Background: The ABC adjuvant trials (5/2007-11/2013) were developed by USOR and NSABP to determine if a regimen of TC for 6 cycles is non-inferior to combination regimens of doxorubicin/cyclophosphamide with docetaxel or paclitaxel (TaxAC) in women with resected high-risk, HER2-negative breast cancer. 1870 patients (pts) from B-49 were combined with 1077 from the TaxAC and TC groups of B-46-I/USOR 07132, and 1295 from USOR 06-090, for a total of 4242. A detailed history of this collaborative effort will be discussed. Methods: The primary endpoint was invasive disease-free survival (iDFS), defined as time to local, regional or distant recurrence, invasive contralateral breast cancer, second primary cancer, or death. Pts were stratified for: parent trial, pos nodes (0, 1-3, 4-9, 10+), and hormonal status (neg, pos). A hazard ratio (HR) from a stratified Cox model of 1.18 or more was pre-defined as inferior. HRs above 1 favor TaxAC. Our pre-specified interim monitoring plan was to report early for futility if HR was >1.18 when 334 iDFS events were observed (50% of planned 668 events for definitive analysis). Results: 2078 pts randomized to TC and 2052 to TaxAC (total 4130) began assigned therapy and comprise the analysis set. Median follow-up: 3.2 yrs. Pt and tumor characteristics are balanced by treatment: 69% hormone pos, 41% node neg, 51% high grade. With 334 iDFS events, observed HR for TC v TaxAC is 1.202 (95% CI 0.97-1.49), which exceeds 1.18, thus we are reporting early for futility. With 397 iDFS events, 3 yr iDFS is 91.7% for TC v 92.4% for TaxAC. For TNBC: 86.6% v 89.6%, HR, 1.42, (1.04-1.94). For hormone pos: 94.1% v 93.7%, HR, 1.08 (0.84-1.40). Tests for treatment interaction by hormone receptor, nodal status, and protocol were negative. Conclusions: Statistical non-inferiority of the non-anthracycline regime could not be demonstrated. Longer follow-up should clarify the clinical utility of these initial findings. SUPPORT: U10CA-180868, -21115, -189867, -180822, -180820; 180821; 180791; Genentech Clinical trial information: NCT01547741