Breast cancer remains the leading malignancy threatening women’s health worldwide. Among its subtypes, hormone receptor-positive/HER2-negative (HR+/HER2⁻) breast cancer is the most common and typically has a better prognosis, having now entered the era of chronic disease management. In the context of long-term, whole-course management—often spanning over a decade—the concept of “patient-centered care” has become central to clinical practice. Reducing the frequency of medication through long-acting therapies can significantly improve the patient experience, enhance quality of life, and boost adherence. On April 24, 2024, the National Medical Products Administration (NMPA) approved the domestic HDAC inhibitor entinostat in combination with an aromatase inhibitor (AI) for the treatment of HR+/HER2⁻ patients with locally advanced or metastatic breast cancer who have relapsed or progressed following endocrine therapy. With its convenient weekly oral dosing, entinostat marks the beginning of a new "weekly therapy" era for HR+ advanced breast cancer in China, offering patients a more accessible and simplified treatment option.Oncology Frontier invited Dr. Ying Wang from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, to discuss how this weekly therapy strategy enhances the treatment experience during chronic management of HR+ breast cancer.
A Chronic Disease Era: Putting Patients at the Center to Safeguard Lives and Health
Breast cancer is the second most common malignancy among women in China, with more than 357,200 new cases reported annually [¹], posing a serious public health challenge. HR+ breast cancer accounts for approximately 70% of all breast cancer cases, making it the most prevalent and generally the most favorable in terms of prognosis [²]. In early-stage HR+ breast cancer, clinical cure is often achievable, with 10-year disease-free survival (DFS) and overall survival (OS) rates exceeding 80% through endocrine therapy. For advanced-stage patients, first-line treatment with CDK4/6 inhibitors combined with endocrine therapy can lead to a median progression-free survival (PFS) exceeding two years and median OS over 60 months. Second-line therapies—such as HDAC inhibitors, PAM pathway inhibitors, and antibody-drug conjugates (ADCs)—further extend survival, ushering breast cancer into the realm of chronic disease management [³].
As early as 2006, the World Health Organization (WHO) classified malignancies under chronic disease management. China reaffirmed this approach in the Healthy China 2030 plan issued in 2015. As one of the most curable and longest-surviving types of cancer, breast cancer requires clinicians to pay greater attention to comprehensive management, long-term follow-up, and holistic intervention during the recovery phase. This aligns with the national strategy of providing “comprehensive and lifelong” health management to improve both survival outcomes and quality of life for patients [⁴].
Today, the principle of “patient-centered care” has become deeply embedded in both clinical trial design and routine practice in breast cancer, advancing the standards of chronic disease management. The concept was first introduced in the 1950s [⁵], and around the same time, the Chinese government advocated the principle of “everything for the patient” [⁶]. With advances in clinical care and the growing body of evidence-based medicine, “patient-centered” approaches have expanded to include physiological, psychological, and social dimensions, emphasizing the importance of the patient’s experience throughout their illness [⁷].
In 2023, China’s Center for Drug Evaluation (CDE) under the NMPA issued three guidance documents focused on patient-centered drug development and clinical trial design, further reinforcing the need to improve treatment experience from the early stages of drug development [⁸]. In sum, as breast cancer enters the chronic management era, patient-centered approaches in drug development and clinical practice have become key strategies endorsed across sectors to ensure the long-term health of patients.
Optimizing Chronic Disease Management: Long-Acting Formulations to Improve Adherence
As breast cancer enters the era of chronic disease management, clinical treatment models have increasingly shifted toward a patient-centered approach. Academician Binghe Xu and other breast cancer experts have emphasized the importance of addressing treatment adherence in HR+ breast cancer, particularly given that endocrine therapy often continues for 10 years or longer [⁹].
International studies have shown that up to 50% of breast cancer patients fail to complete their full course of standard endocrine therapy, resulting in an increased risk of disease recurrence [¹⁰]. A domestic survey investigating medication adherence among outpatient breast cancer patients in China revealed that 42.6% had poor adherence, with half of them missing doses. Drug-related factors were identified as the second most common reason for poor adherence. The more frequent and complex the medication regimen, and the longer the duration of treatment, the greater the psychological burden on patients—leading to missed doses and premature discontinuation of therapy [¹¹].
A meta-analysis has shown that patients with high medication adherence gain 26% more health benefits compared to those with low adherence [¹²]. The treatment regimen itself is a key factor influencing adherence—long-acting formulations, reduced dosing frequency, and simplified protocols are all associated with improved compliance [¹¹]. An analysis encompassing 76 studies further confirmed an inverse relationship between dosing frequency and adherence, with once-daily regimens outperforming multiple daily doses in terms of patient adherence [¹³].
However, even with once-daily dosing, 10% to 40% of patients still experience underdosing issues [¹⁴]. Despite the rapid advancement of digital health technologies that can provide daily medication reminders, studies have indicated that such frequent reminders may have unintended negative effects. In contrast, weekly reminders have been shown to be more effective than daily ones in promoting adherence [¹⁵].
These findings suggest that weekly dosing regimens and reminder systems can significantly enhance medication adherence and, ultimately, treatment outcomes for patients.
The development of long-acting formulations is a necessary strategy for improving both patient adherence and quality of life. Such formulations not only help maintain more stable plasma drug concentrations and reduce dosing frequency, but also contribute to an improved treatment experience, which in turn supports better clinical outcomes [¹⁶].
In the post-CDK4/6 inhibitor era of HR+ breast cancer treatment, histone deacetylase inhibitors (HDACi) play a critical role. Currently, two HDAC inhibitors have been approved in China: chidamide and entinostat. Chidamide has a relatively short terminal elimination half-life of approximately 17 hours, and its standard dosing regimen is 30 mg (six tablets) taken orally twice a week [¹⁷]. In contrast, entinostat has a longer half-life, ranging from approximately 52 to 62 hours, and is administered as a weekly oral dose of 5 mg (one tablet) [¹⁸].
With its longer-acting profile and simplified weekly dosing, entinostat marks the beginning of the “weekly therapy” era for HR+ breast cancer. Its patient-friendly regimen embodies the CDE’s patient-centered design philosophy and reflects the strength of Chinese pharmaceutical innovation in enhancing treatment experiences and improving adherence.
Entinostat Ushers in the Era of Weekly Therapy: Addressing Patients’ Comprehensive Needs
Based on the results of a Phase III randomized, double-blind, placebo-controlled clinical study (EOC103A3101) led by Academician Binghe Xu of the Cancer Hospital, Chinese Academy of Medical Sciences [¹⁹], the National Medical Products Administration (NMPA) officially approved the domestically developed HDAC inhibitor entinostat on April 24, 2024, for use in combination with an aromatase inhibitor (AI) to treat patients with HR+/HER2⁻ locally advanced or metastatic breast cancer who have relapsed or progressed after prior endocrine therapy [²⁰].
The EOC103A3101 study enrolled HR+/HER2⁻ breast cancer patients aged 18–75 years with locally advanced or metastatic disease who had experienced relapse or progression after endocrine therapy. The study population included both premenopausal and postmenopausal women, with pre- and perimenopausal patients required to undergo ovarian suppression therapy.
Patients were randomized in a 2:1 ratio to receive either entinostat (5 mg, orally, once weekly) plus exemestane (20 mg, orally, once daily) or placebo (5 mg, orally, once weekly) plus exemestane (20 mg, orally, once daily). Efficacy was evaluated every 8 weeks using RECIST v1.1 criteria.
The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC). Secondary endpoints included investigator-assessed PFS, overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety.
With a median follow-up of 15.7 months, comparison between the entinostat and placebo groups showed a significant improvement in median progression-free survival (mPFS) as assessed by the Independent Review Committee (IRC): 6.32 months vs. 3.72 months, corresponding to a 24% reduction in the risk of disease progression or death (HR = 0.76).
In the entinostat group, the median overall survival (mOS) reached 38.39 months, extending survival by more than 9 months compared to the placebo group and resulting in a 17% reduction in the risk of death (HR = 0.83), demonstrating a favorable survival benefit.
Notably, entinostat also showed promising efficacy in patients with CDK4/6 inhibitor resistance and those who had previously received salvage chemotherapy. Subgroup analyses revealed consistent benefits across all subgroups, with greater improvements observed in patients without visceral metastases, those with primary endocrine resistance, and those who had not previously received fulvestrant.
In terms of safety, the incidence of Grade ≥3 treatment-related adverse events (TRAEs) was 65.5% in the entinostat group compared to 19.3% in the placebo group. The most common Grade ≥3 hematologic adverse events in the entinostat plus exemestane group were neutropenia (43.8%), thrombocytopenia (8.5%), and leukopenia (6.4%). The most frequently reported non-hematologic Grade ≥3 adverse event was elevated aspartate aminotransferase (2.6%).
Although the rate of Grade ≥3 TRAEs was higher in the entinostat group, patient tolerability remained acceptable. The median treatment duration was 20 weeks in the entinostat arm and 16 weeks in the placebo arm. The rate of treatment discontinuation due to adverse events was 14% in the entinostat group and 5% in the placebo group. Overall, the safety profile of entinostat was manageable, and clinicians are already experienced in handling these adverse events in practice.
In the Phase III ACE trial of another HDAC inhibitor, chidamide, combined with exemestane in postmenopausal patients with HR+ advanced breast cancer and endocrine resistance, investigator-assessed median progression-free survival (mPFS) showed a 25% reduction in the risk of disease progression or death compared to placebo (7.4 vs. 3.8 months; HR = 0.75, 95% CI: 0.58–0.98, P = 0.033), while overall survival (OS) data were still immature. The incidence of Grade ≥3 treatment-related adverse events (TRAEs) in the chidamide group was 76%, with the most common hematologic Grade ≥3 events being neutropenia (51%), thrombocytopenia (27%), and leukopenia (approximately 19%). The most frequent Grade ≥3 non-hematologic adverse events were hypokalemia (6%), hypertriglyceridemia (5%), and elevated gamma-glutamyl transferase (3%) [²¹].
While the two studies differ in design and cannot be directly compared, the EOC103A3101 trial enrolled a broader patient population that included premenopausal women, representing a higher-risk and more representative Chinese population. The PFS outcomes in both studies were similar, with entinostat and chidamide reducing the risk of disease progression or death by 24% and 25%, respectively. However, entinostat is currently the only HDACi to demonstrate a clear OS benefit. In terms of safety, numerically lower adverse event rates were observed with entinostat, though this observation should be interpreted with caution given the absence of head-to-head comparisons.
Conclusion and Outlook
HR+ breast cancer is associated with a favorable prognosis and has entered the era of chronic disease management. With rising economic standards and prolonged survival, greater attention is now being paid by national, societal, and clinical stakeholders to improving patients’ quality of life. “Patient-centered care” has become the prevailing principle in breast cancer treatment.
Given that patients with HR+ breast cancer may remain on treatment for ten years or more, medication adherence is a critical factor that cannot be overlooked. Missed doses or early discontinuation can significantly impact outcomes. The use of long-acting formulations to reduce dosing frequency can greatly improve the patient experience, thereby enhancing adherence.
In the post-CDK4/6 inhibitor treatment era, HDAC inhibitors play a pivotal role. Entinostat, as a long-acting HDACi, introduces a convenient weekly oral regimen, launching the “weekly therapy” era for HR+ breast cancer. With a median overall survival of 38.39 months and a manageable safety profile, entinostat provides patients with a new, more convenient treatment option that reflects the evolution of patient-centered innovation in China.
References
1.Zheng RS,Chen R,Han BF,et al.Zhonghua Zhong Liu Za Zhi.2024;46(3):221-231.doi:10.3760/cma.j.cn112152-20240119-00035
2.Clarke CA,Keegan TH,Yang J,et al.Age-specific incidence of breast cancer subtypes:understanding the black-white crossover.J Natl Cancer Inst.2012;104(14):1094-1101.doi:10.1093/jnci/djs264
3.Huppert LA,Gumusay O,Idossa D,Rugo HS.Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer.CA Cancer J Clin.2023;73(5):480-515.doi:10.3322/caac.21777
4.国家肿瘤质控中心乳腺癌专家委员会,北京乳腺病防治学会健康管理专业委员会.中国乳腺癌随诊随访与健康管理指南(2022版)[J].中华肿瘤杂志,2022,44(1):1-28.DOI:10.3760/cma.j.cn112152-20211029-00798.
5.BALINT M.The doctor,his patient,and the illness.Lancet.1955;268(6866):683-688.doi:10.1016/s0140-6736(55)91061-8
6.刘兵,陈依德,潘安迪.对”以病人为中心创百佳医院”的思考[J].中国医院管理,1998,18(11):2.DOI:CNKI:SUN:YYGL.0.1998-11-022.
7.张鸣明.”以病人为中心”模式的发展史略[J].中华医史杂志,2003,33(03):142-144.DOI:10.3760/cma.j.issn.0255-7053.2003.03.003.
8.国家药物监督管理局药品评审中心,2023年第44号，2023年7月27日.https://www.cde.org.cn/main/news/viewInfoCommon/42c008e28f7004cd19b73949142380bd
9.马飞,徐兵河,邵志敏,等.乳腺癌随访及伴随疾病全方位管理指南[J].中华肿瘤杂志,2019,41(1):13.DOI:10.3760/cma.j.issn.0253-3766.2019.01.006.
10.Yanez B,Gray RJ,Sparano JA,et al.Association of modifiable risk factors with early discontinuation of adjuvant endocrine therapy:a post hoc analysis of a randomized clinical trial[J].JAMA Oncol,2021,7(8)：1-7.DOI：10.1001/jamaoncol.2021.1693.
11.李咏梅,朱莉娜.我院门诊患者用药依从性及其影响因素的调查分析[J].中国药房,2013,24(36):3.DOI:CNKI:SUN:ZGYA.0.2013-36-007.
12.DiMatteo MR,Giordani PJ,Lepper HS,Croghan TW.Patient adherence and medical treatment outcomes:a meta-analysis.Med Care.2002;40(9):794-811.doi:10.1097/00005650-200209000-00009
13.Claxton AJ,Cramer J,Pierce C.A systematic review of the associations between dose regimens and medication compliance.Clin Ther.2001;23(8):1296-1310.doi:10.1016/s0149-2918(01)80109-0
14.Osterberg L,Blaschke T.Adherence to medication.N Engl J Med.2005;353(5):487-497.doi:10.1056/NEJMra050100
15.Granger BB,Bosworth HB.Medication adherence:emerging use of technology.Curr Opin Cardiol.2011;26(4):279-287.doi:10.1097/HCO.0b013e328347c150
16.Li,W.,Tang,J.,Lee,D.et al.Clinical translation of long-acting drug delivery formulations.Nat Rev Mater 7,406–420(2022).https://doi.org/10.1038/s41578-021-00405-w
17.西达本胺说明书，2019年11月18日修订.
18.Wang J,Zhang Q,Li Q,et al.Phase I Study and Pilot Efficacy Analysis of Entinostat,a Novel Histone Deacetylase Inhibitor,in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer.Target Oncol.2021;16(5):591-599.doi:10.1007/s11523-021-00823-4
19.Xu B,Zhang Q,Hu X,et al.Entinostat,a class I selective histone deacetylase inhibitor,plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer:A multicenter,randomized,double-blind,placebo-controlled,phase 3 trial.Acta Pharm Sin B.2023;13(5):2250-2258.doi:10.1016/j.apsb.2023.02.001
20.国家药品监督管理局.Available at:https://www.nmpa.gov.cn/zhuanti/cxylqx/cxypxx/20240430142236103.html
21.Jiang Z,Li W,Hu X,et al.Tucidinostat plus exemestane for postmenopausal patients with advanced,hormone receptor-positive breast cancer(ACE):a randomised,double-blind,placebo-controlled,phase 3 trial.Lancet Oncol.2019;20(6):806-815.doi:10.1016/S1470-2045(19)30164-0
Dr. Ying Wang
Associate Chief Physician, MD, Master’s Supervisor Party Secretary, Breast Cancer Center Deputy Director, Department of Breast Oncology
- 5th “Yangcheng Excellent Physician” Award recipient
- Standing Committee Member, Breast Cancer Professional Committee, Chinese Association of Gerontology and Geriatrics
- Member, Youth Committee, Chinese Society of Clinical Oncology (CSCO)
- Chair, Breast Medical Oncology Management Branch, Guangdong Medical Industry Association
- Vice Chair, Youth Committee, Oncology Branch, Guangdong Medical Association
- Standing Committee Member, Breast Cancer Committee, Guangzhou Anti-Cancer Association
Professor Wang has served as the principal investigator for both Young Scientist and General Projects of the National Natural Science Foundation of China, as well as for the Yat-sen Clinical Research Incubation Project. She has published multiple SCI papers as first or co-first author in journals such as Clinical Cancer Research and Breast Cancer Research and Treatment.
