Breast cancer immune response is important to patient outcome, but the prognostic interaction between tissue-infiltrating immune cell (TIIC) types is not well-characterized. We evaluated the associations between CD8 +, FOXP3+, CD20 +, and CD163+ TIICs and breast cancer-specific survival (BCSS). We developed an AI in Halo to score TIIC percentage by compartment (overall, stromal, or intra-tumoral) in 99,051 microarray images from 12,285 female breast cancers. The associations between log-transformed TIIC scores and BCSS were assessed using Cox regression. CD8+ and FOXP3+ TIICs were associated with better BCSS in ER-negative disease; CD8+ and CD20+ TIICs were associated with a better prognosis in ER-positive disease; and CD163+ TIICs were associated with a poorer prognosis in ER-positive disease in multi-marker models. These results may have implications for breast cancer immunotherapy.

Abstract Background Patient and public involvement and engagement (PPIE) in health research aims to make research more relevant, clear and useful to deliver results that matter most to people. PPIE can be valuable but it is not always easy. It is not yet part of every project. This paper shares a case study and review of PPIE in the Lynch Choices™ ( https://canchoose.org.uk ) co-design project. It adds to the evidence on good practice for PPIE in research. Methods Patient Panel members and community partners completed the Patient Engagement in Research Scale (PEIRS-22). This short survey asked about practical arrangements, ease of taking part, contributions, teamwork, support, feeling valued and expected benefits. Each question was scored on a 5-point scale. We calculated scores for each person and the group. People also wrote personal stories about their experience. A researcher did the same. These stories gave deeper insight into feelings, ideas and experiences the survey might miss. They explained why people felt as they did and highlighted areas for improvement. We then looked for key themes in the stories using deductive and some inductive coding. Results Ten out of 12 Patient Panel members, one Trustee of Lynch Syndrome UK, and one Trustee of Lynch Syndrome Ireland took part (12/14=86% response rate). The average score was 89 out of 100. The middle score was 93 out of 100, above the level called “very meaningful engagement”. Most scores were high in all areas. Quotes from the stories were grouped into seven themes, based on the PEIRS framework. Conclusion This case study shows how trust, open two-way communication and strong working relationships helped make the Lynch Choices™ project a success. Mostly positive feedback was linked to people feeling valued and part of the team. Building these relationships took time. Contributors said that being part of the project was rewarding, enjoyable and motivating. Most suggested the project outputs would help others in practical and meaningful ways. This study adds to the evidence on PPIE in research, with recommendations for how to improve in future. PPIE should be adequately funded and planned from the start of projects. Two-way learning helps to share benefits with the people the research aims to help.

Background There are increasing numbers of cancer survivors who have finished their primary treatment, but whose quality of life remains consistently poor over years. There is limited evidence for pragmatic, brief interventions to support cancer survivors in primary care, where most patients are managed. Objective To develop, trial and assess the effectiveness and cost-effectiveness of a digital intervention to support cancer survivors (named ‘Renewed’) designed to require minimal health service resources. Design Qualitative development of the intervention, then open randomised controlled trial, with a process analysis and health economic analysis. Setting United Kingdom primary care Interventions: Development of the intervention We systematically reviewed the relevant qualitative and quantitative literature to inform initial intervention planning, intervention content and design features of a digital intervention. This was followed by iterative development and optimisation of intervention content and the human support component – in qualitative studies of the views of cancer survivor, and of National Health Service, volunteer and charity workers. Main trial: Participants People who had finished primary treatment for colorectal, breast or prostate cancer with lower quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 score < 85) within the last 10 years. Participants were randomised to one of three groups: (1) ‘generic’ advice: detailed digital National Health Service support for healthier living (‘Living Well’), (2) a bespoke digital intervention (‘Renewed’) addressing symptom management, physical activity, diet, weight, distress and/or fear of recurrence, or (3) ‘Renewed’ plus support (additional brief support by e-mail, telephone, or face to face) Main outcome measures Primary outcome: European Organization for Research and Treatment of Cancer QLQ-C30 (overall score). Secondary outcomes: subscales of European Organization for Research and Treatment of Cancer QLQ-C30 (global self-rated health; functional subscales; symptom subscales), EuroQol-5 Dimensions, five-level version, psychological measures and costs. Results At the primary time point of 6 months, there were clinically important improvements in European Organization for Research and Treatment of Cancer QLQ-C30 score contrary to the expected trajectory of quality of life in this population, but with no evidence of differences between groups. By 12 months, the Renewed plus support group had continued to improve and was better than generic advice (1.42, 95% confidence intervals 0.33 to 2.51), with the largest differences in the prostate cancer subgroup. 13 of the 14 subscales also improved compared to generic advice, statistically significant for self-rated global health (Renewed: 3.06, 1.39 to 4.74; Renewed plus support: 2.78, 1.08 to 4.48), dyspnoea, constipation and enablement. For Renewed plus support, there were also statistically significant differences for physical, cognitive and emotional functioning and fatigue. Renewed and Renewed plus support were dominant given improved effectiveness combined with and lower mean primary care National Health Service costs per patient (respectively −£141, −153 to −128; −£77, −90 to −65). Limitations Of those sent invitation letters, 14% (7883/59,295) were assessed for eligibility and 35% (2732/7883) of those assessed were eligible and agreed to participate – which is normal with the ‘cold calling’ method of invitation. The digital intervention would not suit people who find technology or the internet difficult to access, but only 25% (2649/10,697) of those who gave reasons for declining did so due to lack of internet access. The extensive generic advice available to participants in the National Health Service limited the ability to assess the specific benefits of Renewed in the short term, but nevertheless longer-term benefit and lower National Health Service costs are likely to be achieved with the bespoke intervention. Conclusions Cancer survivors with lower quality of life given detailed generic online support improve significantly. Providing robustly developed, low-cost, bespoke digital support can provide further modest long-term improvements in enablement, symptom management and self-rated global health, with substantially lower National Health Service costs. Future work The cost-effectiveness and benefits for symptom management on self-rated health suggest a more widespread implementation study should be undertaken. Trial registration This trial is registered as Current Controlled Trials ISRCTN 96374224. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0514-20001) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary We aimed to make and assess a website for use in general practices to support people who have poor quality of life after their initial cancer treatment. We made our website, called ‘Renewed’, based on the few studies about websites or apps. We tested ‘Renewed’ with people who had finished their initial treatment, National Health Service staff and others, and used their feedback to improve it. Then we asked others to join a study to see how well ‘Renewed’ works. Each person invited to join the study had finished initial treatment for bowel, breast or prostate cancer but had poor quality of life. We placed them at random (by chance) into one of three groups: given general advice from the NHS website for more healthy living (‘Living Well’) given ‘Renewed’, with help designed for cancer survivors in managing symptoms, exercise, diet, weight, distress, and fear of cancer coming back given ‘Renewed’, plus brief support by e-mail, telephone or face to face. After 6 months, all groups reported better quality of life. After 12 months, the Renewed plus support group carried on improving and was a little better than general advice for quality of life. At this time both the Renewed groups had improved in their rating of their health, shortness of breath, constipation and feeling more able to manage their problems. People in the Renewed plus support group also had improved physical and emotional functioning and less fatigue. Both Renewed and Renewed plus support not only had improved outcomes but also lower costs for the NHS. This study suggests that the online support provided by the Renewed website can help improve the quality of life of people who have finished initial cancer treatment, with both better outcomes and lower costs for the National Health Service. Scientific summary Background There are increasing numbers of cancer survivors who have finished their primary treatment, but quality of life remains consistently poor over years for many patients. There is limited evidence for pragmatic, brief interventions to support cancer survivors in primary care, where most patients are managed. Objective To develop, trial and assess the effectiveness and cost-effectiveness of a digital intervention to support cancer survivors (‘Renewed’) designed to require minimal health service resources. Methods Intervention development Collating the evidence Rapid review of web-based interventions designed to improve quality of life in adults who have completed primary treatment for breast, prostate and colorectal cancer. A range of study designs were included, and information about intervention characteristics, experiences and outcomes was extracted. The data were analysed using thematic analysis. Rapid scoping review of barriers and facilitators. A search identified studies during the past 20 years and further studies were identified by experts in the team and examination of reference lists. Development of Guiding Principles The rapid scoping review was used to identify key context-specific behavioural issues, and key intervention features were developed to meet each design objective. These Guiding Principles were improved in consultation with the development team and an expert stakeholder panel. Behavioural analysis A behavioural analysis table documented likely barriers for target behaviours, and for each barrier, interventions were described and coded according to three theoretical frameworks [Behaviour Change Techniques Taxonomy (BCTv1); Behaviour Change Wheel (BCW); Normalisation Process Theory (NPT)]. Logic model Using Medical Research Council guidance, the behavioural analysis was used to develop the logic model – describing the problem, intervention targets/ingredients to resolve the problem, mechanisms of action, and outcomes. Qualitative research: think-aloud interviews with cancer survivors Think-aloud interviews were conducted with 32 cancer survivors. Positive and negative comments were then collated, modifications made, and further rounds of interviews conducted with the modified versions of the prototype until no important further changes were required. Qualitative research: focus groups with National Health Service and cancer charity staff and volunteers Seven focus groups were carried out with staff from five general practitioner practices, staff and volunteers from two cancer charities, addressing support and training materials, and the integration of the intervention in everyday practice. Modifications were made and further rounds of focus groups were organised until no further improvements were identified. Main trial Participants For the main trial, people who had finished primary treatment for colorectal, breast or prostate cancer up to 10 years previously, reporting suboptimal quality of life [European Organization for Research and Treatment of Cancer QLQ-C30 (EORTCQLQ-C30) score < 85]. Interventions Participants were randomised to one of three groups: (1) ‘Generic’ advice: detailed digital NHS support for healthier living (‘Living Well’), (2) a bespoke digital intervention (‘Renewed’) addressing symptom management, physical activity, diet, weight loss, distress management and/or fear of recurrence, or (3) ‘Renewed’ with additional brief support by e-mail, telephone, and face to face. Automated randomisation with stratification was implemented using LifeGuide software (www.lifeguideonline.org) with a 1 : 1 allocation ratio stratified by: cancer type: breast/prostate/colorectal and EORTCQLQ-C30 score (64 or less/65 or more). Main outcome measures Primary outcome: EORTCQLQ-C30 (overall score). Secondary outcomes: subscales of EORTCQLQ-C30 (global self-rated health; functional subscales; symptom subscales), psychological measures, quality of life measured by EuroQol-5 Dimensions, five-level version (EQ-5D-5L) and costs. Main statistical analysis All participant data were analysed on an intention-to-treat basis, that is, as randomised. The primary analysis used imputed data, employing a chained equation multiple imputation model for missing data. A complete-case analysis was a sensitivity analysis. Generalised linear mixed regression models were used for continuous variables, controlling for baseline and stratification variables, including a random effect for practice. Pre-planned subgroup analyses were set out in the statistical analysis plan for age, gender and comorbidities. We also performed post hoc within-group analyses documenting the changes from baseline. Health economic analysis Cost per quality-adjusted life-year (QALY) was estimated. The base case took an NHS perspective using primary care consultation and medication costs, but with sensitivity analyses including secondary care costs. Resource use data were collected by a medical record review in primary care. Unit costs of primary care consultation, community services, outpatient visits and accident and emergency attendances were costed based on the Personal Social Services Research Unit. National reference costs were used to cost hospital stay based on corresponding diagnostic categories. Medications were priced based on the British National Formulary. All costs were based on 2019 prices. QALYs were estimated using the EQ-5D-5L and were based on the recommended national tariff. Process analyses Qualitative analysis Forty-two patients were interviewed to explore their experiences of using the Renewed intervention and to understand the potential barriers and facilitators to using Renewed. Quantitative analysis Patients were included if they completed the 12-month follow-up measures and were classified according to how much of the intervention was accessed, and this was then related to the impact on outcomes. Results Intervention development Rapid review The database search identified 6327 papers, and 16 relevant papers relating to 9 interventions fulfilled eligibility criteria. Identified themes addressed aspects of intervention design (participant factors, characteristics of the online intervention, techniques used to change behaviour and preferred features of web-based interventions), including issues of uptake, adherence and attrition, engagement, feasibility, efficacy, positive behaviour change and acceptability of the interventions. Scoping review Facilitators and barriers were grouped according to key characteristics, including factors influencing participation; information included in the intervention; motivation/self-esteem/self-efficacy; self management/monitoring; emotions/mood; social support; intervention design/content; technical aspects and various practical issues. Guiding principles Target users did not see themselves as having health needs, so the content promoted well-being, rather than illness management. Cancer survivors felt that their usual behaviour in part caused their cancer, so suggestions for behavioural change did not stigmatise users’ current behaviour. Target users form a heterogeneous group; hence the intervention provided tailored information to each user, based on answers to baseline questions. Participants wanted brief accessible information; hence short sessions on specific topics were provided and the intervention targeted behaviours which had the potential to improve multiple symptoms. Behavioural analysis Three target behaviours were identified (physical activity, diet and intervention engagement) and specific intervention components included to minimise barriers to each, mapped to elements of the BCTv1, BCW and NPT theoretical frameworks. Qualitative research: think-aloud interview with cancer survivors Participants found the intervention to be generally easy to navigate and the content being relevant and useful. Negative comments described barriers to engagement which resulted in modifications to the prototype; for example some were worried about overdoing physical activity, so changes emphasised that increasing physical activity should be done gradually. Qualitative research: focus groups with National Health Service and cancer charity staff and volunteers Several concerns were raised which led to further modifications; for example some questioned the use of the Congratulate, Ask, Reassure, Encourage approach, so additional information about how to provide support with patients who had not achieved their goals was added. Main trial At the primary time point of 6 months, there were clinically important improvements in EORTCQLQ-C30 score contrary to the expected trajectory of quality of life in this population, but with no evidence of differences between groups. By 12 months, the Renewed plus support group continued to improve and was better than generic advice (1.42, 95% confidence intervals 0.33 to 2.51), with the largest differences in the prostate cancer subgroup. Thirteen of the 14 functional and symptom subscales also improved compared to generic advice, statistically significant for self-rated global health (Renewed: 3.06, 1.39 to 4.74; Renewed plus support: 2.78, 1.08 to 4.48), dyspnoea, constipation and enablement. For Renewed plus support, there were also significant differences for physical, cognitive and emotional functioning and fatigue. Renewed and Renewed plus support demonstrated little or no change in QALY estimates using the EQ-5D-5L, but were dominant – with both a range of better health outcomes while incurring lower mean NHS primary care costs per patient (respectively −£141, −153 to −128; −£77, −90 to −65). Process analyses Qualitative process study The results showed that even limited usage of Renewed Online may provide enough information to motivate behaviour change in those with less need for more tailored support. Novel information may need to be presented earlier in the intervention to motivate further engagement with Renewed in those who need more detailed and tailored information to make behaviour changes. Quantitative process analysis The majority of patients accessed the Core content of Renewed and completed the Core content. Approximately half of participants continued to use Renewed past the Homepage to access the Optional content. Those who used Optional content had higher quality of life (QoL) scores compared to those who only accessed the Core content. Conclusions Cancer survivors with lower quality of life given detailed generic online support improve significantly. Providing robustly developed, low cost, bespoke digital support can provide further modest long-term improvements in enablement, symptom management, and self-rated global health, with substantially lower primary care NHS costs. Implications for health care The current study provides reasonable evidence that a novel bespoke intervention to support cancer survivors could be integrated into current practice since there are both some longer-term benefits combined with lower costs to the NHS. However, all trial participants by definition had to engage with the trial and trial procedures, and so may not represent the wider patient population, and all were followed up with questionnaires and with phone calls where questionnaires were not returned. This could be mimicked in routine practice by brief follow-up contacts, which could be assessed in a larger implementation study. Recommendations for research The cost-effectiveness and benefits for symptom management self-rated health for both Renewed interventions suggest that an implementation study is the next step, including further assessment of the impact in different socio-economic groups and cancer types. To consider using and/or developing more sensitive primary outcome measures among cancer survivors, particularly for briefer, low resource interventions – since the overall EORTCQLQ-C30 summary score is not sensitive to change, in contrast to both symptom subscales and self-rating of health. To develop QALY measures that capture the benefit to QoL for low intensity, low resource interventions among cancer survivors given that neither the EQ-5D-5L or the EORTC-8d reflected important changes in patients’ self-rating of health. Further work is indicated to explore why people with some cancers may not be as willing to use the intervention as others and exploration of the key barriers for those from ethnic minority backgrounds to take part. Trial registration This trial is registered as Current Controlled Trials ISRCTN 96374224. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0514-20001) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 4. See the NIHR Funding and Awards website for further award information.

Women with BRCA1/2 pathogenic variants (PVs) have a high likelihood of developing young onset breast cancer (BC) compared to noncarriers. In women enrolled in the POSH prospective cohort study of young women diagnosed with BC under age 40 or under age 50 if known BRCA1/2 positive, no difference in overall survival was observed in BRCA1/2 carriers vs noncarriers. Treatment options for BC include PARP inhibitors (PARPi) for BRCA1/2 driven tumors and CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy for ER-positive, HER2-negative tumors. In BC from BRCA1/2 carriers unselected for age, up to 10% BRCA1 and 46% BRCA2 carriers do not have loss of heterozygosity (LOH) at the germline variant locus, suggesting non-BRCA1/2 tumorigenesis. It is not known what the tumor molecular landscape, including rates of LOH and homologous recombination deficiency (HRD), is in young BRCA1/2 PV carriers with BC, and whether the tumor molecular features impact disease outcomes or predict therapy response. To elucidate the molecular landscape of breast tumors in young women with BRCA1/2 PVs, we evaluated treatment naïve primary breast tumors from 136 (86 [63.2%] BRCA1; 50 [36.8%] BRCA2) PV carriers in the POSH study. 71 (52.2%) of the tumors were ER-positive. We performed whole exome sequencing and called single nucleotide variants, indels, copy number variants, and BRCA1/2 allele specific LOH in the tumors, calculated HRD scores and tumor mutational burden (TMB), and evaluated single base substitution (SBS) signatures. We found high rates of LOH by gene: BRCA1 (93%) and BRCA2 (96%), and by ER-status: ER-negative (94.4%) and ER-positive (93.8%). Mean HRD scores were significantly higher in tumors with LOH compared to nonLOH tumors in both BRCA1 (57.4 vs 22.6, p<0.0001) and BRCA2 (43.7 vs 23.5, p=0.005) carriers as well as ER-negative (57.6 vs 22.8, p<0.0001) and ER-positive tumors (46.4 vs 22.8, p<0.001). LOH tumors had higher proportional contribution of HRD-associated SBS3 than nonLOH tumors (0.36 vs 0.22, p=0.048). BRCA1 LOH tumors had higher median TMB than BRCA2 LOH tumors (4.8 vs 2.5, p=0.034). Overall survival in women with nonLOH tumors was 100% throughout the follow-up period but was not significantly different from that of women with LOH tumors. Overall survival did not differ by tumor HRD status: analyses were limited by small numbers in the non-LOH and low HRD groups. We found statistically significant enrichment of AURKA (OR:4.2, 95%CI:1.3-16.6, p=0.015) and MYC (OR:2.4, 95%CI:1.0-5.7, p=0.043) amplification which are associated with resistance to CDK4/6i in ER-positive, HER2-negative tumors from POSH cohort PV carriers compared to noncarriers from the TCGA. Given the high levels of LOH and presence of CDK4/6i resistance associated alterations, our data suggest that PARPi may be preferable over CDK4/6i in young BRCA1/2 carriers with ER-positive, HER2-negative BC when both therapies are being considered in the adjuvant setting. Mwangala P. Akamandisa, Mingyi Xia, Wilson Cheah, Bradley Wubbenhorst, Kurt D'Andrea, Mengyao Fan, Jake Shilan, William J. Tapper, Ellen Copson, Ramsey I. Cutress, Diana M. Eccles, Susan M. Domchek, Katherine L. Nathanson. Tumor molecular landscape and therapy implications in young BRCA1/2 carriers with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6596.

Objectives To investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer.Methods and analysis We used data on women diagnosed with invasive breast cancer between 1995 and 2019 from the National Cancer Registration Dataset (NCRD) in England. The data were linked to the Hospital Episode Statistics-Admitted Patient Care dataset to identify BSO delivery. Long-term health outcomes were selected from both datasets. Multivariable Cox regression was used to examine the associations, with BSO modelled as a time-dependent covariate. The associations were investigated separately by age at BSO.Results We identified 568 883 women, 23 401 of whom had BSO after the breast cancer diagnosis. There was an increased risk of total cardiovascular diseases with an HR of 1.10 (95% CI 1.04 to 1.16) in women who had BSO<55 years and 1.07 (95% CI 1.01 to 1.13) for women who had BSO≥55 years. There was an increased risk of ischaemic heart diseases, but there was no association with cerebrovascular diseases. BSO at any age was associated with an increased risk of depression (HR 1.20, 95% CI 1.12 to 1.28) and increased risk of second non-breast cancer in older women (HR 1.21, 95%CI 1.08 to 1.35). BSO in older women was associated with reduced risk of all-cause mortality (HR 0.92, 95% CI 0.87 to 096), but not in women who had BSO<55 years.Conclusion In women with a personal history of breast cancer, BSO before and after the age of 55 years is associated with an increased risk of long-term outcomes. BSO after 55 years is associated with reduced all-cause mortality. Family history or genetic predisposition may confound these associations.

Interindividual variability in hepatic drug metabolism and transport is well-known, and genetic variation in pharmacogenes impacts the efficacy and safety of drug treatments. Recent reports have indicated that the minor allele of the nuclear transcription factor I/B (NFIB), rs28379954 T > C, affects the metabolism of risperidone and clozapine, which are mediated by CYP2D6 and CYP1A2, respectively. First, we reanalyzed the association between rs28379954 T > C and CYP2D6 activity in three independent cohorts exposed to CYP2D6 substrates (propafenone, tamoxifen, and sparteine) which revealed no association. Next, to investigate the effects of all four NFIs expressed in human livers more broadly, 150 well-characterized hepatic tissue samples, along with data on expression quantitative trait loci (eQTL) and genome-wide association (GWA), were used. NFI expression levels significantly correlated with the mRNA and/or protein expression of multiple CYP genes (e.g. CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C19) which was confirmed for NFIA with the metabolism of CYP2C19, CYP1A2, and CYP2A6 probe substrates. While non-genetic factors (e.g. age, inflammation) also control NFI expression, genetic polymorphisms did not reach genome-wide significance. To validate the identified associations, siRNA-mediated knockdowns were used in primary human hepatocytes, followed by RNA sequencing and evaluation of differentially regulated pathways. We identified significant downregulation of several metabolic pathways related to hepatic functionality, PPAR signaling, and drug metabolism for NFIB, NFIC, and NFIX, whereas pathways associated with cancer biology were significantly induced. In summary our findings provide further insight into hepatic CYP regulation via the NFI network with implications for the understanding of interindividual variability of drug metabolism.

IntroductionLow quality of life is common in cancer survivors. Increasing physical activity, improving diet, supporting psychological well-being and weight loss can improve quality of life in several cancers and may limit relapse. The aim of the randomised controlled trial outlined in this protocol is to examine whether a digital intervention (Renewed), with or without human support, can improve quality of life in cancer survivors. Renewed provides support for increasing physical activity, managing difficult emotions, eating a healthier diet and weight management.Methods and analysisA randomised controlled trial is being conducted comparing usual care, access to Renewed or access to Renewed with brief human support. Cancer survivors who have had colorectal, breast or prostate cancer will be identified and invited through general practice searches and mail-outs. Participants are asked to complete baseline measures immediately after screening and will then be randomised to a study group; this is all completed on the Renewed website. The primary outcome is quality of life measured by the European Organization for Research and Treatment of Cancer QLQ-c30. Secondary outcomes include anxiety and depression, fear of cancer recurrence, general well-being, enablement and items relating to costs for a health economics analysis. Process measures include perceptions of human support, intervention usage and satisfaction, and adherence to behavioural changes. Qualitative process evaluations will be conducted with patients and healthcare staff providing support.Ethics and disseminationThe trial has been approved by the NHS Research Ethics Committee (Reference 18/NW/0013). The results of this trial will be published in peer-reviewed journals and through conference presentations.Trial registration numberISRCTN96374224; Pre-results.

The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.

BACKGROUND:Lynch syndrome carriers ('carriers') are presented with complex, emotionally laden choices regarding management of increased genetic cancer risks. Decision aids encourage active involvement in values-based health decisions. This paper aimed to address the research question: How do Lynch syndrome carriers make sense of their chances of developing cancer, and what are the implications for providing support with decision making about genetic cancer risk management? METHODS:Adult carriers were recruited through a genetics service or involvement with Lynch Syndrome UK. Semi-structured interviews explored lived experiences of carriers' access to care with a focus on decision support. Themes were constructed using framework analysis. These were developed into a conceptual model with recommendations for codevelopment of improved information and support including a tailored decision aid to complement integrated healthcare. RESULTS:Twenty participants included 12 women and eight men, half with a history of cancer. Six overarching themes were: (1) finding balance with Lynch; (2) living 'on higher alert'; (3) managing uncertainty: 'I've thought about it a lot'; (4) burden of responsibility: 'It's on me'; (5) access to joined-up care and support: 'There's something missing'; and (6) influence/pressure from others. CONCLUSIONS:This qualitative interview study provided in-depth insights from Lynch syndrome carriers about their lived experiences, informed by their values. Recommendations to empower carriers to make sense of genetic cancer risks and support decisions included accessible, trusted information, educated healthcare professionals, shared decision making, and joined-up integrated care pathways complemented by tailored decision aids.

PURPOSE Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records. METHODS We followed 25,811 females and 480 males diagnosed with BC and tested for germline BRCA1/BRCA2 PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks. RESULTS There were 1,840 BRCA1 and 1,750 BRCA2 female PV carriers. Compared with population incidences, BRCA1 carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. BRCA2 carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without BRCA1/BRCA2 PVs on testing, BRCA1 carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. BRCA2 carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% ( BRCA1 carriers), 12%/3.0%/6.2% ( BRCA2 carriers), and 3.6%/0.4%/4.9% (noncarriers). Male BRCA2 carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers. CONCLUSION Survivors of BC carrying BRCA1 and BRCA2 PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.

The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Background For female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR) gene testing is an effective way of identifying the estimated 3% of EC caused by LS.Methods A retrospective national population-based observational study was conducted using comprehensive national data collections of functional, somatic and germline MMR tests available via the English National Cancer Registration Dataset. For all EC diagnosed in 2019, the proportion tested, median time to test, yield of abnormal results and factors influencing testing pathway initiation were examined.Results There was an immunohistochemistry (IHC) or microsatellite instability (MSI) test recorded for 17.8% (1408/7928) of patients diagnosed with EC in 2019. Proportions tested varied by Cancer Alliance and age. There was an MLH1 promoter hypermethylation test recorded for 43.1% (149/346) of patients with MLH1 protein IHC loss or MSI. Of patients with EC eligible from tumour-testing, 25% (26/104) had a germline MMR test recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222-486).Conclusion This analysis highlights the regional variation in recorded testing, patient attrition, delays and missed opportunities to diagnose LS, providing an informative baseline for measuring the impact of the national guidance from the National Institute for Health and Care Excellence on universal reflex LS testing in EC, implemented in 2020.

The most commonly diagnosed cancer in women worldwide is cancer of the breast. Up to 20% of familial cases are attributable to pathogenic mutations in high-penetrance (BReast CAncer gene 1 [BRCA1], BRCA2, tumor protein p53 [TP53], partner and localizer of breast cancer 2 [PALB2]) or moderate-penetrance (checkpoint kinase 2 [CHEK2], Ataxia-telangiectasia mutated [ATM], RAD51C, RAD51D) breast-cancer-predisposing genes. Most of the breast-cancer-predisposing genes are involved in DNA damage repair via homologous recombination pathways. Understanding these pathways can facilitate the development of risk-reducing and therapeutic strategies. The number of breast cancer patients undergoing testing for pathogenic mutations in these genes is rapidly increasing due to various factors. Advances in multigene panel testing have led to increased detection of pathogenic mutation carriers at high risk for developing breast cancer and contralateral breast cancer. However, the lack of long-term clinical outcome data and incomplete understanding of variants, particularly for moderate-risk genes limits clinical application. In this review, we have summarized the key functions, risks, and prognosis of breast-cancer-predisposing genes listed in the National Health Service (NHS) England National Genomic Test Directory for inherited breast cancer and provide an update on current management implications including surgery, radiotherapy, systemic treatments, and post-treatment surveillance.

Summary: Background: Second primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets. Methods: The cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan–Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression. Findings: Both genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99–2.06) females; 55.4 (35.5–82.4) males) and non-breast (1.10 (1.09–1.11) females, 1.10 (1.00–1.20) males) SPC risks. Non-breast SPC risks were higher for females younger at BC diagnosis (SIR: 1.34 (1.31–1.38) <50 y, 1.07 (1.06–1.09) ≥50 y) and more socioeconomically deprived (SIR: 1.00 (0.98–1.02) least deprived quintile, 1.34 (1.30–1.37) most). Interpretation: Enhanced SPC surveillance may benefit BC survivors, although specific recommendations require more detailed multifactorial risk and cost-benefit analyses. The associations between deprivation and SPC risks could provide clinical management insights. Funding: CRUK Catalyst Award CanGene-CanVar (C61296/A27223). Cancer Research UK grant: PPRPGM-Nov 20∖100,002. This work was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Background The CanRisk tool, which operationalises the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is used by Clinical Geneticists, Genetic Counsellors, Breast Oncologists, Surgeons and Family History Nurses for breast cancer risk assessments both nationally and internationally. There are currently no guidelines with respect to the day-to-day clinical application of CanRisk and differing inputs to the model can result in different recommendations for practice.Methods To address this gap, the UK Cancer Genetics Group in collaboration with the Association of Breast Surgery and the CanGene-CanVar programme held a workshop on 16th of May 2023, with the aim of establishing best practice guidelines.Results Using a pre-workshop survey followed by structured discussion and in-meeting polling, we achieved consensus for UK best practice in use of CanRisk in making recommendations for breast cancer surveillance, eligibility for genetic testing and the input of available information to undertake an individualised risk assessment.Conclusions Whilst consensus recommendations were achieved, the meeting highlighted some of the barriers limiting the use of CanRisk in clinical practice and identified areas that require further work and collaboration with relevant national bodies and policy makers to incorporate wider use of CanRisk into routine breast cancer risk assessments.

Background National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission.Methods In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4).Results Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored.Conclusion The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.

BACKGROUND:Testing for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation. METHODS:Representatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions. RESULTS:Meeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients. CONCLUSIONS:Recommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios.