Background: Inclusion of H with chemotherapy has increased pathologic complete response (pCR) rates in HER2 positive breast cancer, and dual HER2 blockade involving H + P further increased efficacy. With dual HER2 blockade and taxane-based (+/-carboplatin followed by anthracycline) chemotherapies, pCR rates reach, 75% in estrogen receptor (ER) negative and 45% in ER+ patients. HER2 targeted therapies also increase the efficacy of anthracyclines but are not routinely combined due to potential cardiotoxicity. The goal of this phase II study was to assess pCR rate when H+P is administered during the entire treatment duration, including the anthracycline phase, of weekly T (80 mg/m²) x 12 followed by FE(75 mg/m²)C x 4 neoadjuvant chemotherapy. Methods: pCR (ypT0/is and ypN0) rate was assessed separately in ER+ and ER- cancers following Simon’s two-stage design to detect improvement in pCR rates to 90% and 70% in the ER- and ER+ cohorts, respectively. Eligibility included age <65, stage I-III, HER2+ disease, and normal cardiac function. Results: The ER- cohort completed full accrual of 25 patients: 23 completed therapy and surgery, 2 patients are still receiving treatment. The pCR rate is 78% (n=18, 95% CI:58-90%). The ER+ cohort was closed after 23 patients were accrued to the first stage due to lower than expected pCR of 26% (n=6, 95% CI:13-46%) at interim analysis. The incidence of grade 3/4 adverse events was 48% (n=24/50), the most common being neutropenia (n=12) and diarrhea (n=7). No patient experienced symptomatic congestive heart failure, one patient had a drop in LVEF to < 50% following completion of chemotherapy. Thirteen patients (27%) had a >10% asymptomatic drop in their LVEF but remained above 50%, LVEF returned to baseline by the next assessment in half of these cases. Conclusions: Neoadjuvant P and H administered concomitantly with weekly T followed by FEC resulted in 78% pCR rate in ER-/HER2+ cancers. This pCR rate is among the highest reported in the literature. The pCR rate was substantially lower in ER+ cancers. Clinical trial information: NCT01855828