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Background: S0221 is a SWOG-coordinated phase Ⅲ adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1)the weekly AC+G regimen is superior to ddAC x 6 and 2)12 weeks of weekly paclitaxel(wP)is superior to q 2 week paclitaxel x 6(ddP).Methods: Between December 2003 and November 2010,2,716 patients were randomized in a 2 × 2 factorial design to 1)AC+G vs ddAC and 2)P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6.If there was no significant interaction between the factors,the trial was powered to find a disease-free survival hazard ratio(HR)≤ 0.82 for weekly vs q 2 week for each factor.At the first interim analysis,the AC randomization was halted for futility,and S0221 was closed to accrual 10 November 2010.S0221 reopened 15 December 2010,after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued.Accrual halted at a total of 3,294 in January 2012.Results: By September 7,2012,487 events and 340 deaths had occurred,prompting the third planned interim analysis.The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed.A Cox model adjusting for the AC arms had a HR = 1.08(95%CI 0.90-1.28; p=0.42),with the 99.5%CI excluding the original alternative hypothesis that the HR=0.82.There was no significant interaction of the two factors.Estimated 5-year progression-free survivals were 82%for weekly P and 81%for ddP.Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P.Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P.Percent grade 3-4 toxicity per arm are shown in the Table.Conclusions: Either ddPx6 or weekly P x 12 are acceptable schedules of P administration.The differences in leukopenia likely reflect ascertainment bias against weekly P.If this is accepted,weekly P x 12 produces less overall toxicity than 6 cycles of ddP.Support: NCI grants CA32102,CA38926,CA21115,CA21076,CA77597,CA25224,CA77202,CCSRI15469,and Amgen,Inc.