Should regional nodal irradiation be given in an adult with clinical T3 N0 HER2‑positive breast cancer who achieved a pathologic complete response after neoadjuvant trastuzumab ± pertuzumab with taxane chemotherapy and has undergone breast‑conserving surgery or mastectomy with clear margins and no prior chest irradiation?

Regional Nodal Irradiation in cT3N0 HER2+ Breast Cancer with Pathologic Complete Response

Yes, you should perform regional nodal irradiation (RNI) in this patient, because radiation therapy decisions must be based on pre-treatment clinical stage (cT3N0), not on the pathologic response to neoadjuvant therapy. 1, 2

Core Principle: Pre-Treatment Stage Determines Radiation Fields

The fundamental guideline principle is that radiation therapy indications after neoadjuvant chemotherapy must be based on the worst (maximal) disease stage from either pre-treatment clinical assessment or post-treatment pathology, whichever is higher, regardless of treatment response. 1, 2

• The NCCN explicitly states that radiation therapy is recommended in patients with clinical stage III disease who achieve pathologic complete response to neoadjuvant chemotherapy. 1, 2
• This principle applies even when patients convert from clinically node-positive to pathologically node-negative status. 1, 2

Specific Indication for cT3 Disease

For tumors larger than 5 cm (clinical T3), the NCCN strongly recommends regional nodal irradiation even when the clinical nodal status is N0. 2

• The NCCN specifically advises consideration of radiation to the ipsilateral supraclavicular area and internal mammary lymph nodes for patients with tumors >5 cm (Category 2A). 2
• In node-negative disease with tumor size >5 cm, clinicians should consider RNI. 2

Recent Contradictory Evidence: The NSABP B-51/RTOG 1304 Trial

However, the 2025 NSABP B-51/RTOG 1304 trial challenges this traditional approach specifically for patients who achieve ypN0 status after neoadjuvant chemotherapy. 3

• This randomized trial of 1,556 patients with cT1-T3N1 disease who achieved ypN0 status after neoadjuvant chemotherapy found that regional nodal irradiation did not significantly increase the invasive breast cancer recurrence-free interval (HR 0.88,95% CI 0.60-1.28, P=0.51). 3
• After median follow-up of 59.5 months, survival free from recurrence or death was 92.7% with RNI versus 91.8% without RNI. 3
• RNI did not improve locoregional recurrence-free interval, distant recurrence-free interval, disease-free survival, or overall survival. 3

Critical Distinction: Your Patient is cN0, Not cN1

The NSABP B-51 trial enrolled only patients with biopsy-proven node-positive disease (cN1) who converted to ypN0. 3 Your patient was clinically node-negative (cN0) from the outset, which represents a different clinical scenario not directly addressed by this trial.

Reconciling Guidelines with Recent Evidence

Despite the negative NSABP B-51 trial results, the established NCCN guidelines still recommend RNI for cT3 tumors based on tumor size alone, independent of nodal status. 2

Why Guidelines Still Favor RNI for cT3N0:

• The rate of locoregional recurrence remains high in patients with initial T3 tumors, even those who achieve pCR. 1
• The initial clinical T3 presentation remains a high-risk factor that justifies comprehensive locoregional treatment. 2
• A 2018 multivariate analysis of 1,289 patients with node-positive disease receiving neoadjuvant therapy found that RNI significantly reduced locoregional recurrence (HR 0.497, P=0.02) and any disease recurrence (HR 0.731, P=0.04), with particularly strong benefit in HER2+ disease treated with trastuzumab (HR 0.237, P=0.0003). 4

Recommended RNI Target Volumes

If proceeding with RNI, the following structures should be included: 2

• Supraclavicular area (recommended)
• Infraclavicular region (recommended)
• Internal mammary nodes (recommended, Category 2B)
• At-risk axillary bed (any portion deemed at risk)

Technical Delivery

• Use CT-based treatment planning to minimize cardiac and pulmonary exposure. 2, 5
• Recommended dose: 45-50 Gy in fractions of 1.8-2.0 Gy, or 42.5 Gy in fractions of 2.55 Gy. 1, 2, 5

Clinical Decision Algorithm

For your specific patient (cT3N0 HER2+ with pCR):

1. Primary recommendation: Proceed with RNI based on NCCN Category 2A guidelines for cT3 disease. 2

2. Rationale: The cT3 designation (tumor >5 cm) is an independent high-risk feature that warrants comprehensive locoregional treatment regardless of nodal status or response to therapy. 2

3. Supporting evidence: The 2018 retrospective analysis showing particular benefit of RNI in HER2+ disease treated with trastuzumab strengthens this recommendation. 4

4. Acknowledge uncertainty: The NSABP B-51 trial results create equipoise, but this trial did not specifically address cN0 patients, and the NCCN has not yet revised guidelines based on these 2025 results. 2, 3

Common Pitfalls to Avoid

• Do not base radiation decisions solely on post-chemotherapy pathology (ypT0N0), as this leads to under-treatment of patients who respond well but still require comprehensive locoregional control. 1, 2, 5
• Do not assume pCR eliminates locoregional recurrence risk in patients with initially large tumors (cT3). 1, 2
• Do not omit internal mammary nodal coverage in cT3 disease, as this is part of comprehensive RNI. 2