Abstract PS5-07-02: NRG-BR008: A phase III randomized trial of radiotherapy optimization for low-risk HER2-positive breast cancer (HERO)

Abstract Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. This is a phase III randomized trial for patients ≥18 years with early-stage, node-negative, HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (≤3 cm) N0 disease, whereas patients receiving neoadjuvant therapy must have clinical T1-2 (≤5 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. Patients with residual non-invasive disease (DCIS) in the surgical specimen (ypTis) are eligible if residual DCIS spans ≤1 cm and surgical margins are negative for DCIS. All patients must receive systemic therapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (60; ≥60), tumor size (≤1 cm; 1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant v neoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of HER2-targeted therapy to complete one year of treatment (Arm 1), or HER2-targeted therapy alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 7.25 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 4.5 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March 2023. Accrual is 103/1,300 as of July 9, 2025. Citation Format: M. P. Mitchell, L. Z. Braunstein, H. Bandos, W. M. Sikov, A. J. Khan, P. Y. Chen, P. A. Ganz, R. Jagsi, J. R. White, R. S. Cecchini, H. Kang, S. L. Puhalla, K. L. Bolton, E. P. Connolly, E. Stringer-Reasor, K. R. Gergelis, T. B. Julian, E. P. Mamounas, N. Wolmark. NRG-BR008: A phase III randomized trial of radiotherapy optimization for low-risk HER2-positive breast cancer (HERO) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-02.