# Evaluating Adjuvant Radiation Therapy Survival Benefit in Early-Stage HER2-Positive Invasive Breast Cancer Following Breast-Conserving Surgery: A National Cohort Aligned with NRG-BR008 HERO Trial

## TL;DR

This study finds that skipping radiation therapy after breast-conserving surgery for early-stage HER2-positive breast cancer is linked to worse survival, especially when systemic therapy is given after surgery.

## Contribution

The study evaluates the survival impact of radiation therapy in HER2-positive breast cancer patients aligned with the NRG-BR008 trial framework using a national database.

## Key findings

- RT omission was associated with a significantly worse overall survival in the adjuvant pathway cohort.
- In the neoadjuvant pathway, RT was linked to a smaller, non-significant survival benefit due to limited events.
- Results suggest continued use of RT outside clinical trials until more data on de-escalation is available.

## Abstract

Radiation therapy (RT) after breast-conserving surgery is standard for invasive breast cancer, but de-escalation is being studied for select low-risk HER2-positive tumors. Using the National Cancer Database, we assembled the following two cohorts aligned with the NRG-BR008 (HERO) trial framework: patients receiving systemic therapy after surgery (adjuvant pathway) and those treated before surgery (neoadjuvant pathway) who achieved a pathologic complete response. We compared overall survival for patients who did versus did not receive postoperative RT using propensity score matching and time-to-event models. RT omission was associated with worse survival in the adjuvant pathway (hazard ratio ~5). In the neoadjuvant pathway, RT was associated with a smaller, statistically non-significant survival difference, consistent with limited events and imprecision. These observational findings support continued RT use outside clinical trials pending prospective de-escalation data.

Background and purpose: The role of adjuvant radiation therapy (RT) in early-stage HER2-positive breast cancer treated with breast-conserving surgery (BCS) and systemic therapy remains uncertain in the era of HER2-targeted regimens. This study evaluates the survival impact of RT in patients aligned with the HERO RT de-escalation trial (NRG-BR008). Materials and methods: We queried the National Cancer Database for patients with early-stage HER2-positive invasive breast carcinoma treated with BCS and systemic therapy, stratified into HERO trial-aligned cohorts: Arm 1 (adjuvant systemic therapy) vs. Arm 2 (neoadjuvant systemic therapy, pathologic complete response). Within each cohort, patients receiving adjuvant RT were compared with those omitting RT. In the primary analysis, patients were propensity score matched (PSM) on demographics, diagnosis years, tumor characteristics, and trial stratification variables. Inverse probability of treatment weighting (IPTW) was additionally performed as a sensitivity analysis. Overall survival was evaluated using Kaplan–Meier, Cox regression, and restricted mean survival time (RMST). Results: In Arm 1 (818 patients, 94 deaths), 5-year OS was 96.9% with RT vs. 88.0% without RT, and 10-year OS was 94.3% vs. 68.5% (log-rank p < 0.001). RT omission was associated with higher mortality in the PSM Cox model (HR, 4.78; 95% CI, 2.84–8.02; p < 0.001), with an RMST advantage favoring RT of +2.86 months at 5 years and +12.55 months at 10 years (p < 0.001). In Arm 2 (176 patients, 10 deaths), 5-year OS was 97.6% with RT vs. 91.1% without RT, and OS at 107 months was 94.8% vs. 91.1% (log-rank p = 0.13). RT omission was not statistically significant in the PSM Cox model (HR, 3.40; 95% CI, 0.82–14.05; p = 0.09), though RMST favored RT (+1.83 months at 5 years, p = 0.004; +3.91 months at 107 months, p = 0.03). IPTW analyses were directionally consistent in Arm 1 (HR, 3.26; 95% CI, 2.52–4.21; p < 0.001) and inconclusive in Arm 2 (HR, 1.78; 95% CI, 0.80–3.95; p = 0.16). Conclusions: In this HERO-aligned national cohort, RT omission was associated with inferior OS in patients treated with adjuvant systemic therapy after BCS. Findings in the neoadjuvant pCR cohort were imprecise and hypothesis-generating. Given the retrospective registry design, lack of recurrence-specific endpoints, and potential residual confounding, results should not be interpreted as causal but support continued RT use outside prospective de-escalation trials.