This study is a response-adapted, multicenter, interventional trial enrolling patients with HER2-positive early or locally advanced breast cancer. All enrolled patients will first receive 2 cycles of standard neoadjuvant THP regimen, consisting of a taxane, trastuzumab, and pertuzumab. After the initial 2-cycle treatment, tumor response will be evaluated by radiologic imaging and patient-derived organoid (PDO) drug sensitivity testing.
Patients with an inadequate response to THP are defined as those with \<50% tumor size reduction on imaging, or failure to reach the PDO sensitivity threshold (\<80% tumor cell killing for HER2+/HR- tumors; \<60% for HER2+/HR+ tumors). These non-responders will switch to receive 4 cycles of trastuzumab rezetecan (SHR-A1811), a novel HER2-targeted antibody-drug conjugate (ADC). Patients with a favorable response (≥50% tumor reduction or meeting the PDO threshold) will continue with an additional 4 cycles of THP.
The primary objective is to evaluate the pathologic complete response (pCR) rate in THP non-responders after switching to trastuzumab rezetecan. Secondary objectives include objective response rate (ORR), event-free survival (EFS), overall survival (OS), 3-year invasive disease-free survival (iDFS), and safety profiles of both treatment strategies. Outcomes in patients who continue THP will be described for exploratory purposes.
A total of 124 patients will be enrolled. This response-adapted, individualized strategy aims to provide an effective option for HER2-positive breast cancer patients with an inadequate early response to conventional THP neoadjuvant therapy.
1.Age ≥18 years. For premenopausal and perimenopausal patients, a negative pregnancy test is required, and the patient must agree to use effective contraception during treatment.
2.Pathologically confirmed invasive breast cancer, stage II-III according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system, with HER2-positive disease defined as: immunohistochemistry (IHC) 3+; or IHC 2+ with confirmed HER2 gene amplification by fluorescence in situ hybridization (FISH).
3.At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
4.No prior chemotherapy, immunotherapy, endocrine therapy, radical surgery, or radiotherapy for breast cancer.
1.Male breast cancer or inflammatory breast cancer.
2.Metastatic breast cancer (Stage IV).
3.Presence of other concurrent malignancies or history of malignancy other than breast cancer within the past 5 years, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
4.Receipt of any other concurrent anti-cancer therapy or participation in another clinical trial.
Sequential
THP Regimen (Taxane + Trastuzumab + Pertuzumab)
DrugNeoadjuvant combination therapy consisting of a taxane, trastuzumab, and pertuzumab. Administered as initial treatment to all patients, and continued for responders.
Trastuzumab Rezetecan (SHR-A1811)
DrugHER2-targeted antibody-drug conjugate (ADC). Administered to patients with inadequate response to initial THP therapy.
Pathologic Complete Response (tpCR) Rate
Proportion of patients achieving pathologic complete response (tpCR), defined as the absence of invasive carcinoma in both the breast primary lesion and axillary lymph nodes (ypT0/is ypN0) after neoadjuvant therapy and surgery. Ductal carcinoma in situ (DCIS) is allowed.
Objective Response Rate (ORR)
Proportion of patients achieving complete response (CR) or partial response (PR) as assessed by the investigator according to RECIST version 1.1 criteria.
Event-Free Survival (EFS)
Time from study enrollment to the first occurrence of invasive disease recurrence (local, regional, or distant), death from any cause, or contralateral invasive breast cancer.
Overall Survival (OS)
Time from study enrollment to death from any cause.
3-Year Invasive Disease-Free Survival (iDFS) Rate
Proportion of patients alive and free from invasive breast cancer recurrence (local, regional, or distant) or contralateral invasive breast cancer at 3 years after study enrollment.
Safety and Tolerability
Incidence, nature, and severity of adverse events (AEs), including serious adverse events (SAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exposure to study treatment will also be summarized.
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