ORIGINAL ARTICLE Paclitaxel, Carboplatin, and Trastuzumab in a Neo-adjuvant Regimen for HER2-positive Breast Cancer Gabe S. Sonke, MD, PhD,* Ingrid A. Mandjes, † Marjo J. Holtkamp, MANP,* Margaret Schot, MANP,* Erik van Werkhoven, MSc, ‡ Jelle Wesseling, MD, PhD, § Marie-Jeanne Vrancken Peeters, MD, PhD, ¶ Sjoerd Rodenhuis, MD, PhD,* and Sabine C. Linn, MD, PhD* *Department of Medical Oncology; † Department of Data Center; ‡ Department of Biometrics; § Department of Pathology; and ¶ Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands n Abstract: To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohisto- chemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m 2 , carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node-positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty-seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carbopla- tin–paclitaxel–trastuzumab neo-adjuvant regimen is highly active in HER2-positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines. n Key Words: breast cancer, chemotherapy, neo-adjuvant, trastuzumab T he majority of patients with stage II and stage III breast cancer has distant micrometastases and will die of breast cancer when systemic treatment is withheld. With modern multi-modality approaches incorporating chemotherapy and endocrine therapy, progression-free and overall survival have significantly improved. Administering systemic therapy before sur- gery (neo-adjuvant) has the advantage of (i) early treat- ment of distant micrometastases, (ii) in vivo response monitoring, and (iii) a higher breast-conserving therapy (BCT) rate. For patients with locally advanced breast cancer in good general condition, anthracycline-based chemotherapy is often initiated as part of their multi-modality treatment. Although anthracyclines are very active in breast cancer, important side effects occur including cardiotoxicity and secondary malignancies. Alternative treatment strategies are thus required. Approximately, 20% of invasive breast cancers exhibit overexpression of the human epidermal growth factor receptor HER2 tyrosine kinase receptor [1]. HER2 activation mediates intracellular signaling cascades, thereby inducing cell proliferation and inhib- iting apoptosis. Trastuzumab is a monoclonal anti- body that binds to the extracellular HER2 receptor to promote cell cycle arrest and apoptosis [2]. Treatment with trastuzumab has shown to be very effective in HER2-positive breast cancer, in the metastatic [3,4], adjuvant setting [5,6], and neo-adjuvant setting [7–9], although cardiotoxicity is a well-known side effect. The cardiotoxicity of trastuzumab may be aggravated by combined treatment with anthracyclines [3]. Consequently, treatment with trastuzumab is often delayed pending the administration of anthracyclines. Although some of the studies that treated patients Address correspondence and reprint requests to: Gabe S Sonke, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands, or e-mail: g.sonke@nki.nl. DOI: 10.1111/tbj.12124 © 2013 Wiley Periodicals, Inc., 1075-122X/13 The Breast Journal, Volume 19 Number 4, 2013 419–426