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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). Methods: Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer–Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5–<8% 10-year) to have appointments to discuss prevention and additional screening. Results: Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to <10% with BC-Predict only (P < 0.0001). Risk appointment attendance was highest for those at high risk (40.6%); 77.5% of those opted for preventive medication. Discussion: We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. Trial registration: Retrospectively registered with clinicaltrials.gov (NCT04359420). [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. Methods: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44). Results: Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. Conclusions: These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers. Trial registration: Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control – a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19; registered on 15 July 2015. [ABSTRACT FROM AUTHOR]

Background: Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer.Methods: In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.Findings: Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6-11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0-13·2) in the capivasertib group versus 4·8 months (3·1-7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39-0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related.Interpretation: Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials.Funding: AstraZeneca and Cancer Research UK. [ABSTRACT FROM AUTHOR]

Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women. The work carried out by TEB was supported by MRC grant MR/P014070/1. [Extracted from the article]

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.)

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: 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: 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.)

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.)

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.)

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.)

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.)

Background: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited., Methods: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered ( PIK3CA , AKT1 , or PTEN ) tumors. Safety was assessed., Results: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo., Conclusions: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes., Methods: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952., Findings: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment., Interpretation: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial., Funding: AstraZeneca and Cancer Research UK., Competing Interests: Declaration of interests SJH received grant support for this study from AstraZeneca; research grants from Eli Lilly; consulting fees from Eli Lilly and Pfizer; honoraria from Pfizer; and participates on a trial steering committee for AstraZeneca. AC received grant support for the study from AstraZeneca and Cancer Research UK. RB received funding from the All Wales Medical Genetics Service (as head of the service) to do the original biomarker testing. PB reports honoraria from AstraZeneca and support from Eli Lilly related to meeting attendance and advisory or safety board participation. SMoo reports support for attending meetings from Eli Lilly and honoraria from AstraZeneca unrelated to the submitted work. CT received funding from AstraZeneca for the costs of doing this trial, as well as consulting fees and honoraria from AstraZeneca unrelated to the submitted work. SW declares honoraria from Novartis, consulting fees from Sanofi and Novartis, and travel expenses from Eli Lilly. ECdeB, GS, and AF are employees of and hold shares in AstraZeneca. AF receives funding from AstraZeneca to attend congresses and funding for capivasertib studies. RHJ reports grants from AstraZeneca and Cancer Research UK, and personal fees from Roche unrelated to the submitted work. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Excess adiposity at diagnosis and weight gain during chemotherapy is associated with tumour recurrence and chemotherapy toxicity. We assessed the efficacy of intermittent energy restriction (IER) vs continuous energy restriction (CER) for weight control and toxicity reduction during chemotherapy., Methods: One hundred and seventy-two women were randomised to follow IER or CER throughout adjuvant/neoadjuvant chemotherapy. Primary endpoints were weight and body fat change. Secondary endpoints included chemotherapy toxicity, cardiovascular risk markers, and correlative markers of metabolism, inflammation and oxidative stress., Results: Primary analyses showed non-significant reductions in weight (-1.1 (-2.4 to +0.2) kg, p = 0.11) and body fat (-1.0 (-2.1 to +0.1) kg, p = 0.086) in IER compared with CER. Predefined secondary analyses adjusted for body water showed significantly greater reductions in weight (-1.4 (-2.5 to -0.2) kg, p = 0.024) and body fat (-1.1 (-2.1 to -0.2) kg, p = 0.046) in IER compared with CER. Incidence of grade 3/4 toxicities were comparable overall (IER 31.0 vs CER 36.5%, p = 0.45) with a trend to fewer grade 3/4 toxicities with IER (18%) vs CER (31%) during cycles 4-6 of primarily taxane therapy (p = 0.063)., Conclusions: IER is feasible during chemotherapy. The potential efficacy for weight control and reducing toxicity needs to be tested in future larger trials., Clinical Trial Registration: ISRCTN04156504., (© 2021. The Author(s).)

Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC., Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53., Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83-66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58-23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52-29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2., Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC., (© 2021. The Author(s).)

Background: A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored., Results: Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women's IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer., Conclusions: Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk., (© 2022. The Author(s).)

Purpose: Women at increased familial breast cancer risk have been offered screening starting at an earlier age and increased frequency than national Screening Programmes for over 30 years. There are limited data on longer-term largescale implementation of this approach on cancer diagnosis., Methods: Women at our institution at ≥ 17% lifetime breast cancer risk have been offered enhanced screening with annual mammography starting at age 35 or 5-years younger than youngest affected relative, with upper age limit 50 for moderate and 60 for high-risk. Breast cancer pathology, stage and receptor status were assessed as well as survival from cancer diagnosis by Kaplan-Meier analysis., Results: Overall 14,311 women were seen and assessed for breast cancer risk, with 649 breast cancers occurring in 129,119 years follow up (post-prevalent annual incidence = 4.55/1000). Of 323/394 invasive breast cancers occurring whilst on enhanced screening, most were lymph-node negative (72.9%), T1 (≤ 20 mm, 73.2%) and stage-1 (61.4%), 126/394 stage2-4 (32%). 10-year breast cancer specific survival was 91.3% (95% CI 87.4-94.0) better than the 75.9% (95% CI 74.9-77.0) published for England in 2013-2017. As expected, survival was significantly better for women with screen detected cancers (p < 0.001). Ten-year survival was particularly good for those diagnosed ≤ 40 at 93.8% (n = 75; 95% CI 84.2-97.6). Women with lobular breast cancers had worse 10-year survival at 85.9% (95% CI 66.7-94.5). Breast cancer specific survival was good for 119 BRCA1/2 carriers with 20-year survival in BRCA1:91.2% (95% CI 77.8-96.6) and 83.8% (62.6-93.5) for BRCA2., Conclusions: Targeted breast screening in women aged 30-60 years at increased familial risk is associated with good long-term survival that is substantially better than expected from population data., (© 2021. The Author(s).)

Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2&#95;PGV) and the CHEK2 c.1100delC (CHEK2&#95;1100delC) PGV to familial breast and ovarian cancer, and PALB2&#95;PGV associated breast cancer pathology., Methods: Outcomes of germline PALB2&#95;PGV and CHEK2&#95;1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2&#95;PGV cases from extended families., Results: Thirty-five PALB2 and 44 CHEK2&#95;1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P < 0.0001). PALB2&#95;PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20-39 = 11/520, P = 0.04) but not for CHEK2&#95;1100delC (MS < 15 = 29/1,762, MS 20-39 = 4/520). PALB2 PGVs showed perfect segregation in 20/20 first-degree relatives with breast cancer, compared with 7/13 for CHEK2&#95;1100delC (P = 0.002)., Conclusion: PALB2 PGVs and CHEK2&#95;1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors., (© 2021. The Author(s).)

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.

Purpose: Estimated glomerular filtration rate (eGFR) is commonly used to calculate carboplatin doses and capping the eGFR may be used to reduce the risk of excessive dosing and toxicity. We sought to retrospectively examine the impact of our carboplatin guidelines on pathological complete response rates (pCR) and toxicity in women with HER2+ breast cancer receiving neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP)., Methods: The delivered area under the curve (dAUC) was calculated [(actual carboplatin dose at cycle 1 ÷ dose calculated with uncapped/unbanded eGFR) × 6] and dichotomized at the median value. The impact of this and other clinical factors on pCR rate, dose intensity (DI) and toxicity was assessed., Results: 124 eligible patients were identified of whom 63.7% (79/124) achieved pCR. The median dAUC at cycle 1 was 5.75 mg × ml/min. Those with lower dAUC were more frequently younger and overweight/obese. Patients with lower dAUC had significantly inferior pCR rates of 54.8% (34/62) vs 72.6% (45/62), respectively (p = 0.040). Similar results were seen in the ER+ subgroup; 45.2% (19/42) vs 68.3% (28/41), p = 0.037%, whereas no significant difference was seen among ER- patients; 75.0% (15/20) vs 81.0% (17/21), p = 0.72. DI and toxicity were comparable between the two dAUC groups., Conclusions: The overall pCR rate was high in patients with HER2+ breast cancer receiving the TCHP regimen; however, carboplatin dose capping resulted in inferior pCR rates, particularly in the ER+ subgroup. To ensure optimal dosing, isotopic measurement of renal function is warranted in patients who would otherwise have their eGFR and dose capped.

Estrogen-receptor-positive breast tumors are treated with anti-estrogen (AE) therapies but frequently develop resistance. Cancer stem cells (CSCs) with high aldehyde dehydrogenase activity (ALDH + cells) are enriched following AE treatment. Here, we show that the interleukin-1β (IL-1β) signaling pathway is activated in ALDH + cells, and data from single cells reveals that AE treatment selects for IL-1 receptor (IL1R1)-expressing ALDH + cells. Importantly, CSC activity is reduced by an IL1R1 inhibitor in AE-resistant models. Moreover, IL1R1 expression is increased in the tumors of patients treated with AE therapy and predicts treatment failure. Single-cell gene expression analysis revealed that at least two subpopulations exist within the ALDH + population, one proliferative and one quiescent. Following AE therapy the quiescent population is expanded, which suggests CSC dormancy as an adaptive strategy that facilitates treatment resistance. Targeting of ALDH + IL1R1 + cells merits testing as a strategy to combat AE resistance in patients with residual disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)