Recent landmark findings from the NRG-NSABP B-51/RTOG 1304 clinical trial have delivered a paradigm-shifting insight into the management of breast cancer patients whose axillary lymph nodes convert from positive to negative status following neoadjuvant chemotherapy. The study’s latest data, published in the prestigious New England Journal of Medicine, challenges the long-held view that regional nodal irradiation (RNI) universally reduces invasive breast cancer recurrence and suggests a more nuanced approach to radiation therapy in this select patient population.
Traditionally, RNI has been a cornerstone of breast cancer treatment for patients with node-positive disease at presentation, reducing rates of regional and distant failures when added to surgery and systemic therapy. However, this rigorous multi-institutional trial specifically targeted patients who initially presented with pathologically involved axillary nodes but achieved nodal pathologic complete response (pCR) after neoadjuvant chemotherapy, thereby becoming node-negative. This distinction is critical because it identifies a biologically distinct group whose residual disease burden after systemic therapy is minimal or absent, raising the question of whether additional regional radiotherapy confers any incremental benefit.
The trial enrolled 1,641 women who were randomized post-surgery to receive either RNI or no additional nodal radiation. Stratification was meticulous, balancing groups according to surgery type (mastectomy versus lumpectomy), hormone receptor status including estrogen (ER) and progesterone (PgR), HER2 receptor expression, use of adjuvant chemotherapy, and achievement of pCR within the breast tissue itself. Mandatory anti-HER2 therapy for HER2-positive tumors and endocrine therapy for hormone receptor-positive tumors ensured contemporary standard-of-care systemic treatments were uniformly administered.
The primary efficacy endpoint was invasive breast cancer recurrence-free interval (IBCRFI), a comprehensive measure encompassing both local and distant disease events. The trial was designed for a final analysis after either 172 IBCRFI events or ten years of follow-up. At the time of this data cut, 109 events had been confirmed, representing 63% of the targeted event number, enabling an interim but statistically impactful evaluation of the hypothesis.
Contrary to expectations based on prior radiation trials in upfront surgery patients, the addition of RNI in this cohort did not significantly reduce invasive breast cancer recurrence. The hazard ratio stood at 0.88 with a 95% confidence interval ranging between 0.60 and 1.28, and the p-value was 0.51, indicating no statistical significance. Five-year estimated IBCRFI rates were nearly identical between arms—91.8% without RNI and 92.7% with RNI. Crucially, secondary outcomes including loco-regional recurrence-free interval, distant recurrence-free interval, overall disease-free survival, and overall survival likewise showed no improvement attributable to RNI.
These findings bear enormous implications for clinical practice. They emphasize that a pathologic complete response in axillary nodes after neoadjuvant chemotherapy may serve as a robust biomarker identifying a subset of patients who derive little to no benefit from additional regional nodal radiation. This contrasts with historical data showing RNI benefits in patients with residual nodal disease or node-positive status upfront, underscoring the distinct biology and treatment responsiveness of breast cancer following neoadjuvant treatment.
Dr. Eleftherios Mamounas, the study’s lead author and an esteemed oncologist at AdventHealth Cancer Institute, underscored the clinical importance of these results. He noted that while radiation’s value in upfront node-positive surgery patients is well-established, this trial uniquely clarifies that patients converting to node-negative status post-chemotherapy can safely omit RNI without compromising recurrence outcomes. Dr. Mamounas stressed ongoing follow-up is warranted to assess long-term durability of these findings.
From a mechanistic standpoint, the lack of benefit with RNI in this context likely relates to effective systemic eradication of micrometastatic disease by neoadjuvant chemotherapy, coupled with pathologic clearance of nodal tumor deposits—events that substantially reduce the tumor cell reservoir that regional radiotherapy aims to eliminate. The therapeutic redundancy of RNI in this scenario also suggests that radiation-associated toxicities may be avoidable in these patients, improving quality of life without undermining oncologic control.
The trial’s robust design and diversity also enhance the generalizability of its conclusions. Incorporating both mastectomy and breast-conserving surgery patients, a wide spectrum of molecular subtypes, and standard adjunct systemic therapies ensures the findings are applicable to a broad breast cancer population in routine clinical care. Moreover, the large sample size and meticulous stratification reinforce the validity and precision of the results.
This investigation was supported by multiple funding sources, including grants from the National Cancer Institute (NCI) and the Susan G. Komen Foundation, exemplifying the collaborative commitment to advancing breast cancer treatment through rigorous clinical trials. It also reflects the integrative efforts of NRG Oncology, a leading research consortium dedicated to conducting practice-changing investigations in cancer care worldwide.
Looking forward, these insights will likely recalibrate clinical guidelines, promoting more personalized radiation strategies. Tailoring radiation therapy to patients’ response milestones post-neoadjuvant chemotherapy can minimize overtreatment, reduce morbidity associated with unnecessary radiation exposure, and optimize resource utilization. Furthermore, the study sets a precedent for leveraging pathologic response as a biomarker to guide locoregional therapy in other malignancies.
In sum, the NRG-NSABP B-51/RTOG 1304 trial heralds a pivotal shift in breast cancer radiation oncology by demonstrating that RNI does not provide added benefit in patients with initially node-positive disease who achieve node-negative status after neoadjuvant chemotherapy. This evidence fosters a more refined, biologically driven paradigm in managing regional nodal irradiation and underscores the transformative potential of integrating pathologic response into therapeutic decision-making algorithms. Ongoing longitudinal follow-up and additional translational research will further delineate the durability and mechanistic underpinnings of these groundbreaking clinical findings.
Subject of Research: People
Article Title: Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy
News Publication Date: 4-Jun-2025
Web References: https://www.nejm.org/toc/nejm/392/21
References: Mamounas EP, Bandos H, White JR, et al. Omitting Regional Nodal Irradiation in Responders to Neoadjuvant Chemotherapy; New England Journal of Medicine, 2025;392:2113-2124; DOI:10.1056/NEJMoa2414859
Keywords: Medical specialties, breast cancer, regional nodal irradiation, neoadjuvant chemotherapy, pathologic complete response, radiation therapy, oncology clinical trials, invasive breast cancer recurrence
