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Sacha J Howell,1 Kimberley Hockenhull,1 Zena Salih,1 D Gareth Evans2,3 1Department of Medical Oncology, The Christie NHS Foundation Trust, 2Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, 3Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by mutation/deletion of the NF1 gene. The gene product, neurofibromin, is a tumor suppressor which represses the activity of the Ras oncogene. Central nervous system (CNS) tumors have long been associated with NF1, but their association with several other malignancies has been demonstrated. In this review, we summarize the epidemiological data that irrefutably support a link between NF1 and an increased risk of early-onset breast cancer, to levels at which annual mammography is currently recommended in national high-risk screening programs. We discuss the reasons for the observed adverse breast cancer prognosis in NF1 cases, including late presentation and more aggressive tumor subtypes, and recommend that a collaborative breast screening study be initiated to better serve this currently underserved population of women. Keywords: breast cancer, neurofibromatosis type 1, NF1

Background: In CAPItello-291, capivasertib-fulvestrant significantly improved progression-free survival (PFS) versus placebo-fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib-fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan., Methods: Adults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall and PIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint., Results: Of 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib-fulvestrant and 41 to placebo-fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib-fulvestrant arm (hazard ratio 0.73; 95% CI 0.40-1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors, PFS favored the capivasertib-fulvestrant arm (hazard ratio 0.65; 95% CI 0.29-1.39), consistent with the global population. The adverse event profile of capivasertib-fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified., Conclusion: Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen., (© 2024. The Author(s).)

Background: Breast cancer is the most frequent female malignancy in the UK. Around 20% of cases are linked to weight gain, excess weight and health behaviours. We designed a weight gain prevention, health behaviour intervention for young women at increased risk., Methods: The study comprised a single arm observational study over 2 months testing acceptability and usability of the intervention: online group welcome event, app and private Facebook group. Females aged 18-35 years at moderate or high risk of breast cancer (>17% lifetime risk) were recruited via invite letters and social media posts. The app included behaviour change techniques and education content. Online questionnaires were completed at baseline, as well as at 1 and 2 months. We also assessed feasibility of study procedures., Results: Both recruitment methods were successful. Thirty-five women were recruited, 26% via social media posts. Median age was 33 (interquartile range = 28.2-34.5) years, the majority (94.1%) were of White ethnicity. Thirty-four participants were included in the analyses, of which 94% downloaded the app. Median self-monitoring logs per participant during the study period was 10.0 (interquartile range = 4.8-28.8). App quality mean (SD) score was 3.7 (0.6) at 1 and 2 months (scale: 1-5). Eighty-nine per cent rated the app at average or above at 1 month and 75.0% at 2 months. Nineteen women (55.9%) joined the Facebook group and there were 61 comments and 83 reactions and votes from participants during the study period., Conclusions: This first iteration of the app and intervention was well received and is suitable to progress to the next stage of refining and further testing., (© 2024 The Author(s). Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Competing Interests: Competing interests: DGE has received consultancy fees from Everything Genetic Ltd.

Background: Identifying women aged 30-39 years at increased risk of developing breast cancer would allow them to receive screening and prevention offers. For this to be feasible, the practicalities of organising risk assessment and primary prevention must be acceptable to the healthcare professionals who would be responsible for delivery. It has been proposed that primary care providers are best placed to deliver a breast cancer risk assessment and primary prevention pathway. The present study aimed to investigate a range of primary care provider's views on the development and implementation of a breast cancer risk assessment and primary prevention pathway within primary care for women aged 30-39 years., Methods: Twenty-five primary care providers working at general practices in either Greater Manchester or Cambridgeshire and Peterborough participated in five focus groups (n = 18) and seven individual interviews. Data were analysed thematically and organised using a framework approach., Results: Three themes were developed. Challenges with delivering a breast cancer risk assessment and primary prevention pathway within primary care highlights that primary care are willing to facilitate but not lead delivery of such a pathway given the challenges with existing workload pressures and concerns about ensuring effective clinical governance. Primary care's preferred level of involvement describes the aspects of the pathway participants thought primary care could be involved in, namely co-ordinating data collection for risk assessment and calculating and communicating risk. Requirements for primary care involvement captures the need to provide a training and education package to address deficits in knowledge prior to involvement. Additionally, the reservations primary care have about being involved in the management of women identified as being at increased risk are discussed and suggestions are provided for facilitating primary care to take on this role., Conclusions: Despite optimism that primary care might lead a breast cancer risk assessment and primary prevention pathway, participants had a range of concerns that should be considered when developing such a pathway., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hindmarch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Background: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit., Patients and Methods: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted., Results: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs., Conclusions: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: CAPItello-291 is an ongoing phase 3 trial in which capivasertib-fulvestrant significantly improved progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA, AKT1, or PTEN-altered tumours. This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291., Methods: This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy. Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing. The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA, AKT1, or PTEN-altered tumours. The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes. Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article. Data were collected at baseline and prespecified timepoints. Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23. Time to deterioration was described using the Kaplan-Meier method. PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle. Patient-reported outcomes were not prospectively powered for statistical comparison. The trial is registered with ClinicalTrials.gov, NCT04305496., Findings: Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib-fulvestrant (n=355) or placebo-fulvestrant (n=353). The median age of the patients was 59 years (IQR 51-67) in the capivasertib-fulvestrant group and 58 years (IQR 49-66) in the placebo-fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1-16·7) for capivasertib-fulvestrant and 12·7 months (IQR 2·0-16·4) for placebo-fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of -2·5 [95% CI -4·5 to -0·6] with capivasertib-fulvestrant vs -5·6 [-7·9 to -3·4] with placebo-fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib-fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo-fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib-fulvestrant group than in the placebo-fulvestrant group (HR 2·75, 95% CI 2·01-3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools "frequently" or "almost constantly" was 29% higher at cycle 1, day 15 in the capivasertib-fulvestrant group than in the placebo-fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported "not at all" or "a little bit" of bother from treatment side-effects., Interpretation: Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib-fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit-risk profile of capivasertib-fulvestrant in this population., Funding: AstraZeneca., Competing Interests: Declaration of interests MOl has received honoraria from Eisai, Gilead Sciences, Libbs, Eli Lilly, Novartis, Pfizer, Roche, Seagen, AstraZeneca Taiwan, and Merck Sharp & Dohme; has received research funding from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche, Seagen, Zenith Epigenetics, Gilead Sciences, Ayala Pharmaceuticals, and Genentech; has received travel grants from Eisai and Gilead Sciences; has served as a consultant for AstraZeneca, Daiichi Sankyo, Gilead Sciences, ITeos Therapeutics, Eli Lilly, Merck Sharp & Dohme, Relay Therapeutics, Roche, Seagen, and Pierre Fabre; and serves as the head on the board of directors for the SOLTI Breast Cancer Research Group. HSR has served as a consultant or advisor for Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, and Daiichi Sankyo, and has received research funding from OBI Pharma, Pfizer, Novartis, Eli Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Astellas Pharma, Taiho Oncology, Veru, GlaxoSmithKline, Genentech/Roche, and Stemline Therapeutics. SJH has received institutional grants from Eli Lilly; has served as a consultant for Pfizer; has received payments to their institution per patient from AstraZeneca (study sponsor); has participated on a Data Safety Monitoring Board or Advisory Board for Eli Lilly; has received honoraria from Eli Lilly, Pfizer, Novartis, and AstraZeneca; and has received support for attending meetings and travel from Novartis. FD has received honoraria from Eli Lilly, Gilead Sciences, and AstraZeneca and has received travel grants from Daiichi Sankyo, Novartis, Gilead Sciences, and Pfizer. JC has served as a consultant or advisor for Celgene, Cellestia Biotech, AstraZeneca, Roche, Seagen, Daiichi Sankyo, ERYTECH Pharma, Polyphor, Athenex Oncology, Eli Lilly, SERVIER, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, Ellipses Pharma, HiberCell, Bioinvent, GEMoaB Monoclonals, Gilead Sciences, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, Bridgebio, and BioNTech; has received travel grants from Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo, Gilead Sciences, AstraZeneca, Merck Sharp & Dohme, and Stemline Therapeutics; holds stock in Leuko and MAJ3 Capital; holds two patents, WO 2014/199294 A and US 2019/ 0338368 A1; has received honoraria from Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Eli Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Gilead Sciences, and Stemline Therapeutics; and has received research funding from ARIAD Pharmaceuticals, AstraZeneca, Baxalta, Bayer, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Puma Biotechnology, Queen Mary University of London, Roche, and Piqur. HLG has served as a consultant or advisor for AstraZeneca; has received research funding from Merck Sharp & Dohme; and has served on speakers’ bureaus for Roche, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Technofarma, and Novartis. MT has served on advisory boards for Athenex Oncology, Bertis, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kansai Medical Net, and Terumo; has received compensation as an invited speaker from AstraZeneca, Bertis, Bristol Myers Squibb, Chugai, Devicore Medical Japan, Eisai, Eli Lilly, Exact Science, Kyowa-Kirin, Merck Sharp & Dohme, Nippon-Kayaku, Novartis, Pfizer, Shimadzu, Sysmex, Taiho, Takeda, and Yakult; has received research funding from AFI Technology, Astellas, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, GL Science, Kansai Medical Net, Luxonus, Pfizer, Sanwa Shurui, Shimadzu, Takeda, The Japan Breast Cancer Research Group association, The Kyoto Breast Cancer Research Network association, and Yakult; has served on steering committees for AstraZeneca, Chugai, and Daiichi Sankyo; and serves as a member of the board of directors for the Organisation for Oncology and Translational Research, The Japan Breast Cancer Research Group association, The Japanese Onco-Cardiology Society, The Kyoto Breast Cancer Research Network association, and The Japanese Breast Cancer Society. KJ has served on advisory boards for Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genentech, AbbVie, Eli Lilly, BluePrint Medicines, Seagen, Daiichi Sankyo, Biotheranostics, Sun Pharma Advanced Research Company, Taiho Oncology, Sanofi, Gilead Sciences, and Scorpion Therapeutics; has received research funding from Novartis, Genentech, Debiopharm Group, ADC Therapeutics, Pfizer, Novita Pharmaceuticals, Clovis Oncology, Eli Lilly, Zymeworks, Immunomedics, Puma Biotechnology, VelosBio/Merck, AstraZeneca, Context Therapeutics, Scorpion Therapeutics, and Blueprint Medicines; and has received travel grants from Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca, Intellisphere, Eli Lilly, Gilead Sciences, and Genentech/Roche. SL has served as a consult or on advisory boards for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, Gilead Sciences, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, Seagen, and AGO (German Gynecological Oncology Group) Kommission Mamma; has served as an invited speaker at AstraZeneca, DSI, Gilead Sciences, Novartis, Pfizer, Roche, Seagen, Stemline-Menarini, and Medscape; is a full or part-time employee at GBG Forschungs GmbH; has received licensing or royalties from VMscope GmbH, and research funding from AbbVie, AstraZeneca, Celgene, Daiichi Sankyo, Greenwich Life Sciences, Immunomedics/Gilead Sciences, Molecular Health, Novartis, Pfizer, and Roche; and has served as a principal investigator at PI Aphinity. YHP has received research funding from MSD, Pfizer, Roche, Novartis, AstraZeneca, Gencurix, and Genome Insight; has received honoraria from AstraZeneca, Pfizer, Eli Lilly, MSD, Roche, Daiichi Sankyo, Novartis, and Gilead Sciences; has received consulting fees from AstraZeneca, Pfizer, Eli Lilly, Gilead Sciences, MSD, Eisai, Roche, Daiichi Sankyo, Menarini, Everest, and Novartis; has received travel grants from Gilead Sciences, Pfizer, and AstraZeneca; has served on advisory boards for AstraZeneca, Pfizer, Roche, Menarini, Novartis, Daiichi Sankyo; and has received equipment, materials, drugs, medical writing, gifts, or other services from Dong-A ST, Sanofi, Roche, and Pfizer. JHS has received research funding from MSD, Roche, Novartis, Eli Lilly, Pfizer, Daiichi Sankyo, AstraZeneca, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Seagen, Qurient, Dragonfly Therapeutics, Eikon Therapeutics, Gilead Sciences, Celcuity, Bristol Myers Squibb, HLB Pharmaceutical, Sermonix Pharmaceuticals, Olema Oncology, Hanmi, Ildong Pharmaceutical, and Samyang Holdings. ET has received honoraria from Eli Lilly, Daiichi Sankyo, AstraZeneca, and Chugai. NCT has served on the advisory board for AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche/Genentech, GlaxoSmithKline, Repare Therapeutics, Relay Therapeutics, Gilead Sciences, Inivata, Guardant Health, and Exact Sciences and received research funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Invitae, Inivata, Personalis, and Natera. CD’C, HA, MF, and IW are employees of AstraZeneca, and may hold AstraZeneca stocks or shares. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored., Objectives: The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence., Design: Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR)., Setting: Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020., Patients: With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery., Main Outcome Measures: (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis., Results: Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ± 8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse., Conclusion: Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines., Trial Registration: NCT03016936., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Purpose: The identification of germline BRCA1/BRCA2 pathogenic variants (PV) infer high remaining lifetime breast/ovarian cancer risks, but there is paucity of studies assessing breast cancer risk after ovarian cancer diagnosis., Methods: We reviewed the history of breast cancer in 895 PV heterozygotes (BRCA1 = 541). Cumulative annual breast cancer incidence was assessed at 2, 5, 10, and >10 years after ovarian cancer diagnosis date., Results: Breast cancer annual rates were evaluated in 701 assessable women with no breast cancer at ovarian diagnosis (BRCA1 = 425). Incidence was lower at 2 years (1.18%) and 2 to 5 years (1.13%) but rose thereafter for BRCA1 with incidence post 10 years in excess of 4% annually. Breast cancer pathology in BRCA1 PV heterozygotes showed less high-grade triple-negative breast cancer and more lower-grade hormone-receptor-positive cancer than women with no prior ovarian cancer. In the prospective cohort from ovarian cancer diagnosis, <4% of all deaths were caused by breast cancer, although 50% of deaths in women with breast cancer after ovarian cancer diagnosis were due to breast cancer., Conclusion: Women can be reassured that incidence of breast cancer after ovarian cancer diagnosis is relatively low. It appears likely that this effect is due to platinum-based chemotherapy. Nonetheless women need to be aware that incidence increases thereafter, especially after 10 years., Competing Interests: Conflict of Interest D. Gareth Evans has received consultancy fees from AstraZeneca and EverythingGenetic Ltd. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Male breast cancer (MBC) affects around 1 in 1000 men and is known to have a higher underlying component of high and moderate risk gene pathogenic variants (PVs) than female breast cancer, particularly in BRCA2 . However, most studies only report overall detection rates without assessing detailed family history., Methods: We reviewed germline testing in 204 families including at least one MBC for BRCA1 , BRCA2 , CHEK2 c.1100DelC and an extended panel in 93 of these families. Individuals had MBC (n=118), female breast cancer (FBC)(n=80), ovarian cancer (n=3) or prostate cancer-(n=3). Prior probability of having a BRCA1/2 PV was assessed using the Manchester Scoring System (MSS)., Results: In the 204 families, BRCA2 was the major contributor, with 51 (25%) having PVs, followed by BRCA1 and CHEK2, with five each (2.45%) but no additional PVs identified, including in families with high genetic likelihood on MSS. Detection rates were 85.7% (12/14) in MSS ≥40 and 65.5% with MSS 30-39 but only 12.8% (6/47) for sporadic breast cancer. PV rates were low and divided equally between BRCA1/2 and CHEK2. CONCLUSION: As expected, BRCA2 PVs predominate in MBC families with rates 10-fold those in CHEK2 and BRCA1 . The MSS is an effective tool in assessing the likelihood of BRCA1/2 PVs., Competing Interests: Competing interests: DGE receives consultancy fees from EverythingGenetic Ltd. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Aims: Despite the highest prevalence of stroke, obesity, and diabetes across races/ethnicities, paradoxically, Hispanic/Latino populations have the lowest prevalence of atrial fibrillation and major Minnesota code-defined ECG abnormalities. We aimed to use Latent Profile Analysis in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) population to obtain insight into epidemiological discrepancies., Methods and Results: We conducted a cross-sectional analysis of baseline HCHS/SOL visit. Global electrical heterogeneity (GEH) was measured as spatial QRS-T angle (QRSTa), spatial ventricular gradient azimuth (SVGaz), elevation (SVGel), magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). Statistical analysis accounted for the stratified two-stage area probability sample design. We fitted a multivariate latent profile generalized structural equation model adjusted for age, sex, ethnic background, education, hypertension, diabetes, smoking, dyslipidaemia, obesity, chronic kidney disease, physical activity, diet quality, average RR' interval, median beat type, and cardiovascular disease (CVD) to gain insight into the GEH profiles. Among 15 684 participants (age 41 years; 53% females; 6% known CVD), 17% had an increased probability of likely abnormal GEH profile (QRSTa 80 ± 27°, SVGaz -4 ± 21°, SVGel 72 ± 12°, SVGmag 45 ± 12 mVms, and SAIQRST 120 ± 23 mVms). There was a 23% probability for a participant of being in Class 1 with a narrow QRSTa (40.0 ± 10.2°) and large SVG (SVGmag 108.3 ± 22.6 mVms; SAIQRST 203.4 ± 39.1 mVms) and a 60% probability of being in intermediate Class 2., Conclusion: A substantial proportion (17%) in the Hispanic/Latino population had an increased probability of altered, likely abnormal GEH profile, whereas 83% of the population was resilient to harmful risk factors exposures., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Breast density is associated with the risk of developing cancer and can be automatically estimated using deep learning models from digital mammograms. Our aim is to evaluate the capacity and reliability of such models to predict density from low-dose mammograms taken to enable risk estimates for younger women., Approach: We trained deep learning models on standard-dose and simulated low-dose mammograms. The models were then tested on a mammography dataset with paired standard- and low-dose images. The effect of different factors (including age, density, and dose ratio) on the differences between predictions on standard and low doses is analyzed. Methods to improve performance are assessed, and factors that reduce the model quality are demonstrated., Results: We showed that, although many factors have no significant effect on the quality of low-dose density prediction, both density and breast area have an impact. The correlation between density predictions on low- and standard-dose images of breasts with the largest breast area is 0.985 (0.949 to 0.995), whereas that with the smallest is 0.882 (0.697 to 0.961). We also demonstrated that averaging across craniocaudal-mediolateral oblique (CC-MLO) images and across repeatedly trained models can improve predictive performance., Conclusions: Low-dose mammography can be used to produce density and risk estimates that are comparable to standard-dose images. Averaging across CC-MLO and model predictions should improve this performance. The model quality is reduced when making predictions on denser and smaller breasts., (© 2024 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Purpose . To improve breast cancer risk prediction for young women, we have developed deep learning methods to estimate mammographic density from low dose mammograms taken at approximately 1/10th of the usual dose. We investigate the quality and reliability of the density scores produced on low dose mammograms focussing on how image resolution and levels of training affect the low dose predictions. Methods . Deep learning models are developed and tested, with two feature extraction methods and an end-to-end trained method, on five different resolutions of 15,290 standard dose and simulated low dose mammograms with known labels. The models are further tested on a dataset with 296 matching standard and real low dose images allowing performance on the low dose images to be ascertained. Result s. Prediction quality on standard and simulated low dose images compared to labels is similar for all equivalent model training and image resolution versions. Increasing resolution results in improved performance of both feature extraction methods for standard and simulated low dose images, while the trained models show high performance across the resolutions. For the trained models the Spearman rank correlation coefficient between predictions of standard and low dose images at low resolution is 0.951 (0.937 to 0.960) and at the highest resolution 0.956 (0.942 to 0.965). If pairs of model predictions are averaged, similarity increases. Conclusions . Deep learning mammographic density predictions on low dose mammograms are highly correlated with standard dose equivalents for feature extraction and end-to-end approaches across multiple image resolutions. Deep learning models can reliably make high quality mammographic density predictions on low dose mammograms., (Creative Commons Attribution license.)

Improved screening and treatment have decreased breast cancer mortality, although incidence continues to rise. Women at increased risk of breast cancer can be offered risk reducing treatments, such as tamoxifen, but this has not been shown to reduce breast cancer mortality. New, more efficacious, risk-reducing agents are needed. The identification of novel candidates for prevention is hampered by a lack of good preclinical models. Current patient derived in vitro and in vivo models cannot fully recapitulate the complexities of the human tissue, lacking human extracellular matrix, stroma, and immune cells, all of which are known to influence therapy response. Here we describe a normal breast explant model utilising a tuneable hydrogel which maintains epithelial proliferation, hormone receptor expression, and residency of T cells and macrophages over 7 days. Unlike other organotypic tissue cultures which are often limited by hyper-proliferation, loss of hormone signalling, and short treatment windows (< 48h), our model shows that tissue remains viable over 7 days with none of these early changes. This offers a powerful and unique opportunity to model the normal breast and study changes in response to various risk factors, such as breast density and hormone exposure. Further validation of the model, using samples from patients undergoing preventive therapies, will hopefully confirm this to be a valuable tool, allowing us to test novel agents for breast cancer risk reduction preclinically., (© 2024. The Author(s).)

Background: In 2022, the European Society of Cardiology updated guidelines for preoperative evaluation. The aims of this study were to quantify: (1) the impact of the updated recommendations on the yield of pathological findings compared with the previous guidelines published in 2014; (2) the impact of preoperative B-type natriuretic peptide (NT-proBNP) use for risk estimation on the yield of pathological findings; and (3) the association between 2022 guideline adherence and outcomes., Methods: This was a secondary analysis of MET-REPAIR, an international, prospective observational cohort study (NCT03016936). Primary endpoints were reduced ejection fraction (EF<40%), stress-induced ischaemia, and major adverse cardiovascular events (MACE). The explanatory variables were class of recommendations for transthoracic echocardiography (TTE), stress imaging, and guideline adherence. We conducted second-order Monte Carlo simulations and multivariable regression., Results: In total, 15,529 patients (39% female, median age 72 [inter-quartile range: 67-78] yr) were included. The 2022 update changed the recommendation for preoperative TTE in 39.7% patients, and for preoperative stress imaging in 12.9% patients. The update resulted in missing 1 EF <40% every 3 fewer conducted TTE, and in 4 additional stress imaging per 1 additionally detected ischaemia events. For cardiac stress testing, four more investigations were performed for every 1 additionally detected ischaemia episodes. Use of NT-proBNP did not improve the yield of pathological findings. Multivariable regression analysis failed to find an association between adherence to the updated guidelines and MACE., Conclusions: The 2022 update for preoperative cardiac testing resulted in a relevant increase in tests receiving a stronger recommendation. The updated recommendations for TTE did not improve the yield of pathological cardiac testing., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC., Methods: Outcomes of germline BRCA1 , BRCA2 and CHEK2 &#95;c.1100delC testing were recorded in 1514 women (743-isolated, 771-familial), and for PALB2 in 846 women (541-isolated, 305-familial), with TNBC and smaller numbers for additional genes. Breast cancer free controls were identified from Predicting Risk Of Cancer At Screening and BRIDGES (Breast cancer RIsk after Diagnostic GEne Sequencing) studies., Results: BRCA1 &#95;PGVs were detected in 52 isolated (7.0%) and 195 (25.3%) familial cases (isolated-OR=58.9, 95% CI: 16.6 to 247.0), BRCA2 &#95;PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated-OR=5.0, 95% CI: 2.3 to 11.2), PALB2&#95; PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated-OR=8.8, 95% CI: 2.5 to 30.4) and CHEK2&#95;c .1100delC in 0 isolated and 3 (0.45%) familial cases (isolated-OR=0.0, 95% CI: 0.00 to 2.11). BRCA1 &#95;PGV detection rate was >10% for all familial TNBC age groups and significantly higher for younger diagnoses (familial: <50 years, n=165/538 (30.7%); ≥50 years, n=30/233 (12.9%); p<0.0001). Women with a G3&#95;TNBC were more likely to have a BRCA1&#95; PGV as compared with a BRCA2 or PALB2 &#95;PGV (p<0.0001). 0/743 isolated TNBC had the CHEK2&#95; c.1100delC PGV and 0/305 any ATM &#95;PGV, but 2/240 (0.83%) had a RAD51D &#95;PGV., Conclusion: PGVs in BRCA1 are associated with G3&#95;TNBCs. Familial TNBCs and isolated TNBCs <30 years have a >10% likelihood of a PGV in BRCA1. BRCA1 &#95;PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC with CHEK2 or ATM PGVs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular circadian rhythms in noncancerous and cancerous human breast tissues and their clinical relevance are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For noncancerous breast tissue, inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of luminal A samples exhibit continued, albeit dampened and reprogrammed rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude luminal A tumors. Surprisingly, patients with high-magnitude tumors had reduced 5-y survival. Correspondingly, 3D luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis., Competing Interests: Competing interests statement:J.B.H. is on the scientific advisory board for Synchronicity Pharma. The other authors declare no competing interest.

Introduction: Breast cancer incidence starts to increase exponentially when women reach 30-39 years, hence before they are eligible for breast cancer screening. The introduction of breast cancer risk assessment for this age group could lead to those at higher risk receiving benefits of earlier screening and preventive strategies. Currently, risk assessment is limited to women with a family history of breast cancer only. The Breast CANcer Risk Assessment in Younger women (BCAN-RAY) study is evaluating a comprehensive breast cancer risk assessment strategy for women aged 30-39 years incorporating a questionnaire of breast cancer risk factors, low-dose mammography to assess breast density and polygenic risk. This study will assess the feasibility and acceptability of the BCAN-RAY risk assessment strategy., Methods and Analysis: This study involves women undergoing risk assessment as part of the BCAN-RAY case-control study (n=750). They will be aged 30-39 years without a strong family history of breast cancer and invited to participate via general practice. A comparison of uptake rates by socioeconomic status and ethnicity between women who participated in the BCAN-RAY study and women who declined participation will be conducted. All participants will be asked to complete self-report questionnaires to assess key potential harms including increased state anxiety (State Trait Anxiety Inventory), cancer worry (Lerman Cancer Worry Scale) and satisfaction with the decision to participate (Decision Regret Scale), alongside potential benefits such as feeling more informed about breast cancer risk. A subsample of approximately 24 women (12 at average risk and 12 at increased risk) will additionally participate in semistructured interviews to understand the acceptability of the risk assessment strategy and identify any changes needed to it to increase uptake., Ethics and Dissemination: Ethical approval was granted by North West-Greater Manchester West Research Ethics Committee (reference: 22/NW/0268). Study results will be disseminated through peer-reviewed journals, conference presentations and charitable organisations., Trial Registration Number: NCT05305963., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

What Is This Summary About?: This is a summary of the article discussing the results of the CAPItello-291 study. In the study, participants had advanced breast cancer that could not be completely removed with surgery, and that was diagnosed as a type of breast cancer where tumor cells had hormone receptors (HR-positive) but did not have HER2 receptors (HER2-negative). All participants were also required to have previously received treatment with a type of therapy called an aromatase inhibitor (with or without a CDK4/6 inhibitor), but over time their cancer cells had still grown or spread. The CAPItello-291 study researchers wanted to find out if a treatment combination of the medications capivasertib plus fulvestrant worked better than placebo plus fulvestrant. Capivasertib is a drug that blocks the activity of a protein called AKT, which is found inside breast cancer cells., What Are the Key Takeaways?: The main finding was that participants who took capivasertib plus fulvestrant lived longer without their disease getting worse (progressing) compared with those treated with placebo plus fulvestrant. This is called progression-free survival. This result was seen across all participants (median progression-free survival of 7.2 months with capivasertib plus fulvestrant vs 3.6 months with placebo plus fulvestrant). It was also seen in participants whose tumors had detectable genetic alterations in genes called PIK3CA, AKT1, and/ or PTEN (median progression-free survival of 7.3 months with capivasertib plus fulvestrant vs 3.1 months with placebo plus fulvestrant). The most common side effects experienced by participants included diarrhea and different types of rash. These were as expected (given how capivasertib works). The CAPItello-291 study is still ongoing, and more results are expected to be released in the future., What Were the Main Conclusions Reported by the Researchers?: Results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved progression-free survival in participants with HR-positive/ HER2-negative advanced breast cancer whose cancer had grown or spread despite hormone therapy (with/without a CDK4/6 inhibitor). Clinical Trial Registration: NCT04305496 (CAPItello-291) (ClinicalTrials.gov).

Background: Self-reported functional capacity measures have an uncertain role in the pre-operative cardiovascular risk stratification., Aim: This substudy aimed to evaluate whether self-reported metabolic equivalent (MET) could improve the prediction of postoperative myocardial injury (MI) over other well-established cardiovascular risk factors., Methods: This is a post hoc analysis of an international multicenter prospective cohort study. We recruited patients ≥45 years old who had elective elevated-risk noncardiac surgery in 45 centers across 17 countries between June 2017 and April 2020. The primary outcome was MI defined according to the Fourth Universal Definition of Myocardial Infarction. We measured the proportion of new prognostic information added by self-reported MET using multivariable logistic regression., Results: In total, 860 (41.3%) patients suffered MI. In patients without systematic troponin surveillance, the odds ratio for MI with each 1-point increment in MET equaled 1.03 (95% confidence interval [CI], 0.99-1.07). The new prognostic information, according to the likelihood ratio adequacy index, accounted for 1.5%. Sensitivity analysis, including centers with >90% of patients with routine high-sensitivity troponin T monitoring, showed that MET added 21.8% of new information to the baseline model, and each additional point was associated with a lower risk of MI (odds ratio, 0.86; 95% CI, 0.81-0.91)., Conclusions: In elevated-risk noncardiac surgery, self-reported functional capacity measures do not significantly improve the prediction of MI; however, they add new prognostic information in centers with routine perioperative troponin monitoring.

Competing Interests: Funding Support and Author Disclosures This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Importance: Nearly 16 million surgical procedures are conducted in North America yearly, and postoperative cardiovascular events are frequent. Guidelines suggest functional capacity or B-type natriuretic peptides (BNP) to guide perioperative management. Data comparing the performance of these approaches are scarce., Objective: To compare the addition of either N-terminal pro-BNP (NT-proBNP) or self-reported functional capacity to clinical scores to estimate the risk of major adverse cardiac events (MACE)., Design, Setting, and Participants: This cohort study included patients undergoing inpatient, elective, noncardiac surgery at 25 tertiary care hospitals in Europe between June 2017 and April 2020. Analysis was conducted in January 2023. Eligible patients were either aged 45 years or older with a Revised Cardiac Risk Index (RCRI) of 2 or higher or a National Surgical Quality Improvement Program, Risk Calculator for Myocardial Infarction and Cardiac (NSQIP MICA) above 1%, or they were aged 65 years or older and underwent intermediate or high-risk procedures., Exposures: Preoperative NT-proBNP and the following self-reported measures of functional capacity were the exposures: (1) questionnaire-estimated metabolic equivalents (METs), (2) ability to climb 1 floor, and (3) level of regular physical activity., Main Outcome and Measures: MACE was defined as a composite end point of in-hospital cardiovascular mortality, cardiac arrest, myocardial infarction, stroke, and congestive heart failure requiring transfer to a higher unit of care., Results: A total of 3731 eligible patients undergoing noncardiac surgery were analyzed; 3597 patients had complete data (1258 women [35.0%]; 1463 (40.7%) aged 75 years or older; 86 [2.4%] experienced a MACE). Discrimination of NT-proBNP or functional capacity measures added to clinical scores did not significantly differ (Area under the receiver operating curve: RCRI, age, and 4MET, 0.704; 95% CI, 0.646-0.763; RCRI, age, and 4MET plus floor climbing, 0.702; 95% CI, 0.645-0.760; RCRI, age, and 4MET plus physical activity, 0.724; 95% CI, 0.672-0.775; RCRI, age, and 4MET plus NT-proBNP, 0.736; 95% CI, 0.682-0.790). Benefit analysis favored NT-proBNP at a threshold of 5% or below, ie, if true positives were valued 20 times or more compared with false positives. The findings were similar for NSQIP MICA as baseline clinical scores., Conclusions and Relevance: In this cohort study of nearly 3600 patients with elevated cardiovascular risk undergoing noncardiac surgery, there was no conclusive evidence of a difference between a NT-proBNP-based and a self-reported functional capacity-based estimate of MACE risk., Trial Registration: ClinicalTrials.gov Identifier: NCT03016936.

Purpose: ER+/HER2- advanced breast cancer (ABC) with visceral crisis (VC) or impending VC (IVC) is commonly treated with chemotherapy instead of CDK4/6 inhibitors (CDK4/6i). However, there is little evidence to confirm which treatment is superior. This study compared outcomes of patients with ER+/HER2- ABC and IVC/VC treated with CDK4/6i or weekly paclitaxel., Methods: Patients with ER+/HER2- ABC receiving first line treatment at a large tertiary UK cancer centre from 1-Mar-2017 to 30-Jun-2021 were retrospectively identified. Hospital records were screened for IVC/VC affecting the liver, lungs/mediastinum, gastrointestinal tract and/or bone marrow. Baseline demographics, clinical data and survival outcomes were recorded up to 30-Jul-2022., Results: 27/396 (6.8%) patients with ABC who received CDK4/6i and 32/86 (37.2%) who received paclitaxel had IVC/VC. Median time to treatment failure (TTF), progression-free survival (PFS) and overall survival (OS) were significantly longer in the CDK4/6i compared to paclitaxel cohort: TTF 17.3 vs. 3.5 months (HR 0.33, 95%CI 0.17-0.61, p = 0.0002), PFS 17.8 vs. 4.5 months (HR 0.38, 95%CI 0.21-0.67, p = 0.002), OS 24.6 vs. 6.7 months (HR 0.37, 95%CI 0.20-0.68, p = 0.002). The median time to first improvement in IVC/VC was similar in patients receiving CDK4/6i compared to paclitaxel (3.9 vs. 3.6 weeks, p = 0.773). Disease control at 4 months was not significantly different in the CDK4/6i and paclitaxel cohorts (77.8% vs. 59.4%, p = 0.168). In multivariate analysis, treatment with CDK4/6i was independently associated with a longer PFS compared to paclitaxel (HR 0.31, 95%CI 0.12-0.78, p = 0.015)., Conclusion: In this retrospective study, patients with ER+/HER2- ABC and IVC/VC treated with CDK4/6i had a significantly better survival compared to those treated with weekly paclitaxel. Further prospective studies that minimise possible selection bias are recommended., (© 2023. The Author(s).)

Purpose: To investigate the frequency of germline pathogenic variants (PVs) in women with bilateral breast cancer., Methods: We undertook BRCA1/2 and CHEK2 c.1100delC molecular analysis in 764 samples and a multigene panel in 156. Detection rates were assessed by age at first primary, Manchester Score, and breast pathology. Oestrogen receptor (ER) status of the contralateral versus first breast cancer was compared on 1081 patients with breast cancer with BRCA1 /B RCA2 PVs., Results: 764 women with bilateral breast cancer have undergone testing of BRCA1/2 and CHEK2 ; 407 were also tested for PALB2 and 177 for ATM . Detection rates were BRCA1 11.6%, BRCA2 14.0%, CHEK2 2.4%, PALB2 1.0%, ATM 1.1% and, for a subset of mainly very early onset tumours, TP53 4.6% (9 of 195). The highest PV detection rates were for triple negative cancers for BRCA1 (26.4%), grade 3 ER+HER2 for BRCA2 (27.9%) and HER2+ for CHEK2 (8.9%). ER status of the first primary in BRCA1 and BRCA2 PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER- in BRCA1 heterozygotes, and 50% were ER- in BRCA2 heterozygotes if the first was ER-., Conclusion: We have shown a high rate of detection of BRCA1 and BRCA2 PVs in triple negative and grade 3 ER+HER2- first primary diagnoses, respectively. High rates of HER2+ were associated with CHEK2 PVs, and women ≤30 years were associated with TP53 PVs. First primary ER status in BRCA1/2 strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)