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

Phase 2Not Yet RecruitingNCT07801898

The Second Hospital of Anhui Medical University36 enrolled

Overview

The goal of this investigator-initiated, open-label, phase II clinical trial is to evaluate the efficacy and safety of neoadjuvant chemotherapy combined with endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, Ki67 \> 20% invasive breast cancer. The main questions it aims to answer are: What is the objective response rate (ORR) assessed by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria at the completion of neoadjuvant treatment? What are the changes in Ki-67 proliferation index, pathological tumor response, pathological complete response (pCR) rate, disease-free survival (DFS), and safety profile? Participants will receive standard anthracycline- and taxane-based chemotherapy with letrozole. The chemotherapy regimen was either six cycles of docetaxel, epirubicin, and cyclophosphamide (TEC) every 3 weeks or four cycles of epirubicin plus cyclophosphamide followed by four cycles of a taxane (EC→T). The investigator could replace docetaxel or paclitaxel with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), depending on the patient's clinical features and treatment tolerance. Patients took letrozole 2.5 mg orally once daily throughout neoadjuvant systemic therapy. Premenopausal patients also received ovarian function suppression with leuprorelin acetate (3.75 mg) subcutaneously every 28 days, from the start of neoadjuvant treatment until definitive surgery. A safety assessment will be conducted for each treatment cycle in the patient. During the neoadjuvant therapy phase, tumor assessment will be performed at least after 4 cycles and preoperatively; postoperatively, assessments will be conducted every 3 months using imaging modalities to evaluate the tumor status until disease progression, death, or completion of 3 years postoperatively occurs. Following surgery, all patients will receive adjuvant therapy selected by the investigator based on their individual clinical condition.

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.

Interventions

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 leuprolideDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Objective Response Rate (ORR)

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.

Time frame: At the end of Cycle 4 and prior to surgery (each cycle is 21 days)

Secondary Outcomes

pCR

pCR defined as no residual invasive disease in the breast or axillary lymph nodes (ypT0/is ypN0)

Time frame: At time of definitive surgery (each cycle is 21 days)

Pathological Response

Pathological response defined as Miller-Payne grade 3-5

Time frame: At time of definitive surgery (each cycle is 21 days)

Paired change in Ki67 between biopsy and surgery

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.

Time frame: From baseline biopsy to definitive surgery (each cycle is 21 days)

Disease-Free Survival (DFS)

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.

Time frame: From definitive surgery to 36 months post-surgery (each cycle is 21 days)

Treatment-related adverse events (TRAEs)

Patient safety was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) (Version 5.0) developed by the National Cancer Institute (NCI).

Time frame: From first dose to 30 days after last dose