Breast cancer remains the most frequently diagnosed cancer among women worldwide, and the pursuit of novel therapies continues to command global attention. In the setting of HR+/HER2− advanced breast cancer, the introduction of entinostat, a novel histone deacetylase inhibitor (HDACi), marks a significant therapeutic advancement. With a distinctive mechanism of action, entinostat not only extends overall survival (OS) but also demonstrates a favorable safety profile. Its innovative once-weekly dosing schedule enhances treatment convenience and patient adherence. When combined with an aromatase inhibitor, entinostat opens a new chapter in second-line management for patients progressing after CDK4/6 inhibitors, pushing breast cancer treatment toward a more personalized and precision-based era.Shifting the Focus: From Cure to Long-Term Control and Quality Survival
The definition of “cure” in oncology continues to evolve with medical progress. Traditionally, it refers to the complete No Evidence of Disease (NED) sustained for five years or longer after treatment. In this context, five-year survival rates serve as a critical benchmark of treatment success.
According to the World Health Organization’s Global Cancer Observatory, 2.26 million new breast cancer cases were reported globally in 2020, overtaking lung cancer as the most common malignancy worldwide. Breast cancer is also the leading cause of cancer-related death among women. In China alone, 420,000 new cases were diagnosed the same year, accounting for nearly 20% of all newly diagnosed female cancers. As precision medicine and therapeutic innovation continue to advance, survival outcomes have improved significantly. Data from China’s National Cancer Center show that the five-year survival rate for breast cancer surpassed 83% in 2015, reaching parity with developed nations[¹].
However, true cure remains elusive for patients with advanced disease. In these cases, the goal of treatment shifts toward prolonging survival and enhancing quality of life. With the development of targeted therapies and improved care strategies, many patients with advanced breast cancer are living longer, healthier lives. The 2022 edition of the Chinese Guidelines for Standardized Diagnosis and Treatment of Advanced Breast Cancer acknowledges that, while cure may not be attainable, long-term disease control is increasingly possible with appropriate therapies that reduce tumor burden, alleviate symptoms, and improve patient well-being[²].
Similarly, the 2024 edition of the CBCS Guidelines highlights the primary therapeutic goals in advanced disease: delaying progression, improving quality of life, and extending survival[³]. Among efficacy endpoints in clinical trials, progression-free survival (PFS) and overall survival (OS) are the gold standards. Of these, OS remains the definitive measure of patient benefit. Increasingly, long-term survival—while managing cancer as a chronic condition—is becoming a realistic objective for many patients.
CDK4/6 Inhibitors and Endocrine Therapy: Establishing a Foundation for HR+ Advanced Breast Cancer
The HR+/HER2− subtype accounts for approximately 70% of all breast cancer cases. For patients with advanced HR+ disease, CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have transformed the treatment landscape, significantly improving both PFS and OS.
Multiple large-scale trials have validated the efficacy of CDK4/6i in this population. The MONALEESA-2, PALOMA-2, MONARCH-3, and DAWNA-2 studies all enrolled postmenopausal women with HR+/HER2− metastatic breast cancer receiving first-line therapy. Despite variations in median PFS across studies, all demonstrated a substantial reduction in the risk of progression when CDK4/6i were added to aromatase inhibitors—hazard ratios ranging from 0.51 to 0.56—confirming the synergy between CDK4/6i and ET[⁴].
As a result, CDK4/6i + ET combinations are now recognized as the standard first-line treatment for HR+/HER2− metastatic breast cancer by major guidelines worldwide, including those from the NCCN and CSCO[⁷–⁹]. This therapeutic strategy has laid a strong foundation for extending OS and maximizing quality-adjusted survival in these patients.
Entinostat in the Post-CDK4/6i Era: Enhancing Survival with Safety and Convenience for HR+ Advanced Breast Cancer
As CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) continue to demonstrate significant survival benefits for patients with HR+/HER2− advanced breast cancer, clinical resistance or disease progression remains a key challenge. The urgent need for effective treatment options beyond CDK4/6i has brought attention to a variety of post-progression strategies, although a universally accepted standard of care has yet to be established.
CDK4/6i Sequencing: Limited Efficacy in Cross-Line Use
Cross-line CDK4/6i therapy—switching from one CDK4/6 inhibitor to another after initial progression—has yielded only modest results in current studies. Among them, the phase II MAINTAIN trial[¹⁰] and the phase III postMONARCH trial[¹¹] reported preliminary benefits; however, neither study has yet delivered mature overall survival (OS) data, and the level of evidence supporting this approach remains relatively low.
Chemotherapy: Modest Benefit, Higher Toxicity
Chemotherapy remains a conventional option, but its efficacy in HR+ MBC post-CDK4/6i is limited. The YOUNG BC-9 study[¹²] demonstrated a median progression-free survival (PFS) of just 5.6 months following chemotherapy in patients progressing after CDK4/6i, and the incidence of treatment-related adverse events was notably high.
PAM Pathway Inhibitors: Biomarker-Dependent with Constrained Utility
Targeted agents aimed at the PI3K/AKT/mTOR (PAM) pathway, such as everolimus and alpelisib, have shown promise in selected biomarker-positive populations. The BOLERO-2 trial confirmed that everolimus combined with exemestane significantly prolonged PFS (11.0 vs. 4.1 months) compared to exemestane monotherapy in patients with AI-resistant advanced breast cancer. However, toxicity—especially stomatitis, which occurred in nearly 60% of patients—remains a key concern[²].
In the CAPItello-291 trial, the combination of the AKT inhibitor capivasertib and fulvestrant demonstrated a PFS benefit over fulvestrant alone in patients with prior AI failure (7.3 vs. 3.1 months), including a notable benefit among CDK4/6i-pretreated individuals (approx. 70% of the cohort). However, OS data remain immature[¹³]. Subgroup analysis in Asian populations revealed frequent adverse events such as diarrhea (60.6%) and hyperglycemia (57.7%) in the combination arm[¹⁴]. Despite these results, PAM pathway inhibitors are primarily indicated for patients harboring specific genetic mutations (e.g., PIK3CA, AKT, PTEN), necessitating comprehensive biomarker testing. Their efficacy in broader clinical practice remains to be validated, and tolerability issues may compromise adherence.
HDAC Inhibition: A Novel Mechanism with Broad Applicability
Entinostat, a novel histone deacetylase inhibitor (HDACi), represents a mechanistically distinct approach to post-CDK4/6i treatment. By altering histone acetylation, entinostat modulates chromatin structure and gene expression, thereby inhibiting tumor proliferation. It also overcomes CDK4/6i resistance by activating p21, upregulating PTEN, and exerting immunomodulatory effects.
On April 24, 2024, China’s National Medical Products Administration (NMPA) approved entinostat in combination with an aromatase inhibitor (AI) for the treatment of HR+/HER2− advanced or locally recurrent breast cancer in patients who progressed following prior endocrine therapy[¹⁴]. The approval was based on results from the phase III EOC103A3101 trial, led by Academician Binghe Xu at the Chinese Academy of Medical Sciences[¹⁵].
The EOC103A3101 trial enrolled patients aged 18–75 years with HR+/HER2− advanced or locally recurrent breast cancer who had progressed on prior endocrine therapy. Participants were randomized in a 2:1 ratio to receive either entinostat plus exemestane or placebo plus exemestane.
The trial results demonstrated a statistically significant improvement in progression-free survival (PFS) with entinostat. Patients in the entinostat group achieved a median PFS of 6.32 months, compared to 3.72 months in the placebo group, representing a 24% reduction in the risk of disease progression or death (hazard ratio [HR] 0.76; 95% confidence interval [CI]: 0.58–0.98; P=0.046).
In terms of overall survival (OS), the entinostat group achieved a median OS of 38.39 months, extending survival by more than 9 months compared to the placebo group. This corresponded to a 17% reduction in the risk of death (HR 0.83; 95% CI: 0.62–1.10); however, the difference did not reach statistical significance (P=0.184).
Notably, entinostat is currently the only HDAC inhibitor to demonstrate a median overall survival (OS) exceeding 38 months, offering patients a substantial survival advantage. Importantly, its clinical benefit extends to patients who have developed resistance to CDK4/6 inhibitors as well as those previously treated with salvage chemotherapy—further underscoring its therapeutic potential in the post-CDK4/6i setting.
Entinostat has also demonstrated a favorable safety and tolerability profile in clinical studies. While some patients may experience hematologic adverse events such as neutropenia or thrombocytopenia, these events are typically mild to moderate in severity and can be effectively managed through appropriate clinical intervention. In addition, the convenience of once-weekly oral dosing significantly enhances patient adherence by minimizing treatment burden and improving the overall patient experience.
Conclusion
As a novel histone deacetylase inhibitor (HDACi), entinostat has emerged as a promising treatment option for patients with HR+/HER2− advanced breast cancer. Through epigenetic modulation, immune activation, and the ability to overcome CDK4/6 inhibitor resistance, entinostat delivers meaningful clinical benefits—most notably, a median OS beyond 38 months, a benchmark not previously achieved by other HDAC inhibitors in this setting.
Its compelling combination of efficacy, manageable safety profile, and patient-friendly administration positions entinostat as a key therapeutic advancement in the post-CDK4/6i landscape. As its clinical use expands, entinostat is poised to support longer survival and improved quality of life for a broader population of patients, while driving breast cancer care toward greater personalization and precision.
References
[¹] 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．
[²] 国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2022版) [J] . 中华肿瘤杂志, 2022, 44(12) : 1262-1287. DOI: 10.3760/cma.j.cn112152-20221007-00680.
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[⁴] 国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. CDK4/6抑制剂治疗激素受体阳性人表皮生长因子受体2阴性乳腺癌临床应用专家共识(2023版)[J]. 中华肿瘤杂志, 2023, 45(12):1003-1017. DOI: 10.3760/cma.j.cn112152-20230428-00188.
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Dr. Jing Cheng, PhD
Chief Physician, Professor, Doctoral Supervisor Director, Department of Breast Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Vice Chair, Breast Cancer Committee, Hubei Anti-Cancer Association
- Standing Committee Member, Breast Cancer Expert Committee, CSCO
- Standing Committee Member, Chemotherapy Committee, Chinese Anti-Cancer Association
- Member, Breast Cancer Committee, Precision Medicine Branch, Chinese Medical Doctor Association
- Vice President, Hubei Breast and Thyroid Society
- Executive Member, Asia-Pacific Society for Medical Immunology
- Chair, Radiotherapy and Immunology Committee, Hubei Medical Immunology Society
- Reviewer for national medical journals and NSFC expert
- Published 10+ SCI papers; lead investigator of 4 national/provincial research projects
- Editor-in-chief of 4 academic books; awarded provincial science achievement honors
- Specialized in multidisciplinary treatment of recurrent/metastatic breast cancer and radiotherapy
