title: Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer.
abstract: OBJECTIVE
  To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
  
  
  METHODS
  Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response.
  
  
  RESULTS
  Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001).
  
  
  CONCLUSIONS
  Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.
authors.affiliation: Dana-Farber Cancer Institute. Lyndsay.harris@yale.edu
authors.forename: Lyndsay N
authors.initials: LN
authors.lastname: Harris
authors.forename: Fanglei
authors.initials: F
authors.lastname: You
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
authors.forename: Agnes
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.forename: Paula D
authors.initials: PD
authors.lastname: Ryan
authors.forename: Steven E
authors.initials: SE
authors.lastname: Come
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Burstein
authors.forename: Beth-Ann
authors.initials: BA
authors.lastname: Lesnikoski
authors.forename: Madhavi
authors.initials: M
authors.lastname: Kamma
authors.forename: Paula N
authors.initials: PN
authors.lastname: Friedman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gelman
authors.forename: J Dirk
authors.initials: JD
authors.lastname: Iglehart
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008297:Male; D011237:Predictive Value of Tests; D011300:Preoperative Care; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000068878:Trastuzumab; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine