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Background: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery., Methods: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice. Interviews were transcribed verbatim and analysed thematically. Trial registration number: ISRCTN18238549., Results: A total of 27 women from 12 centres were interviewed. Out of these, 12 had chosen oncoplastic breast-conserving surgery and 15 had chosen a mastectomy with or without immediate breast reconstruction. Overwhelmingly, women's decisions were guided by their surgical teams. Decision-making for and against oncoplastic breast-conserving surgery was influenced by three key inter-related factors: perceptions of oncological safety; the importance of maintaining/restoring femininity and body image; and practical issues. Oncological safety was paramount. Women who reported feeling reassured that oncoplastic breast-conserving surgery was oncologically safe were happy to choose this option. Those who were not reassured were more likely to opt for a mastectomy, as a perceived 'safer' option. Most women wished to maintain/restore femininity, with the offer of immediate breast reconstruction essential to make a mastectomy an acceptable option. Practical issues such as the perceived magnitude of the surgery were a lesser concern., Conclusion: Decision-making is complex and heavily influenced by the surgical team. High-quality, accurate information about surgical options, including appropriate reassurance about the short- and long-term oncological safety of oncoplastic breast-conserving surgery is vital if women are to make fully informed decisions., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Breast-conserving surgery with adjuvant radiotherapy and mastectomy are currently offered as equivalent surgical options for early-stage breast cancer based on RCTs from the 1970s and 1980s. However, the treatment of breast cancer has evolved and recent observational studies suggest a survival advantage for breast-conserving surgery with adjuvant radiotherapy. A systematic review and meta-analysis was undertaken to summarize the contemporary evidence regarding survival after breast-conserving surgery with adjuvant radiotherapy versus mastectomy for women with early-stage breast cancer., Methods: A systematic search of MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase that identified studies published between 1 January 2000 and 18 December 2023 comparing overall survival after breast-conserving surgery with adjuvant radiotherapy versus mastectomy for patients with unilateral stage 1-3 breast cancer was undertaken. The main exclusion criteria were studies evaluating neoadjuvant chemotherapy, rare breast cancer subtypes, and specific breast cancer populations. The ROBINS-I tool was used to assess risk of bias, with the overall certainty of evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. Studies without critical risk of bias were included in a quantitative meta-analysis., Results: From 11 750 abstracts, 108 eligible articles were identified, with one article including two studies; 29 studies were excluded from the meta-analysis due to an overall critical risk of bias, 42 studies were excluded due to overlapping study populations, and three studies were excluded due to reporting incompatible results. A total of 35 observational studies reported survival outcomes for 909 077 patients (362 390 patients undergoing mastectomy and 546 687 patients undergoing breast-conserving surgery with adjuvant radiotherapy). The pooled HR was 0.72 (95% c.i. 0.68 to 0.75, P < 0.001), demonstrating improved overall survival for patients undergoing breast-conserving surgery with adjuvant radiotherapy. The overall certainty of the evidence was very low., Conclusion: This meta-analysis provides evidence suggesting a survival advantage for women undergoing breast-conserving surgery with adjuvant radiotherapy for early-stage breast cancer compared with mastectomy. Although these results should be interpreted with caution, they should be shared with patients to support informed surgical decision-making., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Evidence-based clinical guidelines are essential to maximize patient benefit and to reduce clinical uncertainty and inconsistency in clinical practice. Gaps in the evidence base can be addressed by data acquired in routine practice. At present, there is no international consensus on management of women diagnosed with atypical lesions in breast screening programmes. Here, we describe how routine NHS breast screening data collected by the Sloane atypia project was used to inform a management pathway that maximizes early detection of cancer and minimizes over-investigation of lesions with uncertain malignant potential. A half-day consensus meeting with 11 clinical experts, 1 representative from Independent Cancer Patients' Voice, 6 representatives from NHS England (NHSE) including from Commissioning, and 2 researchers was held to facilitate discussions of findings from an analysis of the Sloane atypia project. Key considerations of the expert group in terms of the management of women with screen detected atypia were: (1) frequency and purpose of follow-up; (2) communication to patients; (3) generalizability of study results; and (4) workforce challenges. The group concurred that the new evidence does not support annual surveillance mammography for women with atypia, irrespective of type of lesion, or woman's age. Continued data collection is paramount to monitor and audit the change in recommendations., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Background: Breast reconstruction is offered to improve quality of life for women after mastectomy for breast cancer, but information regarding the long-term patient-reported outcomes of different reconstruction procedures is currently lacking. The Brighter study aimed to evaluate long-term patient-reported outcomes after immediate breast reconstruction (IBR) in a population-based cohort., Methods: Women who underwent mastectomy with IBR for breast cancer in England between 1 January 2008 and 31 March 2009 were identified from National Health Service Hospital Episode Statistics. Surviving women were invited to complete the BREAST-Q, EQ-5D-5L™, and ICECAP-A at least 12 years after the index procedure. Questionnaires were scored according to developers' instructions and compared by IBR type., Results: Some 1236 women underwent IBR; 343 (27.8 per cent) had 2-stage expander/implant, 630 (51.0 per cent) latissimus dorsi, and 263 (21.3 per cent) abdominal flap reconstructions, with a mean(s.d.) follow-up of 13.3(0.5) years. Women who underwent abdominal flap reconstruction reported higher scores in all BREAST-Q domains than those who had other procedures. These differences remained statistically significant and clinically meaningful after adjusting for age, ethnicity, geographical region, socioeconomic status, smoking, BMI, and complications. The greatest difference was seen in scores for satisfaction with breasts; women who had abdominal flap reconstructions reported scores that were 13.17 (95 per cent c.i. 9.48 to 16.87) points; P < 0.001) higher than those among women who had two-stage expander/implant procedures. Women who underwent latissimus dorsi reconstruction reported significantly more pain/discomfort on the EQ-5D-5L™, but no other differences between procedures were seen., Conclusion: Long-term patient-reported outcomes are significantly better following abdominal flap reconstruction than other traditional procedure types. These findings should be shared with women considering IBR to help them make informed decisions about their surgical options., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Key Words: Breast cancer, mastectomy, breast conserving surgery, post-mastectomy reconstruction, older women, quality of life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Purpose: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources., Methods: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb-July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis., Results: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32-81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7-8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months' treatment duration; median of 4 mm [IQR - 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month's duration of BrET., Discussion: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials., (© 2023. The Author(s).)

Background: Women considering immediate breast reconstruction require high-quality information about the likely need for secondary reconstruction and the long-term risk of revisional surgery to make fully informed decisions about different reconstructive options. Such data are currently lacking. This study aimed to explore the impact of reconstruction type on the number of revisions and secondary reconstructions performed 3, 5, and 8 years after immediate breast reconstruction in a large population-based cohort., Methods: Women undergoing unilateral mastectomy and immediate breast reconstruction for breast cancer or ductal carcinoma in situ in England between 1 April 2009 and 31 March 2015 were identified from National Health Service Hospital Episode Statistics. Numbers of revisions and secondary reconstructions in women undergoing primary definitive immediate breast reconstruction were compared by procedure type at 3, 5, and 8 years after index surgery., Results: Some 16 897 women underwent immediate breast reconstruction with at least 3 years' follow-up. Of these, 14 069 had a definitive reconstruction with an implant only (5193), latissimus dorsi flap with (3110) or without (2373) an implant, or abdominal free flap (3393). Women undergoing implant-only reconstruction were more likely to require revision, with 69.5 per cent (747 of 1075) undergoing at least one revision by 8 years compared with 49.3 per cent (1568 of 3180) in other reconstruction groups. They were also more likely to undergo secondary reconstruction, with the proportion of women having further reconstructive procedures increasing over time: 12.8 per cent (663 of 5193) at 3 years, 14.3 per cent (535 of 3752) at 5 years, and 17.6 per cent (189 of 1075) at 8 years., Conclusion: Long-term rates of revisions and secondary reconstructions were considerably higher after primary implant-based reconstruction than autologous procedures. These results should be shared with patients to support informed decision-making., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Purpose: Ki67 assessed at diagnosis (Ki67 baseline ) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67 2week ) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67 2week ) with recurrence-free survival. The aim was to define the association between Ki67 baseline and after aromatase inhibitor (AI) exposure ∆Ki67 2week and Ki67 2week with key prognostic and biologic factors utilising data from the POETIC study., Patients and Methods: In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression., Results: Established associations of Ki67 baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67 baseline . In control group Ki67 2week was 18% lower than Ki67 baseline (p < 0.001) when Ki67 2week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki67 2week ) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type., Conclusions: The magnitude of this study allowed characterisation of relationships between Ki67 baseline , ∆Ki67 2week and Ki67 2week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki67 2week or Ki67 2week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies., (© 2023. The Author(s).)

Introduction: Shared learning is imperative in the assessment and safe implementation of new healthcare interventions. Magnetic seeds (Magseed®) potentially offer logistical benefit over wire localisation for non-palpable breast lesions but few data exist on outcomes comparing these techniques. A national registration study (iBRA-NET) was conducted to collate device outcomes. In order to share learning, thematic analysis was conducted to ascertain early clinical experiences of Magseed® and wire guided localisation and explore how learning events may be applied to improve clinical outcomes., Methods: A qualitative study of 27 oncoplastic surgeons, radiologists and physicians was conducted in January 2020 to ascertain the feasibility and challenges associated with Magseed® versus wire breast localisation surgery. Four focus groups were asked to discuss experiences, concerns and shared learning outcomes which were tabulated and analysed thematically., Results: Three key themes were identified comparing Magseed® and wire localisation of breast lesions relating to preoperative, intraoperative and postoperative learning outcomes. Percutaneous Magseed® detection, instrument interference and potential seed or wire dislodgement were the most common issues identified. Clinician experience suggested Magseed® index lesion identification was non-inferior to wire placement and improved the patient pathway in terms of scheduling and multi-site insertion., Conclusions: Prospective shared learning suggested Magseed® offered additional non-clinical benefits over wire localisation, improving the efficiency of the patient pathway. Recommendations for improving breast localisation technique, appropriate patient selection and clinical practice through shared learning are discussed that may aid other surgeons in the adoption of this relatively new technique., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs., Methods: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk ). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering., Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki67 2wk . Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14-5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes., Interpretation: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse., Funding: Cancer Research UK (CRUK/07/015)., Competing Interests: Declaration of interests MB reports grants from Fundacion Alonso Martin Escudero and has a patent filed for the novel molecular subgroups identified in this paper. ELK has a patent filed for the novel molecular subgroups identified in this paper. HT and LK report grants from Cancer Research UK, during the conduct of the study. JMB reports grants from Cancer Research UK, during the conduct of the study; grants and non-financial support from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Eli Lilly, and Roche, outside the submitted work. MD receives consulting fees from AstraZeneca, Lilly, Roche, Radius, H3 Biomedicine and G1. He also receives honoraria from Nanostring. M.C.U.C. has a patent for Breast Cancer Classifier: US Patent No. 9,631,239 with royalties paid and receive research funding from NanoString Technologies and Veracyte advisory role. And has a patent filed for the novel molecular subgroups identified in this paper. All other authors declare no competing interests. The information in this manuscript is subject to a pending patent application., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To explore the impact of PMRT on PROs of IBBR performed with and without mesh., Summary of Background Data: PMRT is increasingly given to improve breast cancer outcomes but can adversely impact complications after IBBR.Little; however, is known about the impact of PMRT on the PROs of IBBR, especially when mesh is used., Methods: The implant Breast Reconstruction evAluation prospective cohort study recruited consecutive women undergoing immediate IBBR from 81 UK breast and plastic surgical units. Demographic, operative, oncological, and 3-month complication data were collected, and patients consented to receive validated PRO questionnaires at 18-months. The association between IBBR, PMRT, and PROs were investigated using mixed-effects regression models adjusted for clinically-relevant confounders and including a random-effect to account for potential clustering by center., Results: A total of 1163 women consented to receive 18-month questionnaires of whom 730 (63%) completed it. Patients undergoing PMRT (214 patients) reported worse PROs in 3 BREAST-Q domains: satisfaction with breasts [-6.27 points, P = 0.008, 95% confidence interval (CI) (-10.91, -1.63)], satisfaction with outcome [-7.53 points, P = 0.002, CI (-12.20, -2.85)] and physical well-being [-6.55 points, P < 0.001, CI (-9.43, -3.67)]. Overall satisfaction was worse in the PMRT group [OR 0.497, P = 0.002, CI (0.32, 0.77)]. These effects were not ameliorated by mesh use., Conclusions: PMRT may adversely affect PROs after IBBR irrespective of whether mesh is used. These findings should be discussed with all patients considering IBBR and when indications for PMRT are borderline to enable informed decision-making regarding oncological and reconstructive treatment options., Trial Registration: ISRCTN37664281., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Wire localization is historically the most common method for guiding excision of non-palpable breast lesions, but there are limitations to the technique. Newer technologies such as magnetic seeds may allow some of these challenges to be overcome. The aim was to compare safety and effectiveness of wire and magnetic seed localization techniques., Methods: Women undergoing standard wire or magnetic seed localization for non-palpable lesions between August 2018 and August 2020 were recruited prospectively to this IDEAL stage 2a/2b platform cohort study. The primary outcome was effectiveness defined as accurate localization and removal of the index lesion. Secondary endpoints included safety, specimen weight and reoperation rate for positive margins., Results: Data were accrued from 2300 patients in 35 units; 2116 having unifocal, unilateral breast lesion localization. Identification of the index lesion in magnetic-seed-guided (946 patients) and wire-guided excisions (1170 patients) was 99.8 versus 99.1 per cent (P = 0.048). There was no difference in overall complication rate. For a subset of patients having a single lumpectomy only for lesions less than 50 mm (1746 patients), there was no difference in median closest margin (2 mm versus 2 mm, P = 0.342), re-excision rate (12 versus 13 per cent, P = 0.574) and specimen weight in relation to lesion size (0.15 g/mm2versus 0.138 g/mm2, P = 0.453)., Conclusion: Magnetic seed localization demonstrated similar safety and effectiveness to those of wire localization. This study has established a robust platform for the comparative evaluation of new localization devices., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER + /HER2 - breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers., Experimental Design: 307 postmenopausal women with ER + /HER2 - primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1., Results: Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP, and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3-9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment., Conclusions: High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3-9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the "off" week of its schedule., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Implant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure following mastectomy. IBBR techniques are evolving rapidly, with mesh-assisted subpectoral reconstruction becoming the standard of care and more recently, prepectoral techniques being introduced. These muscle-sparing techniques may reduce postoperative pain, avoid implant animation and improve cosmetic outcomes and have been widely adopted into practice. Although small observational studies have failed to demonstrate any differences in the clinical or patient-reported outcomes of prepectoral or subpectoral reconstruction, high-quality comparative evidence of clinical or cost-effectiveness is lacking. A well-designed, adequately powered randomised controlled trial (RCT) is needed to compare the techniques, but breast reconstruction RCTs are challenging. We, therefore, aim to undertake an external pilot RCT (Best-BRA) with an embedded QuinteT Recruitment Intervention (QRI) to determine the feasibility of undertaking a trial comparing prepectoral and subpectoral techniques., Methods and Analysis: Best-BRA is a pragmatic, two-arm, external pilot RCT with an embedded QRI and economic scoping for resource use. Women who require a mastectomy for either breast cancer or risk reduction, elect to have an IBBR and are considered suitable for both prepectoral and subpectoral reconstruction will be recruited and randomised 1:1 between the techniques.The QRI will be implemented in two phases: phase 1, in which sources of recruitment difficulties are rapidly investigated to inform the delivery in phase 2 of tailored interventions to optimise recruitment of patients.Primary outcomes will be (1) recruitment of patients, (2) adherence to trial allocation and (3) outcome completion rates. Outcomes will be reviewed at 12 months to determine the feasibility of a definitive trial., Ethics and Dissemination: The study has been approved by the National Health Service (NHS) Wales REC 6 (20/WA/0338). Findings will be presented at conferences and in peer-reviewed journals., Trial Registration Number: ISRCTN10081873., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured., Methods: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1-6 and 27-35; low oestrogen and low progesterone) or W2 (days 7-26; high oestrogen and high or low progesterone)., Results: The invasion module score of RS was lower (- 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72-0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%., Conclusion: There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements., (© 2021. The Author(s).)

Introduction: Breast reconstruction (BR) is offered to improve quality of life for women with breast cancer undergoing mastectomy. As most women will be long-term breast cancer survivors, high-quality information regarding the long-term outcomes of different BR procedures is essential to support informed decision-making. As different techniques vary considerably in cost, policymakers also require high-quality cost-effectiveness evidence to inform care. The Brighter study aims to explore the long-term clinical and patient-reported outcomes (PROs) of implant-based and autologous BR and use health economic modelling to compare the long-term cost-effectiveness of different reconstructive techniques., Methods and Analysis: Women undergoing mastectomy and/or BR following a diagnosis of breast cancer between 1 January 2008 and 31 March 2009 will be identified from hospital episode statistics (HES). Surviving women will be contacted and invited to complete validated PRO measures including the BREAST-Q, EQ-5D-5L and ICECAP-A, or opt out of having their data included in the HES analysis. Long-term clinical outcomes will be explored using HES data. The primary outcome will be rates of revisional surgery between implant-based and autologous procedures. Secondary outcomes will include rates of secondary reconstruction and reconstruction failure. The long-term PROs of implant-based and autologous reconstruction will be compared using BREAST-Q, EQ-5D-5L and ICECAP-A scores. Multivariable regression will be used to examine the relationship between long-term outcomes, patient comorbidities, sociodemographic and treatment factors. A Markov model will be developed using HES and PRO data and published literature to compare the relative long-term cost-effectiveness of implant-based and autologous BR., Ethics and Dissemination: The Brighter study has been approved by the South-West -Central Bristol Research Ethics Committee (20/SW/0020), and the Confidentiality Advisory Group (20/CAG/0021). Results will be published in peer-reviewed journals and presented at national meetings. We will work with the professional associations, charities and patient groups to disseminate the results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL)., Methods: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires., Results: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months., Conclusion: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy., Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage., Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed., Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient., Trial Registration: ISRCTN 46099296., (© 2021. The Author(s).)

Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions., Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting., Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey., Conclusions: The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

Introduction: Older patients with early breast cancer (EBC) derive modest survival benefit from chemotherapy but have increased toxicity risk. Data on the impact of chemotherapy for EBC on quality of life in older patients are limited, but this is a key determinant of treatment acceptance. We aimed to investigate its effect on quality of life in older patients enrolled in the Bridging the Age Gap study., Materials and Methods: A prospective, multicentre, observational study of EBC patients ≥70 years old was conducted in 2013-2018 at 56 UK hospitals. Demographics, patient, tumour characteristics, treatments and adverse events were recorded. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaires (EORTC-QLQ) C30, BR23 and ELD 15 plus the Euroqol-5D (eq-5d) over 24 months and analysed at each time point using baseline adjusted linear regression analysis and propensity score-matching., Results: Three thousand and four hundred sixteen patients were enrolled in the study; 1520 patients undergoing surgery and who had high-risk EBC were included in this analysis. 376/1520 (24.7%) received chemotherapy. At 6 months, chemotherapy had a significant negative impact in several EORTC-QLQ-C30 domains, including global health score, physical, role, social functioning, cognition, fatigue, nausea/vomiting, dyspnoea, appetite loss, diarrhoea and constipation. Similar trends were documented on other scales (EORTC-QLQ-BR23, EORTC-QLQ-ELD15 and EQ-5D-5L). Its impact was no longer significant at 18-24 months in unmatched and matched cohorts., Conclusions: The negative impact of chemotherapy on quality-of-life is clinically and statistically significant at 6 months but resolves by 18 months, which is crucial to inform decision-making for older patients contemplating chemotherapy., Trial Registration Number Isrctn: 46099296., Competing Interests: Conflict of interest statement The authors declare no conflict of interest. Professors Stephen Walters and Thompson Robinson are National Institute for Health Research (NIHR) Senior Investigators; Jenna Morgan is a NIHR Clinical Lecturer; and Kate Lifford is funded by the NIHR as part of this project. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET., Methods: Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET., Findings: A total of 3416 women (median age 77, range 69-102) were recruited from 56 breast units-2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23-0.33, P < 0.001). Unmatched breast cancer-specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29-0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53-0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40-1.37, P = 0.34) although at 4-5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance., Interpretation: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4-5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/)., Trial Registration Number: ISRCTN: 46099296., Competing Interests: Conflict of interest statement None declared., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67 2W ) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67 B ). The POETIC trial aimed to test these two hypotheses., Methods: POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing., Findings: Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67 B and Ki67 2W (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67 B and low Ki67 2W (high-low) and 21·5% (17·1-27·0) with high Ki67 B and Ki67 2W (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported., Interpretation: POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67 B or low POAI-induced Ki67 2W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki67 2W remains high might benefit from further adjuvant treatment or trials of new therapies., Funding: Cancer Research UK., (Copyright © 2020 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: Breast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin. Rivaroxaban (Xarelto®, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients., Methods: This UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-naïve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18-36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy. The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation., Discussion: Laboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer., Trial Registration: UK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT 2014-004909-33 , registered 27 July 2015. ISRCTN14785273 .

Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation., Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER + invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring., Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. ( n = 17) produced significant decreases from baseline versus placebo ( n = 11) in pGSK3β (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. ( n = 5) and 240 mg b.i.d. ( n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident., Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers., (©2019 American Association for Cancer Research.)

Background: Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance., Methods: Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (control n = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67., Results: High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2- tumours. In HER2- tumours, baseline expression of 48 genes associated with poor antiproliferative response (p < 0.005) including PERP and YWHAQ, the two most significant, and the transcription co-regulators (SAP130, HDAC4, and NCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, and IGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2- and HER2+ patients., Conclusions: There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors., Trial Registration: ISRCTN, ISRCTN63882543, registered on 18 December 2007.

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy., Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July-December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored., Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays., Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients.

Purpose: CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy., Patients and Methods: Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the  MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase., Results: Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v -0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia., Conclusion: Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

Introduction: Immediate breast reconstruction (IBR) is routinely offered to improve quality of life for women with breast cancer requiring a mastectomy, but there are concerns that more complex surgery may delay the delivery of adjuvant oncological treatments and compromise long-term oncological outcomes. High-quality evidence, however, is lacking. iBRA-2 is a national prospective multicentre cohort study that aims to investigate the effect of IBR on the delivery of adjuvant therapy., Methods and Analysis: Breast and plastic surgery centres in the UK performing mastectomy with or without (±) IBR will be invited to participate in the study through the trainee research collaborative network. All women undergoing mastectomy ± IBR for breast cancer between 1 July and 31 December 2016 will be included. Patient demographics, operative, oncological and complication data will be collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR will be compared to determine the impact that IBR has on the time of delivery of adjuvant therapy. Prospective data on 3000 patients from ∼50 centres are anticipated., Ethics and Dissemination: Research ethics approval is not required for this study. This has been confirmed using the online Health Research Authority decision tool. This novel study will explore whether IBR impacts the time to delivery of adjuvant therapy. The study will provide valuable information to help patients and surgeons make more informed decisions about their surgical options. Dissemination of the study protocol will be via the Mammary Fold Academic and Research Collaborative (MFAC) and the Reconstructive Surgery Trials Network (RSTN), the Association of Breast Surgery (ABS) and the British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS). Participating units will have access to their own data and collective results will be presented at relevant surgical conferences and published in appropriate peer-reviewed journals., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Gene expression is widely used for the characterisation of breast cancers. Variability due to tissue heterogeneity or measurement error or systematic change due to peri-surgical procedures can affect measurements but is poorly documented. We studied the variability of global gene expression between core-cuts of primary ER+ breast cancers and the impact of delays to tissue stabilisation due to sample X-ray and of diagnostic core cutting., Methods: Twenty-six paired core-cuts were taken immediately after tumour excision and up to 90 minutes delay due to sample X-ray; 57 paired core-cuts were taken at diagnosis and 2 weeks later at surgical excision. Whole genome expression analysis was conducted on extracted RNA. Correlations and differences were assessed between the expression of individual genes, gene sets/signatures and intrinsic subtypes., Results: Twenty-three and 56 sample pairs, respectively, were suitable for analysis. The range of correlations for both sample sets were similar with the majority being >0.97 in both. Correlations between pairs for 18 commonly studied genes were also similar between the studies and mainly with Pearson correlation coefficients >0.6 except for a small number of genes, which had a narrow-dynamic range (e.g. MKI67, SNAI2). There was no systematic difference in intrinsic subtyping between the first and second sample of either set but there was c.15 % discordance between the subtype assignments between the pairs, mainly where the subtyping of individual samples was less certain. Increases in the expression of several stress/early-response genes (e.g. FOS, FOSB, JUN) were found in both studies and confirmed findings in earlier smaller studies. Increased expression of IL6, IGFBP2 and MYC (by 17 %, 14 % and 44 %, respectively) occurred between the samples taken 2 weeks apart and again confirmed findings from an earlier study., Conclusions: There is generally good correlation in gene expression between pairs of core-cuts except where genes have a narrow dynamic range. Similar correlation coefficients to the average gene expression profiles of intrinsic subtype, particularly LumA and LumB, can lead to discordances between assigned subtypes. Substantial changes in expression of early-response genes occur within an hour after surgery and in IL6, IGFB2 and MYC as a result of diagnostic core-cut biopsy., Trial Registration: Trial number CRUK/07/015 . Study start date September 2008.

Background: Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS., Methods: In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358., Results: Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6-8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64-1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58-1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen., Conclusions: No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences., Funding: Cancer Research UK, National Health and Medical Research Council Australia, Breast Cancer Research Fund, AstraZeneca, Sanofi Aventis., (Copyright © 2016 Forbes et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Objective: Emotional distress after a diagnosis of cancer is normal and, for most people, will diminish over time. However, a significant minority of patients with cancer experience persistent or recurrent symptoms of emotional distress for which they need help. A model developed in mental health, the self-regulatory executive function model (S-REF), specifies that maladaptive metacognitive beliefs and processes, including persistent worry, are key to understanding why such emotional problems persist. This cross-sectional study explored, for the first, time whether metacognitive beliefs were associated with emotional distress in a cancer population, and whether this relationship was mediated by worry, as predicted by the S-REF model., Method: Two hundred twenty-nine participants within 3 months of diagnosis of, and before treatment for, primary breast or prostate cancer completed self-report questionnaires measuring anxiety, depression, posttraumatic stress disorder (PTSD) symptoms, metacognitive beliefs, worry, and illness perceptions., Results: Regression analysis showed that metacognitive beliefs were associated with symptoms of anxiety, depression, and PTSD, and explained additional variance in these outcomes after controlling for age, gender, and illness perceptions. Structural equation modeling was consistent with cross-sectional hypotheses derived from the theory that metacognitive beliefs cause and maintain distress both directly and indirectly by driving worry., Conclusions: The findings provide promising first evidence that the S-REF model may be usefully applied in cancer. Further study is required to establish the predictive and clinical utility of these findings., (PsycINFO Database Record (c) 2015 APA, all rights reserved.)

Objective: Recent research recognises that many individuals experience positive psychological changes following a diagnosis of cancer. Such positive change is related to well-being, and some psychological interventions have promoted such change in women with breast cancer. However, neither qualitative nor quantitative studies have adequately explained the process of this change., Method: This grounded theory study explored the process whereby positive emotional changes arose in 20 women (mean age 53 years) diagnosed with breast cancer., Results: Most women experienced several positive changes as a result of their breast cancer. Analyses suggested that changed priorities in life and increased empathy for others emerged from the patients' reflections upon the suffering they endured during their illness. By contrast, increased self-confidence appeared to emerge from reflecting on how they managed their illness, and from concluding that they had been courageous in doing so. Factors promoting reflections included acceptance of breast cancer, ending treatments, and communication from others that emphasised rather than minimised the personal significance of cancer., Conclusions: Findings extend current trauma-processing theories and can inform the timing and design of clinical interventions to improve adjustment to breast cancer., (2010 John Wiley & Sons, Ltd.)

Objective: The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant-a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects-administered as a prolonged-release IM formulation., Methods: Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1-T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables., Results: A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma concentrations at 28 days were 2- to 5-fold lower than the maximum value. Plasma concentration data for the 250-mg dose were best described by a 2-compartment pharmacokinetic model, with an apparent terminal phase half-life of approximately 49 days, beginning approximately 3 weeks after administration. Mean area under the plasma concentration-time curve for days 0 through 28 (AUC 0-28) was proportional for fulvestrant 50, 125, and 250 mg. For a doubling of the dose, an analysis of covariance model of the pharmacokinetic data projected an estimated increase in AUC 0-28 of a factor of 1.84 (95% CI, 1.67 to 2.04)., Conclusions: The IM formulation of fulvestrant used in this study had predictable, dose-linear pharmacokinetics. The prolonged-release properties of this formulation suggested that it may be well suited for the once-monthly dosing schedule intended for clinical use.