Highlight
– In the phase 2 MUKDEN 05 trial (NCT05400993), neoadjuvant chidamide combined with sequential epirubicin–cyclophosphamide (EC) and docetaxel achieved a residual cancer burden (RCB) 0–I rate of 35.2% (19/54) in stage II–III, treatment-naïve HR+/HER2– breast cancer.
– The regimen was associated with frequent grade 3–4 hematologic toxicity (neutropenia 70%, leukopenia 67%); no treatment-related deaths were reported.
– Results are hypothesis-generating; randomized studies and translational biomarkers are required to define benefit and patient selection.
Background: disease context and unmet need
Hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer constitutes the largest molecular subtype of breast cancer. Compared with HER2-positive or triple-negative tumors, HR+/HER2– cancers generally have lower pathological complete response (pCR) rates to neoadjuvant chemotherapy and more heterogenous biology, with a spectrum from luminal A (lower proliferation) to luminal B (higher proliferation). Because pCR correlates imperfectly with long-term outcome in HR+/HER2– disease, residual cancer burden (RCB), which grades the extent of residual disease after neoadjuvant therapy (RCB 0 = pCR; RCB I = minimal residual disease), is frequently used as a clinically relevant endpoint to assess efficacy.
Novel strategies to improve neoadjuvant outcomes for HR+/HER2– disease are desirable — either to increase the proportion of patients achieving minimal residual disease or to identify patients in whom escalation of systemic therapy will meaningfully alter recurrence risk. Epigenetic modifiers, including histone deacetylase (HDAC) inhibitors, have shown preclinical activity in breast cancer and potential to modulate endocrine resistance, cell cycle regulation, and antitumor immunity, supporting clinical testing in combination regimens.
Study design
MUKDEN 05 is a multicentre, open-label, single-arm phase 2 trial conducted at three hospitals in China, enrolling women aged 18–75 years with previously untreated, stage II–III HR+/HER2– breast cancer and ECOG performance status 0–1. Key eligibility criteria included centrally or locally confirmed estrogen and/or progesterone receptor positivity and HER2 negativity per accepted guidelines.
Treatment comprised oral chidamide 20 mg on days 1, 4, 8, and 11 of each 21-day cycle given concurrently with standard cytotoxic chemotherapy: four cycles of epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) every three weeks (EC), followed by four cycles of docetaxel (100 mg/m2) every three weeks. Surgery was planned after completion of neoadjuvant therapy and patients underwent pathologic assessment to determine RCB class. The primary endpoint was the proportion of patients achieving RCB 0–I. Key safety endpoints recorded adverse events graded by NCI CTCAE criteria.
The trial is registered at ClinicalTrials.gov (NCT05400993) and funded by the Shenyang Municipal Science and Technology Program and Shenzhen Chipscreen Biosciences Co., Ltd.
Key findings
Between May 23, 2022 and July 6, 2023, 54 female patients were enrolled (median age 50 years, range 26–75). The principal efficacy and safety outcomes reported were as follows.
Efficacy: RCB 0–I rate and interpretation
The RCB 0–I rate was 35.2% (19 of 54 patients; 95% confidence interval [CI], 22.7%–49.4%). This represents the proportion of patients with either pathologic complete response (RCB 0) or minimal residual disease (RCB I) at the time of definitive surgery following the neoadjuvant regimen.
How should this number be interpreted? In HR+/HER2– breast cancer, pCR rates to standard anthracycline–taxane regimens are generally low compared with other subtypes; rates of true pCR are commonly reported in the single digits for luminal-A–type tumors and somewhat higher for more proliferative luminal-B tumors. RCB 0–I combines pCR with minimal residual disease and therefore can capture clinically meaningful downstaging beyond pCR alone. A 35% RCB 0–I rate in an unselected stage II–III HR+/HER2– cohort is notable and suggests chidamide may have contributed to improved tumor cytoreduction when added to EC → docetaxel, although direct comparisons with historical controls are limited by differences in patient case-mix, disease stage, and endpoint definitions.
Safety and tolerability
The regimen was associated with substantial hematologic toxicity. The most frequent grade 3–4 adverse events were decreased neutrophil count (70%) and decreased white blood cell count (67%). Non-hematologic grade 3–4 toxicity was not highlighted as frequent in the primary report, and importantly, there were no treatment-related deaths. The high incidence of severe neutropenia and leukopenia likely reflects the expected myelosuppression from anthracycline–taxane chemotherapy; whether chidamide contributed incrementally to marrow toxicity cannot be definitively concluded from a single-arm study without pharmacodynamic or comparative safety data.
Other outcomes and subgroup observations
The primary paper reports the RCB 0–I rate and toxicity as the principal results. The trial report did not present mature long-term outcomes (event-free survival, distant recurrence-free survival, or overall survival), nor were correlative biomarker data (such as baseline proliferation index, genomic subtype, or immune markers) reported in detail in the primary analysis. Those data, if forthcoming, will be important to define which patients benefit most.
Expert commentary and contextualization
Biological plausibility. HDAC inhibitors act by altering chromatin acetylation, leading to changes in gene transcription that can restore expression of tumor suppressor genes, alter hormone receptor signaling, and modulate the tumor microenvironment. Preclinical models have shown that HDAC inhibition can sensitize breast cancer cells to cytotoxic agents and endocrine therapy and may have immune-modulatory effects that enhance antitumor responses.
Prior clinical evidence. HDAC inhibitors have been explored in breast cancer predominantly in the metastatic setting, often in combination with endocrine therapy in patients with resistance to aromatase inhibitors. Results have been mixed and, in some cases, disappointing when taken to phase III testing. The neoadjuvant setting offers the advantage of a short course of systemic therapy with a pathologic endpoint and the opportunity to obtain pre- and post-treatment tissue for translational study, making it an attractive setting to test novel combinations such as chidamide plus chemotherapy.
Strengths of MUKDEN 05. The trial is multicentre and prospectively enrolled a defined HR+/HER2– population using a clear treatment protocol and a clinically meaningful pathological endpoint (RCB). The use of sequential EC → docetaxel mirrors a common neoadjuvant chemotherapy backbone, supporting pragmatic interpretation.
Limitations. The single-arm design limits causal inference: without a randomized control group receiving identical chemotherapy, it is not possible to separate the effect of chidamide from the expected activity of anthracycline–taxane chemotherapy or from patient selection. The sample size is modest (n=54), and the confidence interval around the RCB 0–I estimate is wide. Toxicity attribution is uncertain. The absence of reported biomarker correlates and no mature survival endpoints limits the ability to extrapolate whether the observed pathological responses will translate to improved long-term outcomes.
Clinical implications. The 35% RCB 0–I rate is hypothesis generating but not practice changing. Before incorporating chidamide into routine neoadjuvant management for HR+/HER2– breast cancer, randomized data comparing chemotherapy with and without chidamide are required, ideally with stratification by molecular subtype (e.g., luminal A vs luminal B) and incorporation of translational endpoints to define predictive biomarkers and mechanisms of benefit. Safety strategies to manage the notable hematologic toxicity should also be clarified (growth factor support, dose modifications, and monitoring schedules).
Mechanistic considerations and translational opportunities
Potential mechanisms by which HDAC inhibition might enhance neoadjuvant chemotherapy responses include reversal of epigenetically mediated drug resistance pathways, down-modulation of survival signaling, induction of apoptosis, and changes in tumor immune milieu (for example, upregulation of tumor antigen presentation and modulation of immune checkpoints). Future trials should embed correlative studies: pretreatment and on-treatment biopsies for chromatin and transcriptome profiling, immune-cell infiltration assays, and circulating tumor DNA (ctDNA) dynamics to correlate biological changes with pathologic response and early molecular residual disease.
Conclusions and next steps
The MUKDEN 05 phase 2 trial demonstrates that adding oral chidamide to a standard EC → docetaxel neoadjuvant chemotherapy regimen in stage II–III HR+/HER2– breast cancer produced an RCB 0–I rate of 35.2% in a cohort of 54 patients, with frequent grade 3–4 neutropenia but no treatment-related deaths. These results are promising but preliminary.
Critical next steps include randomized controlled trials comparing the same chemotherapy backbone with and without chidamide to establish whether the addition provides a true incremental benefit in pathological response and, more importantly, long-term oncologic outcomes. Trials should prospectively incorporate translational endpoints to identify predictive biomarkers and mechanisms of action, and should define safety management protocols to mitigate hematologic toxicity. Given the heterogeneity of HR+/HER2– disease, biomarker-enriched strategies (for example, selecting higher-proliferation luminal-B tumors or those with specific epigenetic signatures) may maximize the likelihood of benefit.
Funding and trial registration
Funding: Shenyang Municipal Science and Technology Program (Grant No. 22-321-32-18), Shenzhen Chipscreen Biosciences Co., Ltd.
ClinicalTrials.gov: NCT05400993.
References
1. Xue J, Shan H, Qiu F, Niu N, Chen G, Xu Q, Gu X, Xing F, Xu Y, Zheng X, He G, Xu H, Zhang H, Song D, Han Y, Tang M, Cao S, Song Y, Zheng R, Zhao Y, Jiao G, Liu M, Liu C. Neoadjuvant chidamide combined with chemotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (MUKDEN 05): a multicentre, single-arm, phase 2 trial. Lancet Reg Health West Pac. 2025 Sep 27;63:101700. doi: 10.1016/j.lanwpc.2025.101700. PMID: 41080407; PMCID: PMC12510053.
2. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002 Apr;1(4):287–299. doi:10.1038/nrd772.
Author note
This article synthesizes the primary results of the MUKDEN 05 trial and provides contextual interpretation for clinicians and researcher–physicians. It is not a guideline and does not substitute for individualized clinical judgment.
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A clinical research montage showing a thoughtful female patient silhouette in profile, a stylized breast cancer awareness ribbon, an infusion bag icon and a tablet representing oral medication, and abstract chromatin strands with highlighted histone tails being acetylated/deacetylated; cool clinical-blue and muted accent colors; high-resolution, modern medical-infographic style suitable for an academic article thumbnail.
