British Journal of 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.

Background The faecal immunochemical test (FIT) is central to triaging symptomatic patients with suspected colorectal cancer (CRC) in UK primary care, yet only about one in eleven patients above the NICE 10 ug/g threshold have CRC. Existing prediction models attempting to improve on FIT have relied on conventional statistics and limited predictors. Methods GP-requested FITs with linked data (Jan 2017 - May 2025) were extracted from the Oxford University Hospitals (OUH) datawarehouse. Patients aged [≥]18 with core bloods and 180-day CRC follow-up were included. Machine learning (ML) models were trained on up to 1,025 predictors: FIT, age, sex, blood tests and their time series slopes, diagnoses/procedures/prescriptions, deprivation, BMI, and ethnicity. Models comprised penalised logistic regression, generalised additive models (EBM, NAM, SNAM, NODE-GAM), decision tree ensembles (random forests, XGBoost), and a multilayer perceptron. Referral reduction versus FIT [≥]10 ug/g was evaluated at model risk score thresholds capturing the same cancers (conservative) or same proportion of cancers (less conservative) as FIT. Potential to prioritise referred patients was assessed by examining whether positive predictive value (PPV) is very high (>30%) at any substantial sensitivity (>10%). Nested twice-repeated five-fold cross-validation provided unbiased estimates. An existing COLOFIT model was evaluated alongside. Findings 62,219 individuals (746 CRC) were analysed; 30,862 patients (315 CRC) with high/low risk symptoms and buffered FITs formed the primary subset. At [≥]10 ug/g, FIT had 91.4% sensitivity, 84.2% specificity, 5.6% PPV, and 99.9% NPV. No model reduced referrals when required to capture the same cancers as in the FIT [≥]10 ug/g cohort. Generalised additive models achieved up to 18.5% referral reduction when detecting the same proportion but some different cancers as FIT [≥]10 ug/g (EBM: 18.5%, NODE-GAM: 17.5%, SNAM: 17.4%, COLOFIT: 16.7%). At 30% sensitivity, EBM, NAM and NODE-GAM had average PPVs between 34.6%-35.0%, while FIT had a PPV of 14.6%. Interpretation Generalised additive models (GAMs) reduced referrals on average by 19% if a small proportion of the FIT-positive CRCs were substituted with originally FIT-negative CRCs by the models. No model, including COLOFIT, reduced referrals while capturing all FIT-positive cancers. Generalised additive models could detect about a third of CRCs faster, as one in three patients flagged by the models had CRC at 30% sensitivity. Funding EPSRC Centre for Doctoral Training in Health Data Science; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre; Cancer Research UK. Keywords Colorectal cancer, faecal immunochemical test, machine learning, positive predictive value

Carriers of germline BRCA1 or BRCA2 alterations have a substantially increased lifetime risk of high-grade serous ovarian carcinoma (HGSOC), which originates from the secretory cells of the fallopian tube. However, comparative multi-omic analyses of bulk fallopian tube tissue from BRCA1/2 carriers and the general population have, to date, revealed only limited differences. New molecular biomarkers of early malignant transformation in the FT are needed to enable non-surgical cancer interception in high-risk individuals through window-of-opportunity trials prior to risk-reducing surgery. We performed a comprehensive single-cell, multi-regional analysis of fallopian tubes from 34 women, including 15 carriers of germline BRCA1/2 alterations. Using a metacell-based approach applied to single-cell transcriptomic data, we identify both established and previously unrecognised cellular populations, and characterise phenotypic variation associated with menopausal status, menstrual cycle phase, hormonal contraception use, and anatomical region of the fallopian tube. Menopause was associated with depletion of ciliated cells, whilst both secretory (SEC) and ciliated epithelial cells (CEC) shifted to a glandular phenotype in the luteal phase. Previous hormonal contraception usage had lasting effects including depletion of CD163-positive tissue resident macrophages and progesterone-specific increase of MHC-II expression in SECs. Metacell analysis further identified distinct subpopulations of SECs, most frequently in BRCA1/2 carriers, characterised by high TP53 expression and markedly elevated histone levels. This phenotype is consistent with replication stress, cell-cycle arrest, and activation of innate immune signalling pathways. Protein-level validation in matched samples showed enrichment of cells with increased {gamma}H2AX expression and persistent 53BP1 foci in BRCA1/2 carriers. Together our data supports the role of BRCA1/2 in maintaining genomic integrity and a BRCA1/2 haploinsufficient phenotype characterised by increased replication stress in the fallopian tube epithelium. Our findings provide evidence for distinct immune responses in users of hormonal contraception and demonstrate early events in malignant transformation. They establish potential biomarkers in microscopically normal FT and a framework for measurement of cancer risk with the goal of enabling molecularly informed cancer interception in high-risk individuals.

Introduction Patients undergoing polypectomy at colonoscopy remain at risk of metachronous neoplasia despite surveillance guided by histopathological features. Mutational profiling of adenomas, including canonical driver mutations in APC, KRAS, and TP53, may offer additional predictive value. This study aimed to determine whether mutational status in index adenomas was associated with metachronous lesion risk. Methods The INCISE cohort included patients aged 50 to 74 years who underwent polypectomy within the Scottish Bowel Screening Programme and subsequent surveillance colonoscopy within 6 years. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded polyps. Driver mutation frequency, tumour mutational burden (TMB), and variant allele frequency (VAF) were analysed and correlated with histopathological features and metachronous outcomes using appropriate statistical models. Results A total of 895 adenomas from 723 patients were analysed. In conventional adenomas, as the number of high-risk histopathological features (size >=10mm, villous architecture, and high-grade dysplasia) increased there was a stepwise increase in the proportion of samples with a mutation in KRAS from 13% to 51% (padj<0.001) and TP53 from 8% to 35% (padj<0.001). However, neither mutation frequency (p=0.901), nor median tumour mutation burden (TMB) (2.27 vs 2.15 mut/Mb, p=0.242), in index adenomas was associated with the development of metachronous lesions. Conclusions While classical driver mutations reflect histopathological progression within adenomas, they do not predict metachronous lesion risk post-polypectomy. Targeted mutation profiling alone is insufficient for surveillance risk stratification, highlighting the need for integrated molecular approaches in this setting.

Aims: Serrated lesions contribute substantially to colorectal cancer (CRC), while routine management of small distal hyperplastic polyps (HPs) assumes low risk. Surveillance guidelines nevertheless incorporate uncertainty at the HP/SSL interface and recommend shortened intervals for large serrated lesions. We tested whether fibroblast activation protein-alpha; (FAPalpha) expression by stromal fibroblasts within expert-reviewed HPs stratifies risk of subsequent neoplasia. Methods and results: In a single centre historical cohort, FAPalpha; immunohistochemistry (Abcam ab53066, 1:200) was performed on FFPE colon tissues from 64 patients (normal colon n=10; HP n=39; low grade TA n=6; high-grade TA n=4; adenocarcinoma n=5). FAPalpha positive stromal fibroblasts were quantified in 20 randomly selected fields at magnification 1000 by two blinded readers (ICC 0.93). Among 39 patients with expert reviewed index HPs and colonoscopic follow up, the endpoint was metachronous adenoma occurring in the same general colonic area as the index HP, with proximal defined as ascending colon and distal as descending colon. Follow-up colonoscopies were scheduled every 2 years for up to 10 years. ROC analysis identified an optimal threshold of [&ge;]9 FAPalpha positive fibroblasts (AUC 0.8658; sensitivity 81.25%, specificity 87.93%). FAPalpha high status (44% of HPs) was associated with shortened neoplasm free survival (log-rank p=0.0012): five-year neoplasm free survival 41% versus 91% for FAPalpha; no/low. In multivariable Cox modelling, FAPalpha high status remained independently associated with metachronous adenoma (HR 4.5, 95% CI 1.2-16.8, p=0.022). Conclusion: FAPalpha+ fibroblasts in expert-reviewed colorectal HPs identify a high-risk subgroup for metachronous adenoma, supporting stromal activation markers as a feasible pathology-anchored stratification tool.

Background The number of novel cancer therapies approved for use in England by the National Institute for Health and Care Excellence is increasing. Monitoring the adoption of new therapies is important to assess equity of access and evaluate real-world prescribing practices. OpenPrescribing Hospitals has recently been launched to facilitate analysis of open secondary care medicines data in England. Using this platform, we set out to describe the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including the frequency of dose reductions, within National Health Service (NHS) hospitals in England between January 2019 and December 2024. Methods The monthly proportion of each CDK4/6 inhibitor relative to total CDK4/6 inhibitor use was calculated at hospital level. Regional variation was assessed across Cancer Alliances by comparing the proportions of each CDK4/6 inhibitor used within each alliance in 2021 and 2024. Use of lower strength palbociclib and abemaciclib was used as a proxy for dose reductions. Findings There was more than a 3-fold increase in the use of CDK4/6 inhibitors between 2019 and 2024. In 2019, 78.6%, 11.9% and 9.5% of CDK4/6 inhibitors used were palbociclib, abemaciclib and ribociclib, compared with 40.2%, 41.2% and 18.6% in 2024. There was variation in the relative percentage change in use of each agent by Cancer Alliance. Use of lower strengths was common for both palbociclib (60%) and abemaciclib (63%). Interpretation Changes in usage appeared responsive to publication of key evidence and regulatory milestones. There was a higher apparent frequency of dose reductions than reported in clinical trials. OpenPrescribing Hospitals is an accessible, publicly available tool for understanding uptake and use of medicines in NHS hospitals in England.

AbstractAdrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy originating from the adrenal cortex with limited effective treatment options. The underlying pathophysiology of ACC is uniquely characterized by abnormal steroid production and increased metabolic activity, highlighting the critical role of mitochondria in adrenal steroid hormone biosynthesis and tumor metabolism. In this study, we investigated the therapeutic potential of TR-107, a novel and highly selective small-molecule agonist targeting the mitochondrial protease ClpP. Pharmacologic hyperactivation of ClpP disrupts mitochondrial proteostasis and bioenergetics and has shown promising antitumor activity in various preclinical models. Our results demonstrated that TR-107 induces potent dose-dependent cytotoxic effects at nanomolar concentrations in ACC cell lines NCI-H295R and mACC3 as well as short-term ACC patient-derived organoid (PDO) models, markedly reducing cell viability and confluency in vitro. Metabolic analyses revealed that TR-107 significantly impaired oxygen consumption, indicating a disruption of oxidative phosphorylation and substantial attenuation of basal cellular respiration. Mechanistic studies showed dose-dependent increases in reactive oxygen species (ROS) levels and upregulation of proteins involved in mediating the ferroptotic rheostat. Pharmacokinetic assessment uncovered that TR-107 was not a substrate of the ABCB1 (MDR1/P-glycoprotein) efflux transporter, suggesting potential to overcome common multidrug resistance mechanisms. Given the importance of IGF-2 signaling in ACC, we further explored the combinatorial effects of TR-107 with IGF-1 receptor (IGF-1R) inhibitors and discovered that co-treatment produced synergistic reductions in cell viability across NCI-H295R, mACC3, and ACC PDOs. Collectively, these findings support the potential of mitochondrial ClpP hyperactivation as a promising therapeutic strategy for ACC and demonstrate that TR-107 exhibits significant antitumor activity as a monotherapy or in combination with IGF-1R inhibitors. These findings provide a strong rationale for advancing ClpP agonists into clinical development for the management of ACC.

Purpose: To analyze the effect of radiotherapy timing relative to surgery on patients' survival and mortality rates in uveal melanoma (UM). Design: Retrospective cohort study using registry data from the Surveillance, Epidemiology, and End Results (SEER) database. Subjects: A total of 1,198 patients with UM were extracted from the SEER database and divided into three groups: preoperative radiotherapy, intraoperative radiotherapy (IORT), and postoperative radiotherapy. Methods: UM cases were extracted from the SEER database. Survival curves were generated based on the Kaplan-Meier method. An extended Cox regression was used to estimate the cancer-specific and all-cause mortality. Main Outcome Measures: Overall survival (including median survival) and hazard reductions for cancer-specific and all-cause mortality. Results: Preoperative radiotherapy revealed the highest median survival (4.93 years), followed by postoperative radiotherapy (4.76 years), and IORT (4.02 years). The preoperative strategy reduced the hazard of all-cause mortality by 42%, 50%, and 60% at 5-, 7-, and 10-year follow-up, respectively, compared with IORT. Findings were consistent in the cancer-specific sensitivity analysis (45%, 53%, and 62% reductions at the same time points). However, postoperative radiotherapy did not significantly reduce the cancer-specific mortality in comparison to IORT. Conclusions: Preoperative radiotherapy was associated with higher median overall survival and lower all-cause and cancer-specific mortality than IORT over 10 years of follow-up. Postoperative radiotherapy showed intermediate outcomes that did not differ significantly from IORT. Prospective studies with more detailed data on the temporal relation of radiotherapy timing and surgery are needed to confirm these findings.

This review evaluates the biological pathways linking soft drink consumption with the risk of several cancers within the framework of the Global Cancer Update Programme (CUP Global). Soft drink consumption has been associated with increased risk of multiple cancers, and glucose or insulin dysregulation has been proposed as a potential underlying mechanism. We applied a three-stage framework. In the first stage, we identified insulin sensitivity as the key biological process potentially linking soft drink consumption (sugar-sweetened or artificially sweetened) to cancer risk, with glucose-related and insulin-related biomarkers as potential intermediate phenotypes, using a combination of expert knowledge and a web-based text mining tool. In the second stage, we conducted targeted PubMed searches to identify studies examining associations between consumption of soft drinks and these intermediate phenotypes (IPs) and between these IPs and the risk of several cancers in adult humans. In the third stage, the evidence was evaluated by the Expert Committee on Cancer Mechanisms (MEC), who assessed the strength of the evidence for these associations. The MEC concluded that there was weak evidence supporting a role of glucose or insulin-related processes as a potential mechanistic pathway linking the consumption of sugar-sweetened or artificially sweetened beverages to the risk of various cancers evaluated.

Purpose: Response-adapted bladder preservation has emerged as a potential alternative to immediate radical cystectomy for selected patients with muscle-invasive bladder cancer (MIBC), but biomarkers to guide treatment de-escalation are lacking. We report the clinical outcomes of the phase II RETAIN2 trial together with a retrospective circulating tumor DNA (ctDNA) analysis of the RETAIN1 and RETAIN2 studies. Patients and Methods: RETAIN2 prospectively evaluated neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) plus nivolumab followed by response-adapted management based on clinical restaging. A retrospective tumor-informed ctDNA analysis evaluated longitudinal ctDNA dynamics and associations with clinical outcomes. Results: Seventy one evaluable patients were enrolled in RETAIN2. The trial met its primary endpoint, with a 2 year metastasis free rate of 77.5% after a median follow-up of 34.7 months. Among 22 patients managed with active surveillance, 15 (68.2%) remained metastasis free with an intact, non irradiated bladder and 3 (13.6%) developed metastatic disease. In a sensitivity analysis using time to metastasis, the Kaplan Meier estimated 2 year metastasis free probability was 83.7% overall and 85.5% with active surveillance. Retrospective ctDNA analyses were performed in 111 patients from RETAIN1 and RETAIN2. Baseline and post-treatment ctDNA positivity were associated with metastatic progression and inferior overall survival. Among patients managed with active surveillance who were ctDNA-negative after treatment, the 2 year Kaplan Meier estimated metastasis free probability and overall survival were 91% and 97%, respectively. Plasma ctDNA predicted metastatic progression but not intravesical recurrence. Conclusion: Response adapted bladder preservation after neoadjuvant AMVAC plus nivolumab achieved encouraging long term outcomes in selected patients with MIBC. Retrospective ctDNA analyses suggest that plasma ctDNA reflects occult systemic disease rather than bladder confined recurrence and may refine patient selection for bladder preservation. These findings support prospective evaluation of ctDNA guided strategies while emphasizing the continued need for bladder directed surveillance and complementary urinary biomarkers.

Preclinical cancer sojourn time, defined here as the duration a cancer is undetected but detectable, is important for understanding disease progression and evaluating screening policies. This study aims to robustly characterise empirical evidence and existing knowledge over mean sojourn times across 21 stageable tumour sites, including stage-specific preclinical cancer sojourn times and the sojourn time of circulating tumour DNA (ctDNA)-positive cancers. We updated an existing systematic review through to February 2025 to extract population-level empirical sojourn time estimates derived from mathematical models of primary screening data. To synthesise this heterogeneous literature, quantify uncertainty, and obtain estimates for cancer-sites lacking empirical evidence, we conducted a formal Structured Expert Elicitation involving 15 clinical experts. The elicitation was grounded on the systematic review results, supplemented by an evidence dossier that included survival data and outcomes from relevant ctDNA cancer studies. The systematic review revealed heterogeneity in existing literature, which focused on a small subset of screened cancers (e.g., breast, cervical, colorectal). The elicitation successfully generated comprehensive probability distributions of overall mean sojourn times for all 21 cancer-sites (representing the site of tumour origin), as well as stage-specific sojourn times and overall sojourn times for ctDNA-positive cancers across 14 cancer-sites. This study used robust methodology to quantitatively describe existing evidence and experts' beliefs on the sojourn time of multiple cancer-sites, also describing uncertainty. Such estimates are important for future evaluations of the clinical impact, potential for overdiagnosis and subsequent cost-effectiveness of emerging screening technologies, including multi-cancer detection tests.

Objectives To compare trends in incidence and mortality rates for cancers with rising incidence in younger adults in England, and to assess whether increasing incidence is observed for early-stage, late-stage or both types of disease. Methods and analysis We used cancer incidence and mortality data from English National Disease Registration Service (2001-2023). Analyses focused on 12 cancers with increasing incidence (on average) in younger adults (20-49 years) and more than 500 cases diagnosed in 2023. Trends were quantified by estimating the average annual percentage changes (AAPCs) and 95% confidence intervals (CI) using Joinpoint regression and by calculating the excess number of cancer cases in 2023 compared to 2001. Age-standardised rates (ASRs) of early (stage 1-2) and late-stage (stage 3-4) disease were compared between 2013 (the earliest year available) to 2023. Results There were 31,385 cancers diagnosed in younger adults in 2023 compared to 244,384 in older adults. The most common cancers diagnosed in younger adults were female breast (n=8,504), colorectal (n=2,977) and melanoma (n=2,767). Of the 12 cancers that were increasing in younger adults between 2001 and 2023, only two also had increasing mortality rates: endometrial (AAPC[95%CI]= incidence 2.9%[2.4-3.4%] and mortality 4.0%[2.1-6.0%]) and colorectal cancer (AAPC[95%CI]= incidence 3.2%[2.8-3.6%] and mortality 1.9%[1.1-2.7%]). For thyroid cancer mortality rates were stable and for the other cancers (female breast, testicular, ovarian, kidney, brain, prostate, Hodgkin lymphoma and leukaemia) although incidence rates were increasing, mortality rates were decreasing, on average. Of the ten cancers with available stage data six showed increases in incidence rates for both early and late-stage disease between 2013 and 2023. Four cancers showed increases only in late-stage disease (female breast, ovarian, melanoma and Hodgkin lymphoma), while thyroid cancer showed an increase only in early-stage disease. Conclusions These population-wide analyses of national data from England, combining cancer incidence, mortality and stage-stratified incidence trends, highlight several public health and research priorities. These include identifying the causes of increasing colorectal cancer incidence in younger adults, given the marked increases in mortality and late-stage disease, and of increasing breast cancer incidence, which affects the largest number of younger adults and is increasing only for late-stage disease.

Microsatellite-stable/microsatellite instability-low colorectal cancer (MSS/MSI-L CRC) is generally resistant to immune checkpoint blockade, but the biological states underlying this resistance are heterogeneous. We integrated TCGA COAD/READ patient transcriptomic profiles, MSIsensor-based MSS/MSI-L classification, curated immune and stromal module scoring, focused differential expression and DepMap CRISPR dependency data to prioritize candidate vulnerabilities in immune-cold MSS CRC. Among 494 MSS/MSI-L tumours, 218 were classified as MSS intermediate, 102 as MSS immune-cold, 91 as MSS hot/inflamed and 83 as MSS barrier-high. MSS immune-cold tumours showed lower cytotoxic, IFN{gamma}-chemokine and antigen-presentation programmes than MSS hot/inflamed tumours, including reduced NKG7, CD8A, CXCL9, CXCL10 and LAG3 expression. MSS barrier-high tumours showed enrichment of stromal and extracellular-matrix programmes, including COL1A1, COL1A2 and COL3A1. Integration with DepMap CRISPR gene-effect data from 1208 cancer models, including 63 colorectal cancer models, separated tumour-cell-intrinsic dependencies from patient-derived microenvironmental signatures. Candidate target classes included ERBB2, VEGFA, PIK3CB, ATR/WEE1/CHEK1, HDAC1/HDAC3/BRD4 and BCL2L1/MCL1, while collagen genes were interpreted as stromal-barrier markers rather than tumour-cell dependencies. ERBB2 expression was higher in MSS immune-cold than MSS hot/inflamed tumours and further elevated in MSS barrier-high tumours, supporting ERBB2 as a candidate subset-associated signal that requires orthogonal HER2 validation. These findings support a stratified therapeutic framework for immune-cold, barrier-high and intermediate MSS CRC.

Background: Trastuzumab deruxtecan (T-DXd) is active in HER2-expressing solid tumours, but trials excluded HER2 immunohistochemistry (IHC) 1+ disease, and data in pretreated ovarian cancer are lacking. We evaluated real-world T-DXd activity and genomic correlates in pretreated ovarian cancer, predominantly high-grade serous (HGSOC). Methods: HER2 expression was assessed in an unselected ovarian cancer cohort (N=74). Fifteen patients receiving off-label T-DXd (14 HGSOC, 1 clear cell; IHC 1+ to 3+) had HER2 status centrally confirmed using gastric-type criteria. Activity was assessed by intra-patient growth modulation index (GMI; progression-free survival [PFS] on T-DXd divided by PFS on the prior line; [&ge;] 1.33 considered meaningful). Patients on treatment at data cut-off were censored. Objective response (RECIST 1.1) was assessed centrally where imaging was available (n=8). Results: Of the 40 HER2-expressing tumours, 15 received T-DXd, limited mainly by reimbursement. Among 14 evaluable patients (median 5 prior lines), 9 reached a GMI [&ge;] 1.33 (median 1.69); 8 remained on treatment at cut-off, making durability preliminary. Confirmed partial responses occurred across the HER2 spectrum. Benefit was independent of homologous-recombination (HR) status: one HR-proficient, CCNE1-wild-type patient achieved prolonged control and was rendered disease-free after radiotherapy to an oligoprogressive lesion. Exploratory analysis showed all four evaluable CCNE1-amplified tumours had reduced or non-durable benefit. Conclusions: T-DXd shows preliminary, clinically meaningful activity in HER2 IHC 1+ ovarian cancer independent of HR status. CCNE1 amplification may attenuate benefit, a candidate biomarker for WEE1-inhibitor combinations. Approval restricted to IHC 3+ disease would exclude most responders in this cohort. Prospective validation is required.

Background: A subset of uveal melanomas can be treated using either enucleation or proton beam therapy (PBT), which offer similar oncological outcomes. The most appropriate treatment depends on a patient's preference. To allow patients to genuinely determine their preference, it is recommended to describe options as neutrally as possible. This study assesses to what extent ocular oncologists use and perceive non-neutral framing behaviour, and if it is related to patient satisfaction with decision-making. Methods: Consultations of ocular oncologists with patients newly-diagnosed with uveal melanoma were audio recorded, transcribed verbatim, and coded for ocular oncologists' explicit and implicit non-neutral framing behaviours. Explicit non-neutral framing was defined as: explicitly mentioning a preferred option at least once, without relating it to the patient. Implicit non-neutral framing was defined as: describing an option (un)favourably, without providing a medically substantive clarification alongside. Results: 110 patients provided consent for the audio recordings. Non-neutral framing was found in 84% (n=92/110) of consultations. We found explicit behaviour in 38% (42/110) and implicit behaviour in 76% (84/110, median=1, range, 0-4) of consultations. The most frequent implicit framing was presenting options by positively or negatively emphasizing one option. Non-neutral framing behaviours were not significantly related to patient satisfaction with decision-making. Conclusion: This study shows that in most consultations some non-neutral framing was present, which did not impact patients' satisfaction with decision-making. Nonetheless, ocular oncologists should be aware that how they describe options may influence preferences in ways that do not align with the patient's values.

Intra-tumour heterogeneity is a major obstacle to durable responses to targeted cancer therapy, yet how different resistant cell states interact within the same tumour remains poorly understood. In this study, we demonstrate cooperativity between co-occurring resistant states in a single tumour. Using BRAF mutant melanoma as a paradigm, we generate three different resistant states within a single model and demonstrate that they exhibit varying differentiation states and migratory capacities and share few common therapeutic vulnerabilities. Through a combination of experiments, including using Cre-mediated recombination to generate heterogeneity in existing tumours, and in silico modelling, we show that intra-tumour heterogeneity is the most favoured state for therapy resistant tumours. This is underpinned by signalling between different melanoma states, with YAP1 active cells providing supporting signals for other cells but inhibiting their own proliferation. Optimal disease control requires targeting both the YAP1 active cell state and the inter- cellular communication networks. We identify the histone demethylase inhibitor GSK-J4 as being particularly effective in targeting both features of resistant tumours and demonstrate its ability to control melanoma with multiple concurrent resistance mechanisms.

Background: Evidence suggests chronic distress influences ovarian cancer (OC) etiology and metabolomic profiles. Here, we evaluated the association of a metabolite-based distress score (MDS) and OC risk. Methods: We included two matched case-control studies nested within the Nurses' Health Studies (N=584) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=348). Metabolites were measured 3-27 years before diagnosis using liquid-chromatography tandem mass spectrometry. We examined the association of quintiles of MDS and 19 constituent metabolites with OC risk using unconditional logistic regression and stratified by tumor histotype, menopausal status, and age at diagnosis. Results: We observed women in the highest versus lowest quintile of MDS had an increased OC risk (OR=1.62,95%CI=1.03-2.54,ptrend=0.07), and type 2 tumors (OR=1.71,95%CI=1.03-2.83,ptrend=0.11). Associations were suggestively stronger for premenopausal and <69-year-old women, and driven by pseudouridine, and N2,N2-dimethylguanosine. Conclusion: Our findings suggest chronic distress-associated metabolic dysregulation may represent a novel OC risk factor, especially among younger women.

Background: Observational research reports positive associations between type 2 diabetes mellitus (T2DM) and obesity-related cancers (ORCs), but causality remains unclear due to confounding (namely the shared risk factor of obesity, commonly approximated as body mass index, BMI), immortal time bias, and detection-time bias. Here, we aimed to use causal inference methods to minimise the above problems and estimate causal associations between new-onset T2DM and incident cancer. Methods: We performed a cohort study within UK Biobank, comparing new-onset T2DM with unexposed individuals matched 1 to 3 on BMI, age, and sex using a sequential longitudinal approach. The primary outcomes were total incident cancer, divided into ORCs and non-obesity-related cancers (NORCs). The secondary outcomes were site-specific cancers. We developed Cox models to estimate time-split hazard ratios (tsHRs) and 95% confidence intervals (CIs) stratified by sex. Findings: 23,771 participants with new-onset T2DM were matched with 71,170 unexposed participants. During a median follow-up of 5 years, there were 7694 (T2DM: 2432; unexposed: 5262) incident cancers. In men, there was evidence for an effect of T2DM on obesity-related cancer (tsHR 1.39, 95% CI 1.21-1.59), particularly on hepatocellular carcinoma (tsHR 3.97, 95% CI 2.38-6.65), pancreatic (tsHR 1.77, 95% CI 1.15-2.72) and kidney (tsHR 1.62, 95% CI 1.13-2.32) cancers. In women, there was evidence for an effect on obesity-related cancers (tsHR 1.33, 95% CI 1.16-1.52). Importantly, there were no associations with post-menopausal breast and endometrial cancers, two cancer types consistently associated with elevated BMI. There was no effect of new-onset T2DM on incidence of NORCs. There was evidence of detection-time bias, particularly in men. Interpretation: This is the first large-scale study to demonstrate evidence of a BMI-independent associations between new-onset T2DM and incident cancer. In men, this was primarily driven by hepatocellular carcinoma, pancreatic cancer, and kidney cancer. In women, the underlying cancers driving this relationship were less clearly defined. Funding: This study was funded by Cancer Research UK and administered through the Manchester Cancer Research Centre MB-PhD scheme (SEBCATP-2023/100010).

Background Therapy resistance in pancreatic ductal adenocarcinoma (PDAC) is facilitated by the desmoplastic tumor microenvironment (TME) orchestrated by cancer associated fibroblasts (CAFs). Upon activation, pancreatic stellate cells (PSCs) deplete their intracellular retinoic acid (RA)-containing lipid droplets and secrete stromal remodeling proteins like pentraxin 3 (PTX3), leading to cancer progression. Preclinical evidence indicates that all-trans RA (ATRA) reprograms the TME, while circulating vitamin A and PTX3 were proposed as biomarkers for ATRA response in PDAC. To support further clinical development of RA-based therapies in PDAC, we studied the effects of ATRA on CAFs and patient-derived organoids (PDO) and evaluated the clinical relevance of these biomarkers in PDAC patients. Methods We employed viability assays in human and murine organoid mono- and co-culture models to explore the efficacy of adding ATRA to gemcitabine (GEM). In parallel, we conducted a prospective observational study and assessed vitamin A and PTX3 as response biomarkers in peripheral blood collected before first treatment and at cycles 2 and 4 of treatment among patients with advanced PDAC receiving GEM with or without nab-paclitaxel (NAB-P). Results In PDO monocultures, a significant additive effect of ATRA in combination with GEM on viability was observed in 5 (41%) of 12 PDOs and this effect was numerically more frequent in organoids from patients who had clinically responded to GEM. In human and murine 3D PDO+PSC/CAF co-cultures, ATRA demonstrated an additional direct impact on the viability of stromal cells. Clinically, among 18 patients with PDAC treated with GEM+/-NAB-P, patients with no treatment response (n=10) showed an increase in PTX3 and concomitant decrease in vitamin A levels under therapy. In contrast, response was associated with stable vitamin A levels and a trend towards lower PTX3 levels during chemotherapy. Conclusions Our preclinical data support the repurposing of ATRA, an agent with favorable toxicity profile, to potentiate the efficacy of GEM in PDAC treatment. Complementing these results, our clinical data suggest vitamin A and PTX3 as promising response biomarkers in PDAC treatment, not restricted to ATRA containing regimens.

Cisplatin resistance remains a major barrier in head and neck squamous cell carcinoma (HNSCC) treatment. ATP-binding cassette (ABC) transporters contribute to chemoresistance by limiting intracellular drug accumulation. Bitter taste receptor 10 (T2R10) has been implicated in ABC transporter regulation, but its role in HNSCC remains undefined. HNSCC cell lines were treated with T2R10-agonist caffeine (100 or 200 M), cisplatin, or a combination, and viability was assessed by crystal violet assay. T2R10 promoter activity and expression following caffeine exposure were evaluated using a promoter-driven mCherry reporter and RT-qPCR. ABC transporter expression was measured after caffeine treatment and T2R10 gene (TAS2R10) knockdown or overexpression. Associations between tumor TAS2R10 expression and survival were assessed using TCGA data through GEPIA2. Caffeine enhanced the cisplatin-associated reduction in viability in a cell line- and concentration-dependent manner, with the strongest effect seen in UM-SCC47. A significant effect was observed in FaDu at 200 M of caffeine, and minimal response in RPMI 2650. RPMI 2650 cells and FaDu cells exhibited lower baseline TAS2R10 expression and RPMI 2650 cells did not demonstrate enhanced cisplatin sensitivity following caffeine treatment. Caffeine treatment increased TAS2R10 promoter activity and expression and was associated with decreased ABCG2 expression. TAS2R10 knockdown increased ABCG2 and ABCF1 expression, whereas TAS2R10 overexpression reduced ABCG2 and ABCC1 expression. High tumor TAS2R10 expression was associated with improved disease-free survival (log-rank p=0.0071; HR=0.61) but not overall survival. Caffeine enhances cisplatin sensitivity in selected HNSCC models. Caffeine exposure is associated with increased TAS2R10 expression and reduced expression of chemoresistance-associated transporters, particularly ABCG2.