Patients with early-stage, node-positive breast cancer whose nodes are pathologically tumor-free (ypN0) after neoadjuvant chemotherapy may safely skip post-mastectomy nodal irradiation without increasing the risk of invasive breast cancer recurrence or death, according to results from a clinical trial published recently in The New England Journal of Medicine. (1)
“These results are truly practice-changing, confirming that adjuvant nodal irradiation for this patient population provides no additional benefits,” said radiation oncologist Atif Jalees Khan, MD, MS, Director of Breast Radiotherapy Services at MSK. “We now have solid evidence affirming that women who convert from node positive to negative with neoadjuvant chemotherapy can safely avoid nodal irradiation and its potential toxicities.”
The prospective, phase 3, international, randomized clinical trial, the National Surgical Adjuvant Breast and Bowel Project B-51 Radiation Therapy Oncology Group 1304 trial (B-51), was designed, conducted, and overseen by NRG Oncology, a member of the National Clinical Trials Network. The study was sponsored by the National Institutes of Health (NCT01872975) and received no funding support from industry. (1)
The B-51 trial evaluated whether regional nodal irradiation after a mastectomy or a lumpectomy improved outcomes in patients with stage T1 to T3, N1, and M0 node-positive breast cancer that converted to being node-negative after neoadjuvant chemotherapy. There were no significant differences between groups in five-year oncologic outcomes, including the interval to any invasive recurrence, as well disease-free survival (DFS) or overall survival (OS). (1)
As a radiation co-principal investigator of the B-51 trial, Dr. Khan contributed to the study design and conduct in his capacity as an MSK expert and member of the NRG Oncology Breast Core Committee. He was also one of four investigators overseeing quality assurance in the delivery of radiation therapy, ensuring accurate delivery and quality of treatment across study sites according to protocol-specified goals for target coverage and avoiding organs at risk.
Radiation oncologist Beryl McCormick, MD, FACR, was the site principal investigator of the trial at MSK and, togther with Dr. Khan, ensured MSK’s engagement in the study, resulting in MSK being the single largest accruing center for the trial. International sites included medical institutions in Australia, Canada, Ireland, Israel, Japan, and South Korea.
Toxicities Associated with Nodal Irradiation
“The two most common issues associated with nodal irradiation after chemotherapy and surgery are lymphedema and reconstruction complications, which affect about 10% to 20% of patients. While these negative effects are not life-threatening, they are very bothersome for quality of life,” said Dr. Khan.
“More serious side effects include toxicity to the underlying lung or heart, or later development of secondary malignancies. While these serious effects occur at very low rates, considering how many women are treated with regional nodal irradiation in the country and across the world, the toxicity savings can be significant, even if the rate of a given toxicity is low. Ultimately, a day without radiation is a good day for normal cells,” he said.
Study Design
Eligible patients had clinical stage T1 to T3 breast cancer, N1, and M0, indicating spread to movable, ipsilateral level I and II axillary lymph nodes but no distant metastasis, and operable at diagnosis, with pathologically confirmed axillary node involvement. Patients also had completed at least eight weeks of standard neoadjuvant chemotherapy with an anthracycline- or taxane-based regimen, or both. Those with HER2+ tumors had received neoadjuvant anti-HER2 therapy with all or part of neoadjuvant chemotherapy, unless otherwise contraindicated. (1)
After neoadjuvant chemotherapy, patients underwent lumpectomy or mastectomy followed by pathological assessment of axillary lymph nodes. There were 772 patients in the irradiation group compared with 784 patients in the no-nodal irradiation group. Those in the irradiation group received 50 Gray (Gy) in 25 fractions delivered to the retained portion of level I to level III axillary nodes after sentinel-lymph node biopsy or axillary-lymph-node dissection, supraclavivular nodes, and internal mammary nodes within the first three to four intercostal spaces, alonw with the chest wall after mastectomy or the whole breast after lumpectomy. (1)
Patients randomized to the no-nodal irradiation group received no radiation after mastectomy or received whole-breast irradiation after lumpectomy (50 Gy in 25 fractions followed by boosts totalling 12 to 14 Gy in six to seven fractions delivered to the surgery site). A radiation boost was required after whole-breast irradiation, but was allowed only with permission after chest wall irradiation. (1)
The B-51 trial protocol required reporting results either after a certain number of events were noted in the study population or 10 years from study activation, which began in 2013. (1)
Study Findings
Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence-free interval (hazard ratio = 0.88; p = 0.51). It also did not increase the locoregional or distant recurrence-free intervals, DFS, or OS. (1)
Of note, only about 20% of the study population had estrogen receptor (ER) positive, human epidermal growth factor 2 (HER2) negative breast cancer, the most common breast cancer subtype. (1)
“ER+/HER2- breast cancer does not respond as well to preoperative chemotherapy as the other subtypes, and patients with ER+/HER2- disease are also more likely to have later recurrences over time than the other subtypes,” said Dr. Khan. “Keep in mind that B-51 is the first study to report five-year outcomes for de-escalating nodal irradiation after neoadjuvant chemotherapy. For patients with ER+/HER2- breast cancer, a more conservative or cautious approach to nodal irradiation until we have longer-term evidence may be prudent. Still, this caution for that particular subgroup does not detract from the real benefits of avoiding nodal irradiation for patients with HER2+ or triple-negative breast cancer who achieve node-negative status after neoadjuvant chemotherapy.”
Broader Implications
Note that most recent advances in neoadjuvant breast cancer therapies, such as the use of dual anti-HER2 therapy for HER2+ breast cancer and carboplatin and checkpoint inhibitors for triple-negative breast cancer, were not part of standard clinical practice during the B-51 trial enrollment period. (1)
“Therefore, we anticipate the number of patients whose axillary nodes convert from positive to negative will continue to increase over time, meaning that more patients will be able to skip nodal irradiation in the future,” said Dr. Khan.
Advancing Breast Cancer Research at MSK
The multidisciplinary Breast Cancer team at MSK includes more than 80 breast cancer experts, including radiation oncologists, surgeons, medical oncologists, reconstruction surgeons, and advanced practice providers. MSK treats more than 4,500 patients with breast cancer annually.
In addition to clinical care, MSK breast cancer experts are dedicated to advancing research to improve patient outcomes. Recent research news includes Groundbreaking Survival Advances for Patients with ER+/HER2- Advanced Breast Cancer, presented at ASCO 2025.
Learn more about breast cancer clinical trials at MSK.