title: Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study.
abstract: OBJECTIVE
  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.
  
  
  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/m(2) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. E.hburstein@partners.org
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Burstein
authors.forename: Lyndsay N
authors.initials: LN
authors.lastname: Harris
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gelman
authors.forename: Susan C
authors.initials: SC
authors.lastname: Lester
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Nunes
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Kaelin
authors.forename: Leroy M
authors.initials: LM
authors.lastname: Parker
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.forename: Michele A
authors.initials: MA
authors.lastname: Gadd
authors.forename: Roger L
authors.initials: RL
authors.lastname: Christian
authors.forename: Patricia Rae
authors.initials: PR
authors.lastname: Kennedy
authors.forename: Virginia F
authors.initials: VF
authors.lastname: Borges
authors.forename: Craig A
authors.initials: CA
authors.lastname: Bunnell
authors.forename: Jerry
authors.initials: J
authors.lastname: Younger
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Smith
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use; D010865:Pilot Projects; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab