SHR-A1811 Versus Trastuzumab Plus Pertuzumab in ctDNA-Positive HER2-Positive Early Breast Cancer After Pathologic Complete Response

Inclusion Criteria:

1. Written informed consent before any study-specific procedure and willingness to comply with study visits and sample collection.
2. Female, aged 18 years or older.
3. Histologically confirmed invasive breast carcinoma at initial diagnosis, without distant metastasis.
4. HER2-positive tumor at initial diagnosis, defined as IHC 3+ or IHC 2+ with ISH amplification; hormone receptor status must be known.
5. Initial clinical anatomic stage IIB-IIIC according to the AJCC 8th edition.
6. Completion of at least 6 cycles and at least 16 weeks of standard neoadjuvant systemic therapy.
7. Definitive breast surgery and appropriate axillary staging or dissection, with pathologically complete resection.
8. Pathologic complete response, defined as no residual invasive carcinoma in the breast or regional lymph nodes (ypT0/is ypN0); residual ductal carcinoma in situ is permitted.
9. Postoperative ctDNA positivity confirmed by the designated central testing laboratory 14-42 days after the last definitive surgery and before initiation of any adjuvant systemic therapy.
10. No clinical, pathologic, or radiographic evidence of locoregional recurrence or distant metastasis before randomization; baseline chest CT is required to assess interstitial lung disease/noninfectious pneumonitis.
11. Randomization within 12 weeks after the last definitive surgery; extension to 14 weeks may be permitted for documented surgical complications, reoperation, or sequential radiotherapy with principal investigator approval.
12. ECOG performance status 0 or 1.
13. Left ventricular ejection fraction at least 50% within 28 days before randomization, without clinically significant cardiac dysfunction.
14. Adequate bone marrow, hepatic, renal, and coagulation function.
15. Negative pregnancy test for participants of childbearing potential and agreement to use highly effective contraception for the protocol-specified period.

Exclusion Criteria:

1. Clinical, radiographic, or pathologic evidence of unresectable locally advanced, recurrent, or metastatic disease, or disease progression during neoadjuvant therapy.
2. Failure to achieve ypT0/is ypN0 or any residual invasive carcinoma in the breast or regional lymph nodes.
3. Prior ipsilateral or contralateral breast cancer, including ductal carcinoma in situ; lobular carcinoma in situ is permitted.
4. Any postoperative systemic anticancer therapy before randomization, including trastuzumab, pertuzumab, another anti-HER2 agent, chemotherapy, antibody-drug conjugate, or endocrine therapy; bridging therapy is not permitted.
5. Prior neoadjuvant treatment with T-DM1, trastuzumab deruxtecan, SHR-A1811, or another HER2-directed antibody-drug conjugate.
6. Prior or current interstitial lung disease/noninfectious pneumonitis requiring corticosteroid treatment, active interstitial lung disease on screening imaging, clinically significant pulmonary fibrosis, severe chronic obstructive pulmonary disease, resting hypoxemia, or another pulmonary disorder that would interfere with pulmonary toxicity assessment.
7. Clinically significant cardiovascular disease, including symptomatic heart failure or NYHA class II-IV heart failure, myocardial infarction or unstable angina within 6 months before screening, uncontrolled clinically significant arrhythmia, QTcF greater than 470 ms, or blood pressure above 150/90 mmHg despite appropriate treatment.
8. Active or uncontrolled infection requiring systemic treatment, or active HBV/HCV or HIV not meeting protocol and institutional control criteria.
9. Toxicities from prior therapy not recovered to grade 1 or lower, except alopecia, hyperpigmentation, and stable grade 2 peripheral neuropathy judged clinically insignificant by the investigator.
10. Another malignancy within 5 years before screening, except adequately treated basal or squamous cell skin cancer, cervical carcinoma in situ, or another malignancy with a low risk of recurrence.
11. Severe hypersensitivity to a study drug or any of its excipients.
12. Pregnancy, breastfeeding, or plans for pregnancy during the protocol-specified period.
13. Any serious medical or psychosocial condition that, in the investigator's judgment, would make study treatment, follow-up, or interpretation of results unsafe or unreliable.