Background: TNBC is an aggressive disease and the only subtype with no specific targeted therapy. PI3K pathway activation occurs frequently in TNBC and confers susceptibility to mTOR inhibitors as RAD001. mTOR inhibition synergistically enhances taxane-induced cytotoxicity in breast cancer cells including TNBC in vitro and in vivo. Methods: We conducted a single institution phase II study in patients (pts) with primary TNBC randomized to T-FEC (paclitaxel 80mg/m2 IV weekly for 12 weeks, followed by 5FU 500mg/m2, epirubicin 100mg/m2, and cyclophosphamide 500mg/m2 every 3 weeks for 4 cycles) vs TR-FEC (paclitaxel 80mg/m2 IV and RAD001 30mg PO weekly for 12 weeks, followed by 5FU 500mg/m2, epirubicin 100mg/m2, and cyclophosphamide 500mg/m2 IV every 3 weeks for 4 cycles). Clinical endpoints included 12-week response rate (12wk RR, complete or partial response), pathological complete response (pCR), and toxicity. Tumor samples were collected to assess molecular changes in the PI3K pathway, at baseline, 48-hours, 12-weeks and at surgery (data not presented). Results: 62 pts were registered, and 50 were randomized from August 2007 to August 2010: 27 received T-FEC and 23 received TR-FEC. Median age was 48 (range 31-75). 12wk RR by ultrasound were (8/27) 29.6% vs (11/23) 47.8% for T-FEC and TR-FEC respectively (p=0.15 one-sided). At the time of submission, the last pt was scheduled for surgery; pCR data will be presented at the meeting. Main NCI grade 3/4 toxicities included anemia 4% vs. 13% (P=0.322), leukopenia 11% vs. 17%, (P=0.689), rash/desquamation 7% vs. 9%, (P>0.999), vomiting 4% vs. 13% (P=0.322), in T-FEC and TR-FEC respectively. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. Conclusions: The addition of RAD001 to paclitaxel in the neoadjuvant setting was well tolerated. TR was associated with a higher 12wk RR rate than T; this did not reach statistical significance given our small sample size. Larger, studies are warranted to study this combination. Biomarker analysis in ongoing to further optimize patient selection.