Neoadjuvant Endocrine Therapy Combined With Chemotherapy in ER-positive, HER2-negative Stage I-III Breast Cancer

The investigators assessed radiological response with contrast-enhanced breast magnetic resonance imaging (MRI) at baseline, after four cycles of therapy, and after neoadjuvant treatment but before surgery. Best radiological response was classified according to the RECIST version 1.1. Best percentage tumour reduction was the largest reduction in target-lesion size from baseline across serial MRI examinations. Positive values denoted shrinkage; negative values denoted growth. The investigators scheduled definitive surgery about 3-6 weeks after neoadjuvant therapy, once treatment-related toxicities had resolved adequately and the patient was medically fit. A multidisciplinary team chose the type and extent of surgery after considering pretreatment disease characteristics, radiological response, patient preference, and surgical feasibility.

Dedicated breast pathologists reviewed the pretreatment core-needle biopsies and postoperative surgical specimens according to institutional practice. They graded pathological response with the Miller-Payne system and recorded residual invasive tumour size and postoperative pathological stage (ypT and ypN). They assessed estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 by immunohistochemistry using standardized institutional procedures.

The treating team selected postoperative radiotherapy, endocrine therapy, and other systemic treatment according to pathological findings, recurrence risk, and current institutional and national guidelines. Follow-up then continued according to institutional practice until the predefined data cut-off of 15 July 2026.

• NaCET: For chemotherapy, the TEC or EC-T regimen is selected; for endocrine therapy, letrozole is administered; for premenopausal patients, an LHRH agonist-goserelin or leuprolide (Drug): Patients received NaCET consisting of standard anthracycline- and taxane-based chemotherapy administered concurrently with letrozole. The preferred chemotherapy regimen was TEC, comprising docetaxel, epirubicin, and cyclophosphamide, administered every 3 weeks for six cycles. A sequential EC→T regimen, consisting of four cycles of epirubicin plus cyclophosphamide followed by four cycles of a taxane, was also permitted. At the investigator's discretion, nab-paclitaxel could be substituted for docetaxel or paclitaxel according to individual patient characteristics, treatment tolerance, and clinical considerations. Letrozole was administered orally at 2.5 mg once daily throughout the entire neoadjuvant chemotherapy period. Premenopausal patients additionally received ovarian function suppression with leuprorelin 3.75 mg subcutaneously every 28 days, beginning at initiation of neoadjuvant treatment and continuing throughout the preoperative treatment period.

Primary outcomes

• Objective Response Rate (ORR) [At the end of Cycle 4 and prior to surgery (each cycle is 21 days)]: ORR defined as the proportion of patients whose best radiological response during neoadjuvant treatment was complete response (CR) or partial response (PR) according to RECIST version 1.1.

Secondary outcomes

• pCR [At time of definitive surgery (each cycle is 21 days)]: pCR defined as no residual invasive disease in the breast or axillary lymph nodes (ypT0/is ypN0)
• Pathological Response [At time of definitive surgery (each cycle is 21 days)]: Pathological response defined as Miller-Payne grade 3-5
• Paired change in Ki67 between biopsy and surgery [From baseline biopsy to definitive surgery (each cycle is 21 days)]: The Ki-67 labeling index was visually assessed independently and in a blinded manner by two breast pathologists according to specific instructions. The average value obtained from both observers was used as the final value for each case. For pCR patients, the postoperative Ki-67 value was replaced by the minimum value of 0.01.
• Disease-Free Survival (DFS) [From definitive surgery to 36 months post-surgery (each cycle is 21 days)]: Disease-free survival (DFS) is defined as the time from definitive surgery to the first occurrence of invasive disease recurrence (local, regional, or distant), contralateral invasive breast cancer, or death from any cause. Patients alive without any of these events will be censored at the date of last known disease-free status. Tumor assessments will be performed every 3 months post-surgery for up to 3 years, using imaging modalities (MRI, CT, or ultrasound) as per clinical practice.
• Treatment-related adverse events (TRAEs) [From first dose to 30 days after last dose]: Patient safety was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) (Version 5.0) developed by the National Cancer Institute (NCI).

Sex: All, ages: 18 Years to 18 Years

Inclusion Criteria:

* Eligible patients were aged ≥18 years
* Histologically confirmed estrogen ER-positive, HER2-negative breast cancer with a Ki67 proliferation index >20%.
* ER-positivity was defined as nuclear staining in ≥1% of tumor cells by immunohistochemistry (IHC). HER2-negative disease was defined as an IHC score of 0 or 1+, or an IHC score of 2+ with negative fluorescence in situ hybridization(FISH).
* Patients were required to have stage I-III operable or locally advanced breast cancer according to the eighth edition of the American Joint Committee on Cancer staging system.
* Patients with clinically node-negative disease (cN0) were additionally required to have high-risk clinical features, including a primary tumor classified as cT2 or higher and/or a markedly elevated Ki67 proliferation index.
* Other inclusion criteria were the presence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow and major organ function, and no previous systemic chemotherapy or endocrine therapy for breast cancer.

Exclusion Criteria:

* Previous chemotherapy or endocrine therapy for breast cancer;
* Pregnancy or lactation;
* Severe or uncontrolled infection;
* Clinically significant cardiovascular disease, including New York Heart Association class III or IV heart failure, unstable angina, or myocardial infarction within 6 months before enrollment;
* Left ventricular ejection fraction <50%;
* A history of organ transplantation requiring ongoing immunosuppressive therapy;
* Known human immunodeficiency virus infection;
* A concurrent or previous malignancy that could interfere with the assessment of study outcomes;
* Psychiatric, cognitive, or other medical conditions that could impair treatment adherence or compliance with study procedures.

• Study Protocol and Statistical Analysis Plan (PDF, 2024-02-22)