ABSTRACT
BACKGROUND: Overexpression of the HER-2/neu oncoprotein has been reported to occur in 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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Disease-Free Survival , Docetaxel , Enzyme-Linked Immunosorbent Assay , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Prostatic Neoplasms/pathology , Taxoids/administration & dosage , Trastuzumab , Treatment Outcome , Up-RegulationABSTRACT
BACKGROUND: The overexpression of HER-2/neu is found in 20-30% of patients with breast carcinoma and is an adverse prognostic factor. HER-2 overexpression also has been reported in up to 60% of patients with hormone-refractory prostate carcinoma (HRPC) and was correlated with shortened survival. Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds to the HER-2 receptor and has antitumor activity in patients with HER-2-overexpressing breast carcinoma. The authors report the results of HER-2 screening from a Phase II trial of chemotherapy with trastuzumab and docetaxel in patients with HER-2-overexpressing prostate carcinoma. METHODS: Archival paraffin embedded tumor tissue was obtained from potentially eligible patients and was screened for HER-2 expression by immunohistochemistry (IHC) using a specialized test kit. Shed HER-2 antigen in serum also was determined using an enzyme-linked immunosorbent assay (ELISA). HER-2 gene amplification was assessed by fluorescent in situ hybridization (FISH). Patients with IHC scores of 2+ or 3+ were considered to have HER-2 overexpression and were eligible for the trial. To date, 62 patients with HRPC have been screened. RESULTS: The median patient age was 72 years, and Gleason scores were < 5 in 1 patients, 5-7 in 24 patients, > 7 in 23 patients, and not specified in 14 patients. IHC HER-2 expression was 0 in 28 patients, 1+ in 14 patients, 2+ in 4 patients, and 3+ in 1 patients. Fifteen patients had either suboptimal tissue (13 patients) for interpretation or had pending results (2 patients). Therefore, 8% of all patients screened (5 of 62 patients) had HER-2 overexpression by IHC. Quantitative ELISA for shed HER-2 was available in 32 patients; this level was elevated (> 15 ng/mL) in only 2 patients, and neither had HER-2 expression by IHC. Of the 5 patients with 2+ or 3+ HER-2 expression by IHC, none had elevated shed HER-2 antigen levels by ELISA. FISH for HER-2 amplification was performed on 12 specimens; 5 of these specimens were uninterpretable due to specimen artifact, and none of the remaining 7 specimens had HER-2 amplification, defined as a ratio > 1. Patient age and Gleason score were not correlated with HER-2 status. CONCLUSIONS: Unlike breast carcinoma and contrary to prior reports, HER-2 overexpression by IHC in archival prostate tissue from patients who eventually developed hormone-refractory disease was infrequent. There did not appear to be any correlation between HER-2 overexpression by IHC and shed HER-2 antigen levels in serum by ELISA in this tumor type. Whether trastuzumab possesses single-agent activity or modulates chemotherapy response in tumor types other than breast carcinoma remains to be determined.
