This is a multicenter, two-arm, exploratory clinical study designed to evaluate the efficacy and safety of a response-guided neoadjuvant treatment strategy in patients with HER2-positive early or locally advanced breast cancer.

Breast cancer is the most common malignancy in women worldwide, and HER2-positive disease accounts for approximately 15-20% of cases and is associated with aggressive tumor biology and a higher risk of recurrence. The introduction of HER2-targeted therapies, including trastuzumab and pertuzumab, has significantly improved patient outcomes. However, a proportion of patients exhibit suboptimal response to standard neoadjuvant therapy, highlighting the need for more effective treatment strategies.

In this study, approximately 100 eligible patients will be enrolled. All patients will initially receive 2 cycles of standard neoadjuvant therapy with trastuzumab, pertuzumab, and chemotherapy (THP or TCbHP). Tumor response will be assessed according to RECIST version 1.1 criteria. Patients with tumor reduction greater than 40% will continue the same regimen for an additional 4 cycles. Patients with tumor reduction of 40% or less will switch to an alternative regimen consisting of SHR-A1811, a novel HER2-targeted antibody-drug conjugate, in combination with pertuzumab for 4 cycles.

SHR-A1811 is an investigational HER2-targeted antibody-drug conjugate designed to deliver a cytotoxic payload directly to tumor cells, potentially overcoming resistance to prior HER2-targeted therapies. Emerging clinical data have demonstrated promising anti-tumor activity and manageable safety in HER2-positive breast cancer.

Clinical data, including baseline characteristics, imaging findings, and pathological markers such as Ki-67, will be collected throughout the study. Efficacy will be evaluated based on imaging assessments according to RECIST 1.1 criteria and pathological response at surgery, while safety will be monitored during treatment.

The primary objective of this study is to explore whether switching to SHR-A1811 in combination with pertuzumab in patients with suboptimal early response can improve pathological complete response (pCR) rates. Secondary objectives include evaluation of safety and tolerability of the treatment strategies.

This study aims to provide evidence for an individualized, response-adapted neoadjuvant treatment approach in HER2-positive breast cancer, and to optimize treatment outcomes for patients with inadequate response to standard therapy.

HER2-positive breast cancer is driven by overexpression or amplification of the HER2 receptor, leading to activation of downstream signaling pathways such as MAPK and PI3K/AKT that promote tumor growth and survival. Although dual HER2 blockade with trastuzumab and pertuzumab in combination with chemotherapy has become a standard neoadjuvant treatment, a subset of patients exhibit insufficient tumor response, indicating biological heterogeneity and potential resistance to therapy.

Pathological complete response (pCR) after neoadjuvant treatment is associated with improved long-term outcomes in HER2-positive breast cancer. Therefore, early identification of patients with suboptimal response and timely treatment modification may represent an effective strategy to improve prognosis.

Antibody-drug conjugates (ADCs) are designed to selectively deliver cytotoxic agents to tumor cells through antigen-specific targeting. SHR-A1811 is an investigational HER2-directed ADC composed of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload via a cleavable linker. Preclinical data have demonstrated potent anti-tumor activity in HER2-expressing models, including those with reduced sensitivity to prior HER2-targeted therapies.

Emerging clinical evidence supports the antitumor activity and manageable safety profile of SHR-A1811 in HER2-positive breast cancer. Its mechanism of action suggests potential benefit in patients with inadequate response to standard HER2-targeted neoadjuvant regimens.

This study is designed to investigate a response-adapted treatment strategy, in which early tumor response is used to guide subsequent therapy selection. By incorporating an alternative HER2-targeted approach for patients with suboptimal response, this study aims to explore strategies to improve treatment efficacy while maintaining an acceptable safety profile.

The results of this study are expected to provide evidence to support individualized neoadjuvant treatment strategies for patients with HER2-positive breast cancer.

Inclusion Criteria:

Participants must meet all of the following criteria:

1. Age ≥18 and ≤70 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
3. At least one measurable lesion according to RECIST version 1.1.
4. Histologically confirmed invasive breast cancer with clinical stage:

Stage II (T2N0-1M0 or T3N0M0), or Stage III (T2N2-3M0, T3N1-3M0, or T4N0-3M0). 5.HER2-positive invasive breast cancer confirmed by histopathology, defined as: HER2 immunohistochemistry (IHC) 3+, or HER2 IHC 2+ with fluorescence in situ hybridization (FISH) positivity, as determined by the pathology department of the participating center. 6.Adequate organ function, defined as:

1. Hematologic function (no blood transfusion, blood products, granulocyte colony-stimulating factor [G-CSF], or other hematopoietic growth factors within 14 days prior to testing):

   Hemoglobin (Hb) ≥100 g/L; Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Platelet count (PLT) ≥100 × 10⁹/L.

2. Biochemical function:

   Total bilirubin (TBIL) ≤1 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 × ULN; Alkaline phosphatase (ALP) ≤2.5 × ULN; Blood urea nitrogen (BUN) and serum creatinine (Cr) ≤1.5 × ULN.

3. Cardiac function:

Left ventricular ejection fraction (LVEF) ≥55% by echocardiography; QT interval corrected by Fridericia's formula (QTcF) ≤450 ms. 7.Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and agree to use effective contraception during the study and for at least 8 weeks after the last dose of study treatment.

8.Willingness to participate in the study, provide written informed consent, and comply with study procedures and follow-up.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded:

1. Prior receipt of any anti-tumor therapy not specified in the study protocol, including but not limited to chemotherapy, radiotherapy, targeted therapy, or endocrine therapy for the current breast cancer.

2. Concurrent receipt of any other anti-tumor therapy during the study. Bilateral breast cancer, inflammatory breast cancer, or occult breast cancer. Stage IV (metastatic) breast cancer.

3. History of other malignancies within the past 5 years, except for adequately treated carcinoma in situ of the cervix.

4. Severe dysfunction of major organs, including but not limited to cardiac, hepatic, or renal insufficiency.

5. Participation in another interventional clinical trial within 4 weeks prior to enrollment.

6. Known hypersensitivity to any component of the study drugs; history of immunodeficiency, including positive human immunodeficiency virus (HIV) test, active hepatitis C virus (HCV) infection, active hepatitis B infection, congenital or acquired immunodeficiency disorders, or history of organ transplantation.

   History of significant cardiac disease, including but not limited to:

   Clinically significant arrhythmia requiring treatment; Myocardial infarction; Heart failure;

7. Any other cardiac condition that, in the investigator's judgment, makes the participant unsuitable for the study.

8. Pregnant or breastfeeding women; women of childbearing potential with a positive pregnancy test at baseline or unwilling to use effective contraception throughout the study period.

9. Any serious concomitant disease that, in the investigator's judgment, may compromise patient safety or interfere with study participation, including but not limited to uncontrolled hypertension, severe diabetes, or active infection.

   History of neurological or psychiatric disorders, including epilepsy or dementia.

10. Any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in this study.

Individual participant data that underlie the results reported in this study, after de-identification, will be made available upon reasonable request. The study protocol, statistical analysis plan, and informed consent form may also be available. Data will be available beginning 6 months after publication and ending 3 years after publication. Requests should be directed to the corresponding author or sponsor.