Dalpiciclib With or Without Entinostat and Letrozole in HR+/HER2- Early Breast Cancer

For patients with HR-positive, HER2-negative early or locally advanced breast cancer, achieving a clinical complete response with traditional neoadjuvant chemotherapy is challenging, and treatment tolerance is often suboptimal. Endocrine therapy plays an important role in both early-stage and advanced HR+/HER2- breast cancer; however, its efficacy in the neoadjuvant setting remains to be further clarified. Existing studies have shown that, compared with neoadjuvant chemotherapy, neoadjuvant endocrine therapy in HR+/HER2- breast cancer yields comparable clinical complete response and breast-conserving surgery rates, with substantially lower toxicity. Therefore, strategies to further improve response to neoadjuvant endocrine therapy may be more meaningful than intensifying chemotherapy in this population. With the clinical availability of CDK4/6 inhibitors, the efficacy of neoadjuvant endocrine therapy has been further improved. Results from DAWNA-1, DAWNA-2, and DAWNA-A have strengthened the evidence base supporting the use of the domestically developed CDK4/6 inhibitor dalpiciclib in the adjuvant treatment of breast cancer. However, some studies have found that increased histone deacetylase (HDAC) activity in the estrogen receptor (ER) promoter region can suppress ER expression and lead to endocrine therapy resistance. Entinostat is an oral HDAC inhibitor that selectively inhibits class I (primarily HDAC1 and HDAC3) and class IV HDACs. In the phase III study EOC103A3101 conducted in China, entinostat significantly improved median progression-free survival (PFS) compared with placebo (6.32 vs. 3.72 months), reducing the risk of disease progression or death by 24% (HR 0.76). Median overall survival (OS) was also prolonged in the entinostat group (38.39 months), with a 17% reduction in mortality risk (HR 0.83), demonstrating clinically meaningful survival benefits. Based on these findings, the present study aims to further evaluate whether the combination of dalpiciclib, entinostat, and letrozole as neoadjuvant therapy for patients with HR-positive, HER2-negative early breast cancer may provide an improved clinical strategy compared with current standards.