Journal of Clinical Oncology, Vol 21, Issue 1
(January), 2003: 46-53
© 2003 American Society for Clinical Oncology
Preoperative Therapy With Trastuzumab and Paclitaxel Followed by Sequential Adjuvant Doxorubicin/Cyclophosphamide for HER2 Overexpressing Stage II or III Breast Cancer: A Pilot Study
Harold J. Burstein,
Lyndsay N. Harris,
Rebecca Gelman,
Susan C. Lester,
Raquel A. Nunes,
Carolyn M. Kaelin,
Leroy M. Parker,
Leif W. Ellisen,
Irene Kuter,
Michele A. Gadd,
Roger L. Christian,
Patricia Rae Kennedy,
Virginia F. Borges,
Craig A. Bunnell,
Jerry Younger,
Barbara L. Smith,
Eric P. Winer
From the Departments of Medical Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Departments of Medicine, Surgery, and Pathology, Brigham and Women’s Hospital and Massachusetts General Hospital; Department of Surgery, Faulkner Hospital; Department of Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, MA.
Address reprint requests to Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; email: E: hburstein{at}partners.org.
Purpose: Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer.
Patients and Methods: Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg x 1, then 2 mg/kg/wk x 11) in combination with paclitaxel (175 mg/m2 every 3 weeks x 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially.
Results: Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment.
Conclusion: Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.
Supported in part from research grants-in-aid from Bristol Myers Squibb, Bayer, and Genentech.
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