Background: This phase III randomized post-NC trial will evaluate if CWRNRT after mastectomy (Mx) or whole breast irradiation (WBI) with RNRT after breast-conserving surgery (BCS) significantly reduces the rate of IBCR-FI in pts who present with histologically positive Ax nodes but become histologically negative Ax nodes →NC. Secondary aims are OS, LRR-FI, DRFI, DFS-DCIS, and second primary cancer. Correlative science will examine the effect of RT by tumor subtype, molecular predictors of outcome for pts with residual disease, and the development of predictors of degree of reduction in loco-regional recurrence. Methods: Eligible pts with clinical T1-3, N1 breast cancer with pathologic Ax nodes (positive FNA or core needle biopsy) must complete ≥12 wks of NC (anthracycline and/or taxane-based regimen). HER2-positive pts must receive neoadjuvant trastuzumab or other anti-HER2 therapy (tx). After NC either BCS or Mx will be performed. Ax nodes must be histologically cancer free on sentinel node biopsy with or without axillary dissection (AND) or AND alone. ER/PR and HER-2 neu status before NC is required. All pts will receive additional required systemic tx. Site radiation credentialing with a facility questionnaire and case benchmarking is required. Randomization for Mx pts will be to no CWRNRT or CWRNRT and for BCS pts to WBI or WBIRNRT. 1,636 pts will be enrolled over 5 yrs with definitive analysis at 7.5 yrs. The study is powered at 80% to test the main hypothesis that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-year cumulative rate of 4.6%. Analysis will be on intent-to-treat with 3 formal interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events. Current accrual is 10. 736 enrolled pts will be evaluated with targeted pt-reported outcome instruments focusing on the effect of RT. Pt assessments will be prior to randomization and then at 3, 6, 12, and 24 mos. Clinical trial information: NCT01872975.