Her-2/Neu Expression in Prostate Cancer: High Level of Expression Associated With Exposure to Hormone Therapy and Androgen Independent Disease

Shi, Yan; Brands, F.; Chatterjee, Sumana; Feng, An Chen; Groshen, Susan; Schewe, Jörg; Lieskovsky, Gary; Côté, Richard J.

doi:10.1016/s0022-5347(05)65822-3

Cited by 102 publications

(68 citation statements)

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“…Detection of HER2 at different times might correspond to restart in the cycle of survival cells. The role of HER2 in prostate cancer progression is still debated, with divergent reports about the level of HER2 expression in HRPC Shi et al, 2001;Di Lorenzo et al, 2002;Fossa et al, 2002;Mendoza et al, 2002;Savinainen et al, 2002;Calvo et al, 2003;Hernes et al, 2004). These discrepancies could be due to the methodology used for detecting HER2, designed for detection in breast cancers, and it might be inadequate for prostate cancer tissue (Simon et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study in prostate cancer cell lines showed that an HER2/ERBB3 signalling pathway protected the AR from degradation by the ubiquitin -proteasome pathway and enhanced AR transcriptional activity at low androgen concentrations (Mellinghoff et al, 2004). Studies of clinical prostate cancer samples, however, have produced mixed data, failing to firmly establish a relationship between HER2 overexpression and progression to hormone independence (Osman et al, 2001;Shi et al, 2001;Savinainen et al, 2002;Calvo et al, 2003). HER2 gene is overexpressed in 20 -25% of invasive breast cancers and in 60% of HRPC.…”

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Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms

et al. 2007

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Antitumour activity of docetaxel (Taxotere s ) in hormone-dependent (HD) and hormone-independent (HID) prostate cancer PAC120 xenograft model was previously reported, and its level was associated with HER2 protein expression. In the present study, we evaluate the antitumour effects of docetaxel combined with trastuzumab (Herceptin s ), an anti-HER2 antibody. Although trastuzumab alone had no effect on tumour growth, it potentiated the antitumour activity of docetaxel in HD tumours and more strongly in HID variants. Using the HID28 variant, we show that docetaxel treatment of tumour-bearing mice induces an increased HER2 mRNA expression of the tyrosine kinase receptor of 25-fold 24 h after docetaxel treatment, while HER2 protein and p-AKT decreased. This was followed by an increase of HER2 protein 3 days (two-fold) after docetaxel treatment and by a strong HER2 release in the serum of treated mice; expression of phospho-ERK, p27, BCL2 and HSP70 concomitantly increased. Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment. We show that in addition to its known effects on tubulin and mitotic spindles, docetaxel induces complex signalisation pathway mechanisms in surviving cells, including HER2, which can be pharmacologically targeted. This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer. Escape from androgen ablation therapy is a constant feature of prostate cancer progression, leaving patients with few therapeutic options. Hormone-refractory prostate cancer (HRPC) was regarded as chemoresistant, until the recent demonstration of taxane activity (Petrylak et al, 1999). A preclinical in vivo study using our PAC120 model of hormone-dependent (HD) human prostate cancer xenograft confirmed these data (de Pinieux et al, 2001;Oudard et al, 2003). A randomised phase II study demonstrated the efficacy of docetaxel-based chemotherapy vs a mitoxantroneprednisone combination, significantly decrease PSA and prolongs time to progression of metastatic HRPC patients (Oudard et al, 2005). Despite these encouraging preclinical and clinical data, the therapeutic efficacy of taxane-based chemotherapy of HRPC remains modest. A better knowledge of the mechanisms of tumour hormonal escape and of key molecular targets is needed to design more effective combination therapies for HRPC.Several preclinical studies have implicated the ERBB family of tyrosine kinase receptors, especially HER2, in the progression of prostate cancer to a hormone-refractory state. The CWR22 hormone-independent prostate cancer xenograft expresses HER2 and its growth is inhibited in vivo by an anti-HER2 antibody (Agus et al, 1999;Mendoza et al, 2002). Increased hormone independence in prostate cancer cells was associated with androgen receptor (AR) phosphorylation mediated by transfected HER2 (Craft et al, 1999;Yeh e...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms

et al. 2007

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“…26 In an initial Phase II trial of single-agent trastuzumab therapy in patients with prostate carcinoma, no responders were observed among patients whose tumor specimens were HER-2 negative, 27 suggesting that a targeted strategy directed at HER-2-positive HRPC populations was likely to be a more optimal approach. The current study thus attempted to provide, in a larger cohort of patients with prostate carcinoma, a broader estimate of HER-2 status and to test the hypothesis that a trastuzumab-taxane combination would improve treatment outcomes in an enriched HRPC population with HER-2-positive disease.…”

Section: Discussionmentioning

confidence: 99%

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

Lara

Chee

Longmate

et al. 2004

Cancer

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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.

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“…60 High C-ERB-B2 expression is associated with anti-androgen therapy and may contribute to androgen-independence in PC. 61 Sadasivan et al 62 found that C-ERB-B2 expression correlated with advanced stages and higher Gleason scores. Conversely Kuhn et al 63 in a preliminary study of 53 radical prostatectomy (RP) cases, found that C-ERB-B2 protein expression did not predict serological or clinical recurrence.…”

Section: The C-myc Oncogenementioning

confidence: 99%

Molecular biology of prostate cancer

Karayi

Markham

2004

Prostate Cancer Prostatic Dis

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Development of any cancer reflects a progressive accumulation of alterations in various genes. Oncogenes, tumour suppressor genes, DNA repair genes and metastasis suppressor genes have been investigated in prostate cancer. Here, we review current understanding of the molecular biology of prostate cancer. Detailed understanding of the molecular basis of prostate cancer will provide insights into the aetiology and prognosis of the disease, and suggest avenues for therapeutic intervention in the future.

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Her-2/Neu Expression in Prostate Cancer: High Level of Expression Associated With Exposure to Hormone Therapy and Androgen Independent Disease

Cited by 102 publications

References 26 publications

Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms

Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms

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

Molecular biology of prostate cancer

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