Carcinoma of an unknown primary: are EGF receptor, Her-2/neu, and c-Kit tyrosine kinases potential targets for therapy?

Abstract

Carcinomas of an unknown primary site (CUP) are heterogeneous tumours with a median survival of only 8 months. Tyrosine kinase inhibitors are promising new drugs. The aim of this study was to determine the expression of EGF-receptor, Her-2/neu, and c-Kit tyrosine kinases in CUP. Paraffin-embedded specimens were obtained from 54 patients with a CUP who were included in the GEFCAPI 01 randomised phase II trial. Immunohistochemistry was performed using the Dako autostainer with antibodies directed against HER-2/neu protein, EGFR protein, and c-Kit protein (CD117). EGFR expression was found in 36 out of 54 samples (66%). In contrast, Her-2/neu overexpression and c-Kit positivity were only detected in 4 and 10% of patients, respectively. No significant association was found between the expression of the tyrosine kinase receptors and prognosis. EGFR expression was significantly associated with response to cisplatin-based chemotherapy: the response rates were 50 and 22% in patients with EGFR-positive tumours and EGFR-negative tumours, respectively (Po0.05). This study shows that EGFR is frequently expressed in CUP. This finding may prompt clinical trials investigating EGFR inhibitors in this setting. In contrast, c-Kit expression and Her-2/neu overexpression occur infrequently in CUP. EGFR expression was correlated to tumour chemosensitivity.

Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial

“…A recent pilot study combining bevacizumab and erlotinib in heterogeneous patients has shown considerable efficacy in CUP with a median overall survival of 7.4 months and 33% of patients alive at 1 year (Hainsworth et al, 2007). A high level of EGFR expression of 66% was observed in another study, with EGFR-expressing patients responding considerably better to platinum-based therapy (Massard et al, 2007). The German CUP study group has recently launched a randomised trial comparing the carboplatin/paclitaxel regimen used in this study with and without cetuximab to test the effectiveness of this EGFR inhibitor in patients with CUP.…”

Carcinoma of Unknown Primary – an Orphan Disease?

“…Analogous to several other tumor entities, progress in the treatment of patients with CUP might come from the use of agents with novel mechanisms of action. Although data on CUP biology including mutation status and expression levels of oncogenes and tumor suppressors are scarce, it has recently been reported that, in contrast to HER2 and c-Kit which were detected in only 4 and 10% of CUP patients, respectively, the epidermal growth factor receptor (EGFR) is expressed in 66% of CUP tumors [63]. Of note, EGFR expression was correlated to tumor chemosensitivity towards platinum-based chemotherapy in this study.…”

Irinotecan plus carboplatin for patients with carcinoma of unknown primary site

“…Several studies have demonstrated the immunohistochemical expression of relevant molecular targets at high frequencies in tissue specimens (Massard et al, 2007). A phase II trial of bevacizumab plus erlotinib revealed substantial activity of this combination in patients treated previously or patients who had not received treatment because of the presence of poor-prognostic features (Hainsworth et al, 2007).…”