title: Trastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma: final results from the California Cancer Consortium Screening and Phase II Trial.
abstract: BACKGROUND
  Overexpression of the HER-2/neu oncoprotein has been reported to occur in </= 60% of patients with prostate carcinoma and to correlate with shortened survival. Trastuzumab is a humanized monoclonal antibody to the HER-2 receptor and has activity against HER-2-positive breast carcinoma, more so when combined with a taxane. The authors screened for HER-2 overexpression in patients developing hormone-refractory prostate carcinoma (HRPC) and conducted a Phase II trial of trastuzumab plus docetaxel in HER-2-positive patients.
  
  
  METHODS
  Paraffin-embedded tumor specimens from potentially eligible patients were screened for HER-2 expression by immunohistochemistry (IHC) and/or amplification by fluorescent in situ hybridization (FISH). Shed HER-2 was also assessed by enzyme-linked immunoradsorbent assay (ELISA). Patients with HER-2-positive tumor specimens (IHC 2+ or 3+ or FISH ratio > 2) were initially randomized to receive either single-agent trastuzumab or docetaxel. After two treatment cycles, nonresponding patients received the trastuzumab/docetaxel combination. Treatment was comprised of 30 mg/m(2) of docetaxel weekly for 6 weeks followed by a 2-week break and 4 mg/kg of trastuzumab intravenously during Week 1 then 2 mg/kg per week thereafter. The cycle length was 8 weeks.
  
  
  RESULTS
  One hundred patients with HPRC were screened. IHC results were as follows: 3+ (n = 1), 2+ (n = 6), 1+ (n = 26), 0 (n = 39), and insufficient tissue specimen/not tested (n = 28). Only 3 of 37 patients had elevated shed HER-2 by ELISA (> 15 mg/mL). None overexpressed HER-2 by IHC. FISH amplification was found in 0 of 34 tissue samples. Of seven patients with IHC 3+ or 2+, four were tested by ELISA and two by FISH. None were abnormal. Age and Gleason score did not correlate with IHC status. Of the seven patients eligible for the Phase II study, only four agreed to participate. The trial was thus closed for nonfeasibility (the overall HER-2 positivity rate was < 20%). No patient responded to trastuzumab alone. The median survival was not reached and the median progression-free survival was 7 months.
  
  
  CONCLUSIONS
  HER-2 overexpression by IHC in archival prostate carcinoma specimens was infrequent. There was no apparent correlation among IHC, ELISA, and FISH, although the sample size was limited. Conclusions regarding the predictive value of HER-2 status on outcome after trastuzumab-based therapy were not reached and were only drawn after larger-scale screening efforts. The authors estimated that 1000 patients need to be screened to complete accrual to a 40-patient efficacy trial.
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of California-Davis Cancer Center, Sacramento, California 95817, USA. primo.lara@ucdmc.ucdavis.edu
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Karen Giselle
authors.initials: KG
authors.lastname: Chee
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.forename: Christopher
authors.initials: C
authors.lastname: Ruel
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Meyers
authors.forename: Carl R
authors.initials: CR
authors.lastname: Gray
authors.forename: Regina Gandour
authors.initials: RG
authors.lastname: Edwards
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gumerlock
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D000077143:Docetaxel; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab