Entinostat Plus Pyrotinib and Endocrine Therapy in Advanced Triple-Positive Breast Cancer After Trastuzumab Failure

Inclusion criteria

• Age ≥ 18 and ≤ 75 years, female, premenopausal or postmenopausal.
• Histologically confirmed HR+/HER2+ breast cancer (HER2 positive defined as IHC 3+ or FISH confirmed by the pathology department of the study center).
• Histologically confirmed locally advanced breast cancer (not amenable to curative local therapy) or recurrent/metastatic breast cancer.
• Prior treatment with trastuzumab and taxane-based anticancer therapy.
• Received 1-2 prior lines of systemic anticancer therapy in the advanced setting.
• Life expectancy ≥ 3 months.
• At least one measurable lesion per RECIST v1.1.
• ECOG performance status 0-2.
• All acute toxicities from prior anticancer therapy resolved to Grade 0-1 (per NCI CTCAE v5.0), except alopecia and toxicities deemed by the investigator to pose no safety risk.
• Adequate bone marrow function: ANC ≥ 1.5×10\^9/L, platelet ≥ 100×10\^9/L, hemoglobin ≥ 90 g/L.
• Adequate hepatic and renal function: TBIL ≤ 1.5×ULN; ALT and AST ≤ 2.5×ULN (or ≤ 5×ULN in the presence of liver metastases); BUN and Cr ≤ 1.5×ULN with creatinine clearance ≥ 50 mL/min.
• Voluntarily participate and sign written informed consent. -

Exclusion criteria

• Factors significantly affecting oral drug absorption, such as inability to swallow, chronic diarrhea, or intestinal obstruction.
• Prior treatment with any HDAC inhibitor for antitumor therapy.
• Prior or current use of any HER2-targeted tyrosine kinase inhibitor (including lapatinib, neratinib, pyrotinib, etc.).
• Known allergy to any component of the study drugs.
• Other malignancy within 5 years prior to enrollment, except cured papillary thyroid carcinoma, cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin.
• Participation in another drug clinical trial within 4 weeks prior to enrollment.
• History of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or history of organ transplantation.
• Uncontrolled significant cardiovascular disease: clinically significant QTc interval prolongation or QTc \> 450 ms at screening; severe cardiac impairment (NYHA \> Class II); unstable angina or myocardial infarction within 6 months; or severe arrhythmia.
• Pregnant or lactating women, or positive pregnancy test at baseline; or women of childbearing potential who are unwilling to use effective contraception during the study and for at least 8 weeks after the last dose.
• Concomitant diseases that, in the investigator's judgment, could seriously endanger patient safety or affect study completion (e.g., severe hypertension, diabetes, thyroid disease, active infection).
• Known history of neurological or psychiatric disorders, including epilepsy or dementia.
• Active hepatitis (HBV: HBsAg positive with HBV DNA ≥ 500 IU/mL; HCV: HCV antibody positive with HCV RNA \> ULN).
• Any condition that, in the investigator's judgment, makes the patient unsuitable for study participation.