{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T02:01:34Z","timestamp":1774922494423,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004945","name":"Nankai University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004945","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Acquired resistance to endocrine therapy (ET) remains a big challenge in the management of metastatic breast cancer (MBC). A novel therapeutic agent, histone deacetylase inhibitors (HDACi), targets the abnormal epigenetic modification and may overcome acquired resistance. However, HDACi efficacy and the safety profile for hormone receptor (HoR)-positive\/human epidermal growth factor receptor 2 (HER2)-negative MBC remain controversial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two independent reviewers searched PubMed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies on HDACi and HoR+\/HER2- MBC. Demographic and clinicopathological parameters were extracted and presented as means and proportions, and between-group differences were assessed by Pearson chi-square test. Fixed- or random-effects models were used for meta-analysis based on inter-study heterogeneity. Pooled results were presented as L\u2019Abb\u00e9 plot and forest plot. Funnel plot and Egger\u2019s test were employed for evaluation of publication bias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four studies with 1,457 patients were included for meta-analysis. The overall objective response rates (ORRs) of HDACi + ET (HE) and placebo + ET (PE) groups were 11.52% and 6.67%, respectively. The HE regimen significantly increased ORR (odds ratio [OR] 1.633, 95% confidence interval [CI] = 1.103\u20132.418, <jats:italic>p<\/jats:italic> &amp;lt; 0.05) and showed higher clinical benefit rate (CBR) than the PE regimen (HE vs. PE groups: 38.82% vs. 30.58%, OR 1.378, 95% CI = 1.020\u20131.861, <jats:italic>p<\/jats:italic> &amp;lt; 0.05). Additionally, the HE regimen was associated with prolonged progression-free survival (PFS) (hazard ratio [HR] 0.761, 95% CI = 0.650\u20130.872, <jats:italic>p<\/jats:italic> &amp;lt; 0.001) and overall survival (OS) (HR 0.849, 95% CI = 0.702\u20130.996, <jats:italic>p<\/jats:italic> &amp;lt; 0.001). Regarding safety profile, the HE regimen had increasing toxicity in terms of higher overall adverse event (AE), Grade \u22653 AE, dose modification, and discontinuation rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This meta-analysis validated that the HE regimen had superior efficacy over control in terms of ORR, CBR, PFS, and OS, but was accompanied with increasing toxicity. HDACi plus ET could serve as an important option in managing HoR+\/HER2- MBC. Future studies may focus on the clinical difference among different HDACi and AE managements to enhance tolerability.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.901152","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T04:36:18Z","timestamp":1653971778000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Efficacy and Safety Profile of Histone Deacetylase Inhibitors for Metastatic Breast Cancer: A Meta-Analysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Changjun","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanjiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yidong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenggang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813904","article-title":"Alpelisib for PIK3CA -Mutated, Hormone Receptor\u2013Positive Advanced Breast Cancer","volume":"380","author":"Andr\u00e9","year":"2019","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109653","article-title":"Everolimus in Postmenopausal Hormone-Receptor\u2013Positive Advanced Breast Cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1810527","article-title":"Overall Survival With Palbociclib and Fulvestrant in Advanced Breast Cancer","volume":"379","author":"Turner","year":"2018","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1001\/jamaoncol.2019.4782","article-title":"The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor\u2013Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy\u2014MONARCH 2: A Randomized Clinical Trial","volume":"6","author":"Sledge","year":"2020","journal-title":"JAMA Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1517\/13543784.2014.867017","article-title":"Overview of Cyclins D1 Function in Cancer and the CDK Inhibitor Landscape: Past and Present","volume":"23","author":"Casimiro","year":"2014","journal-title":"Expert Opin Investig Drugs"},{"key":"B6","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.canlet.2021.05.030","article-title":"Endocrine Resistance and Epigenetic Reprogramming in Estrogen Receptor Positive Breast Cancer","volume":"517","author":"Dimitrakopoulos","year":"2021","journal-title":"Cancer Lett"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2015.117","article-title":"ESR1 Mutations\u2014a Mechanism for Acquired Endocrine Resistance in Breast Cancer","volume":"12","author":"Jeselsohn","year":"2015","journal-title":"Nat Rev Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21405","article-title":"Obesity and Adverse Breast Cancer Risk and Outcome: Mechanistic Insights and Strategies for Intervention","volume":"67","author":"Picon-Ruiz","year":"2017","journal-title":"CA Cancer J Clin"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6072357","article-title":"DNA Methylation and Chromatin Remodeling: The Blueprint of Cancer Epigenetics","volume":"2016","author":"Bhattacharjee","year":"2016","journal-title":"Scientifica"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119504","article-title":"Epigenetic Modulation and Understanding of HDAC Inhibitors in Cancer Therapy","volume":"277","author":"Ramaiah","year":"2021","journal-title":"Life Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/45257","article-title":"Induction of Autophagy and Inhibition of Tumorigenesis by Beclin 1","volume":"402","author":"Liang","year":"1999","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13746","article-title":"How do Tumor Cells Respond to HDAC Inhibition","volume":"283","author":"Newbold","year":"2016","journal-title":"FEBS J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707608","article-title":"Inhibitors of Histone Deacetylase (HDAC) Restore the P53 Pathway in Neuroblastoma Cells","volume":"153","author":"Condorelli","year":"2008","journal-title":"Br J Pharmacol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.306","article-title":"Histone Deacetylase Inhibitors Induce Thyroid Cancer-Specific Apoptosis Through Proteasome-Dependent Inhibition of TRAIL Degradation","volume":"29","author":"Borbone","year":"2010","journal-title":"Oncogene"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2008.11.012","article-title":"Targeting Tumor Angiogenesis With Histone Deacetylase Inhibitors","volume":"280","author":"Ellis","year":"2009","journal-title":"Cancer Lett"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201948375","article-title":"Class I HDAC Inhibitors Enhance YB-1 Acetylation and Oxidative Stress to Block Sarcoma Metastasis","volume":"20","author":"El-Naggar","year":"2019","journal-title":"EMBO Rep"},{"key":"B17","article-title":"Histone Deacetylase Inhibitors as a New Anticancer Option: How Far can We Go With Expectations? Delivery Systems","volume":"23","author":"Garmpi","year":"2018","journal-title":"J BUON Off J Balk Union Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.156","article-title":"A Phase II Study of the Histone Deacetylase Inhibitor Vorinostat Combined With Tamoxifen for the Treatment of Patients With Hormone Therapy-Resistant Breast Cancer","volume":"104","author":"Munster","year":"2011","journal-title":"Br J Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.43.7251","article-title":"Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor","volume":"31","author":"Yardley","year":"2013","journal-title":"J Clin Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30164-0","article-title":"Tucidinostat Plus Exemestane for Postmenopausal Patients With Advanced, Hormone Receptor-Positive Breast Cancer (ACE): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial","volume":"20","author":"Jiang","year":"2019","journal-title":"Lancet Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.00944","article-title":"E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor\u2013Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group","volume":"39","author":"Connolly","year":"2021","journal-title":"J Clin Oncol"},{"key":"B22","unstructured":""},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies","volume":"370","author":"von Elm","year":"2007","journal-title":"Lancet Lond Engl"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.592998","article-title":"Platinum-Based Neoadjuvant Chemotherapy for Breast Cancer With BRCA Mutations: A Meta-Analysis","volume":"10","author":"Wang","year":"2020","journal-title":"Front Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/1745-6215-8-16","article-title":"Practical Methods for Incorporating Summary Time-to-Event Data Into Meta-Analysis","volume":"8","author":"Tierney","year":"2007","journal-title":"Trials"},{"key":"B26","doi-asserted-by":"publisher","first-page":"GS1","DOI":"10.1158\/1538-7445.SABCS21-GS1-06","article-title":"Abstract GS1-06: A Randomized Control Phase III Trial of Entinostat, a Once Weekly, Class I Selective Histone Deacetylase Inhibitor, in Combination With Exemestane in Patients With Hormone Receptor Positive Advanced Breast Cancer","volume":"82","author":"Xu","year":"2022","journal-title":"Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.93","article-title":"Targeting the Cancer Epigenome for Therapy","volume":"17","author":"Jones","year":"2016","journal-title":"Nat Rev Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.02.011","article-title":"HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma","volume":"29","author":"Pei","year":"2016","journal-title":"Cancer Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2388","article-title":"C-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer","volume":"23","author":"Nebbioso","year":"2017","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.28.9066","article-title":"Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma","volume":"28","author":"Whittaker","year":"2010","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-3-5","article-title":"Novel Histone Deacetylase Inhibitors in Clinical Trials as Anti-Cancer Agents","volume":"3","author":"Tan","year":"2010","journal-title":"J Hematol Oncol J Hematol Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1586\/14737140.8.3.413","article-title":"Histone Deacetylase Inhibitors in Lymphoma and Solid Malignancies","volume":"8","author":"Rasheed","year":"2008","journal-title":"Expert Rev Anticancer Ther"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1039\/C9RA02985K","article-title":"Next-Generation of Selective Histone Deacetylase Inhibitors","volume":"9","author":"Yang","year":"2019","journal-title":"RSC Adv"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-011-1766-x","article-title":"Chidamide (CS055\/HBI-8000): A New Histone Deacetylase Inhibitor of the Benzamide Class With Antitumor Activity and the Ability to Enhance Immune Cell-Mediated Tumor Cell Cytotoxicity","volume":"69","author":"Ning","year":"2012","journal-title":"Cancer Chemother Pharmacol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.901152\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T04:36:22Z","timestamp":1653971782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.901152\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":34,"alternative-id":["10.3389\/fonc.2022.901152"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.901152","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]},"article-number":"901152"}}