title: HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.
abstract: OBJECTIVE
  HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.
  
  
  METHODS
  We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
  
  
  RESULTS
  Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).
  
  
  CONCLUSIONS
  This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. modis@mskcc.org
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.forename: Alison
authors.initials: A
authors.lastname: Stopeck
authors.forename: Hannah
authors.initials: H
authors.lastname: Linden
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Andrea
authors.forename: Maura
authors.initials: M
authors.lastname: Dickler
authors.forename: Mary E
authors.initials: ME
authors.lastname: Moynahan
authors.forename: Steven
authors.initials: S
authors.lastname: Sugarman
authors.forename: Weining
authors.initials: W
authors.lastname: Ma
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy; D018572:Disease-Free Survival; D005260:Female; D018734:Genes, erbB-2; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019233:Retreatment; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D000068878:Trastuzumab