China is a country with a high incidence of breast cancer. For operable hormone receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) breast cancer, traditional neoadjuvant chemotherapy often fails to achieve clinical complete response (CCR) and has poor tolerability. Endocrine therapy plays a significant role in the treatment of advanced and early-stage HR+/HER2- breast cancer, but its efficacy in neoadjuvant settings needs further exploration. Studies have shown that the CCR and breast conservation rate of neoadjuvant endocrine therapy for HR+/HER2- breast cancer are similar to those of neoadjuvant chemotherapy, with lower toxicity. Therefore, by precisely stratifying the recurrence risk of HR+/HER2- patients and treating them according to different risk levels, the response rate to neoadjuvant endocrine therapy can be further improved, which would be more beneficial for the patients. With the clinical application of CDK4/6 inhibitors, the effectiveness of neoadjuvant endocrine therapy is expected to be enhanced.
In PALLET study, the combination of palbociclib and letrozole significantly inhibited Ki-67 expression, leading to a higher number of patients achieving a state of cell cycle arrest (CCCA) (defined as Ki-67≤2.7%). NeoMONARCH study suggests that a regimen containing abemaciclib is significantly superior to anastrozole monotherapy, with statistical significance (P \< 0.001). The NeoPAL and CORALLEEN studies indicate that neoadjuvant endocrine therapy with palbociclib or ribociclib is comparable in efficacy to neoadjuvant chemotherapy, yet has fewer side effects.
EndoPredict (12-gene assay, EPclin) is a second-generation multigene testing scoring tool that combines the molecular biological status of the tumor with clinical factors (tumor size and lymph node status). For early-stage HR+/HER2- breast cancer patients, the EPclin test result helps to distinguish between low and high recurrence risk populations, allowing for a more precise assessment of patient prognosis. In the validation study for premenopausal patients, a total of 385 patients with stage ≤pT3 and pN0\~1, who received only endocrine therapy for ER+/HER2- early invasive breast cancer, were enrolled. The results showed that the 10-year distant recurrence-free survival (DRFS) rate for patients in the EPclin low-risk group reached 97%, while the 10-year DRFS rate for the EPclin high-risk group was 76% (P=0.004). For postmenopausal patients, the prognostic value of EPclin was independently validated through the ABCSG6\&8 study. The study included 1,702 patients with ER+/HER2- early invasive breast cancer who underwent surgery and received only five years of endocrine therapy. The results showed that the 10-year distant recurrence rate for patients in the EPclin low-risk group was 4%, while the 10-year distant recurrence rates for patients in the EPclin high-risk group were 28% and 22% (P\<0.001). A retrospective analysis of ABCSG-34 demonstrated that for patients undergoing neoadjuvant endocrine therapy, the application of EPclin for prognostic assessment revealed a negative correlation between risk levels and residual cancer burden (RCB). That is, among patients receiving neoadjuvant endocrine therapy (NET), a higher proportion of low-risk patients compared to high-risk patients ultimately had an RCB of 0-I.
This study focuses on early-stage HR+/HER2- breast cancer, conducting recurrence risk analysis through EPclin multigene testing, and integrating the dynamic changes of Ki67 after two weeks of neoadjuvant endocrine therapy. Patients are risk-stratified and treated with or without CDK4/6 inhibitors. The study explores the improvement in PEPI scores after surgery and analyzes the effectiveness of multigene testing combined with Ki67 dynamic changes as a predictor for the efficacy of CDK4/6 inhibitor treatment in HR+/HER2- breast cancer with high recurrence risk and insensitivity to endocrine therapy. The study also seeks to explore methods for predicting sensitivity to CDK4/6 inhibitor treatment.
