New Study Published in the New England Journal of Medicine Shows the Addition of Regional Nodal Irradiation Does Not Decrease Rate of Invasive Breast Cancer Recurrence in Patients with Negative Axillary Nodes Following Neoadjuvant Chemotherapy

Recent results from the NSABP B-51-RTOG 1304 clinical trial showed that the addition of regional nodal irradiation (RNI) does not improve outcomes in breast cancer patients who present with biopsy-proven positive axillary lymph nodes and whose nodes convert to pathologically negative after neoadjuvant chemotherapy. The findings were published on June 5, 2025, in the New England Journal of Medicine. Eleftherios (Terry) Mamounas, MD, medical director of the breast program and research activities at AdventHealth Cancer Institute, was the lead author.

Use of Regional Nodal Irradiation in Breast Cancer
RNI targets lymph nodes in the armpit (axillary), near the collarbone (supraclavicular) and under the breastbone (internal mammary). Used after breast surgery, including lumpectomy or mastectomy, it is generally a standard part of treatment for breast cancer in patients with pathologically positive axillary nodes and aims to reduce the risk of cancer recurrence by killing any remaining cancer cells in those nodes. 

However, with the increasing use and efficacy of neo-adjuvant chemotherapy, clinicians often encounter patients who initially present with axillary lymph node involvement (clinically node-positive status) but whose axillary lymph nodes convert to pathologically tumor free (ypN0) after neoadjuvant chemotherapy.

“The benefit of RNI in this population of patients was unclear,” shares Dr. Mamounas. “No prospective outcome data exist showing benefit, and this had led to clinical uncertainty and variability in practice. Our clinical trial aimed to bridge this knowledge gap.”

About the NSABP B-51–RTOG 1304 Study
Activated in August 2013 and closed to enrollment in December 2020, the NSABP B-51–RTOG 1304 study was a prospective, phase III, multicenter randomized clinical trial. It enrolled 1,641 patients stratified by type of surgery (mastectomy, lumpectomy), hormone receptor status (ER-positive and/or PgR-positive; ER- and PgR-negative), HER2 (human epidermal growth factor receptor 2) status, adjuvant chemotherapy, and pCR (pathologic complete response) in the breast. Study participants were then randomized to the RNI arm vs. no RNI. Anti-HER2 therapy was required for HER2+ patients as was endocrine therapy for hormone-receptor positive patients.

The primary endpoint was invasive breast cancer recurrence-free interval (IBCRFI). Final analysis was planned after 172 events or 10 years post-study initiation. At the time of analysis, 109 IBCRFI events (63% of the planned 172) were confirmed. This trial was designed, conducted, and overseen by NRG Oncology, a member of the National Clinical Trials Network, and sponsored by the National Cancer Institute (NCI). 

Key Findings
The researchers found that RNI did not significantly improve IBCRFI (HR=0.88, 95%CI 0.60-1.28; p=0.51, five-year point estimates: no RNI:91.8%, RNI:92.7%) or improve any secondary endpoints of loco-regional recurrence-free interval, distant recurrence-free interval, disease-free survival, or overall survival.

“The results of our trial indicate that patients with positive axillary lymph nodes who become pathologically tumor free after neoadjuvant chemotherapy have low rates of disease recurrence and do not receive a statistically significant or clinically meaningful benefit from regional nodal irradiation at 5 years,” concludes Dr. Mamounas. “These results support a shift in treatment strategy. We will continue follow-up for evaluation of longer-term outcomes for these patients.”