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Anthracyclines are associated with enhanced oxidative stress responsible for adverse events in patients with breast cancer. However, no study has investigated the potential anti-inflammatory role of statins in counteracting anthracycline toxicity. In this retrospective study utilizing a federated health network (TriNetX), patients with breast cancer (ICD code C50) treated with anthracyclines were categorized into two groups: statin users (for at least 6 months); and statin non-users. The primary outcome was the 5-year risk of all-cause death. Secondary outcomes were the risk of myocardial infarction, stroke, atrial fibrillation, ventricular arrhythmias, heart failure, and pulmonary embolism. Cox-regression analyses were used to produce hazard ratios (HRs) and 95% confidence intervals (CI) following 1:1 propensity score matching (PSM). We identified 3,701 statin users (68.8 ± 10.4 years) and 37,185 statin non-users (59.6 ± 12.8 years). After PSM, the 5-year risk of all-cause death was significantly lower in statin users (HR 0.82, 95% CI 0.74-0.91) compared to statins non-users. Analyzing the risk for secondary outcomes, only the risk of stroke was significantly increased in statin users (HR 1.27, 95% CI 1.01-1.61), while no associations were found for the other cardiovascular events. The risk of all-cause death in statin users was the lowest during the first year after the anthracycline's initiation. No significant difference was found between lipophilic and hydrophilic statins. In patients with breast cancer treated with anthracyclines, statin use is associated with a reduced risk of all-cause death. Prospective studies are needed to investigate the potential beneficial effect of statin initiation in cancer patients without other indications., (© 2024. The Author(s).)

Purpose: Genomic alterations have been identified in patients with breast cancer brain metastases (BCBMs), but large structural rearrangements have not been extensively studied., Materials and Methods: We analyzed the genomic profiles of 822 BCBMs and compared them with 11,988 local, breast-biopsied breast cancers (BCs) and 15,516 non-CNS metastases (Non-CNS M) derived from formalin-fixed paraffin-embedded material using targeted capture sequencing., Results: Nine genes with structural rearrangements were more prevalent within BCBMs as compared with local BCs and Non-CNS M (adjusted- P < .05) and displayed a prevalence of >0.5%. The most common rearrangements within BCBMs involves cyclin-dependent kinase 12 ( CDK12 ; 3.53%) as compared with the local BC (0.86%; adjusted- P = 7.1 × 10 -8 ) and Non-CNS M specimens (0.68%; adjusted- P = 3.7 × 10 -10 ). CDK12 rearrangements had a significantly higher frequency within human epidermal growth factor receptor 2 (HER2)-positive BCBMs (14.59%) compared with HER2-positive BCs (7.80%; P = 4.6 × 10 -3 ) and HER2-positive Non-CNS M (7.87%; P = 4.8 × 10 -3 )., Conclusion: The most common structural rearrangements involve CDK12 with the higher prevalence in HER2-positive BCBMs. These data support more detailed investigation of the role and importance of CDK12 rearrangements in BCBMs.

Purpose: Digistain Index (DI), measured using an inexpensive mid-infrared spectrometer, reflects the level of aneuploidy in unstained tissue sections and correlates with tumor grade. We investigated whether incorporating DI with other clinicopathological variables could predict outcomes in patients with early breast cancer., Methods: DI was calculated in 801 patients with hormone receptor-positive, HER2-negative primary breast cancer and ≤ 3 positive lymph nodes. All patients were treated with systemic endocrine therapy and no chemotherapy. Multivariable proportional hazards modeling was used to incorporate DI with clinicopathological variables to generate the Digistain Prognostic Score (DPS). DPS was assessed for prediction of 5- and 10-year outcomes (recurrence, recurrence-free survival [RFS] and overall survival [OS]) using receiver operating characteristics and Cox proportional hazards regression models. Kaplan-Meier analysis evaluated the ability of DPS to stratify risk., Results: DPS was consistently highly accurate and had negative predictive values for all three outcomes, ranging from 0.96 to 0.99 at 5 years and 0.84 to 0.95 at 10 years. DPS demonstrated statistically significant prognostic ability with significant hazard ratios (95% CI) for low- versus high-risk classification for RFS, recurrence and OS (1.80 [CI 1.31-2.48], 1.83 [1.32-2.52] and 1.77 [1.28-2.43], respectively; all P < 0.001)., Conclusion: DPS showed high accuracy and predictive performance, was able to stratify patients into low or high-risk, and considering its cost and rapidity, has the potential to offer clinical utility., (© 2024. The Author(s).)

Background: The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control)., Methods and Analysis: This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy., Trial Registration: The study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022., Competing Interests: Matthew Northgraves, Chao Huang and Marta Soares have nothing to declare. Judith Cohen reports a grant from commercial funder Exact Sciences for the conduct of the study. Henry Cain reports a grant for the conduct of this study as well as, honoraria for presentations/educational events, and consulting fees from Exact Sciences. James Harvey reports a consultancy fee from Genomic Health. Carlo Palmieri reports consulting fees from Exact Sciences along with AstraZeneca, Daiichi Sankyo, Eli Lilly, Eisai, Gilead, Medac, MSD, Novartis, Pfizer, Roche, Seagen; grants from Daiichi Sankyo, Gilead, Pfizer, Seagen; honoraria for presentations/educational events from Pfizer, AZ, Seagen; receipt of equipment from Pfizer, Seagen; travel and meeting support from Gilead, Roche, Novartis and a role with the NCRI. Sarah Pinder reports honoraria for presentations/educational events, travel support and participation on advisory boards and workshops for Exact Sciences. Pankaj .G. Roy reports personal fees from Exact Sciences, outside the submitted work. Sarah Reynia reports employment from, and stock in Exact Sciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Northgraves 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.)

Background: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease., Methods: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032)., Findings: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug., Interpretation: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer., Funding: GTx., Competing Interests: Declaration of interests CP reports grants or contracts from Seagen, Daiichi-Sankyo, Pfizer, and Exact Science (outside of this work); consulting for Seagen, Daiichi-Sankyo, Exact Science, MEDAC, Gilead, and Pfizer; honoraria from Pfizer, Seagen, AstraZeneca, Roche, Eisai, and Novartis; travel support from Roche and Novartis; leadership role in Advise Make 2nd Count (unpaid); and stock in Digistain. HL reports grants or contracts from Sanofi, Zionexa, Tolmar, Pfizer, Zeno Pharmaceutical, Zymeworks, and Veru (outside of this work); consulting for Sanofi, GE Healthcare, Lilly, Novartis, and Gilead; and honoraria from Sanofi, GE Healthcare, Lilly, Novartis, and Gilead. EL reports research funding from Pfizer and Ellipses Pharma (outside of this work); honoraria for Ellipses Pharma, Pfizer, AstraZeneca, Gilead, MSD, and Lilly; patents planned, issued, or pending with Walter & Eliza Hall Institute; advisory board with Ellipses Pharma, Novartis, Pfizer, AstraZeneca, Gilead, MSD, Lilly (all paid to institution); and leadership in Breast Cancer Trials Australia, American Society of Clinical Oncology Research Committee. TEH reports grant funding from Australian National Health and Medical Research Council and National Breast Cancer Foundation (Australia). ARD reports grant funding from Australian National Health and Medical Research Council and National Breast Cancer Foundation (Australia); research support from Ellipses Pharma (outside of this work); and travel support from Fusion Conferences. HSR reports grants from Astellas Pharma, AstraZeneca, Daiichi Sankyo, F. Hoffmann-La Roche AG/Genentech, Gilead Sciences, GlaxoSmithKline, Lilly, Merck, Novartis Pharmaceutical Corporation, Pfizer, Fionyr Immunotherapeutics, Sermonix Pharmaceuticals, Taiho Oncology, and Veru; and honoraria from Daiichi Sankyo, Mylan, NAPO, and Puma Biotechnology. PC reports research support from GTx. JAO reports consulting for AbbVie, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol-Myers Squibb, Carrick Therapeutics, GlaxoSmithKline, Genentech, Genzyme, Gilead Sciences, Immunomedics, Incyte Corporation, Lilly, Merck, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Stemline Therapeutics, Theralink, Synthon and Veru; and honoraria from AbbVie, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol-Myers Squibb, Carrick Therapeutics, GlaxoSmithKline, Genentech, Genzyme, Gilead Sciences, Immunomedics, Incyte Corporation, Lilly, Merck, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Stemline Therapeutics, Theralink, Synthon and Veru. SJ reports research funding from Pfizer, Puma Biotechnology, Lilly, AstraZeneca, Novartis, Roche/Genentech (outside of this work); consulting or advisory role for Lilly, AstraZeneca, Puma Biotechnology, Pfizer, Novartis, and Sanofi Genzyme; and honoraria from Pfizer, Eisai, AstraZeneca, and Roche/Genentech. WDT reports grant funding from Australian National Health and Medical Research Council; research support from Ellipses Pharma (outside of this work); and consulting for HavaH. AB reports consulting for AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, SeaGen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma Biotechnology, Myriad, and Gilead. BO reports funding from GTx; research support from Eisai and Incyte (outside of this work); and Chief Medical Advisory role for the Milburn Foundation (unpaid)., (Copyright © 2024 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: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients., Methods: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents., Results: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1., Conclusions: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ERC: Consultant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Sanofi; Speaker fees: Novartis; Research grant: AstraZeneca; Educational grant: Daiichi Sankyo; Provision of research equipment: seca; Congress support: Novartis, Roche. JEA: Research grant: AstraZeneca; Speaker fees: Eisai, Pfizer. JPB: Nothing to disclose. DC: Consultant: AstraZeneca, Exact Sciences, Lilly, Novartis, Roche; Research funding: Exact Sciences, Novartis, Roche. SAMcI: Consultant: Lilly, MSD, Roche; Fees for non-CME services: BD; Congress support: Lilly, Roche; Research funding: Novartis. COM: Nothing to disclose. AFCO: Research funding: Pfizer, Roche; Consultant: AstraZeneca, Pfizer, Roche, Seagen; Speaker fees: AstraZeneca, Gilead, Lilly, Pfizer, Seagen; Congress support: AstraZeneca; Lilly. CP: Consultant: AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Exact Sciences, Gilead, Lilly, Novartis, Pfizer, Seagen; Research funding: Daiichi Sankyo, Exact Sciences, Pfizer, Seagen; Congress support: Gilead, Roche. FR: Consultant: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche; Congress support: AstraZeneca, MSD, Novartis, Roche. RR: Consultant: AstraZeneca, Daiichi Sankyo, G1 Therapeutics, IQVIA, Lilly, Pfizer; Congress support: BMS, Daiichi Sankyo, Roche; Grants to institution: NIHR. SS: Consultant: Lilly, Pfizer., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd., Patients and Methods: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded., Results: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred., Conclusion: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration., Competing Interests: Disclosure CP reports grant funding support: Pfizer, Daiichi Sankyo, Exact Sciences, Gilead and Seagen. Honoraria for advisory boards: Pfizer, Roche, Daiichi Sankyo, Novartis, Exact Sciences, Gilead, SeaGen and Eli Lilly. Support for travel and conferences: Roche, Novartis and Gilead. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The development of therapies that can suppress invasion and prevent metastasis, 'anti-metastatic drugs', is an important area of unmet therapeutic need. The new results of a recent open-label, multicentre randomised trial published in J Clin Oncol showed a significant disease-free survival (DFS) benefit for breast cancer patients receiving presurgical, peritumoral injection of lidocaine, an amide local anaesthetic, which blocks voltage-gated sodium channels (VGSCs). VGSCs are expressed on electrically excitable cells, including neurons and cardiomyocytes, where they sustain rapid membrane depolarisation during action potential firing. As a result of this key biophysical function, VGSCs are important drug targets for excitability-related disorders, including epilepsy, neuropathic pain, affective disorders and cardiac arrhythmia. A growing body of preclinical evidence highlights VGSCs as key protagonists in regulating altered sodium influx in breast cancer cells, thus driving invasion and metastasis. Furthermore, prescription of certain VGSC-inhibiting medications has been associated with reduced cancer incidence and improved survival in several observational studies. Thus, VGSC-inhibiting drugs already in clinical use may be ideal candidates for repurposing as possible anti-metastatic therapies. While these results are promising, further work is required to establish whether other VGSC inhibitors may afford superior metastasis suppression. Finally, increasing preclinical evidence suggests that several other ion channels are also key drivers of cancer hallmarks; thus, there are undoubtedly further opportunities to harness ion transport inhibition that should also be explored., (© 2023. The Author(s).)

Background: The Ibrance® Patient Program was established to provide access to palbociclib for UK National Health Service (NHS) patients with metastatic breast cancer (MBC), pending a funding decision., Methods: Non-interventional cohort study involving a retrospective medical record review of patients commenced on palbociclib between April and December 2017 at eight UK centres. Primary outcomes included clinicopathological characteristics, treatment patterns, clinical outcomes and selected adverse events., Results: Overall, 191 patients were identified, median age of 57.0 years (range 24.3-90.9); 30% were diagnosed with de novo MBC; 72% received first-line and 10% as ≥ second-line treatment. Median progression-free survival (95% CI) was 22.8 months (16.5-not reached [NR]) in first-line; NR in patients with de novo MBC; 7.8 months (6.8-NR) in ≥ second-line (median follow-up: 24 months). Median overall survival (OS) was NR in the overall cohort; OS rate (95% CI) at 24 months was 74.2% (67.1-81.9%) in first-line; 82.1% (72.6-92.8%) in patients with de novo MBC; 55.0% (37.0-81.8%) in ≥ second-line. Forty-seven per cent of patients developed grade 3-4 neutropenia; 3% febrile neutropenia., Conclusion: This study supports the effectiveness of palbociclib and demonstrates the benefit to patients of early access schemes that bridge the gap between regulatory approval and NHS funding for new medicines., Clinical Trial Registration: Clinical trial: ClinicalTrial.gov:NCT03921866., (© 2023. The Author(s).)

Purpose: To determine the experiences, information, support needs and quality of life of women in the UK living with metastatic breast cancer (MBC) to provide content for educational materials., Methods: An online survey, hosted for 3 months on a UK MBC charity website, comprised sections covering issues such as communication about MBC treatment and management, helpful and less helpful things that healthcare professionals, family and friends did or said and completion of the Patient Roles and Responsibilities Scale (PRRS)., Results: A total of 143 patients participated; 48/143(33%) presented de novo; 54/143(38%) had been living with MBC > 2 years. PRRS analysis revealed that MBC imposed a serious impact upon most respondents' own caring abilities and social lives. A majority 98/139 (71%) wished they had known more about MBC before their diagnosis; 63/134(47%) indicated that they still did not fully understand their illness; merely 78/139(56%) had access to a specialist nurse and only 69/135(51%) had been offered any additional support. Respondents reported little consideration given to their lifestyle/culture during consultations and inconsistent information, support services, continuity of care or access to clinical trials. They commented upon things health care professionals/friends and family did or said that were useful and cited other behaviours that were especially unhelpful., Conclusions: MBC exerted a deleterious impact upon patients' activities of daily living which were exacerbated in part by significant gaps in support, communication and information., Implications for Cancer Survivors: LIMBER results are informing the content of educational materials currently being developed for patients' formal and informal carers., (© 2023. The Author(s).)

Background: Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined., Materials and Methods: The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString™, nCounter™ Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined., Results: There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate <0.01, log2 fold-change >1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P < 0.01) compared to estrogen receptor-positive BCBMs. ARG2 was one of four genes up-regulated in BCBMs. High ARG2 mRNA expression in primary BCs was associated with worse distant metastasis-free survival (P = 0.038), while ARG2 protein expression was associated with worse breast-brain metastasis-free (P = 0.027) and overall survival (P = 0.019). High transcript levels of ARG2 correlated to low levels of cytotoxic and T cells in both BC and BCBM (P < 0.01)., Conclusion: This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome., Competing Interests: Disclosures The authors have declared no conflicts of interest. Data sharing The data generated in this study are available within the article and its supplementary data files., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Breast cancer is the most commonly diagnosed female malignancy globally, with better survival rates if diagnosed early. Mammography is the gold standard in screening programmes for breast cancer, but despite technological advances, high error rates are still reported. Machine learning techniques, and in particular deep learning (DL), have been successfully used for breast cancer detection and classification. However, the added complexity that makes DL models so successful reduces their ability to explain which features are relevant to the model, or whether the model is biased. The main aim of this study is to propose a novel visualisation to help characterise breast cancer patients using Fisher Information Networks on features extracted from mammograms using a DL model. In the proposed visualisation, patients are mapped out according to their similarities and can be used to study new patients as a 'patient-like-me' approach. When applied to the CBIS-DDSM dataset, it was shown that it is a competitive methodology that can (i) facilitate the analysis and decision-making process in breast cancer diagnosis with the assistance of the FIN visualisations and 'patient-like-me' analysis, and (ii) help improve diagnostic accuracy and reduce overdiagnosis by identifying the most likely diagnosis based on clinical similarities with neighbouring patients., (© 2022. The Author(s).)

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre., Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded., Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%)., Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate., Competing Interests: CP received grant from Pfizer and Daiichi Sankyo and honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, SeaGen, and Eli Lilly., (Copyright © 2022 Benjamin James Hall et al.)

Background: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally., Patients and Methods: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site., Results: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific., Conclusions: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area., Competing Interests: Disclosure ER reports consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, and Pfizer; research funding from Novartis, Demo Pharmaceutical, Celldex, Radius Health, Tesaro, Parexel, and AnaBIOsis Pharmaceuticals; travel funding from Sanofi, Ipsen, Genesis Pharmaceuticals, LEO Pharma, Merck, Roche, and GENEKOR. CP reports grant funding from Pfizer and Daiichi Sankyo; honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, Seagen, and Eli Lilly. VM reports honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Seagen, Novartis, Roche, Teva, Janssen-Cilag, and Gilead; playing an advisory role for Hexal, Roche, Pfizer, Amgen, Daiichi-Sankyo, Nektar, Seagen, Gilead, and Eisai; research funding from Roche, Novartis, Seagen, Pfizer, and Genentech. RB reports advisory role for Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, and Seagen; lecture honoraria from Astra-Zeneca, Daiichi, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, and Seagen; research support from Daiichi, MSD, Novartis, and Roche. GR reports research funding (institution) from AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, Servier, Biovica, GlaxoSmithKline, and Sanofi/Aventis; and patents, royalties, other intellectual property from Agendia for MammaPrint due to the collaboration on the conduct of the MINDACT trial (Institution). SPG reports honoraria from Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; advisory/consultancy roles with Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; research grant from Roche; travel/accommodation/expenses from Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, and Daiichi Sankyo. HCK reports honoraria and travel support from AstraZeneca, Pfizer, Roche, Daiichi Sankyo, Tesaro, MSD, Onkowissen, Eli Lilly, SurgVision, Exact Sciences, and Genomic Health; and Stock ownership from Theraclion and Phaon scientific. NZ is on the advisory board for Lilly, Eisai, and AstraZeneca; reports receiving honorarium from Roche, Pfizer, Eisai, and Amgen; research funding (institutional) from Pfizer, Roche, and GSK; education funding from Roche, Novartis, and Amgen (none considered relevant to the current work). MP is on the advisory boards, and has participated in educational programs and conferences for Pfizer, BMS, Novartis, Astellas, Janssen, MD Serono, Merck, Amgen, and Sanofi; reports research funding (institutional) from Astellas, Novartis, Roche, Merck, BMS, Sanofi, and AstraZeneca. RMC has received (to institution) an unrestricted educational grant from Pfizer; and research funds from MSD Ireland and Pfizer. HT reports employment or management position with Partner and Medical Director Oncology Practice at Bethanien Hospital, Frankfurt; honoraria from Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science; consulting activities for Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science. AM reports advisory/consultant role, honoraria, and research grant from Lilly and Roche; advisory/consultant role for Novartis, Merck, Seagen, and Daiichi-Sankyo. LDM reports grants from Eli Lilly during the conduct of the study; personal fees from Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Seagen, Ipsen, and Gilead; personal fees and nonfinancial support from Roche, Pfizer, and Eisai, outside the submitted work. CC reports honoraria from Amgen, AstraZeneca, BMS, Genesis, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche. SO reports lecture fees, honoraria, or other fees paid by a single company or for-profit organization for the time or labor of a researcher engaged for conference attendance from Chugai, Lilly, AstraZeneca, and Pfizer. IM reports performing consultancy roles for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer, and Roche; travel/conference registration activities for Eli Lilly, Daiichi Sankyo, Gilead, and Novartis. ME serves on the advisory boards of Pfizer and Novartis; lecturing for Astra Zeneca (institution), but has no conflicts of interest related to this publication. KZ serves on the advisory board or performs talk for AstraZeneca, Daiichi, Exact Sciences, Lilly, Pierre Fabre, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Viatris/Mylan; unrestricted funding for organization of academic symposium from Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead, Novartis, Pfizer, Roche, Seagen, Viatris/Mylan, and Vifor; support for participation in international congress from AstraZeneca, Daiichi, Pierre Fabre, and Roche; is a member of steering committee of Eleanor study (Pierre Fabre); and research funding from Roche. MV reports honoraria from Roche, Novartis, Pfizer, and Daiichi; consulting or advisory role for Novartis and Roche; travel funds from Roche and Pfizer. DF’s institution receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi, and Pfizer for the conduct of clinical trials outside the submitted work. MG-G reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, and Pierre Fabre; travel/attending meetings for Pfizer, Roche, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo and AstraZeneca. BL reports consulting or advisory role for AstraZeneca, Pfizer, Merck, Eli Lilly, Pierre Fabre, and Daiichi Sankyo. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: The introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However, HER2 positive breast cancer has a predilection for the central nervous system (CNS) which is associated with significant morbidity and mortality. Understanding the intracranial activity of novel HER2 directed agents is key to developing treatments as well as possible preventative strategies for HER2-positive CNS disease., Observations: Using protocols and data from published phase III clinical trials for locally advanced/metastatic HER2-positive breast cancer since the licensing of single agent trastuzumab for advanced BC we review the central nervous system related aspects. This includes CNS related entry criteria, use of baseline and on study cross-sectional imaging of the CNS and protocol and non-protocol defined CNS end points and reported data., Conclusions: and Relevance: This review found heterogeneity between studies with regard to the entry criteria, use of CNS imaging and reported end points within the pivotal phase III studies. Based on these data, a standardisation of both entry criteria and end points with regard to the CNS should be developed and applied to future studies of HER2-positive advanced BC. Such an approach would enable the generation of comparable data and allow a meaningful analysis of different treatment approaches with regard to the CNS. This in turn would allow the development of the most optimal treatment approaches for HER2 positive CNS disease and ultimately the development of preventative strategies., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Estrogen receptor-positive breast cancer patients have a good prognosis, but 30% of these patients will experience recurrence due to the development of resistance through various signaling pathways. This study aimed to evaluate the mode of anticancer effects of 1'-acetoxychavicol acetate, which is isolated from the rhizomes of Alpinia galanga in estrogen receptor positive (MCF7) human epidermal growth factor receptor 2-overexpressed (MCF7/HER2), and endocrine-resistant breast cancer cells (MCF7/LCC2 and MCF7/LCC9). 1'-Acetoxychavicol acetate showed antiproliferation in a concentration- and time-dependent fashion and had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines. This was associated with down-regulation of human epidermal growth factor receptor 2, pERK1/2, pAKT, estrogen receptor coactivator, cyclin D1, and MYC proto-oncogene while in vivo and significant reduction in the tumor mass of 1'-acetoxychavicol acetate-treated zebrafish-engrafted breast cancer groups. The anti-invasive effects of 1'-acetoxychavicol acetate were confirmed in vitro by the matrigel invasion assay and with down-regulation of C - X-C chemokine receptor type 4, urokinase plasminogen activator, vascular endothelial growth factor, and basic fibroblast growth factor 2 genes. The down-regulation of urokinase plasminogen activator and fibroblast growth factor 2 proteins was also validated by molecular docking analysis. Moreover, 1'-acetoxychavicol acetate-treated cells exhibited lower expression levels of the anti-apoptotic Bcl-2 and Mcl-1 proteins in addition to enhanced stress-activated kinases/c-Jun N-terminal kinase 1/2 and poly-ADP ribose polymerase cleavage, indicating apoptotic cell induction by 1'-acetoxychavicol acetate. Moreover, 1'-acetoxychavicol acetate had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines regarding its inhibition on human epidermal growth factor receptor 2, pAKT, pERK1/2, PSer 118 , and PSer 167 -ER α proteins. Our findings suggest 1'-acetoxychavicol acetate mediates its anti-cancer effects via human epidermal growth factor receptor 2 signaling pathway., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer., Materials and Methods: Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform., Results: One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1 , TP53 , and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations., Conclusion: We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1 , TP53 , and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs., Competing Interests: Daniel Fernandez-Garcia Employment: Almirall (I) Stock and Other Ownership Interests: Exonate Ltd (I) Travel, Accommodations, Expenses: Almirall (I) Carlo Palmieri Honoraria: Pfizer Consulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle Genetics Research Funding: Pfizer, Daiichi-Sankyo Travel, Accommodations, Expenses: Roche Simak Ali Stock and Other Ownership Interests: Carrick Therapeutics Research Funding: Carrick Therapeutics, AstraZeneca Patents, Royalties, Other Intellectual Property: Royalty from Carrick Therapeutics Uncompensated Relationships: Carrick Therapeutics Justin Stebbing Leadership: BB Healthcare Trust, Xerion Healthcare, Springer Nature Consulting or Advisory Role: Vaccitech, Celltrion, TLC Biopharmaceuticals, Vor Biopharma, Lansdowne, Vitruvian, Singapore Biotech, Benevolent AI R. Charles Coombes Research Funding: DNAe, Pfizer, AstraZeneca Patents, Royalties, Other Intellectual Property: I have shares in Carrick ltd and I am also a patent holder in the drug CT7001 that Imperial College has licensed to them No other potential conflicts of interest were reported. Daniel Fernandez-Garcia Employment: Almirall (I) Stock and Other Ownership Interests: Exonate Ltd (I) Travel, Accommodations, Expenses: Almirall (I) Carlo Palmieri Honoraria: Pfizer Consulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle Genetics Research Funding: Pfizer, Daiichi-Sankyo Travel, Accommodations, Expenses: Roche Simak Ali Stock and Other Ownership Interests: Carrick Therapeutics Research Funding: Carrick Therapeutics, AstraZeneca Patents, Royalties, Other Intellectual Property: Royalty from Carrick Therapeutics Uncompensated Relationships: Carrick Therapeutics Justin Stebbing Leadership: BB Healthcare Trust, Xerion Healthcare, Springer Nature Consulting or Advisory Role: Vaccitech, Celltrion, TLC Biopharmaceuticals, Vor Biopharma, Lansdowne, Vitruvian, Singapore Biotech, Benevolent AI R. Charles Coombes Research Funding: DNAe, Pfizer, AstraZeneca Patents, Royalties, Other Intellectual Property: I have shares in Carrick ltd and I am also a patent holder in the drug CT7001 that Imperial College has licensed to them No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Brain metastases (BM) are an increasing clinical problem. This study aimed to assess paired primary breast cancers (BC) and BM for aberrations within TP53, PIK3CA, ESR1, ERBB2 and AKT utilising the MassARRAY® UltraSEEK® technology (Agena Bioscience, San Diego, USA)., Methods: DNA isolated from 32 paired primary BCs and BMs was screened using the custom UltraSEEK® Breast Cancer Panel. Data acquisition and analysis was performed by the Agena Bioscience Typer software v4.0.26.74., Results: Mutations were identified in 91% primary BCs and 88% BM cases. TP53, AKT1, ESR1, PIK3CA and ERBB2 genes were mutated in 68.8%, 37.5%, 31.3%, 28.1% and 3.1% respectively of primary BCs and in 59.4%, 37.5%, 28.1%, 28.1% and 3.1% respectively of BMs. Differences in the mutations within the 5 genes between BC and paired BM were identified in 62.5% of paired cases. In primary BCs, ER-positive/HER2-negative cases harboured the most mutations (70%), followed by ER-positive/HER2-positive (15%) and triple-negatives (13.4%), whereas in BMs, the highest number of mutations was observed in triple-negative (52.5%), followed by ER-positive/HER2-negative (35.6%) and ER-negative/HER2-positive (12%). There was a significant association between the number of mutations in the primary BC and breast-to-brain metastasis-free survival (p = 0.0001) but not with overall survival (p = 0.056)., Conclusion: These data demonstrate the discordancy between primary BC and BM, as well as the presence of clinically important, actionable mutations in BCBM. The UltraSEEK® Breast Cancer Panel provides a tool for BCBM that can be utilised to direct more tailored treatment decisions and for clinical studies investigating targeted agents., (© 2021. The Author(s).)

Importance: Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking., Objective: To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)-negative primary breast cancer., Design, Setting, and Participants: The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020., Interventions: Patients received celecoxib, 400 mg, or placebo once daily for 2 years., Main Outcomes and Measures: The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete., Results: A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients' tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rank P = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference., Conclusions and Relevance: In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years' treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility., Trial Registration: ClinicalTrials.gov Identifier: NCT02429427 and isrctn.org Identifier: ISRCTN48254013.

Background: The recommended starting dose of eribulin in patients with hepatic impairment is based on the Child-Pugh score, largely informed by a pharmacokinetic study of 18 patients. In the pivotal studies of eribulin in metastatic breast cancer (Study 301 and Study 305 [EMBRACE]), entry criteria and dose modifications were based on liver-function test (LFT) results rather than Child-Pugh score. In populations such as patients with metastatic breast cancer, in which metastatic infiltration is the predominant cause of hepatic impairment, using Child-Pugh score may be problematic; in clinical practice, it has been more common for oncologists to make dosing decisions based on LFTs. To address this, the effects of abnormal baseline LFT results on eribulin efficacy and safety were investigated., Methods: In this pooled post hoc analysis, 1062 patients who were randomized to receive eribulin in Studies 301 and 305 were divided into 4 groups: (A) no elevated LFT results (no liver impairment); (B) increased levels of aspartate aminotransferase and/or alanine aminotransferase; (C) decreased albumin and/or increased levels of aspartate aminotransferase and/or alanine aminotransferase but not increased bilirubin; and (D) increased bilirubin. Patients were subcategorized by presence of liver metastasis. Drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs) were analyzed., Results: Eribulin mesylate mean dosage was 0.82 (group A)-0.65 mg/m 2 /week (group D). Group D had shorter treatment, more dose reductions/delays, more TEAEs leading to dose modifications, and numerically lower objective response rates and clinical benefit rates versus groups A-C. TEAE rates leading to dose modification were similar between group D (45.5%) and groups A-C (range, 43.5-54.9%) in the absence of liver metastases, but higher in group D (91.3%) compared with groups A-C (range, 41.7-54.3%) if liver metastases were present., Conclusions: Mild elevations in bilirubin levels were associated with increased toxicity and a greater requirement for dose modifications. Based both on these study data and existing recommendations, we propose a novel scheme to guide initial dose selection in patients with metastatic breast cancer and hepatic impairment that is based on LFTs rather than Child-Pugh score.

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

People with metastatic breast cancer face many challenges and disparities in obtaining optimal cancer care. These challenges are accentuated in underserved patient populations across Europe, who are less likely to receive quality healthcare for reasons including socioeconomic inequalities, educational or cultural status, or geographic location. While there are many local and national initiatives targeted to address these challenges, there remains a need to reduce disparities and improve access to healthcare to improve outcomes, with a focus on multidisciplinary stakeholder engagement. In October 2019, a range of experts in metastatic breast cancer, including healthcare professionals, patient representatives, policymakers and politicians, met to discuss and prioritize the critical needs of underserved patient populations with metastatic breast cancer in Europe. Six key challenges faced by these communities were identified: the need for amplification of the metastatic breast cancer patient voice, better and wider implementation of high-quality guidelines for metastatic breast cancer, more collaboration between stakeholders, tailored support for patients from different cultural and ethnic backgrounds, improved data sharing, and work-related issues. The Expert Panel then conceived and discussed potential actionable goals to address each key challenge. Their conclusions present a set of interrelated approaches to address the different challenges and could serve as the basis for concerted improvement of the lives of patients with metastatic breast cancer in Europe., Competing Interests: Declaration of competing interest Emilio Alba: None. Concepción Biurrún: None. Fatima Cardoso:. Consultancy role for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seattle Genetics, Teva. PierFranco Conte: Speaker (Novartis, Roche, AstraZeneca); Travel grant (Novartis, Celgene, Tesaro); Institutional research grant (Novartis, Merck KGa, Roche, Bristol Myers Squibb) Rosanna D’Antona: None. Jacques De Grève: None. Joseph Gligorov: None. Françoise Meunier: None. Carlo Palmieri: Advisory boards and funding for clinical studies (Pfizer). Oriol Sola-Morales: Dr. Sola-Morales has consulted for most of the multinational pharmaceutical companies, including all ‘top 10’. He has received fees and honoraria for such consultancies and is currently engaged in several projects with many of these companies. He holds ownership of several start-up companies in the healthcare field and has had in the past stock ownership of ‘Top 10’ pharmaceutical companies. Luzia Travado: None. Catherine Ubaysi: Compensation for representing Patients en réseau at events. Roberta Ventura: None. Eduard Vrdoljak: Support for clinical trials and scientific projects (Pfizer, Roche, Bristol Myers Squibb, AstraZeneca); Speaker fees and consulting (Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Novartis, PharmaSwiss, Pfizer, Roche, Sanofi, MSD, Merck). Andrew Walker: Pharmaceutical & biotechnology companies (Abbvie, Akcea, Albireo, Alexion, Allergan, Astellas, AstraZeneca, Autolus, Avexis, Biocrysta, Bristol Myers Squibb, Calico, Celgene, Chiesi, Daiichi-Sankyo, Deciphera, Eli Lilly, Ferring, Galapagos, GSK, GW Pharma, Intercept, Ipsen, Janssen, Jazz, Kite/Gilead, Les Laboratories Servier, Lundbeck, Merck Serono, Mundibiopharma, Mylan, Norgine, Novartis, NovoNordisk, Pfizer, Pierre Fabre, RegenXBio, Takeda, UCB, Vertex). Consultancy companies (Adeptfield, Atheneum Partners, Bresmed, CB Partners, Charles Rivers Associates, Creativ Ceutical, Datamonitor, de Facto Research, Dolon, DRG, Evidera, Executive Insight, Fiecon, Fingerpost Consulting, Galbraith Wight, Guidehouse, Health Advances, HiTT, Huron Consulting Group, Inbeeo, Informa/Data Monitor, IQVIA, M2Econ, Market Access Transformation, Miller Economics, Mirador, Mtech Access, Navigant, Open Access, Pagoda S&L Int. Services, Parexel, Partners 4 Access, Plich Advisory Services, Precision Xtract, PRMA, PWC, QualWorld, Remap, Research Partnership, RJW Partners, SAI Med Partners, Simon Kucher, Therapeutic Challenges, Two Labs, Valid Insight, Verto, Wellmera, Windrose, ZS Associates). Public sector: University of Aberdeen. Theresa Wiseman: None. Lieve Wierinck: None. Rachel Wuerstlein: Agendia, Amgen, Aristo, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Onkowissen, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro, Teva., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management., Methods: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item., Results: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT., Discussion: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.

Breast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Activating transcription factor-2 (ATF2), a member of the leucine zipper family of DNA binding proteins, has been implicated as a tumour suppressor in breast cancer. However, its exact role in breast cancer endocrine resistance is still unclear. We have previously shown that silencing of ATF2 leads to a loss in the growth-inhibitory effects of tamoxifen in the oestrogen receptor (ER)-positive, tamoxifen-sensitive MCF7 cell line and highlighted that this multi-faceted transcription factor is key to the effects of tamoxifen in an endocrine sensitive model. In this work, we explored further the in vitro role of ATF2 in defining the resistance to endocrine treatment., Materials and Methods: We knocked down ATF2 in TAMR, LCC2 and LCC9 tamoxifen-resistant breast cancer cell lines as well as the parental tamoxifen sensitive MCF7 cell line and investigated the effects on growth, colony formation and cell migration. We also performed a microarray gene expression profiling (Illumina Human HT12&#95;v4) to explore alterations in gene expression between MCF7 and TAMRs after ATF2 silencing and confirmed gene expression changes by quantitative RT-PCR., Results: By silencing ATF2, we observed a significant growth reduction of TAMR, LCC2 and LCC9 with no such effect observed with the parental MCF7 cells. ATF2 silencing was also associated with a significant inhibition of TAMR, LCC2 and LCC9 cell migration and colony formation. Interestingly, knockdown of ATF2 enhanced the levels of ER and ER-regulated genes, TFF1, GREB1, NCOA3 and PGR, in TAMR cells both at RNA and protein levels. Microarray gene expression identified a number of genes known to mediate tamoxifen resistance, to be differentially regulated by ATF2 in TAMR in relation to the parental MCF7 cells. Moreover, differential pathway analysis confirmed enhanced ER activity after ATF2 knockdown in TAMR cells., Conclusion: These data demonstrate that ATF2 silencing may overcome endocrine resistance and highlights further the dual role of this transcription factor that can mediate endocrine sensitivity and resistance by modulating ER expression and activity.

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 .

Background: A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects., Methods/design: CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy., Discussion: The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit., Trial Registration: ISRCTN, ISRCTN92755158, Registered on 17 February 2016.

Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space., (© 2019 Royal Australasian College of Surgeons.)

Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.

There is a need for novel strategies to treat aggressive breast cancer subtypes and overcome drug resistance. ZnO nanoparticles (NPs) have potential in cancer therapy due to their ability to potently and selectively induce cancer cell apoptosis. Here, we tested the in vitro chemotherapeutic efficacy of ZnONPs loaded via a mesoporous silica nanolayer (MSN) towards drug-sensitive breast cancer cells (MCF-7: estrogen receptor-positive, CAL51: triple-negative) and their drug-resistant counterparts (MCF-7TX, CALDOX). ZnO-MSNs were coated on to gold nanostars (AuNSs) for future imaging capabilities in the NIR-II range. Electron and confocal microscopy showed that MSN-ZnO-AuNSs accumulated close to the plasma membrane and were internalized by cells. High-resolution electron microscopy showed that MSN coating degraded outside the cells, releasing ZnONPs that interacted with cell membranes. MSN-ZnO-AuNSs efficiently reduced the viability of all cell lines, and CAL51/CALDOX cells were more susceptible than MCF7/MCF-7-TX cells. MSN-ZnO-AuNSs were then conjugated with the antibody to Frizzled-7 (FZD-7), the receptor upregulated by several breast cancer cells. We used the disulphide (S-S) linker that could be cleaved with a high concentration of glutathione normally observed within cancer cells, releasing Zn2+ into the cytoplasm. FZD-7 targeting resulted in approximately three-fold amplified toxicity of MSN-ZnO-AuNSs towards the MCF-7TX drug-resistant cell line with the highest FZD-7 expression. This study shows that ZnO-MSs are promising tools to treat triple-negative and drug-resistant breast cancers and highlights the potential clinical utility of FZD-7 for delivery of nanomedicines and imaging probes specifically to these cancer types.

Purpose: The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES)., Methods: Of the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini-Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (p BH )., Results: Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (p BH  = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (p BH  > 0.05 for all)., Conclusions: This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.

Purpose: The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations., Patients and Methods: The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations., Results: Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ 2  = 79.35, p < 0.001] and altered the LASTDT category in 68% (34/50) of cases (p < 0.001), 74% of which were to forgo chemotherapy. With knowledge of RS, universal concordance rose from 14% to 64% [K = 0.328: K = 0.729]., Conclusions: The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219; validation cohort, n = 418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P = 0.015) and validation (HR, 0.50; P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts ( P < 0.0001). Among the combined ERα-positive cases, those with comparable or higher levels of AR (AR:ERα-positivity ratio >0.87) had the best outcomes ( P < 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer. Clin Cancer Res; 24(10); 2328-41. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane., Patients and Methods: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated., Results: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4., Conclusion: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.

Background: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67., Methods: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels., Results: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17β-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2., Conclusions: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.

The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER., (© 2016 Society for Endocrinology.)

Background: The hormonal manipulation 5-Fluoro-uracil Epirubicin Cyclophosphamide (HMFEC) trial was developed at a time of uncertainty around the dose intensity of chemotherapy given to premenopausal patients with node positive breast cancer and to the benefits of tailored endocrine therapy in such patients., Patients and Methods: HMFEC was a multi-centre, phase III, open label, randomised controlled trial with a 2 × 2 factorial design. Eligible patients were premenopausal with node positive early breast cancer; significant cardiac disease or uncontrolled hypertension was exclusion criterion. Patients were allocated to receive either eight cycles of FE50C or FE75C (given 3 weekly) with or without hormone manipulation (HM; tamoxifen or luteinising hormone releasing hormone (LHRH) agonists according to residual hormone levels at the end of chemotherapy) irrespective of ER status. The primary end-point was disease free survival (DFS). Principal analyses were by intention to treat (ITT); however, to reflect contemporary practice, subgroup analyses according to ER status were also conducted. The mature follow-up now available from this modest sized trial enables presentation of definitive results., Results: Between 1992 and 2000 a total of 785 patients were randomised into the HMFEC trial (203 FE50C-HM, 191 FE50C+HM, 198 FE75C-HM, 193 FE75C+HM). At a median follow-up of 7.4 years, 245 DFS events have been reported (92 ER-, 153 ER+/unknown). The effects on DFS were not statistically significantly different according to epirubicin dose (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.63-1.06; p = 0.13 FE75C versus FE50C); however, FE75C appeared to induce more alopecia and neutropenia. No statistically significant evidence was observed to support an improvement in DFS in patients allocated HM either overall (HR = 0.88, 95% CI 0.68-1.13; p = 0.32) or in patients with ER+/unknown disease (HR = 0.85, 95% CI 0.62-1.17; p = 0.32) although effect sizes are consistent with worthwhile clinical effects. Overall, there was no evidence of a difference in survival between any of the four treatment groups of the trial., Conclusion: Higher doses of epirubicin cause more adverse events in the absence of clear improvement in overall survival. Endocrine therapy with either tamoxifen or goserelin provided no significant added benefit to cytotoxic chemotherapy in this group of patients., Trial Registration Number: ISRCTN98335268., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37-1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10-0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46-2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC.

Purpose: The steroid receptor coactivator SRC3 is essential for the transcriptional activity of estrogen receptor α (ERα). SRC3 is sufficient to cause mammary tumorigenesis, and has also been implicated in endocrine resistance. SRC3 is posttranslationally modified by phosphorylation, but these events have not been investigated with regard to functionality or disease association. Here, we investigate the spatial selectivity of SRC3-pS543/DNA binding over the human genome and its expression in primary human breast cancer in relation with outcome., Experimental Design: Chromatin immunoprecipitation, coupled with sequencing, was used to determine the chromatin binding patterns of SRC3-pS543 in the breast cancer cell line MCF7 and two untreated primary breast cancers. IHC was used to assess the expression of SRC3 and SRC3-pS543 in 1,650 primary breast cancers. The relationship between the expression of SRC3 and SRC3-pS543, disease-free survival (DFS), and breast cancer specific survival (BCSS) was assessed., Results: Although total SRC3 is selectively found at enhancer regions, SRC3-pS543 is recruited to promoters of ERα responsive genes, both in the MCF7 cell line and primary breast tumor specimens. SRC3-pS543 was associated with both improved DFS (P = 0.003) and BCSS (P = 0.001) in tamoxifen untreated high-risk patients, such a correlation was not seen in tamoxifen-treated cases, the interaction was statistically significant (P = 0.001). Multivariate analysis showed SRC3-pS543 to be an independent prognostic factor., Conclusions: Phosphorylation of SRC3 at S543 affects its genomic interactions on a genome-wide level, where SRC3-pS543 is selectively recruited to promoters of ERα-responsive genes. SRC3-pS543 is a prognostic marker, and a predictive marker of response to endocrine therapy., (©2015 American Association for Cancer Research.)

Background: High-dose oestrogen (HDE) is effective but toxic in postmenopausal women with advanced breast cancer (ABC). Prolonged oestrogen deprivation sensitises BC cell lines to estrogen and we hypothesised that third-generation aromatase inhibitors (AIs) would sensitise BCs to low-dose estradiol (LDE)., Methods: A single-arm phase II study of LDE (2 mg estradiol valerate daily) in postmenopausal women with estrogen receptor-positive (ER+) ABC. The primary end-point was clinical benefit (CB) rate. If LDE was ineffective, HDE was offered. If LDE was effective, retreatment with the pre-LDE AI was offered on progression., Results: Twenty-one patients were recruited before the trial was closed early due to slow accrual; 19 were assessable for efficacy and toxicity. CB was seen in 5 in 19 patients (26%; 95% confidence interval 9.1-51.2%), all with prolonged SD (median duration 16.8 months; range 11.0-29.6). Treatment was discontinued for toxicity in 4 in 19 patients (21%) and 8 in 11 women without hysterectomy experienced vaginal bleeding (VB). After primary LDE failure, three patients received HDE and one achieved a partial response (PR). Following CB on LDE, four patients restarted pre-LDE AI and three achieved CB including one PR. Those with CB to LDE had a significantly longer duration of first-line endocrine therapy for ABC than those without (54.9 versus 16.8 months; p < 0.01) CONCLUSION: LDE is an effective endocrine option in women with evidence of prolonged sensitivity to AI therapy. LDE is reasonably well tolerated although VB is an issue. Re-challenge with the pre-LDE AI following progression confirms re-sensitisation as a true phenomenon., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms., Patients and Methods: Primary tumour samples were available for 1256 patients (27% IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs., Results: Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS., Conclusion: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE₁₀₀C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Activating transcription factor-2 (ATF-2) has been implicated as a tumour suppressor in breast cancer (BC). c-JUN N-terminal kinase (JNK) and p38 MAPK phosphorylate ATF-2 within the activation domain (AD), which is required for its transcriptional activity. To date, the role of ATF-2 in determining response to endocrine therapy has not been explored. Effects of ATF-2 loss in the oestrogen receptor (ER)-positive luminal BC cell line MCF7 were explored, as well as its role in response to tamoxifen treatment. Genome-wide chromatin binding patterns of ATF-2 when phosphorylated within the AD in MCF-7 cells were determined using ChIP-seq. The expression of ATF-2 and phosphorylated ATF-2 (pATF-2-Thr71) was determined in a series of 1,650 BC patients and correlated with clinico-pathological features and clinical outcome. Loss of ATF-2 diminished the growth-inhibitory effects of tamoxifen, while tamoxifen treatment induced ATF-2 phosphorylation within the AD, to regulate the expression of a set of 227 genes for proximal phospho-ATF-2 binding, involved in cell development, assembly and survival. Low expression of both ATF-2 and pATF-2-Thr71 was significantly associated with aggressive pathological features. Furthermore, pATF-2 was associated with both p-p38 and pJNK1/2 (< 0.0001). While expression of ATF-2 is not associated with outcome, pATF-2 is associated with longer disease-free (p = 0.002) and BC-specific survival in patients exposed to tamoxifen (p = 0.01). Furthermore, multivariate analysis confirmed pATF-2-Thr71 as an independent prognostic factor. ATF-2 is important for modulating the effect of tamoxifen and phosphorylation of ATF-2 within the AD at Thr71 predicts for improved outcome for ER-positive BC receiving tamoxifen.

Background: Aromatase inhibitors (AIs) are central to the management of oestrogen receptor-positive breast cancer in the adjuvant and metastatic setting. Levels of circulating steroid hormones (SHs) were measured in patients established on AIs to investigate: the influence of body mass index (BMI) in both the adjuvant and metastatic setting; the class of AI utilized in the adjuvant setting (steroidal versus non-steroidal); and differences in SH levels between women treated adjuvantly and those receiving a second-line AI for locally advanced/metastatic disease., Methods: Plasma levels of androstenedione, 5-androstene-3β,17β-diol, dehydroepiandrosterone, oestradiol and testosterone were measured by radioimmunoassay in women with breast cancer who were receiving AIs in either an adjuvant or a metastatic setting. Differences between mean SH levels by class of AI, BMI, and second-line versus adjuvant therapy were assessed., Results: Sixty-four women were receiving AI therapy, 45 (70 per cent) in an adjuvant setting and 19 (30 per cent) were taking a second-line AI. There was no significant correlation between BMI and SH levels. However, BMI was significantly higher in the second-line AI cohort compared with the adjuvant cohort (29.8 versus 26.2 kg/m2 respectively; P = 0.026). In the adjuvant setting, patients receiving a steroidal AI had significantly higher levels of all five hormones (P < 0.050). In the second-line AI cohort, oestradiol levels were significantly higher than in the adjuvant cohort (4.5 versus 3.3 pg/ml respectively; P = 0.022). Multivariable analysis adjusted for BMI confirmed the higher residual oestradiol level in the second-line AI group (P = 0.063) and a significantly higher androstenedione level (P = 0.022)., Conclusion: Residual levels of SH were not significantly influenced by BMI. However, the significant differences in residual SH levels between the second-line and adjuvant AI cohort is of relevance in the context of resistance to AI therapy, and warrants further investigation., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: This study aimed to investigate the use of nonpegylated liposomal doxorubicin (NPLD) in the management of metastatic breast cancer (MBC) within routine UK clinical practice and to assess its efficacy and tolerability., Patients and Methods: All patients that received NPLD for MBC at 5 institutions were identified. Clinicopathologic details, echocardiographic data, and toxicities were documented. Response to treatment, outcome, cardiotoxicity, and safety were assessed., Results: 63 patients (median age at NPLD therapy, 53.5 years) who had received NPLD were identified; 18 (29%) were anthracycline-naïve, and 42 (67%) were anthracycline-pretreated (median cumulative dose of epirubicin, 450 mg/m(2)). In 3 cases, prior treatment history was not available. NPLD was most frequently (16 [25%] of 63 patients) administered as first-line chemotherapy (median, third-line; range, 1-9), although it was given later in anthracycline-pretreated patients (median, fourth-line; range, 1-9). Overall, 14 (29%) of 49 evaluable patients achieved an objective response, which increased to 10 (71%) of 14 when NPLD was given first-line (anthracycline-naïve, 8 [100%] of 8; anthracycline-pretreated, 2 [50%] of 4; adjuvant treatment unknown, 2). Median progression-free survival was 7 months (first-line, 18 months, vs. ≥ second-line, 6 months; P = .0066), and median overall survival was 10 months (first-line, 18 months, vs. ≥ second-line, 10 months; P = .0971). Toxicities tended to be grade 1 or 2. Three patients had cardiotoxicity (left ventricular ejection fraction < 50% or a fall of ≥ 10% from baseline), which resolved during treatment., Conclusion: NPLD was used in both anthracycline-naïve patients and those with prior exposure. There is evidence of clinical activity in those with prior exposure to anthracyclines, with a low incidence of cardiotoxicity., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The identification of patients who are more likely to derive benefit from antiangiogenic therapy is a key to refine patient selection and so maximize clinical benefit, and reduce unnecessary treatment costs. Improved patient selection will equally be effective in minimizing the exposure of non-eligible patients to ineffectual treatment which could be associated with adverse effects as well as delaying effective treatment. Herein, we review the literature from clinical trials suggesting that the addition of antiangiogenic agents to chemotherapy for the treatment of HER-2 negative metastatic breast cancer in patients previously exposed to chemotherapy may deliver differential therapeutic benefit and may serve as a selection criteria in the current absence of a robust biomarker.