CDK4/6 Inhibitor Intensification and Chemotherapy De-Escalation for Early-stage Luminal-HER2 Breast Cancer

Chemotherapy Omission in HR-positive/HER2-positive Breast Cancer With Lymph Node Negative Disease Receiving Adjuvant Endocrine Therapy and CDK4/6 Inhibitor Combined With Anti-HER2 Therapy

The investigators designed a phase III clinical trial involving hormone receptor-positive and HER2-positive stage I breast cancer patients. This trial aims to evaluate the efficacy and safety of a treatment regimen combining CDK4/6 inhibitors, endocrine therapy, and anti-HER2 therapy compared with the traditional approach of chemotherapy combined with anti-HER2 therapy.

For patients with hormone receptor-positive and HER2-positive breast cancer, the NCCN guidelines recommend that those with tumors larger than 1 cm or positive lymph nodes should receive standard adjuvant therapy comprising chemotherapy combined with targeted and endocrine therapy. In contrast, for patients with tumors smaller than 1 cm and negative lymph nodes, endocrine therapy alone or in combination with targeted therapy and chemotherapy may be considered. Therefore, in patients with stage I hormone receptor-positive and HER2-positive breast cancer, it remains unclear whether chemotherapy can be omitted by intensifying endocrine therapy through the addition of CDK4/6 inhibitors, particularly considering the intrinsic therapeutic efficacy of endocrine agents and their potential synergistic interaction with anti-HER2 therapy. To further minimize treatment-related toxicity and identify the optimal adjuvant treatment strategy for patients with HER2-positive stage I breast cancer, the investigators designed a phase III clinical trial involving hormone receptor-positive and HER2-positive stage I breast cancer patients. This trial aims to evaluate the efficacy and safety of a treatment regimen combining CDK4/6 inhibitors, endocrine therapy, and anti-HER2 therapy compared with the traditional approach of chemotherapy combined with anti-HER2 therapy.

Inclusion Criteria:

1. Female patients aged between 18 and 75 years;
2. Unilateral invasive carcinoma confirmed by histopathological examination;
3. Postoperative pathological stage I early breast cancer: histologically confirmed invasive carcinoma with a maximum tumor diameter not exceeding 2 cm and no lymph node metastasis (N0);
4. Estrogen receptor (ER) expression ≥ 50%;
5. Immunohistochemical and molecular pathology must meet one of the following criteria: HER-2 overexpression (3+) or HER-2 (0-2+) with gene amplification confirmed by fluorescence in situ hybridization (FISH);
6. Histological grade 1-2 or selected grade 3 tumors with at least one of the following additional features: PAM50 or HER2-based subtyping indicating luminal phenotype , or tumor size ≤ 1 cm );
7. Adequate major organ function, defined as:

(1) Hematologic parameters: hemoglobin (HB) ≥ 90 g/L (without blood transfusion within 14 days), absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, platelet count (PLT) ≥ 100 × 10⁹/L; (2) Biochemical parameters: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN, serum creatinine (Cr) ≤ 1 × ULN, and calculated creatinine clearance > 50 mL/min using the Cockcroft-Gault formula; 8) Cardiac function preserved with left ventricular ejection fraction (LVEF) > 50%; 9) Willing to participate in the study, with signed informed consent, good compliance, and willingness to comply with follow-up requirements.

Exclusion Criteria:

1. Tumors with a maximum diameter exceeding 2 cm and/or presence of positive axillary lymph nodes;
2. HER2-negative status defined as HER2- or HER2+ by immunohistochemistry; or HER2 2+ by immunohistochemistry without gene amplification confirmed by fluorescence in situ hybridization (FISH);
3. Patients who have previously received neoadjuvant therapy or any form of systemic or non-surgical local treatment prior to enrollment, including chemotherapy, targeted therapy, radiotherapy, or endocrine therapy;
4. History of other malignant tumors, excluding cured basal cell carcinoma of the skin and cervical carcinoma in situ;
5. Has metastatic (Stage 4) breast cancer;
6. Pregnant or lactating women, as well as women of childbearing potential who are unable to use effective contraception;
7. Patients currently enrolled in other clinical trials;
8. Severe organ dysfunction involving the cardiovascular, pulmonary, hepatic, or renal systems, including left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiography; history of severe cardiovascular or cerebrovascular events within 6 months prior to enrollment (e.g., unstable angina, chronic heart failure, uncontrolled hypertension > 150/90 mmHg, myocardial infarction, or stroke); patients with poorly controlled diabetes mellitus; patients with severe or uncontrolled hypertension;
9. Active severe or uncontrolled infections;
10. Patients with a history of substance abuse involving psychotropic drugs with ongoing dependency, or a documented history of psychiatric disorders that may interfere with study compliance;
11. Patients deemed unsuitable for participation by the principal investigator or designated study physician.