, 1.60); 1-sided p=0.80) or RR (odds ratio 0.86; 80% CI (0.55, 1.36); 1-sided p=0.66). Grade 3/4 adverse events were 41.2% (wP+V) vs 36.7% (wP+P). Low tumour PTEN expression was associated with longer PFS in the wP+V arm (9.4 vs 4.1m p=0.003) but not in the wP arm (4.8 vs 4.2m p=0.60). Tumour genome-wide copy number (CN) analysis suggested that high CN signature 4 was associated with worse outcome in the wP+P arm (2.3 vs 4.6m p=0.018) but not the wP+V arm (5.4 vs 3.3m). ConclusionsVistusertib did not improve clinical activity of wP in PROC. However, low tumour cell PTEN expression may be a predictive biomarker for vistusertib activity. Translational RelevancePreclinical studies suggest that activation of the PI3K/AKT/mTOR signalling pathway contributes to platinum-resistance in ovarian high grade serous carcinoma (HGSC). Based on activity in a phase I study, we evaluated the clinical efficacy of the dual mTORC1/mTORC2 inhibitor vistusertib in combination with weekly paclitaxel in the OCTOPUS study - a multi-centre, randomised, placebo-controlled, phase II trial in platinum-resistant ovarian (HGSC). In the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer, vistusertib did not improve clinical activity of weekly paclitaxel. However, translational analyses indicated that low tumour cell PTEN expression may be a predictive biomarker for vistusertib activity. We also showed genome-wide copy number (CN) analysis, in particular high exposure to CN signature 4, may also allow identification of patients with greater chance of benefit from dual mTORC inhibition. Potential predictive biomarkers identified in our study should be evaluated in ongoing/future studies.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological cancer with patients routinely diagnosed at advanced stages with widespread disease. Evidence from screening trials indicates that early diagnosis may not reduce cancer-related deaths, possibly due to an underestimation of the true extent of the disease at screening. We aim to characterise the growth kinetics of HGSOC to understand why early detection has failed so far and under what conditions it might prove fruitful. We analysed a dataset of 597 patients with a confirmed HGSOC diagnosis, and identified 37 cases with serial CT scans. We calculated the growth rates of lesions in the ovaries/pelvis and the omentum and estimated the time to metastasis using a population-level Gompertz model. Finally, we simulated ultrasound and CA125 based screening in a virtual population of patients. Growing lesions in the ovaries and the omentum doubled in volume every 2.3 months and 2 months respectively. At both sites, smaller lesions grew faster than larger ones. The 12 cases with growing lesions in both disease sites had a median interval of 11.5 months between disease initiation and the onset of metastasis. Our simulations suggested that over 33% of patients would develop metastases before they could be screen detected. The remaining patients provided a median window of opportunity of only 4.7 months to detect the tumours before they metastasised. Our results suggest that HGSOC lesions have short time to metastasis intervals, preventing effective early detection using current screening approaches.

Suspected colorectal cancer (CRC) referrals based on non-specific symptoms currently lead to large numbers of patients being referred for invasive investigations and poor yield in cancer detection. Secondary care diagnostics, particularly endoscopy, struggle to meet the ever-increasing demand and patients face lengthy waits from the point of referral. Here we propose a blood test utilising high-throughput Raman spectroscopy and machine learning as an accurate triage tool. We present results from the first mixed methods clinical validation study of its kind, evaluating the ability of the test to perform in its target population of primary care patients, and its acceptability to those administering and receiving the test. The test was able to accurately rule out cancer with a negative predictive value of 98.0%. This performance could reduce the number of invasive diagnostic procedures in the cohort by at least 47%. Collectively, our findings promote a novel, non-invasive solution to triage CRC referrals with potential to reduce patient anxiety, accelerate access to treatment and improve outcomes.

BackgroundHistory of Chlamydia trachomatis infection has previously been associated with epithelial ovarian cancer (EOC) in observational studies. We conducted a two-sample univariable Mendelian randomisation (MR) study to examine whether genetically predicted seropositivity to the C. trachomatis major outer membrane protein (momp) D is causally associated with EOC. MethodsMR analyses employed genetic associations derived from UK Biobank as proxies for momp D seropositivity in 25 509 EOC cases and 40 941 controls that participated in the Ovarian Cancer Association Consortium. Findings were replicated using a GWAS meta-analyses of global biobanks including the UK Biobank, FinnGen and BioBank Japan. ResultsGenetically predicted momp D seropositivity was associated with overall and high-grade serous EOC risk in inverse-variance weighted (IVW) and MR-Egger univariable MR analysis (odds ratio (OR) 1.06; 95% confidence interval (CI) 1.02--1.10, and OR 1.08; 95%CI 1.01--1.16, respectively). Replication yielded similar results for overall EOC (OR 1.11; 95%CI 1.01--1.22). ConclusionThis MR study supports a causative link between C. trachomatis infection and overall and high-grade serous EOC.

BACKGROUNDHigh-grade serous ovarian cancer (HGSOC) is characterized by elevated replication stress and an immunosuppressive microenvironment. A synergistic combination of checkpoint kinase 1 inhibitor (CHK1i) with low-dose hydroxyurea (LDHU) promotes a unique ATR-independent moderate replication stress response with potent anti-tumour effects. The ability of this approach to reprogram the tumour immune microenvironment (TIME) to overcome the immunosuppression and promote an anti-tumour immune response in HGSOC is the focus of this study. METHODSWe investigated the therapeutic potential of CHK1i+LDHU in established HGSOC cell cultures, fresh tumour cell explants from HGSOC patient ascites, and syngeneic mouse models, assessing tumour cell killing, immunogenic cell death, pro-inflammatory cytokine/chemokine expression, and anti-tumour immune responses. RESULTSCHK1i+LDHU effectively killed ovarian cancer cells regardless of chemotherapy resistance, BRCA2 mutation and homologous recombination repair status in vitro. In vivo, treatment significantly reduced tumour burden and ascites accumulation. CHK1i+LDHU enhanced expression of pro-inflammatory cytokines/chemokines and triggered immunogenic cell death in tumour. In syngeneic models, treatment promoted CD8+ cytotoxic T cell-dependent anti-tumour responses and reduced immunosuppressive signalling within the TIME. CONCLUSIONSCHK1i+LDHU is a promising therapy for chemotherapy-resistant HGSOC, combining direct cytotoxic effects with reprogramming the TIME to reduce immunosuppression and activate a CD8+ T cell-dependent anti-tumour response.

Background: Although perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is the standard neoadjuvant regimen for resectable gastric and gastro-oesophageal junction adenocarcinoma, evidence describing treatment delivery in routine clinical practice remains limited, particularly regarding relative dose intensity (RDI) and treatment completion. Objectives: To evaluate real-world delivery of preoperative FLOT chemotherapy, including treatment completion, progression to surgery, RDI, toxicity and exploratory changes in estimated lean body mass (LBM). Methods: A retrospective single-centre service evaluation included consecutive patients receiving neoadjuvant FLOT during 2024. Outcomes included treatment completion, surgery, RDI, toxicity, pathological response and estimated LBM. Descriptive statistics were used. Results: Twelve patients were included (median age 68.6 years; 91.7% male). Eleven (91.6%) completed all four preoperative cycles and proceeded to surgery. Mean RDI was 76.7%. Pre-emptive dose capping was the predominant dose modification strategy, with only one reactive dose reduction. Two grade 3 adverse events occurred. Major pathological response (Mandard grade 1-2) was observed in 2/12 patients (16.7%). Mean estimated LBM declined from 54.3 to 53.4 kg. Greater LBM loss appeared to coincide with poorer clinical outcomes. Conclusions: High treatment completion and progression to surgery were achieved despite reduced RDI. These findings support prospective evaluation of strategies to optimise chemotherapy delivery while maintaining tolerability in routine clinical practice.

BACKGROUNDCancer is associated with significant economic impacts. Quantifying the scale of these impacts is challenged by confounding variables that jointly influence both cancer status and economic outcomes such as healthcare costs and quality of life. Moreover, the increasing costs attributed to cancer drug development complicate the cost-effective provision of cancer care. METHODSWe address both challenges in this paper by using germline genetic variation in the risk of incident cancer as instrumental variables in Mendelian Randomization analyses of eight cancers. We developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate and thyroid cancers on healthcare costs and quality adjusted life years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used Mendelian Randomization to model a hypothetical population-wide preventative intervention based on a repurposed class of anti-diabetic drugs known as sodium-glucose co-transporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer. RESULTSGenetic liability to prostate cancer and to breast cancer had material causal impacts on healthcare costs and QALYs. Mendelian Randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anti-cancer indication. IMPLICATIONSOur new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision analytic models of cancer interventions such as screening programmes or simulations of longer-term outcomes associated with therapies investigated in RCTs with short follow-ups. Our new method allows us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anti-cancer intervention to inform and complement other means of assessing long-term intervention cost-effectiveness.

Patients with metastatic, Estrogen Receptor (ER) positive, HER2-negative, breast cancer, before initiating CDK4/6 inhibitors, receive either single agent endocrine- or chemotherapy based on their clinical risk. In this first-ever trial-based economic evaluation of Circulating Tumor Cells (CTCs), the cost-effectiveness of standardizing the prescription of endocrine- or chemotherapy using a CTC count threshold (with >5 CTCs/7.5mL indicative of unfavorable disease outcomes) was compared to current clinical practice. N=755 ER+ HER2-patients, enrolled in 17 French centres, were randomized to CTC guided or standard of care and were treated according to either through the CTC score or clinical examination. Health state utilities were calculated by mapping the QLQ-C30 to EQ-5D utilities and used to calculate Quality-Adjusted Life Years (QALY) over a 2-year time horizon. Bootstrapping and additional sensitivity analyses were performed to quantify the impact of uncertainty. Health outcomes in both arms were similar, but costs were higher in the CTC guided arm ({euro}19,403) compared to the usual care ({euro}18,254), resulting in an ICER of {euro}104,078/QALY in favor of usual care. However, when the analysis was performed for the clinically high- and low-risk groups separately, CTC enumeration could be a dominant strategy (cost saving) if treatment is de-escalated in clinically high-risk patients as indicated by CTC scores. However, the current analysis was based on the PFS and OS data reported in 2021 and long-term Overall Survival data is collected since then (JCO, 2023 in press). A further analysis of the health economic impact of CTC enumeration in clinically low and high-risk groups is therefore indicated.

BackgroundCystoscopy is a core component of haematuria investigations but is invasive and resource-intensive. GALEAS Bladder is a DNA-based diagnostic urine test that measures alterations in 23 bladder cancer-associated genes. ObjectiveTo assess the diagnostic performance and clinical utility of GALEAS Bladder as a molecular triage tool in real-world haematuria investigation pathways. MethodsPatients referred for urgent investigation of haematuria were prospectively enrolled across seven UK NHS Urology Departments between October 2024 and June 2025. Urine samples were collected prior to cystoscopy and analysed using the GALEAS Bladder assay (Nonacus Clinical Services, UK). Assay results were compared with cystoscopy findings. Key Findings and LimitationsCystoscopic findings and GALEAS Bladder results were available for 964 participants, including 77 (8.0%) newly-diagnosed with pathology-confirmed BC. The assay demonstrated an overall sensitivity of 92.2% (95% CI: 84.0-96.4%), specificity of 92.0% (95% CI: 90.0-93.6%), and negative predictive value (NPV) of 99.3% (95% CI: 98.4-99.7%) for the diagnosis of BC. For the diagnosis of high-grade BCs, sensitivity was 97.2% (95% CI: 85.8-99.5%) with an NPV of 99.9% (95% CI:99.3-100.0%). Limitations include an absence of subsequent diagnoses for participants with positive GALEAS Bladder test results in the absence of cystoscopically-visible tumour. Conclusions and Clinical ImplicationsGALEAS Bladder is a clinically implementable molecular urine test with very high sensitivity and specificity for the diagnosis of new cases of BC in patients undergoing urgent investigation of haematuria, especially for high-grade BCs. Clinical adoption could permit the molecular triage of haematuria patients to immediate or deferred cystoscopy.

BackgroundThe prostate specific antigen (PSA) test is the most used clinical tool for prostate cancer risk stratification. PSA-based screening remains controversial due to modest predictive power (ROC AUC<0.75), high false-positive rates and racial disparities. Here, we evaluated the prostate cancer risk-stratification potential for the KLK3 protein, measured by Olink(R) Explore-3072, in the UK Biobank. Methods19,364 men in the UK Biobanks proteomics dataset were cancer-free at assessment centre visit. We used logistic regression to evaluate potential of KLK3 to predict prostate cancer within 2, 5, and 10 years of recording, as an independent predictor and with age and genetic risk score. Prostate cancer cases were classified by severity based on clinical action taken post-diagnosis. All predictive models were performed under 5-fold cross validation, and diagnostic accuracy statistics reported for the test set. FindingsKLK3 was strongly associated with prostate cancer incidence (HR per SD: 3.00 (2.87 - 3.13), p<2e-16). ROC AUC for a 2-year prediction horizon was 0.918 (0.906 - 0.93), reducing to 0.854 (0.848 - 0.86) over 10 years. 10-year ROC AUC was stronger in individuals of European ancestry (0.857 (0.851 - 0.863)) than African (0.801 (0.762 - 0.841)) or South Asian (0.795 (0.727 - 0.862)) ancestry. Power to predict highly aggressive cancer cases within 2 years of recording was strong (ROC AUC 0.928 (0.919 - 0.937)) but weaker for a 10-year period (0.87 (0.865 - 0.876)). Inclusion of age and genetic risk score provided small improvements in individuals of primarily genetic European ancestry, but no improvement in African or South Asian ancestry. InterpretationThe ROCAUC values reported are superior to those seen previously for the PSA test. We demonstrate high predictive accuracy across 2-, 5- and 10-year windows. Findings were consistent for low and high-risk cases. These findings suggest that proteomic PSA measurements may be helpful in prostate cancer risk stratification, while highlighting the need for improved predictive models across diverse ancestral groups. FundingThis study was funded by the University of Exeter. We report no conflicts of interest. Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSOn 4th August 2025 we searched the PubMed database using the search terms [(PSA OR KLK3 OR Prostate Cancer) AND (Risk Prediction OR Screening) OR (UK Biobank AND Proteomics)] to establish predictive power of the PSA test alongside prior work on the UK Biobank Proteomics data and identified a number of relevant studies. Large meta-analyses concerning the PSA test documents moderate predictive accuracy (ROC AUC~0.72), a high false positive rate, and no evidence that PSA screening reduces overall mortality. Studies using the UK Biobank Proteomics dataset have taken a phenome-wide or pan-cancer approach, scanning thousands of potential disease-protein pairs. Added value of this studyWe assessed the predictive value of KLK3 (molecularly equivalent to PSA) measured by Olink(R) high-throughput proteomics in 19,392 cancer-free men from the UK Biobank. We evaluated performance over 2-, 5-, and 10-year prediction horizons and stratified results by ancestry and cancer severity. KLK3 was a strong independent predictor of prostate cancer, particularly in a short window following measurement, and outperformed PSA estimates reported in previous literature. Combining KLK3 with age and a polygenic risk score provided modest benefit in men of European ancestry, but no additional benefit in men of African ancestry. This is the first large-scale study to assess proteomic measurement of KLK3 to stratify prostate cancer risk in a general population cohort. Implications of all the available evidenceProteomic measurement of KLK3 offers improved risk prediction for prostate cancer compared to standard PSA testing over a 2-, 5-, and 10-year period. Our findings suggest that KLK3 could enhance risk stratification in population screening and may be particularly useful for identifying individuals at very high risk. Similar to current technologies, proteomic measurement of KLK3 performs worse in African and South Asian populations than in European populations. While this disparity highlights an urgent need to improve and validate predictive models in non-European populations, our reported predictive power in non-European populations that is stronger than the current PSA test for European populations. These results suggest that proteomic measurement of KLK3 in screening applications will result in improved accuracy across populations and for severe prostate cancer outcomes over previous technology.

BackgroundPrimary liver cancer (PLC) remains a global health challenge. Understanding trends in the disease burden and survival is crucial to inform decisions regarding screening, prevention and treatment. MethodsPopulation-based cohort study using UK primary care data from the Clinical Practice Research Datalink (CPRD) GOLD (2000 to 2021), replicated in CPRD Aurum. PLC incidence rates (IR), period prevalence (PP) and survival at one, five and ten years over the study period were calculated, and stratified by age, sex and diagnosis year. ResultsThe crude IR of PLC was 4.56 (95%CI 4.42-4.70) per 100,000 person-years between 2000 and 2021, with an increase over time across age and sex strata. Sex-specific IR for males was higher than females, 6.60 (95%CI 6.36-6.85) vs. 2.58 (95%CI 2.44-2.74) per 100,000 person-years. Crude PP showed a 7-fold increase over the study period, with PP 0.02% (95%CI 0.019%-0.022%) in 2021, and a 2.8-fold higher PP in males. Survival at one, five and ten years after diagnosis was 41.7%, 13.2% and 7.1%, respectively, for both sexes. One-year survival increased only in men, from 33.2% in 2005-2009 to 49.3% in 2015-2019. ConclusionOver the past two decades, there has been a significant increase in the number of patients diagnosed with PLC. Despite a slight improvement in median and one-year survival in men, prognosis remains poor. To improve the survival of PLC patients, it is necessary to understand the epidemiological changes and address the preventable risk factors associated with liver disease and promote early detection and access to care. LAY SUMMARYThis population-based cohort study shows that the incidence and prevalence of primary liver cancer in the UK has increased in the last 20 years across both sexes and age groups, with a 7-fold increase in crude period prevalence over the study period. One-year survival has improved only in males over the study period and, regrettably, no increases in long-term survival were observed. Our findings are a call for awareness to stimulate further research and public health actions on liver cancer.

Cell line models for high grade serous ovarian cancer (HGSOC) are limited in number and are poorly clinically annotated. Consequently, existing models often fail to recapitulate common features of HGSOC, inhibiting mechanistic and therapeutic discovery. We generated and characterised three spontaneously immortalized continuous HGSOC cell lines named CIOV1, CIOV2, and CIOV3 and confirmed that each cell line retained the genomic and pathologic characteristics of its parental tumour. We show that subclonal cell populations present at initiation, expanded and contracted during the culturing process before converging on a stable immortalized line. These lines are new valuable models to study acquired chemoresistance of HGSOC.

ObjectivesThe detection of endometrial cancer recurrence is primarily through patient reported symptoms and can occur many years after primary treatment. Investigation of suspected endometrial cancer recurrence requires clinical examination, imaging, and if a lesion is identified a biopsy for pathological analysis. A blood-based biomarker could support the identification and confirmation of endometrial cancer recurrence. MethodsA systematic review was undertaken to identify studies that reported the use of biomarkers in the monitoring and/or diagnosis of endometrial cancer recurrence (PROSPERO registration CRD42021226204). MEDLINE, Embase, Emcare, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and OpenGrey were searched up to 15th November 2024. Studies were assessed using QUADAS-2. Meta-analysis of sensitivity and specificity was carried out using Bayesian random effects univariate meta-analytic models for sensitivity and specificity individually. ResultsOf the 10,643 references identified, 142 studies underwent full-text assessment and data was extracted from 25 studies. CA125, HE4, circulating free or tumour DNA (cf/ctDNA), and carcinoembryonic antigen (CEA) were the most extensively studied biomarkers. Although ten studies investigated the use of more than one biomarker, the majority were comparing rather than combining their diagnostic ability. Sensitivity was highest for cf/ctDNA, 0.87 (95% CrI: 0.63, 0.99), followed by HE4, 0.74 (95% CrI 0.51-0.90). Specificity was highest for CA125; 0.91 (95% CrI: 0.77, 0.99) followed by cf/ctDNA 0.89 (95% CrI: 0.63-0.99). Conclusionscf/ctDNA had had superior diagnostic accuracy to detect endometrial cancer recurrence compared to CA125 and HE4. Given the concerning rise in endometrial cancer mortality, future research should focus on a potential role for a blood-based biomarker in facilitating the identification of endometrial cancer recurrence and the impact on survival following recurrence. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSBlood-based biomarkers have the potential to monitor and/or detect endometrial cancer recurrence. What this study addscirculating free/tumour DNA had had superior diagnostic accuracy to detect endometrial cancer recurrence compared to other blood-based biomarkers for example CA125 and HE4 How this study might affect research, practice or policythe results indicate a potential role for circulating free/tumour DNA in detecting endometrial cancer.

There are no published data on cancer screening by women using medically assisted reproduction (MAR). Such data would aid interpretation of the cancer incidence and risk profiles for this group. Using linked population-based Australian health registries and administrative datasets, we compared organised publicly funded cervical and breast screening episodes for women who received one of three types of MAR and matched women who did not between 1991 and 2016. We modelled the proportion of women screened in the three years before and after first MAR treatment, adjusting for age, remoteness, parity, socio-economic disadvantage, cancer history, and uptake of the other screening program. After adjustment, a greater proportion of women who received MAR than women who did not had cervical screening before MAR (77.3%-84.1% vs 57.5%-62.0%, depending on treatment) and after MAR (77.0%-78.5% vs 68.1%-68.3%). Contrastingly, breast screening estimates were 7.6%-9.6% vs 9.3%-10.5% before MAR and 11.0%-15.0% vs 12.8%-14.9% after MAR.

This article is the study protocol and statistical analysis plan for the project. This study is set up to identify and quantify "red flag" symptoms associated with the diagnosis of Pancreatic Neuroendocrine Neoplasm (PNEN) and compare these with the symptoms associated with Pancreatic Ductal Adenocarcinoma (PDAC). The results of this study will inform the evidence base for the refinement of the QCancer (Pancreas) tools, which have been integrated into the UK NHS primary care computer systems, to improve the early recognition of PNEN.