Trastuzumab plus docetaxel in HER‐2/neu‐positive prostate carcinoma

Abstract

BACKGROUNDOverexpression 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.METHODSParaffin‐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/m2 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.RESULTSOne 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.CONCLUSIONSHER‐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. Cancer 2004. © 2004 American Cancer Society.

Activating Mutations in ERBB2 and Their Impact on Diagnostics and Treatment

“…Whereas trastuzumab has recently been approved for the treatment of metastatic gastric cancer in combination with cytotoxic agents (Bang et al, 2010), similar studies targeting overexpressed/amplified ERBB2 in NSCLC (Gatzemeier et al, 2004; Langer et al, 2004; Lara et al, 2004b; Zinner et al, 2004; Krug et al, 2005; Herbst et al, 2007) and prostate cancer (Morris et al, 2002; Lara et al, 2004a; Ziada et al, 2004) have reported modest or disappointing results. It remains to be determined whether this primary resistance to trastuzumab results from inaccessibility of the receptor.…”

Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block

“…No agent, however, displayed any meaningful activity in Phase II trials of men with PCa [61-65]. Preclinical studies had also used Pertuzumab (2C4) - a monoclonal antibody directed against ErbB2 but differed from Trastuzumab in that it prevented ErbB2 heterodimerization with other ErbB family members rather than obstructing ErbB2's ligand-binding domain [38].…”

Genomic and epigenomic alterations in prostate cancer

“…These conditions may open new ways to PC therapy. However, when trastuzumab (Lara et al, 2004; Ziada et al, 2004) and pertuzumab (a second generation of anti-HER2 monoclonal antibody; De Bono et al, 2007), as well as the EGFR tyrosine kinase inhibitors (TKIs) gefitinib (Canil et al, 2005) and erlotinib (Gravis et al, 2006) have been tested in PC, it was observed a non-significant single-agent activity. These results suggest that these targets may be of secondary importance or of primary importance only in few cases of PC.…”