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Abstract Background We have previously demonstrated that BEX2 is differentially expressed in breast tumors and has a significant role in promoting cell survival and growth in breast cancer cells. BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In this study we investigated the transcriptional regulation of BEX2 and feedback mechanisms mediating the cellular function of this gene in breast cancer. Results We found a marked induction of BEX2 promoter by c-Jun and p65/RelA using luciferase reporter assays in MCF-7 cells. Furthermore, we confirmed the binding of c-Jun and p65/RelA to the BEX2 promoter using a chromatin immunoprecipitation assay. Importantly, transfections of c-Jun or p65/RelA in MCF-7 cells markedly increased the expression of BEX2 protein. Overall, these results demonstrate that BEX2 is a target gene for c-Jun and p65/RelA in breast cancer. These findings were further supported by the presence of a strong correlation between BEX2 and c-Jun expression levels in primary breast tumors. Next we demonstrated that BEX2 has a feedback mechanism with c-Jun and p65/RelA in breast cancer. In this process BEX2 expression is required for the normal phosphorylation of p65 and IκBα, and the activation of p65. Moreover, it is necessary for the phosphorylation of c-Jun and JNK kinase activity in breast cancer cells. Furthermore, using c-Jun stable lines we showed that BEX2 expression is required for c-Jun mediated induction of cyclin D1 and cell proliferation. Importantly, BEX2 down-regulation resulted in a significant increase in PP2A activity in c-Jun stable lines providing a possible underlying mechanism for the regulatory effects of BEX2 on c-Jun and JNK. Conclusions This study shows that BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. In this process BEX2 is a target gene for c-Jun and p65/RelA and in turn regulates the phosphorylation/activity of these proteins. These suggest that BEX2 is involved in a novel feedback mechanism with significant implications for the biology of breast cancer.

Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority., Objectives: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival., Design: This was a Phase III randomised controlled non-inferiority trial., Setting: The setting was 152 NHS hospitals., Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part., Intervention: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment., Main Outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model., Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p  = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p  = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p  = 0.03 (disease-free-survival) and p  = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p  = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p  < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently., Limitations: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered., Conclusions: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events., Future Work: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned., Trial Registration: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 40. See the NIHR Journals Library website for further project information., Competing Interests: Helena Earl reports grants from Roche (Basel, Switzerland) and Sanofi-Aventis (Paris, France), personal fees and travel expenses from Daiichi Sankyo (Tokyo, Japan), AstraZeneca plc (Cambridge, UK) and Intas Pharmaceuticals (Ahmedabad, India), travel expenses from Pfizer Inc. (New York, NY, USA) and Amgen Inc. (Thousand Oaks, CA, USA) and personal fees from prIME Oncology (Atlanta, GA, USA), all outside the submitted work. Karen McAdam reports grants from Roche and personal fees from Roche, Novartis International AG (Basel, Switzerland), Pfizer and Eisai Co., Ltd (Tokyo, Japan), all outside the submitted work. Daniel Rea reports personal fees and grants from Roche during the conduct of the study, as well as personal fees from Novartis, Pfizer, Genomic Health (Redwood City, CA, USA) and Daiichi Sankyo, and grants from Celgene Corporation (Summit, NJ, USA), all outside the submitted work. Chris Plummer reports personal fees and non-financial support from Roche Products Limited, Novartis UK Limited, Pfizer UK Limited, Celgene and Incyte Corporation (Wilmington, DE, USA) for attending education meetings. He also reports personal fees and non-financial support from Amgen Limited for attending education meetings and advisory boards, all outside the submitted work. Jean Abraham reports fees to her institution, and accommodation and travel expenses from AstraZeneca for session boards and advisory chairs, as well as fees to her institution, and accommodation and travel expenses from Pfizer for a lecture, all outside the submitted work. Carlos Caldas reports grants from Genentech, Inc. (South San Francisco, CA, USA), Roche, Servier Laboratories (Suresnes, France) and AstraZeneca outside the submitted work, and that he is a member of the AstraZeneca iMED External Science Panel. Peter Hall reports grants from Roche, Pfizer, AstraZeneca, Novartis, Eisai and Daiichi Sankyo outside the submitted work. Christopher McCabe’s institution holds research contracts with Roche and reports grants from Roche, all outside the submitted work. David Miles reports personal fees from Roche/Genetech, outside the submitted work. Claire Hulme reports that she is a member of the National Institute for Health Research (NIHR) Health Technology Assessment Commissioning Board. Andrew M Wardley reports personal fees from Roche, Napp Pharmaceuticals Ltd (Cambridge, UK), Amgen, Merck Sharp & Dohme (Hoddesdon, UK), Novartis, Pfizer, AstraZeneca, Laboratoires Pierre Fabre (Paris, France), Accord (Barnstaple, UK), Athenex (Buffalo, NY, USA), Gerson Lehrman Group (New York, NY, USA), Coleman Research Expert Network Group (New York, NY, USA) and Guidepoint Global (New York, NY, USA). He also reports personal fees and other from Eli Lilly and Company (Indianapolis, IN, USA) and Daiichi Sankyo, all outside the submitted work. He is leading the National Cancer Research Institute Breast Group Initiative to develop the next de-escalation trial for HER2-positive breast cancer. David A Cameron reports funds to his institution from Novartis, Astrazeneca, Pfizer, Roche, Eli Lilly and Company, Puma Biotechnology (Los Angeles, CA, USA), Daiichi Sankyo, Synthon (Nijmegen, the Netherlands), SeaGen International GmbH (Zug, Switzerland), Zymeworks (Vancouver, BC, Canada), Elsevier (Amsterdam, the Netherlands), European Cancer Organisation (Brussels, Belgium), Celgene Corporation, Succinct Medical Communications (Wilmington, DE, USA), Immutep (Sydney, NSW, Australia), Oncolytics Biotech (U.S) Inc. (San Diego, CA, USA), Celldex Therapeutics Inc. (Hampton, NJ, USA), San Antonio Breast Cancer Consortium (TX, USA), Highfield Communication (Oxford, UK), Samsung Bioepis Co. Ltd (Incheon, South Korea), prIME Oncology, Merck Sharp & Dohme Ltd, Prima Biomed Ltd, RTI Health Solutions (Research Triangle, NC, USA) and Eisai, all outside the submitted work. Janet A Dunn reports that she is a member of the NIHR Efficacy and Mechanism Evaluation funding board and an NIHR senior investigator.

Introduction: Definition of the tumor bed (TB) is currently guided by intraoperatively placed metal clips. However, this traditional planning method may not be sufficient for tumor cavity defect refilled with modern oncoplastic breast surgery. We explored the impact of a close cooperation between surgeon and oncologist on the accuracy of TB contouring after partial breast reconstruction with chest wall perforator flaps (CWPF)., Patients and Methods: A retrospective review of patients who received radiotherapy after CWPF was performed. TB and boost volume were defined by the surgeon, considering clips and the typical radiologic appearance of the flap, and by a radiation oncologist, and results were compared with the surgical specimen volume (SPV). The boost volume was marked as 5 mm penumbral ring thickness of native breast tissue wall around the replaced flap (nonbreast tissue)., Results: There were no significant differences between SPV and surgeon-defined TB values. Conversely, the radiation oncologist-defined values were significantly smaller than the actual SPV. If a ring-shaped TB boost was delivered, this would have allowed a potential reduction of irradiated tissue of 127.6%., Conclusion: TB definition solely by surgical clips may be prone to inaccuracy in case of volume replacement oncoplastic breast surgery. Our approach of combining the clips with the redefinition of the flap on computed tomographic scan may provide more accurate TB definition. Although an ideal ring-shaped boost might be difficult to reproduce in practice, it introduces a new paradigm: a lower radiation dose inside TB is tolerable, if not desirable, at least in CWPF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival., Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140)., Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001)., Interpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial., Funding: UK National Institute for Health Research, Health Technology Assessment Programme., (Copyright © 2019 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.)