500 Background: Tumor gene expression tests are widely used to assist adjuvant chemotherapy decisions for women with early breast cancer (EBC). OPTIMA (Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis) is an international RCT comparing chemotherapy decisions made with the Prosigna (PAM50) gene expression test with standard treatment in mostly node-positive patients. Methods: Women and men aged >40 recommended to receive chemotherapy for ER+ HER2- EBC with 0-9 involved axillary nodes and T size >30mm if node negative were eligible. Randomization was between standard chemotherapy followed by endocrine therapy (CET) or to a Prosigna test directed chemotherapy decision. Patients with Prosigna ROR score > 60 tumors were assigned CET whilst those with low ROR score (≤60) tumors received endocrine therapy (ET) alone. ET for premenopausal women included ovarian function suppression (OFS) in the absence of chemotherapy-induced ovarian insufficiency. ROR scores were not disclosed, and patients receiving CET were blinded to their randomization. OPTIMA was designed to demonstrate non-inferiority (NI) of 5-year invasive breast cancer free survival (IBCFS) in the test-directed arm with a 3% margin in the per protocol (PP) population using a 5% 1-sided alpha. Control arm testing allowed treatment comparison within the low ROR score population at a 3.5% NI margin. Results: From 16 th Jan 2017 to 12 th Dec 2025 4429 patients were randomized, 2215 to the control arm and 2214 to the test-directed arm of whom 2061 (93%) and 2097 (95%) were included in the respective PP group. Patient characteristics in the PP population were well-balanced; 62% were postmenopausal, 37% premenopausal and 0.8% male. 73% had pN1/pN1sn, 8% had pN0/pN1mi and 19% had pN2 tumors. 68% had low ROR score tumors. With a median follow-up of 3.9 years (interquartile range 2.0-5.9), 280 IBCFS events occurred (141 on control arm; 139 on test directed arm) of which 66% were distant recurrences. The 5-year IBCFS rate in the control arm was 91.5% [95% CI 89.7- 92.9%] and 90.4% [95% CI 88.6- 92.0%] in the test-directed arm, Hazard Ratio (HR) 0.99 [90% CI 0.81- 1.20], NI p = 0.013, thereby meeting the pre-defined NI margin. The corresponding 5-year IBCFS rates for the low ROR score population were 94.9% [95% CI 92.9- 96.4%] and 93.7% [95% CI 91.8- 95.2%] for the two arms respectively, HR 1.06 [90% CI 0.78- 1.46] NI p = 0.0051 again demonstrating non-inferiority. There was no significant outcome heterogeneity between subgroups including for menopausal and nodal status. Conclusions: The OPTIMA trial demonstrates that women and men with ER+ HER2- EBC and ROR score ≤60 tumors can safely avoid chemotherapy. It provides evidence for the utility of test-directed chemotherapy in premenopausal women treated with OFS and patients with high levels of nodal involvement. Clinical trial information: ISRCTN42400492.

Introduction Significant advances in systemic therapy have improved survival for patients with advanced-stage non-small cell lung cancer (NSCLC). However, the present treatment strategies and dose-fractionation for high-dose palliative radiotherapy (RT) are based on trials from the 1990s, when RT planning was simple with less precise delivery. Contemporary lung RT uses 4D-CT, volumetric modulated arc radiotherapy, aided by online verification using cone beam CT, which enables greater accuracy and better target volume coverage, while reducing doses to normal organs at risk. The Shortened High-dose Palliative Radiotherapy for Lung Cancer study aims to evaluate the safety and feasibility of reducing the number of RT fractions and RT duration, using contemporary planning, verification and delivery techniques.Methods and analysis This single-arm, multicentre, phase-II study will test the shortened hypofractionated accelerated palliative RT regimen of 30 Gy in 6 alternate-day fractions, with strict normal tissue dose constraints. We aim to recruit 37 patients across 4 sites within the West Midlands. Quality assurance for the RT is supported by the Radiotherapy Trials Quality Assurance Group (RTTQA). Patients with locally advanced or metastatic NSCLC, who are candidates for high-dose palliative RT, before or after first-line systemic therapy, are eligible for recruitment. The primary objective of this study is to assess the safety of the proposed dose-fractionation. Secondary objectives include evaluating toxicity profiles, patient-reported outcome measures, time to progression, feasibility and the National Health Service cost-saving.Ethics and dissemination This study is conducted in accordance with the International Council for Harmonisation Good Clinical Practice (ICH GCP) guidelines and all applicable regulatory frameworks, including, but not limited to, the UK policy framework for health and social care research, as well as the Health Research Authority and Health and Care Research Wales regulations. Approval for the study was granted on 18 April 2024 (IRAS project ID: 332998; REC reference: 24/WM/0032). The chief investigator is responsible for obtaining informed consent from participants. Any individual delegated this responsibility is thoroughly authorised, trained and competent to conduct the informed consent process. On completion of the trial, the results will be shared with participants in a plain language summary and will be submitted for publication in a peer-reviewed journal. If successful, this study will inform a phase III randomised controlled trial to assess efficacy. For updates on the study, visit the study web page (https://research.mededcoventry.org/About-Us/Meet-The-Team/TMU/Ship-Rt).Trial registration number NCT06483308.

Tamoxifen's pharmacokinetics are strongly influenced by the highly polymorphic CYP2D6, while the influence of other genetic variants has been inconclusive. To further delineate this genotypic-phenotypic impact, we conducted a multi-ancestry genome-wide association study in 636 hormone-receptor-positive (HR+) breast cancer (BC) patients treated with 20 mg tamoxifen daily for ≥8 weeks and validated these genetic determinants in another 869 patients. Association with clinical outcomes was examined in 1326 non-metastatic HR+ patients receiving adjuvant tamoxifen. A genome-wide significant association with Z-endoxifen levels was observed at the CYP2D6 locus on chromosome 22 and its downstream region of TCF20 rs932376 A > G. Both CYP2D6 metabolizer status and TCF20 rs932376 A > G were independent predictors of endoxifen levels in multivariable analysis. CYP2D6 metabolizer status accounted for greater variability of mean endoxifen levels compared to TCF20 rs932376 A > G (91.2% vs 48.8%). These findings were replicated in validation cohorts. Neither TCF20 rs932376 nor CYP2D6 metabolizer status was significantly associated with BC outcomes after adjustment for known prognostic factors. Our study confirmed that CYP2D6 metabolizer status remains as the prime predictor of steady-state Z-endoxifen levels, while TCF20 rs932376 A > G has a smaller, independent effect. Both genetic factors were not associated with BC clinical outcomes.

The Tackling Early Morbidity and Mortality in Myeloma trial (TEAMM) trial recruited 977 newly diagnosed myeloma patients from 93 UK hospitals to assess the advantages and disadvantages of prophylactic antibiotics for the first 12 weeks. This paper analyses the 133 (14%) patients who had previously known precursor disease including monoclonal gammopathy of undetermined significance (MGUS) and smouldering myeloma (SMM), reporting the relative importance of blood-based biomarkers, imaging findings and symptoms in their management. Prior to progression with active myeloma, patients with precursor conditions had symptoms for five times longer than patients with no diagnosed precursor phase. Although only 29% of patients reported new myeloma-related symptoms developing after their first haematology appointment, 70% had a significant rise in paraprotein levels prior to progression. Likewise, risk scores for both MGUS and SMM increased prior to progression. Fractures occurred in 25% of patients despite being monitored for precursor disease. These fractures were difficult to predict as biomarkers lacked specificity and only 40% of patients reported back pain in combination with vertebral fractures. This study highlights the ongoing challenge of promptly recognising disease progression when using patient-reported symptoms and monoclonal immunoglobulin monitoring.

INTRODUCTION:Total intravenous and inhalational anaesthesia are used widely to maintain general anaesthesia for major non-cardiac surgery, yet their comparative cost-effectiveness remains uncertain. The VITAL trial evaluated clinical outcomes, showing no difference in days alive and at home at 30 days. We conducted an economic evaluation alongside VITAL to determine whether total intravenous anaesthesia offers an economic advantage within the UK NHS. METHODS:A within-trial economic evaluation was conducted from the NHS and personal social services perspective over a 6-month time horizon. Resource use was collected from trial records and questionnaires, and health-related quality of life was measured using EuroQol five-dimension five-level instrument at baseline, discharge, 30 days and 6 months. Costs were evaluated using national sources and quality-adjusted life years were calculated using the area under the curve approach. Incremental cost-effectiveness ratios were estimated using imputed datasets, with uncertainty explored through bootstrapping and the probability of cost-effectiveness illustrated using a cost-effectiveness acceptability curve across a range of willingness-to-pay thresholds. RESULTS:A total of 2507 patients were allocated randomly: 1253 (50%) received total intravenous anaesthesia; and 1254 (50%) inhalational anaesthesia. Mean costs and quality-adjusted life years were similar across groups. Incremental cost was -£145 (95%CI -£1510-£1220) and incremental quality-adjusted life years -0.001 (95%CI -0.008-0.005). Total intravenous anaesthesia showed a 56-57% probability of cost-effectiveness at standard willingness-to-pay thresholds. Sensitivity analyses, including complete-case and societal-perspective models, yielded consistent findings of equivalence. DISCUSSION:Total intravenous and inhalational anaesthesia show comparable cost-effectiveness for adults aged ≥ 50 y undergoing major non-cardiac surgery. Given clinical equipoise and equivalent economic outcomes, anaesthetic choice should continue to be guided by patient factors, clinician expertise and organisational context. Further research may be justified given the large population undergoing major surgery.

Importance:Older adults undergoing major noncardiac surgery experience substantial postoperative morbidity and health care use. The comparative effectiveness of total intravenous anesthesia (TIVA) vs volatile-based inhalational anesthesia on recovery and safety remains uncertain. Objectives:To determine whether TIVA improves days alive and at home at 30 days compared with inhalational anesthesia and to evaluate differences in patient-centered outcomes and recovery. Design, Setting, and Participants:Pragmatic, multicenter, open-label randomized clinical trial conducted in 49 UK National Health Service hospitals from January 2022 to April 2024 (final follow-up, October 2024) among patients aged 50 years or older scheduled for elective major noncardiac surgery. Interventions:Participants were randomized 1:1 to receive maintenance of general anesthesia with either TIVA (propofol infusion) (n = 1254) or volatile-based inhalational agents (n = 1254). All other perioperative care was at clinician discretion. Main Outcomes and Measures:The primary outcome was days alive and at home at 30 days. Secondary outcomes included days alive and at home at 90 days; mortality at 30 days, 90 days, and 6 months; Quality of Recovery-15 score at day 3; patient satisfaction (Bauer Patient Satisfaction Questionnaire) at day 1; delirium (4 As Test [4AT]) at day 3; unintentional awareness under anesthesia; and major postoperative complications within 30 days. Results:Among the 2508 randomized participants, the mean age was 67 (SD, 8.9) years, and 55% were male. Characteristics were balanced across randomized groups. Days alive and at home at 30 days were similar between groups (mean, 22.5 [SD, 6.8] days vs 22.4 [SD, 6.6] days for TIVA vs inhalational anesthesia, respectively; incidence rate ratio, 1.00; 95% CI, 0.99-1.02; adjusted P = .68). There were no differences in days alive and at home at 90 days; mortality at 30 days, 90 days, or 6 months; or Quality of Recovery-15 score at day 3. Lower rates of thirst, hoarseness, and nausea and vomiting were reported in the TIVA group. Levels of delirium were similar between groups, with the majority (87.6%) having no delirium at day 3. Major complications occurred in 12.4% of patients overall, with no significant between-group differences. Two cases of certain or probable unintentional awareness under anesthesia were reported, both in the TIVA group. Conclusions and Relevance:Among older adults undergoing major noncardiac surgery, TIVA did not improve days alive and at home at 30 days compared with inhalational anesthesia. Trial Registration:ISRCTN.org Identifier: ISRCTN62903453.

Background:Annual surveillance mammograms for an unspecified period, after treatment for early breast cancer, are widely practised in the United States of America and Europe. Current UK guidelines recommend annual mammograms for 5 years, then reverts to 3-yearly screening. The aim of this trial was to evaluate whether less than annual mammography was non-inferior in terms of breast cancer-specific survival and cost-effectiveness in women aged 50 years or older at diagnosis and 3 years post curative surgery. Methods:We conducted a multicentre, randomised phase III trial of annual mammography versus less-frequent mammography (2-yearly after conservation surgery or 3-yearly after mastectomy). Women were eligible if aged ≥ 50 years at initial diagnosis of breast cancer (invasive or ductal carcinoma in situ) and recurrence-free 3 years post curative surgery. The trial was conducted at 114 NHS hospitals in the UK. Participants were randomly assigned (1 : 1) to annual or less-frequent mammograms; followed up for 6 years. Coprimary outcomes were breast cancer-specific-survival and cost-effectiveness; secondary outcomes included recurrence-free interval and overall survival. Analyses were by intention to treat, with a pre-planned per-protocol analysis. Planned sample size was 5000. Clinical results are now reported. Results:Five thousand two hundred and thirty-five women were randomised between April 2014 and September 2018. With a median of 5.7-year follow-up, 343 women have died, of whom 116 died of breast cancer (61 on annual arm; 55 on less-frequent arm). Breast cancer-specific-survival at 5 years was 98% on both arms with a hazard ratio of 0.92 (95% confidence interval 0.64 to 1.32), which demonstrated non-inferiority of less-frequent mammograms at the 3% margin (non-inferiority p < 0.0001) and the 1% margin (non-inferiority p = 0.003). Non-inferiority was demonstrated at the 2% level for both recurrence-free interval [hazard ratio 1.00 (95% confidence interval 0.83 to 1.28); non-inferiority p = 0.0024] and overall survival [hazard ratio 1.07 (95% confidence interval 0.87 to 1.33); non-inferiority p = 0.008]. Less-frequent mammograms were associated with a significant cost saving (mean difference £544, 95% confidence interval -£1116 to £26), heavily driven by mammogram costs. Incorporating societal costs resulted in a larger cost-saving (£1543 per person, 95% confidence interval -£2416 to -£669), increasing cost-effectiveness. There was no impact of less-frequent mammograms on patients' quality of life. Conclusion:For patients aged ≥ 50 years and 3 years post diagnosis, less-frequent mammograms were non-inferior and cost-effective compared with annual mammograms, with no detriment to patients' quality of life. Mammo-50 provides evidence to inform guideline development. Limitations:Adherence to the mammographic schedules was 76%, though the per-protocol analysis showed no difference compared to the intention to treat results. The majority of the participants had small lower-grade oestrogen receptor-positive tumours and were from a White ethnic group. Future work:More research is needed for women with ductal carcinoma in situ; women aged under 50 years old at diagnosis and different ethnic groups, especially those women of Black ethnicity who tend to present younger. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 11/25/03.

Oestrogen-receptor positive breast cancer patients are typically treated with adjuvant endocrine therapy (AET), some develop AET resistance. Previous research suggests mammographic density (MD) may represent an imaging biomarker, with fewer local or distant recurrences occurring with decreasing MD. We investigate whether reduction in MD after 1 and/or 3 years is associated with improved breast cancer specific survival (BCSS), metastasis-free survival (MFS) or disease-free survival (DFS). This retrospective cohort study was generated from a Mammo-50 trial subset. Participants taking AET (cases) and controls were included. MD was assessed in the AET group using a 0–100

Background De-escalation trials aim to balance clinical outcomes and quality of life (QoL), especially for premenopausal women with early breast cancer (BC), who often experience a greater treatment burden affecting their physical and psychosocial well-being. We sought to understand their patient journey—barriers, facilitators, and expectations—when joining de-escalation trials to inform patient-centered design and implementation. Methods OPTIMA-YOUNG, an EU-co-funded international trial, investigates a genomic assay-guided approach to de-escalate chemotherapy in premenopausal patients with early-stage hormone receptor (HR)+ BC. A Co-creation Board of patients and healthcare professionals (HCPs) ensured stakeholder involvement throughout the trial. Focus groups (FGs) explored decision-making, needs, and QoL priorities related to joining a de-escalation clinical trial. Discussions were recorded, transcribed, anonymized, and analyzed using MAXQDA software. Results The three FGs included 20 participants (11 patients, 9 HCPs) from 14 countries. Three themes emerged: 1) emotional and cognitive responses to BC diagnosis/treatment; 2) environmental, HCP, and social influences on choices; 3) coping with side effects and QoL challenges. Barriers to joining a de-escalation trial included limited emotional support at diagnosis, cross-country variations in shared decision-making, poor communication on long-term side effects, fear of recurrence, and HCPs’ tendency to overtreat younger patients. Developing training for patients and HCPs was seen essential for improving communication, shared decision-making skills, and enhancing symptom management and QoL. Conclusions This pre-implementation study identified factors at the patient, HCP, and system levels that, if addressed, could improve the trial experience. Insights helped refine the OPTIMA-YOUNG protocol and implementation plan and may inform future de-escalation trials.

Background and purpose. The average of two expert assessments of Mammographic Density (MD) using Visual Analogue Scales (VAS) has been related to risk of breast cancer, despite reader variability. Much of the evidence for this method of MD assessment came from a single-centre, single-mammography-vendor setting. We investigate the inter-observer agreement of readers assessing density in images from multiple vendors and its association with mean density and mammography vendor. Methods. We analysed MD assessments from 11 experienced readers who each assessed the cancer-free breast of 50 women with unilateral breast cancer at three time points, with 3-51 mammograms from 6 different vendors. The three vendors with the fewest were grouped. The standard deviation of VAS readings for each mammogram was used as a marker of agreement. Regression analysis was used to investigate agreement with vendor. To further investigate agreement, twenty mammograms showing Low Agreement (LA) between readers and 20 with High Agreement (HA) were selected. Results. Regression analysis found that vendor was not significantly associated with reader agreement (F(3,146) = 1.47, p = 0.225; R-2 = 0.029). Mammogram system vendor accounted for 3% of variability in reader agreement. There was a strong association between reader agreement and VAS density (p < 0.001). Standard deviations were 16.1-21.3% (LA) and 2.2-8.7% (HA). Discussion. Despite the very different appearance of mammograms from different vendors, disagreement was not found to be associated with vendor in this analysis, but it was found to be associated with density. Since reader agreement is low for some cases, averaging multiple visual assessments of breast density may be advisable if resources permit.

Background:Digital pathology refers to the conversion of histopathology slides to digital image files for examination on computer workstations as opposed to conventional microscopes. Prior to adoption, it is important to demonstrate pathologists provide equivalent reports when using digital pathology in comparison to bright-field and immunofluorescent light microscopy, the current standard of care. Objective:A multicentre comparison of digital pathology with light microscopy for reporting of histopathology slides, measuring variation within and between pathologists on both modalities. Design:A blinded crossover 2000-case study estimating clinical management concordance (identical diagnoses plus differences not affecting patient management). Each sample was assessed twice by four pathologists (once using light microscopy, once using digital pathology, the order randomly assigned and a 6-week gap between viewings). Random-effects logistic regression models, including crossed random-effects terms for case and pathologist, estimated percentage clinical management concordance. Findings were interpreted with reference to 98.3% concordance (Azam AS, Miligy IM, Kimani PKU, Maqbool H, Hewitt K, Rajpoot NM, Snead DRJ. Diagnostic concordance and discordance in digital pathology: a systematic review and meta-analysis. J Clin Pathol 2021;74:448-55. https://doi.org/10.1136/jclinpath-2020-206764). Setting:Sixteen consultant pathologists, four for each specialty, from six National Health Service laboratories. Experience ranged from 3 to 35 years. Some were early adopters of digital pathology, but the majority were new to digital pathology. Interventions:Eight viewings per sample (four pathologists with light microscopy and with digital pathology), culminating in a consensus ground truth, enabling measurement of agreement within and between readers. Samples enrolled reflected routine practice, included cancer screening biopsies, and were enriched for areas of difficulty [e.g. dysplasia (7, 10, 11)]. State-of-the-art digital pathology equipment designed for diagnosis, and holding either Conformité Européene or Food and Drug Administration approval, was used. Main outcome:Intra-pathologist variation between reports issued on digital pathology and light microscopy, inter-pathologist variation against ground-truth diagnosis using light microscopy and digital pathology. Secondary outcomes:Pathologist-recorded reporting times, along with their confidence in diagnosis, analysis of eye-tracking evaluating examination techniques, and a qualitative study examining attitudes of pathologists and laboratory staff to digital pathology adoption. Results:Two thousand and twenty-four cases (608 breast, 607 gastrointestinal, 609 skin, 200 renal) were recruited, with breast and gastrointestinal including screening samples [207 (34%) breast, 250 (41%) gastrointestinal]. Overall, in light microscopy versus digital pathology comparisons, clinical management concordance levels were 99.95% (95% confidence interval 99.91 to 99.97). Similar results were observed within specialties [breast: 99.40% (95% confidence interval 99.06 to 99.62); gastrointestinal 99.96% (95% confidence interval 99.89 to 99.99); skin 99.99% (95% confidence interval 99.92 to 100.0); renal 99.99% (95% confidence interval 99.57 to 100.0)], and within screening cases [98.96% (95% confidence interval 98.42 to 99.32), breast 96.27% (94.63 to 97.43), gastrointestinal 99.93% (95% confidence interval 99.68 to 99.98)]. Reporting time between digital pathology and light microscopy was similar, but pathologists became faster on digital pathology with familiarity. Pathologists recorded high levels of confidence in their diagnosis with light microscopy, significantly higher than digital pathology. Limitations:Cytology cases and specialty groups outside those tested were not examined. The study used two digital pathology scanning systems. Other systems available on the market were not tested. Conclusions:Clinical management concordance levels between the two modalities exceed the reference 98.3% in breast, gastrointestinal, skin and renal specialties, and pooled breast and large bowel cancer screening cases. Subgroup analysis of clinically significant differences revealed a range of differences including areas where interobserver variability is known to be high, which were distributed between reads performed with both platforms and without apparent trends to either. Future work:The use of digital pathology for cytology samples remains an area for further research. Study registration:This study is registered as ISRCTN14513591. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/84/07) and is published in full in Health Technology Assessment; Vol. 29, No. 30. See the NIHR Funding and Awards website for further award information.

The De-ESCALaTE trial confirmed the superiority of cisplatin over cetuximab in combination with radiotherapy for the treatment of low risk HPV+ oropharyngeal cancer (HPV + OPC). However, there were concerns about certain toxicities with the use of cisplatin, in particular nausea, vomiting, dehydration and renal toxicities. The De-ESCALaTE trial collected data on several centre level policies on hydration and anti-emetic use. Univariable and backwards stepwise multivariable logistic regression models were used to model the association between centre level policy variables and severe adverse events (SAEs) of interest and severe (grade 3–5) acute toxicities of interest. In addition, the predictive performance of each model was assessed. Centre level policies including the use of a triple anti-emetics regimen pre and post chemotherapy, increased volumes of IV fluids given before and during cisplatin chemotherapy as well as oral fluids advised post chemotherapy, were all associated with a reduced odds of SAEs of interest. Only a policy to give diuretics was associated with a reduction of severe (grade 3–5) acute toxicities of interest. For centres with HPV + OPC patients undergoing chemoradiation, we recommend the use of specific hydration and anti-emetic policies to reduce the rates of relevant SAEs and severe acute toxicities.

Background The frequency of mammographic surveillance for women after diagnosis of breast cancer varies globally. The aim of this study was to evaluate whether less than annual mammography was non-inferior in terms of breast cancer-specific survival in women aged 50 years or older. Methods Mammo-50 was a multicentre, randomised, phase 3 trial of annual versus less frequent mammography (2-yearly after conservation surgery; 3-yearly after a mastectomy) for women aged 50 years or older at initial diagnosis of invasive or non-invasive breast cancer and who were recurrence free 3 years post curative surgery. The trial was conducted at 114 National Health Service hospitals in the UK. Participants were randomly assigned (1:1) to annual or less frequent mammograms at 3 years post curative surgery and were followed up for 6 years. The co-primary outcomes were breast cancer-specific survival and cost-effectiveness. The cost-effectiveness analysis will be reported elsewhere. Breast cancer-specific survival was assessed in the intention-to-treat population. Secondary outcomes were recurrence-free interval, overall survival, and referrals back to the hospital system. 5000 women provided 90% power to detect a 3% absolute non-inferiority margin for breast cancer-specific survival with 25% one-sided significance. The trial was registered with the ISRCTN registry, ISRCTN48534559; recruitment is complete but longer-term followup is ongoing. Findings Between April 22, 2014, and Sept 28, 2018, 5235 women were randomly assigned to annual mammography (n=2618) or less frequent mammography (n=2617). 3858 (736%) women were aged 60 years or older, 4202 (803%) had undergone conservation surgery, 4576 (874%) had invasive disease, 1159 (221%) had node positive disease, and 4330 (827%) had oestrogen receptor-positive tumours. With a median of 57 years follow-up (IQR 50-60; 87 years post curative surgery), 343 women died, including 116 who died of breast cancer (61 in the annual mammography group and 55 in the less frequent mammography group). 5-year breast cancer-specific survival was 981% (95% CI 975-986) in the annual mammography group and 983% (978-988) in the less frequent mammography group (hazard ratio 092, 95% CI 064-132), demonstrating non-inferiority of less frequent mammography at the pre- specified 3% margin (non-inferiority p<00001). 5-year recurrence-free interval was 941% (95% CI 931-949) in the annual mammography group and 945% (935-953) in the less frequent mammography group. Overall survival at 5 years was 947% (95% CI 938-955%) and 945% (935-953), respectively. 224 (649%) of 345 breast cancer events were detected from emergency admissions or symptomatic referrals back to the hospital system, including 108 (617%) of 175 in the annual mammography group and 116 (682%) of 170 in the less frequent mammography group. Interpretation For patients aged 50 years or older and at 3 years post diagnosis, less frequent mammograms were non-inferior compared with annual mammograms for breast cancer-specific survival, recurrence-free interval, and overall survival, and should be considered for this population.

INTRODUCTION:First post-contrAst SubtracTed (FAST) MRI, an abbreviated breast MRI scan, has high sensitivity for sub-centimetre aggressive breast cancer and short acquisition and interpretation times. These attributes promise effective supplemental screening. Until now, FAST MRI research has focused on women above population-risk of breast cancer (high mammographic density or personal history). DYAMOND aims to define the population within the population-risk NHS Breast Screening Programme (NHSBSP) likely to benefit from FAST MRI. The study population is the 40% of screening clients aged 50-52 who have average mammographic density (BI-RADS (Breast Imaging Reporting and Data System) B) on their first screening mammogram. DYAMOND will answer whether sufficient numbers of breast cancers, missed by mammography, can be detected by FAST MRI to justify the inclusion of this group in a future randomised controlled trial. METHODS AND ANALYSIS:Prospective, multicentre, diagnostic yield, single-arm study with an embedded qualitative sub-study: all recruited participants undergo a FAST MRI. An internal pilot will assess the willingness of sites and screening clients to participate in the study. Screening clients aged 50-52, with a clear first NHSBSP mammogram and BI-RADS B mammographic density (by automated measurement) will be invited to participate (recruitment target: 1000). The primary outcome is the number of additional cancers detected by FAST MRI (missed by screening mammography). A Fleming's two-stage design will be used as this allows for early stopping after stage 1, to save participants, funding costs and time continuing to the end of the study if the question can be answered earlier. ETHICS AND DISSEMINATION:The NHSBSP Research and Innovation Development Advisory Committee and the Yorkshire and Humber-Sheffield Research Ethics Committee (23/YH/0268, study ID (IRAS): 330059) approved this research protocol. Participation involves a two-stage informed consent process, enabling screening for eligibility through automated mammographic density measurement. Patients with breast cancer helped shape the study design and co-produced participant-facing documents. They will disseminate the results to the public in a clear and meaningful way. Results will be published with open access in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER:ISRCTN74193022.

Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC) is validated to predict event-free survival (EFS) in breast cancer but has not been studied for invasive lobular carcinoma (ILC). We studied patient-level data from a pooled cohort across 12 institutions. Associations between RCB index, class, and EFS were assessed in ILC and non-ILC with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by RCB components. Of 5106 patients, the diagnosis was ILC in 216 and non-ILC in 4890. Increased RCB index was associated with worse EFS in both ILC and non-ILC ( p = 0.002 and p < 0.001, respectively) and remained prognostic when stratified by receptor subtype and adjusted for age, grade, T category, and nodal status. Recursive partitioning demonstrated residual invasive cancer cellularity as most prognostic in ILC. These results underscore the utility of RCB for evaluating NAC response in those with ILC.

At least 5 years of adjuvant endocrine therapy substantially reduces risks of recurrence and mortality in oestrogen-receptor positive early breast cancer. However, adherence to endocrine therapy is sub-optimal; poor adherence is associated with higher risks of recurrence and death from breast cancer, worse cancer-specific health-related quality-of-life, and increased healthcare costs. The SWEET randomised control trial aims to evaluate effectiveness and cost-effectiveness of the HT Me intervention in reducing poor adherence to adjuvant endocrine therapy and improve cancer-specific health-related quality-of-life in women with oestrogen-receptor positive early breast cancer. This is a UK based, pragmatic, open label randomised control trial. Participants (stages 1–3 oestrogen-receptor positive breast cancer, completed surgery, within 14 weeks of first endocrine therapy prescription; n = 1460) complete a baseline questionnaire, and are randomised to the HT Me intervention plus usual care, or usual care alone. The HT Me intervention is evidence-based, theory-informed and patient-centred. It consists of viewing an animation, two consultations with a SWEET study practitioner (a health care professional trained in delivering the intervention) approximately 3 months apart, access to the interactive HT Me web-app for the 18 months, and regular monthly nudges. All participants complete follow-up questionnaires at 6, 12, and 18 months. A multi-method process evaluation will be conducted involving quantitative analysis exploring mechanisms of action of the intervention, and qualitative interviews with a sample of participants and health care professionals involved in the trial. Primary endpoints are adjuvant endocrine therapy adherence (combined self-report (Medication Adherence Report Scale) and Proportion of Days Covered calculated from prescription encashment records) and cancer-specific health-related quality-of-life (Functional Assessment of Cancer Therapy Scale- General). Secondary endpoints are adjuvant endocrine therapy-specific health-related quality-of-life and within-trial cost-utility analysis which will evaluate cost-effectiveness. The SWEET trial seeks to address a significant issue affecting the growing population of breast cancer survivors: poor adherence to adjuvant endocrine therapy. Challenges addressed and resolved within the protocol include the following: capacity at sites to deliver the intervention; variations in breast cancer services nationally; and measuring adherence. This trial has potential to improve quality of life and adherence to endocrine therapy; reducing numbers of recurrences and breast cancer deaths, benefiting women, their families and the health service. ISRCTN Number: ISRCTN24852890 registered on 02.08.2023.

BACKGROUND:Clinical research is key to improving the outcomes of patients with metastatic breast cancer (MBC). However, participation is low, with little data on patients' attitudes and experiences of clinical research. This study aimed to explore the experience and attitude of patients in accessing and participating in clinical research in the UK. METHODS:An online survey, available between May and November 2021, was open to people living with MBC in the UK; this was complemented with by qualitative interviews. FINDINGS:768 responses were received (766 female, 2 male); median age was 51-60 years with 235 (31 %) having de novo disease. 660 (86 %) respondents were confident in their understanding of clinical research. Discussion of participation in research with an oncologist was reported by 173 (23 %) respondents. Accessing new treatments was the most common reason for study participants wanting to take part in research, 737 (96 %). Of the 107 (14 %) respondents who had taken part in clinical trials, 77 (72 %) reported a positive experience. 276 (36 %) would consider travelling to participate in research and 430 (56 %) would be more likely to travel if expenses were met. Themes emerging from the qualitative interviews include 'lack of information', 'barriers to participation' and 'participants research priorities'. INTERPRETATION:This is the largest UK prospective study in regards to the views of MBC patients towards research. It demonstrates keenness to be involved in research, but participants face barriers as well as a lack of opportunity for participation. Key messages include importance of clinical staff in providing research information, need to develop patient accessible information, and to support travel costs. Improvements within the UK health care system are necessary to enable MBC patients to have equitable access to clinical research.