Response-Adapted Omission of Nodal Boost In N3 Breast Cancer After Neoadjuvant Systemic Therapy

Inclusion criteria

• Female/male, aged 18-75 years. 2. ECOG performance status 0-1. 3. Histologically confirmed unilateral invasive breast cancer. 4. No DM (M0), as confirmed by standard staging. 5. cN3 disease, defined according to AJCC 8th staging system, confirmed by imaging and/or pathology, including any of the following:

• cN3a: metastasis to ipsilateral ICV nodes, with or without level I/II ALN involvement.
• cN3b: metastasis to ipsilateral IMNs with concurrent level I/II ALN involvement.
• cN3c: metastasis to ipsilateral SCV nodes, with or without ALN or IMN involvement.

Imaging confirmation is mandatory for all cN3 designations and may be performed using ultrasound, contrast-enhanced CT, MRI, or [18F]FDG PET-CT [16-18]. Across all modalities, abnormal features include, but are not limited to: abnormal enlargement (short-axis ≥5mm), rounded morphology with loss of the normal oval shape, solid appearance with effacement of the fatty hilum and cortical thickening, with or without irregular margins or necrosis. Modality-specific criteria include: heterogeneous enhancement on CT or MRI, or increased FDG uptake (SUVmax > mediastinal blood pool) on PET-CT. Pathological verification by fine-needle aspiration (FNA) or core needle biopsy (CNB) is recommended for SCV and ICV nodes when clinically feasible. If pathological confirmation is not obtained, the cN3 status is based solely on imaging criteria specified above.

• Completion of NST. Standard-of-care regimens must include at least four cycles of chemotherapy; Anti-HER2 targeted therapy is mandatory for HER2-positive disease, and immunotherapy may be added for eligible triple-negative breast cancer (TNBC). Clinical trial regimens are permitted per protocol, with or without chemotherapy, including novel agents (e.g., antibody-drug conjugates [ADCs], immunotherapies, anti-angiogenics, PARP inhibitors, or other investigational drugs). Both pathways are accepted provided the full protocol-specified course is completed.

• Underwent breast-conserving surgery (BCS) or mastectomy with levels I-II axillary lymph node dissection (ALND); IMN, SCV, and ICV nodes were left undissected. All surgical margins must be negative.

• Post-neoadjuvant imaging confirms no macroscopic residual disease in the initially involved but undissected nodal stations. The preferred modality is [18F]FDG PET-CT; ultrasound, contrast-enhanced CT or MRI are acceptable alternatives if PET-CT is unavailable. Imaging may be performed before or after surgery, but must be completed prior to randomization. For all modalities, cCR is defined as the complete disappearance of all previously involved but undissected lymph nodes. In cases where visible nodes persist on imaging, cCR may still be considered if: on PET-CT, no pathologic uptake; on ultrasound, CT, or MRI, nodes have normalized in size and morphology, and no suspicious features are present. Suspicious or equivocal findings require biopsy confirmation of negativity before randomization. All imaging studies must be interpreted by experienced radiologists using standardized criteria.

• Radiotherapy must start within 12 weeks of last surgery or last adjuvant chemotherapy cycle.

• Adjuvant systemic therapy per guidelines or trial protocols; investigational regimens require active trial enrollment.

• Written informed consent obtained.

Exclusion criteria

• Stage IV (metastatic) breast cancer.
• Prior or synchronous contralateral breast cancer.
• Macroscopic residual disease in the initially involved but undissected nodal stations (ICV, IMN, or SCV) in cN3 patients, as evidenced by post-neoadjuvant imaging and/or biopsy.
• Incomplete NST or no definitive breast/ALN surgery.
• Prior radiotherapy to the breast, CW, or regional nodes.
• History of other malignancies, except for adequately treated basal cell carcinoma of the skin or cervical carcinoma in situ (disease-free >3 years).
• Current pregnancy or lactation.
• Severe uncontrolled comorbidities (e.g., cardiac, hepatic, renal, or infectious) precluding radiotherapy, as judged by the investigator.
• Known intolerance or contraindication to radiotherapy or to the planned adjuvant systemic therapy (chemotherapy, endocrine therapy, anti HER2 therapy, or immunotherapy).
• Inability or unwillingness to comply with protocol requirements.