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The benefit of regional nodal irradiation in women with breast cancer-positive axillary nodes has long been established. What’s less clear is what to do when positive axillary lymph nodes turn negative after neoadjuvant chemotherapy.

Do patients still need regional nodal irradiation, or can they skip it?

New findings indicate that patients are safe to skip regional nodal irradiation.

The study, published online in The New England Journal of Medicine, found that adding regional nodal irradiation did not decrease rates of invasive breast cancer recurrence or death from breast cancer at 5 years in patients whose positive axillary nodes converted to negative following neoadjuvant chemotherapy.

“These results support a shift in treatment strategy in that regional nodal irradiation can be tailored in patients treated with neoadjuvant chemotherapy on the basis of their pathological nodal response,” wrote the investigators, led by Eleftherios P. Mamounas, MD, with AdventHealth Cancer Institute, Orlando, Florida. Earlier findings were first described in an abstract at the San Antonio Breast Cancer Symposium in 2023.

“These results definitely should impact practice for most patients,” Kathy Miller, MD, co-director of the Breast Cancer Program, Indiana University Health Simon Cancer Center, Indianapolis, who wasn’t involved in the study, told Medscape Medical News.

However, she cautioned that patients with inflammatory disease and extensive lymph node disease at diagnosis were excluded. “There will be temptations and variable comfort extrapolating to those patients who have a complete response,” she said.

The other caveat in Miller’s view is the relatively short duration of follow-up — only 5 years — for those with estrogen receptor-positive disease. “That is always an issue given the long timeline in that phenotype. That, however, isn’t a reason to recommend therapy with toxicity and cost,” Miller told Medscape Medical News.

Nancy Chan, MD, breast medical oncologist and clinical research director of breast cancer at NYU Langone Health’s Perlmutter Cancer Center, New York City, would also like to see longer follow-up in this subgroup.

“Hormone-positive tumors can have late recurrences, and we need longer follow-up to have evidence that these results continue to hold,” Chan, who also wasn’t involved in the study, told Medscape Medical News.

Study Details

The trial enrolled 1641 patients with breast cancer with a clinical stage of T1 to T3 (tumor size ≤ 2 cm to > 5 cm), N1, and M0 (indicating spread to 1-3 axillary lymph nodes but no distant metastasis) who reached negative node status following neoadjuvant chemotherapy.

The median age of patients was 52 years. About 60% had T2 disease, and the rest were split about evenly between T1 and T3 disease. More than half of the tumors (56%) were HER2 positive, and nearly a quarter were triple-negative. Slightly more patients had lumpectomy (57.7%) vs mastectomy (42.3%) and sentinel node-only vs full axillary dissections.

Patients were stratified according to the type of surgery (lumpectomy or mastectomy), estrogen-progesterone receptor status (negative or positive), HER2 status (negative or positive), the use of adjuvant chemotherapy (yes or no), and the presence or absence of a pathological complete response in the breast.

Patients were then randomly assigned to regional nodal irradiation (chest-wall irradiation plus regional nodal irradiation after mastectomy or the addition of regional nodal irradiation to whole-breast irradiation after lumpectomy) or to no regional nodal irradiation (no irradiation after mastectomy or whole-breast irradiation only after lumpectomy).

The primary analysis included 1556 patients — 772 randomly assigned to regional nodal irradiation and 784 to no regional nodal irradiation.

After a median follow-up of 59.5 months, 109 primary endpoint events (invasive breast cancer recurrence or death from breast cancer) had occurred, 50 in the irradiation group and 59 in the no-irradiation group.

Regional nodal irradiation did not significantly increase the interval to invasive breast cancer recurrence or death from breast cancer (hazard ratio, 0.88; P = .51). Survival free from any recurrence was 92.7% in the irradiation group and 91.8% in the no-irradiation group. 

Regional nodal irradiation also did not increase the locoregional recurrence-free interval, distant recurrence-free interval, disease-free survival, or overall survival. 

No deaths related to therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group.

Summing up, pathological complete response in axillary lymph nodes predicted a lack of benefit from regional nodal irradiation — a finding that “expands the clinical utility of the neoadjuvant approach,” the researchers said.

Ongoing patient follow-up will provide data on longer-term outcomes overall and in subgroups stratified by breast cancer subtype.

Chan told Medscape Medical News that the B-51 trial provides “important data as we try to figure out how we can optimize treatment and omit toxicity where it’s not necessary.”

“From this study, it looks like we can safely omit radiation for some patients” who achieve a pathological nodal complete response, Chan said.

“However, every breast cancer patient who sits in front of us is different, and there are many different factors to consider, such as subtype, age, and initial nodal burden, when making treatment decisions,” Chan added.

Funding for the study was provided by the National Institutes of Health. Mamounas has been a consultant for AstraZeneca, GE Healthcare, Genomic Health, Hologic, INC., Merck, Novartis, Provepharm, Genentech, and Merck and served as an advisor for TerSera Therapeutics, LLC, Biotheranostics Inc., and Sanofi. Miller and Chan reported no relevant conflicts of interest.