Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy

Mamounas EP, Bandos H, White JR, et al. Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy. N Engl J Med. 2025;392(21):2113-2124

Similar to trials of surgical de-escalation in the axilla following neoadjuvant chemotherapy (NACT), improving pathological response rates have prompted the question ‘can we de-escalate regional nodal irradiation (RNI) to minimise treatment-related morbidity without compromising oncologic outcomes’?

The NSABP B-51/RTOG 1304 was a collaboration by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG). It aimed to personalise radiation treatment, balancing efficacy and toxicity. The study aimed to determine whether omitting RNI in patients with clinical stage T1–T3, N1 breast cancer who convert to pathologically node-negative status (ypN0) after NACT affects invasive breast cancer recurrence-free interval.

This was a phase 3, multicentre randomised controlled trial with participants randomised to receive RNI or no RNI based on their nodal response after chemotherapy. The trial enrolled 1,641 women with clinical stage T1–T3, N1, M0 breast cancer; 1,556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group.

Inclusion criteria: Women with biopsy-proven clinical N1 breast cancer who completed neoadjuvant chemotherapy and achieved ypN0 status upon surgery. Exclusion criteria included patients with metastatic disease or incomplete nodal response.

Median age was 52 years (IQR 44–60) with 40% being <50 years. 58% had lumpectomy, with 42% having a mastectomy and 55% underwent SLNB After a median follow-up of 59.5 months, the invasive breast cancer recurrence-free interval was 92.7% in the RNI group and 91.8% in the no-RNI group, with no statistically significant difference (hazard ratio 0.88; P = 0.51). Point estimates of 5-year overall survival were 93.6% in the irradiation group and 94.0% in the no-irradiation group. Secondary outcomes, including locoregional and distant recurrence-free survival, disease-free survival, and overall survival, showed no significant differences. Toxicity was low in both groups. 

The findings support safely omitting RNI in patients with ypN0 status after neoadjuvant chemotherapy, potentially reducing treatment-related morbidity and healthcare costs. The study results demonstrated that pCR in axillary lymph nodes is predictive of lack of benefit from RNI.

Limitations

Limitations include the median follow-up duration, so late recurrences may not be captured. The trial focused on a specific patient population, limiting generalisability. Patients were assigned to receive regional nodal irradiation received 50 Gy in 25 fractions, but hypofractionated regimens are now standard. The results of the exploratory subset analysis according to breast cancer subgroups should be viewed with caution because the number of patients in each subgroup represents roughly a quarter of the overall patient population, resulting in wide confidence intervals around the estimates. Longer follow-up may influence these results, especially for some biologic subtypes. Overall event rate was low. Therefore longer follow-up is required.

Conclusion 

Omitting regional nodal irradiation in breast cancer patients who achieve ypN0 after NACT does not compromise recurrence-free survival and represents a viable de-escalation strategy in appropriate cases.

Summary author:

Dr Sue Hartup, Consultant Nurse in Breast Research, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, NIHR Senior Clinical and Practitioner Research Award Fellow