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      Efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy for HER2-positive breast cancer: a systematic review and meta-analysis

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          Abstract

          The concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy (NAC) has been proposed to improve the pathologic complete response (pCR) rate, although there are conflicting views about its efficacy and safety. The purpose of this study was to evaluate the efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based NAC for human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer. We systematically searched PubMed, Embase, and Cochrane databases from inception until July 1, 2017, for relevant articles. A total of 13 studies were included in the meta-analysis. The results showed that the pCR rate was significantly higher in the concurrent use of trastuzumab and anthracycline group (45%) than that in the nonconcurrent use group (32%) (OR: 2.36, 95% CI: 1.69–3.30, P<0.0001). Besides, the pooled absolute rate of breast conservation surgery (BCS) was 48% (95% CI: 0.35–0.61) and 38% (95% CI: 0.14–0.62) in the experimental and control groups, respectively (OR: 1.10, 95% CI: 0.64–1.90, P=0.73). No significant differences were found in the left ventricular ejection fraction (LVEF), which decreased by >10% (OR: 1.26, 95% CI: 0.55–2.88, P=0.59), and in terms of cardiac failure (OR: 2.17, 95% CI: 0.24–19.84, P=0.49), when comparing the concurrent use of trastuzumab and anthracyclines with their nonconcurrent use. In conclusion, the concurrent use of trastuzumab and anthracycline-based NAC for certain HER2-positive locally advanced breast cancers significantly improves the pCR rates without obvious increases in the cardiotoxicity.

          Most cited references24

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          Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

          Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. US Food and Drug Administration. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            The nuts and bolts of PROSPERO: an international prospective register of systematic reviews

            Background Following publication of the PRISMA statement, the UK Centre for Reviews and Dissemination (CRD) at the University of York in England began to develop an international prospective register of systematic reviews with health-related outcomes. The objectives were to reduce unplanned duplication of reviews and provide transparency in the review process, with the aim of minimizing reporting bias. Methods An international advisory group was formed and a consultation undertaken to establish the key items necessary for inclusion in the register and to gather views on various aspects of functionality. This article describes the development of the register, now called PROSPERO, and the process of registration. Results PROSPERO offers free registration and free public access to a unique prospective register of systematic reviews across all areas of health from all around the world. The dedicated web-based interface is electronically searchable and available to all prospective registrants. At the moment, inclusion in PROSPERO is restricted to systematic reviews of the effects of interventions and strategies to prevent, diagnose, treat, and monitor health conditions, for which there is a health-related outcome. Ideally, registration should take place before the researchers have started formal screening against inclusion criteria but reviews are eligible as long as they have not progressed beyond the point of completing data extraction. The required dataset captures the key attributes of review design as well as the administrative details necessary for registration. Submitted registration forms are checked against the scope for inclusion in PROSPERO and for clarity of content before being made publicly available on the register, rejected, or returned to the applicant for clarification. The public records include an audit trail of major changes to planned methods, details of when the review has been completed, and links to resulting publications when provided by the authors. Conclusions There has been international support and an enthusiastic response to the principle of prospective registration of protocols for systematic reviews and to the development of PROSPERO. In October 2011, PROSPERO contained 200 records of systematic reviews being undertaken in 26 countries around the world on a diverse range of interventions.
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              Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort.

              The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab. We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495. Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61-78; n=36 events] with trastuzumab, vs 56% [46-65; n=51 events] without; hazard ratio 0.59 [95% CI 0.38-0.90]; p=0.013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs. The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses. F Hoffmann-La Roche. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2018
                26 September 2018
                : 14
                : 1789-1797
                Affiliations
                [1 ]Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China, huihuikp@ 123456163.com
                [2 ]Department of Orthopedics, Children’s Hospital of Chongqing Medical University, Chongqing 400020, China
                [3 ]Department of General Surgery, Children’s Hospital of Chongqing Medical University, Chongqing 400020, China
                Author notes
                Correspondence: Ling-Quan Kong, Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, No 1 You Yi Road, Chongqing 400016, China, Email huihuikp@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                tcrm-14-1789
                10.2147/TCRM.S176214
                6165855
                94e10ce4-0391-45b4-9b6e-baaac1820e47
                © 2018 Wu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Review

                Medicine
                breast cancer,her2,neoadjuvant chemotherapy,trastuzumab,anthracycline
                Medicine
                breast cancer, her2, neoadjuvant chemotherapy, trastuzumab, anthracycline

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