Dr. Qingyuan Zhang: HDAC Inhibitors Offer Precise Epigenetic Regulation and Broader Treatment Options for Patients with HR+ Advanced Breast Cancer

Histone deacetylases (HDACs) are histone-modifying enzymes that play a key role in regulating epigenetic changes, and they are closely linked to the development and drug resistance of breast cancer. HDAC inhibitors (HDACis) can selectively modulate epigenetic features to control tumor cell proliferation, regulate the cell cycle, and repair DNA damage. As a representative class of epigenetically targeted anti-cancer therapies, HDACis are also recommended by Chinese guidelines as an important treatment option for patients with HR+/HER2- advanced breast cancer who have developed resistance to endocrine therapy. we invited Dr. Qingyuan Zhang from Harbin Medical University Cancer Hospital to share her insights into the current treatment landscape of HR+/HER2- advanced breast cancer and to further explore therapeutic options for patients facing endocrine resistance.

How to Sustain Treatment After Progression on First-Line CDK4/6i + ET in HR+ Advanced Breast Cancer

Hormone receptor positive (HR+) breast cancer is the most common molecular subtype of breast cancer, accounting for approximately 70% of all breast cancer cases. As such, it represents the most significant demand in clinical treatment. For patients with advanced HR+ breast cancer, the combination of CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) has become the standard first-line treatment. This regimen can extend the median progression-free survival (PFS) to over two years and the median overall survival (OS) to more than five years [¹].

However, for patients whose disease progresses after CDK4/6i + ET, there is currently no standardized treatment strategy. Each available option presents certain limitations:

Chemotherapy provides only a modest PFS benefit of 3–4 months and is associated with significant toxicities and poor tolerability [²–⁴].
CDK4/6i continuation beyond progression, while supported by some data indicating potential benefits, still lacks robust evidence overall, requiring cautious consideration [⁵]. To date, only one phase 3 trial—postMONARCH—has yielded positive results, but even then, the PFS benefit was marginal (6.0 vs. 5.3 months; HR 0.73; P=0.02), showing just a 0.7-month improvement [⁶].
Biomarker-driven targeted therapies or novel endocrine therapies comprise another major class of post-progression treatments. However, these are limited to specific subgroups of patients with mutations in the PI3K/AKT/mTOR (PAM) pathway, ESR1, BRCA, and others. In clinical practice, challenges persist with gene testing, including inconsistent standards, limited access, and high costs.

Therefore, there is an urgent clinical need to develop more effective, safe, accessible, and affordable treatment options for patients whose disease has progressed on CDK4/6i + ET.

Epigenetic Regulation: A Promising Avenue for Antitumor Drug Development

Unlike genetic mutations, epigenetic changes refer to heritable alterations in gene expression or cellular phenotype that occur without modifying the DNA sequence. These changes are mediated through mechanisms such as DNA methylation, histone acetylation, chromatin remodeling, and non-coding RNAs. Certain gene mutations can also disrupt epigenetic regulation.

Studies examining common gene mutations and tumor mutational burden (TMB) in Chinese breast cancer patients [⁷] have revealed frequent abnormalities in epigenetic regulators such as KMT2C, ARID1A, KAT6A, CREBBP, and KDM5A. These findings highlight the considerable potential of targeting epigenetic dysregulation as a therapeutic strategy in breast cancer.

In 2004, the U.S. FDA approved azacitidine, the world’s first epigenetically targeted anticancer drug, for the treatment of myelodysplastic syndromes (MDS). Over the past two decades, significant progress in epigenetic oncology research has led to the development of various new targeted agents. The most frequently targeted epigenetic proteins include DNA methyltransferases (DNMTs), histone deacetylases (HDACs), isocitrate dehydrogenases (IDHs), and enhancer of zeste homologs (EZHs) [⁸].

Among solid tumors, breast cancer has become one of the most actively researched cancers in the field of epigenetic therapies. A cross-sectional analysis of ClinicalTrials.gov found that, out of 100 clinical trials involving 22 epigenetic agents, 38 trials were focused on breast cancer, with HDAC inhibitors (HDACis) being the most widely studied class of agents—accounting for 45.45% of the trials [⁹].

HDAC Inhibitors: Slowing the Onset of Endocrine Resistance

HDACs are key enzymes that modulate tumor-associated epigenetic changes and regulate a range of processes including tumor cell proliferation and gene expression. As such, they are one of the most common and promising targets in the development of epigenetically driven therapies for breast cancer [¹⁰].

The balance between histone acetylation and deacetylation is critical for normal gene regulation, and its disruption is closely linked to breast cancer development. In a tissue microarray study of 300 patients with invasive ductal carcinoma, 42.3% to 73.0% of cases showed high expression of HDAC1, HDAC2, HDAC4, or HDAC6. Notably, high levels of HDAC1 and HDAC6 were associated with longer overall survival (OS) in HR+ breast cancer [¹¹]. Another study analyzing 24 breast cancer samples found that 75% of tumor tissues had elevated HDAC1 mRNA levels compared to adjacent normal tissues [¹²].

Beyond their widespread expression, HDACs are also deeply involved in mechanisms of resistance to endocrine therapy in breast cancer, and they play a critical role in cell cycle-specific resistance to CDK4/6 inhibitors. For instance, loss of p21 expression is one mechanism by which tumors become resistant to CDK4/6i therapy. HDAC inhibitors can counteract this by directly activating p21 or by upregulating p21 through p53 activation, leading to cell cycle arrest and apoptosis in multidrug-resistant breast cancer cells—thus reversing CDK4/6i resistance [¹³–¹⁵].

In addition, HDAC inhibitors can increase PTEN expression, thereby inhibiting resistance driven by the PI3K/AKT/mTOR (PAM) signaling pathway, which contributes to both endocrine and CDK4/6i resistance [¹⁶].

These findings underscore the pivotal role of HDACs in treatment resistance and further support the use of HDAC inhibitors as a strategic approach to prolong the efficacy of endocrine therapies and overcome resistance in HR+ breast cancer.

These findings clearly demonstrate that HDACs play a critical role in resistance mechanisms related to both endocrine therapy and cell cycle-targeted treatments in breast cancer. Therefore, HDAC inhibition represents an important strategy for delaying resistance to both endocrine therapies and CDK4/6 inhibitors.

Entinostat Offers New Options for Breast Cancer Patients

In April 2024, entinostat received approval from China’s National Medical Products Administration (NMPA) for use in combination with an aromatase inhibitor (AI) for the treatment of locally advanced or metastatic HR+/HER2− breast cancer in patients who have experienced disease recurrence or progression following prior endocrine therapy. This approval marks the official entry of entinostat into clinical practice in China.

The approval of entinostat was primarily based on positive results from a phase 3 clinical trial in China (EOC103A3101) [¹⁷]. This trial enrolled patients with HR+/HER2− locally advanced or metastatic breast cancer who had relapsed or progressed after previous endocrine therapy (either adjuvant or salvage). Participants were randomized to receive either entinostat or placebo, both in combination with exemestane.

The study met its primary endpoint, showing a nearly two-fold increase in median progression-free survival (PFS) in the entinostat group compared to the control group, as assessed by an independent review committee (IRC). The risk of disease progression was reduced by 24% (6.32 vs. 3.72 months; HR 0.76; 95% CI: 0.58–0.98; P = 0.046). The benefit trend was consistent across all subgroups.

Among patients who had previously received CDK4/6 inhibitors, entinostat led to a 43% reduction in the risk of PFS events (HR 0.57). For patients who had undergone salvage chemotherapy, the risk of PFS events was reduced by 29% (HR 0.71).

As for secondary endpoints, entinostat achieved a median overall survival (OS) of 38.39 months, the longest OS reported to date among phase 3 studies of HDAC inhibitors. Compared to the control group, the risk of death was reduced by 17% (HR 0.83).

These results highlight entinostat’s ability to offer a significant clinical benefit, particularly for patients with limited options following progression on prior endocrine or CDK4/6i therapy.

A Favorable Safety Profile and Convenient Dosing Regimen

In terms of safety, the most common grade ≥3 hematologic adverse events associated with entinostat were neutropenia (43.8%), thrombocytopenia (8.5%), and leukopenia (6.4%). Importantly, the incidence rates of these events were numerically lower than those reported with previous HDAC inhibitors [¹⁸]. The most frequent grade ≥3 non-hematologic treatment-related adverse event was elevated aspartate aminotransferase (AST), occurring in 2.6% of patients.

Another notable feature of entinostat is its long average elimination half-life of 61.9 hours [¹⁹], which supports a once-weekly oral dosing schedule. This makes entinostat the first oral weekly therapy introduced into the clinical management of breast cancer, and the extended dosing interval offers the potential for significantly improved treatment adherence.

Conclusion

Epigenetic alterations are widely present in breast cancer and play a fundamental role in tumor development and progression. Therapeutic strategies aimed at precisely modulating the epigenome have emerged as a key area in the development of novel anticancer agents for breast cancer. As a first-in-class HDAC inhibitor, entinostat exemplifies this approach, offering precise epigenetic control in antitumor therapy.

Phase 3 clinical trial data have confirmed that entinostat provides significant PFS benefits and a median OS exceeding 38 months, with a lower hematologic toxicity profile compared to earlier HDAC inhibitors. Additionally, its once-weekly oral administration makes it a convenient and patient-friendly targeted therapy option, marking a meaningful advancement in the treatment landscape for HR+/HER2− advanced breast cancer.

Reference

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About Dr. Qingyuan Zhang Chief Physician, Second-Level Professor, Doctoral Supervisor Leader of the National Key Clinical Specialty in Oncology National High-Level Talent Program Awardee National Distinguished Young and Middle-Aged Expert with Outstanding Contributions Chair, Lymphoma Committee, Chinese Anti-Cancer Association Vice Chair, Breast Cancer Committee, Chinese Anti-Cancer Association Vice Chair, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO) Vice Chair, Chemotherapy Committee, Chinese Anti-Cancer Association

Reference

[8]Bates SE. Epigenetic Therapies for Cancer. N Engl J Med. 2020;383(7):650-663. doi:10.1056/NEJMra1805035

[13]Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review. Int J Cancer. 2019;145(5):1179-1188. doi:10.1002/ijc.32020.

[15]Ito A, Kawaguchi Y, Lai CH, et al. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 2002;21(22):6236-6245. doi:10.1093/emboj/cdf616

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