Cancer Research UK Clinical Trials Unit

Abstract Background: Mammographic screening programmes reduce breast cancer mortality but detect many small good-prognosis tumours which may not progress. Screen-detected cancers are currently treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies are evaluating omission of radiotherapy in low-risk disease. However, there is little evidence for surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of lesions of uncertain malignant potential and benign lesions. SMALL (ISRCTN 12240119) aims to determine the feasibility of using this approach to treat small invasive tumours detected within the UK NHS Breast Screening Programme. Methods: SMALL is a phase III multicentre RCT comparing standard surgery with VAE for screen-detected cancers. Main eligibility criteria are age ≥47 years, unifocal grade 1 tumours with maximum diameter 15mm, strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomised 2:1 to VAE or surgery, with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are1. Non-inferiority comparison of the requirement for a second procedure following excision2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019. Recruitment halted in 2020 for 5 months due to COVID-19. At 9th July 2025, 49 centres are open, with 640 patients randomised. The randomisation rate is approximately 45%, and per site recruitment rate is 0.4-0.5 patients/month. Drawing from QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback is ongoing, and wider feedback is being delivered across sites via recruitment training workshops. Patient interviews are ongoing to explore patient views and experiences of the trial. Conclusion: SMALL continues to have excellent recruitment, is expected to complete recruitment in 2026 and have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme award 17/42/32 Citation Format: S. McIntosh, C. Coles, D. Dodwell, K. Elder, B. Elsberger, J. Foster, C. Gaunt, J. Henderson, C. Mabena, J. Morgan, Z. Nabi, I. Lyburn, S. Paramasivan, S. Pinder, S. Pirrie, S. Potter, T. Roberts, N. Sharma, E. Southgate, H. Stobart, A. Talwalkar, S. Taylor-Phillips, W. Teh, E. Turner, M. Wallis, D. Rea. Small: open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancer - a UK phase III randomised multi-centre trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-12.

ABSTRACT Background Cystoscopy 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. Objective To assess the diagnostic performance and clinical utility of GALEAS™ Bladder as a molecular triage tool in real-world haematuria investigation pathways. Methods Patients 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 Limitations Cystoscopic 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 Implications GALEAS™ 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.

Background and purposeAs more interventional clinical trials in Precision Cancer Medicine (PCM) are introduced, molecular descriptions of tumours have led to multiple subtypes, even within common tumour types. Therefore, the main limitation of these trials is the small number of eligible patients to assess the clinical benefit. The PRIME-ROSE project addresses this limitation by pooling data from multiple European Drug Rediscovery Protocol (DRUP)-like clinical trials, such that slowly accruing cohorts are accelerated. To achieve this task, a well-documented commonly approved procedure for data merging needs to be established.Patient/material and methodsData sharing is achievable when there is an organisation that includes people from different disciplines who can navigate institutional and country-specific information and governance requirements. Furthermore, alignment of all the study procedures are needed before data are shared. Next, the process of merging data requires harmonisation and standardisation. Implementation of the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) facilitates future data aggregation.ResultsBy aggregating data from European DRUP-like clinical trials, cohorts are completed that were unable to do so in stand-alone studies. Since initiation, the PRIME-ROSE project monitors over 300 cohorts across more than 20 treatments encompassing over 1,000 patients. At least 20 cohorts have progressed after interim analysis.InterpretationData sharing across European trials is feasible and enhances the advancements of PCM studies. The methodologies developed in the PRIME-ROSE project provide a foundation for future data integration efforts in PCM clinical trials, underscoring the viability of conducting robust trials in a global context.

For women with chronic or gestational hypertension who remain well, early term birth (at 37-38 weeks' gestation) may reduce maternal complications, caesareans and stillbirths, but it may increase neonatal morbidity compared with expectant care. Expectant care may increase costs. There are no high-quality data to guide care, which currently involves maternal-fetal surveillance and intervention for maternal or fetal compromise, which may be rapid or unexpected. To investigate optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. Pragmatic, unmasked, multicentre randomised trial with a health economic analysis. Fifty United Kingdom hospitals. Inclusion: maternal age ≥ 16 years, chronic or gestational hypertension, singleton pregnancy, live fetus, 36+0-37+6 weeks' gestation and able to give documented informed consent. Exclusion: contraindication to either trial arm (e.g. pre-eclampsia), blood pressure ≥ 160/110mmHg until controlled, major fetal anomaly anticipated to require neonatal care unit admission or participation in another timed birth trial. Planned early term birth at 38+0-3 weeks' (intervention) or 'usual care at term' (control, revised from 'expectant care until at least 40+0 weeks', August 2022). Maternal coprimary: composite of 'poor maternal outcome' (severe hypertension, maternal death or maternal morbidity and superiority hypothesis). Neonatal coprimary: neonatal care unit admission ≥ 4 hours (non-inferiority hypothesis). Each coprimary is measured until primary hospital discharge or 28 days post birth (whichever is earlier). Key secondary: caesarean birth. 1 : 1 ratio, minimised for key prognostic variables: site, hypertension type and prior caesarean. It was not possible to mask care providers or participants to the intervention. For the coprimary maternal outcome, there was local site principal investigator/delegate sign-off based on review, masked to allocated group, of primary case notes. From 2019 to 2022, 403 participants were randomised (37% of target 1080) to intervention (n = 201) or control (n = 202). The funder stopped the trial during the coronavirus disease discovered in 2019 pandemic for delayed recruitment. In the intervention (vs. control) group, birth was a median of 0.9 weeks earlier (38.4, interquartile range 38.3-38.6 vs. 39.3, interquartile range 38.7-39.9 weeks). There was no evidence of a difference in 'poor maternal outcome' (13% vs. 12%, respectively; adjusted risk ratio 1.16, 95% confidence interval 0.72 to 1.87). For 'neonatal care unit admission ≥ 4 hours', the intervention was considered to be non-inferior to control, as the adjusted risk difference, 95% confidence interval upper bound did not cross the 8% pre-specified non-inferiority margin (7% vs. 7%, respectively; adjusted risk difference 0.003, 95% confidence interval -0.05 to +0.06), although event rates were lower than estimated. There was no evidence of a difference in caesarean (29% vs. 36%, respectively; adjusted risk ratio 0.81, 95% confidence interval 0.61 to 1.08). Recruitment was 37% of the anticipated sample size (as above). Despite being unable to recruit to target in this study, we observed that most women with chronic or gestational hypertension required labour induction and planned birth at 380-3 weeks (vs. usual care), which resulted in birth an average of 6 days earlier and there were no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 380-3 weeks as a clinical option for these women. An individual participant data meta-analysis is planned to address whether the intervention (vs. control) reduces caesarean; low adverse event rates would make unfeasible mounting another randomised trial. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/167/123.

Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) have transformed the management of type 2 diabetes and obesity, providing substantial benefits for glycaemic control, weight reduction and cardiometabolic health [1-4]. Their use is rapidly expanding across both general and specialist practices, with an increasing number of patients also accessing these agents privately for weight management [5, 6]. However, ongoing concern has been raised about a potential association between GLP-1 agonists and thyroid cancer, in particular medullary thyroid cancer (MTC). Preclinical rodent studies have found that chronic GLP-1 agonist exposure stimulates calcitonin secretion, induces C-cell hyperplasia and increases the incidence of MTC in a dose- and drug-dependent manner [7, 8]. Based on this preclinical data, the US Food and Drug Administration has issued a boxed warning, contraindicating the use of GLP-1 agonists in those with a personal or family history of MTC or Multiple Endocrine Neoplasia Type 2 (MEN 2) [9]. However, these findings have not been replicated in primates or humans, whose C-cells exhibit minimal GLP-1 receptor activity [10-14]. Clinical evidence remains mixed, but increasingly reassuring. Importantly, no randomised controlled trial in humans has demonstrated a consistent or statistically robust increased incidence of thyroid cancer associated with GLP-1 receptor agonist therapy [15, 16]. Some pharmacovigilance reports and observational studies have suggested a moderately elevated risk of thyroid cancer [14, 17-20]. However, large population-based studies and meta-analyses found no significant association between GLP-1 agonist use and thyroid cancer [15, 16, 21-28]. A recent international meta-analysis of 98,147 patients found no overall excess risk of thyroid cancer in GLP-1 agonist users compared with patients treated with Dipeptidyl Peptidase-4 (DPP-4) inhibitors (adjusted HR: 0.81, 95% CI 0.59−1.12) [22]. However, long-term follow-up is still required. It is also notable that both obesity and diabetes independently increase thyroid cancer risk, complicating the interpretation of observational data [29, 30]. Robust data examining the safety of GLP-1 agonists in patients who have previously been treated for thyroid cancer is limited. For differentiated thyroid cancer (including papillary, follicular and oncocytic subtypes), GLP-1 agonists may be used alongside standard oncological surveillance where clinically indicated. A 2022 systematic review found no increased risk of hyperthyroidism, hypothyroidism, thyroiditis, nodules or goitre with GLP-1 agonists when compared with controls [16]. However, use of GLP-1 agonists should be avoided in patients with a history of MTC, known pathogenic germline RET variants or a family history of MEN2. For this patient subgroup, initiation of GLP-1 agonists should only be considered in exceptional cases within a multidisciplinary (MDT) setting. A statement for patients has also been prepared, included as an appendix, to support clear communication and shared decision-making between clinicians and individuals considering or currently using GLP-1 agonists (Appendix S1). Overall, current available evidence suggests no indication of a clinically meaningful short-term increase in thyroid cancer risk following GLP-1 agonist initiation. In October 2023, the European Medicines Agency (EMA)'s safety committee Pharmacovigilance Risk Assessment Committee (PRAC) concluded that ‘the available evidence does not support a causal association between [GLP-1] receptor agonists… and cancer of the thyroid’ [31]. The benefits of therapy are likely to outweigh any potential thyroid-related risks for most patients. Routine calcitonin measurement or thyroid ultrasound screening is not recommended in unselected patients. Ongoing long-term surveillance studies will be essential to fully clarify potential late effects. The authors received no specific funding for this work. The authors declare no conflicts of interest. Data sharing is not applicable to this article, as no data sets were generated or analysed during the current study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Infectious diseases remain a leading cause of morbidity and mortality in resource-limited settings, exacerbated by inadequate health literacy, poor adherence to preventive measures, and constrained healthcare infrastructure. This paper proposes the Community-Level Infectious Disease Education and Adherence Model (CIDEAM), an integrated, culturally sensitive framework designed to enhance disease prevention, treatment adherence, and health outcomes in underserved populations. The model emphasizes participatory education strategies, community health worker engagement, and context-appropriate communication channels to bridge knowledge gaps and foster behavioral change. Drawing from evidence-based interventions and socio-behavioral theories, CIDEAM incorporates peer-led workshops, visual and audio educational tools in local languages, and interactive community dialogues to improve understanding of disease transmission, symptoms, treatment protocols, and prevention methods. It also integrates adherence monitoring mechanisms such as mobile health (mHealth) reminders, household follow-up visits, and social support groups to reinforce compliance with medical regimens, particularly for chronic and high-burden infections like tuberculosis, HIV/AIDS, and malaria. The model accounts for socio-economic determinants of health by incorporating strategies to address stigma, misinformation, and barriers to accessing healthcare services, thereby promoting trust and collaboration between communities and healthcare providers. Implementation in resource-limited contexts is supported by capacity-building initiatives for community health workers, partnerships with local leaders, and the leveraging of low-cost digital technologies. Pilot studies suggest that CIDEAM can significantly improve treatment adherence rates, reduce infection incidence, and strengthen community resilience against outbreaks. The model’s adaptability ensures relevance across diverse cultural and epidemiological contexts, making it a scalable and sustainable solution for global health initiatives targeting infectious disease control in marginalized populations. By integrating education, adherence support, and socio-cultural considerations, CIDEAM offers a pathway to reducing infectious disease burdens while empowering communities to take ownership of their health outcomes. Keywords: Community Health Education, Infectious Disease Prevention, Treatment Adherence, Resource-Limited Settings, Health Literacy, Mhealth, Community Engagement, Behavioral Change, Disease Control, Global Health.