Background: In a previous randomized trial (SWOG 0012), MC seemed to improve pCR rates compared to standard anthracycline/taxane neoadjuvant chemotherapy (NC). We aimed to evaluate the feasibility of MC with a taxane→anthracycline schedule, which has also been shown potentially superior to the reverse sequence [J Clin Oncol 28:15s, 2010 (suppl; abstr 548)]. We also aimed to establish the feasibility of MC in combination with trastuzumab. Methods: The original accrual goal was 25 HER2+ pts and 40 HER2- pts. HER2- pts received MC consisting of paclitaxel (100mg/m2) x8 weeks followed by doxorubicin (24mg/m2) x9 weeks combined with oral cyclophosphamide (100mg/day), without G-CSF. HER2+ pts also received trastuzumab (4 mg/kg followed by 2mg/kg) concurrently with the entire CT. Objectives: Primary: To evaluate the feasibility of these schedules (defined as a febrile neutropenia [FN] rate no higher than 10%). Secondary: cardiac safety and general tolerability; efficacy as measured by objective clinical, radiological and pathologic complete response (pCR). Results: Almost all pts were staged as III (TraQme 8/9 88% and MeTo 4/11 36%). The HER2+ cohort was prematurely closed after 2 (22%) pts developed G3 pneumonitis (during the metromonic phase). Both responded to medical treatment and recovered. One pt had G2 hand-foot skin reaction (HFS) and another had G2 mucositis. The HER2- cohort was also prematurely closed with only 11 pts because of high rates of mucocutaneous toxicity (G3 HFS in 36%, G3 rash in 9%) and also due to the recent SWOG0221 negative results. There were 2 (18%) cases of FN and 3 (27%) of G4 neutropenia in this cohort, but no cases of pneumonitis. 1/11(9%) HER2- and 5/9HER2+(55%) pts had a pCR. VEGF pathway-related biomarkers were collected and will be presented at a later date. Conclusions: The proposed MC schedules proved too toxic to be considered for further clinical development. In addition, MC resulted in unexpectedly high rates of severe pulmonary toxicity when given in combination with trastuzumab. HER2+ but not HER2- pts had an impressively high pCR rate.