Safely omitting regional nodal irradiation in patients with lymph node-negative disease after neoadjuvant chemotherapy
Some breast cancer (BC) patients shifting from a lymph node-positive to a node-negative status after neoadjuvant chemotherapy (NAC) receive regional nodal irradiation (RNI) after surgery, either alongside chest wall irradiation (CWI+RNI) after mastectomy or whole breast irradiation (WBI+RNI) after breast-conserving surgery. This trial reveals that skipping RNI does not increase the risk of disease recurrence or death within five years post-surgery, suggesting that this treatment can be safely omitted in these patients.
Patients diagnosed with breast cancer (BC) that has spread to regional lymph nodes may undergo neoadjuvant chemotherapy (NAC), which can eliminate cancer from the lymph nodes. Post-surgery treatment for these patients lacks a standardised approach, leading to a debate on categorising them as lymph node-positive (how they were diagnosed) or negative (how they present at the time of surgery). If considered node-positive, they typically undergo regional nodal irradiation (RNI), a form of radiotherapy directed to lymph nodes near the breast and intended to reduce a patients’ risk of disease recurrence after surgery. Options for these patients include chest wall irradiation plus RNI (CWI+RNI) after mastectomy or whole breast irradiation plus RNI (WBI+RNI) after breast-conserving surgery (BCS). Alternatively, if their disease were considered lymph node-negative, RNI may be omitted after surgery.
Notably, some patients may prefer to omit RNI to avoid associated complications, such as pain, fatigue, and lymphedema impacting breast reconstruction. Therefore, evaluating whether RNI can be safely omitted in these patients is important. This phase III trial evaluated whether CWI+RNI after mastectomy or WBI+RNI after BCS significantly improves invasive BC recurrence-free interval (IBC-RFI) in node-positive patients found to be node-negative after NAC.
Methods:
This phase III trial enrolled patients with clinical cT1-3, N1, M0 invasive BC, with axillary lymph node involvement confirmed by a FNA/core needle biopsy who completed ≥8 weeks of NAC (and anti-HER2 therapy if HER2+), and who were ypN0 after mastectomy or BCS and sentinel node biopsy (SLNB, ≥2 nodes), axillary lymph node dissection (ALND), or both. These patients were randomly assigned (1:1) to “No RNI” (i.e., observation after mastectomy or WBI after BCS) or “RNI” (i.e., CWI+RNI after mastectomy or WBI+RNI after BCS). The primary endpoint was IBC-RFI, defined as the time from randomisation until invasive local, regional, or distant recurrence or death from BC. Secondary objectives included loco-regional recurrence-free interval (LRRFI), defined as LRR without evidence of distance recurrence within two months, distant recurrence-free interval (DRFI), disease-free survival (DFS), overall survival (OS) and toxicity
Results:
In total; 1,556 patients were included in the primary event analysis. After a median follow-up of 59.5 months, 109 IBC-RFI events were confirmed (59 vs. 50 in the No RNI and RNI arms, respectively). There was no statistically significant difference between the treatment arms in terms of IBC-RFI (HR[95%CI]: 0.88[0.60-1.29]; p=0.51), with estimated 5-year IBC-RFI rates of 91.8% and 92.7%. Subgroup analyses, including surgery type, hormone receptor status or HER2 status, showed no significant differences between the arms. Interestingly, exploratory analyses revealed a favourable tendency for No RNI in patients with triple-negative breast cancer (TNBC) (HR[95% CI]: 2.30[1.00-5.25]), and a favourable tendency for RNI for patients with ER/PR+/HER2- (HR[95% CI]: 0.41[0.17-0.99])and ER/PR-/HER2+ (HR[95% CI]: 0.63[0.31-1.28]). However, caution is advised in interpreting these data due to the low number of patients and events in these subgroups.
No statistically significant differences were observed for secondary endpoints. There were 15 ILRRFI events, 11 in the No RNI arm and 4 in the RNI arm, with 5-year rates estimated at 98.4% vs. 99.3% (HR[95% CI]: 0.37[0.12-1.16]; p=0.088). Similarly, there were no significant differences in DRFI between the arms (48 vs. 46 events in the No RNI and RNI arms, respectively; HR[95%CI]: 1.00[0.67-1.51]; p=0.99), with a 5-year estimate of 93.4% for both arms. DFS was also comparable between the arms (83 vs. 85 events in the No RNI and RNI arms, respectively; HR[95%CI]: 1.06[0.79-1.44]; p=0.69), with 5-year estimates of 88.5% vs. 88.3%. Finally, no differences were observed in OS, with 45 vs. 49 events (HR[95%CI]: 1.12[0.75-1.68]; p=0.59), with 5-year rates of 94.0% vs. 93.6%.
No study-related deaths or unexpected toxicities occurred. Grade 4 toxicity was rare (0.1% vs. 0.5% in "No RNI" and RNI groups, respectively). Grade 3 toxicity was observed in 6.5% vs. 10.0% of patients, with radiation dermatitis being the most common grade 3 toxicity (3.3% vs. 5.7% in the No RNI and RNI arms, respectively).
Conclusion
In patients who present with biopsy-proven axillary node involvement and convert their axillary nodes to ypN0 after NAC, CWI+RNI after mastectomy, or WBI+RNI after BCS, did not significantly improve IBC-RFI, LRRFI, DRFI, DFS, or OS. These findings suggest that downstaging cancer-positive regional lymph nodes with NAC can allow some patients to skip adjuvant RNI without adversely affecting oncologic outcomes.
Reference
Mamounas E, Bandos H, White J, et al. Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304. Presented at SABCS 2023; Abstract GS02-07.
