Absence of c‐KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer

Abstract

BACKGROUNDGerm cell tumors (GCTs) in adolescent and young males are very sensitive to cisplatin‐based chemotherapy. However, 10–20% of the patients cannot be cured by currently available therapeutic options. Once a tumor does not respond to cisplatin, current therapeutic modalities offer only a chance for short palliation. Recently, new treatment options that interfere with various receptor tyrosine kinases, including c‐KIT and members of the epidermal growth factor receptor (EGFR) family, have been used successfully in chemotherapy‐resistant tumors overexpressing c‐KIT, ERB‐B2, or EGFR.METHODSWe studied the presence of c‐KIT and the four members of the EGFR family by immunohistochemistry, as well as by ERB‐B2 gene amplification using fluorescent in situ hybridization, in a series of 22 patients with cisplatin‐resistant GCTs in search of new treatment targets. The results in these refractory tumors were compared with those of 12 patients with chemosensitive GCTs diagnosed in an advanced metastatic stage.RESULTSThe data obtained in both groups did not differ in any of the investigated biologic markers. c‐KIT was detected in the one case of pure seminoma studied and in the seminomatous components of combined tumors. The presence of EGFR was restricted to trophoblastic giant cells and the syncytiotrophoblastic elements of four nonseminomas including one pure choriocarcinoma and to a secondary non–germ cell malignancy, which had developed most likely from a mature teratoma. ERB‐B2 was moderately positive in the secondary non–germ cell malignancy, in one mature teratoma component of a mixed nonseminoma, and together with EGFR in the syncytiotrophoblastic cells of a pure choriocarcinoma. Of all samples investigated, this latter case was the only one showing an amplification of the ERB‐B2 gene in the syncytiotrophoblasts. ERB‐B3 and ERB‐B4 were detected rarely.CONCLUSIONThe majority of refractory GCTs do not qualify for treatment with new biologic agents targeting the receptor tyrosine kinases EGFR, ERB‐B2, or c‐KIT. The lack of differences between the tumors of refractory and the responsive patients indicates that overexpression of any of these receptor tyrosine kinases does not contribute to a resistant phenotype in GCTs. Cancer 2002;95:301–8. © 2002 American Cancer Society.DOI 10.1002/cncr.10671

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

“…protein phosphatase or protein tyrosine phosphatases) and thereby contribute to the activation of ERK (Lee and Esselman, 2002) Another scenario may be that CDDP ligates growth factor receptors, thereby activating the MEK -ERK pathway, as suggested for the cervical carcinoma cell line HeLa (Wang et al, 2000). Indeed there are even some reports demonstrating that TGCT express an aberrant platelet-derived growth factor areceptor, which is hypothetically capable of activating the MEK -ERK pathway upon ligation (Kollmannsberger et al, 2002;Palumbo et al, 2002).…”

Author reply

“…Kollmannsberger et al expressed severe criticisms of the criteria for immunohistochemical evaluation and the lack of description of EGFR signal distribution in the positive cases that were reported in our previous study. 2 Our data were described as being "in contrast" to theirs. We do not concur with such statements regarding the data described below.…”

“…In our previous study, 2 we meticulously documented EGFR expression and activation in the ␤-human chorionic gonadotropin (HCG)-positive components of mixed NSGCTs. Furthermore, in agreement with what is generally believed, we considered immunohistochemistry not to be a reliable quantitative assay, even in the case of a quantitative evaluation by a scoring system; reverse transcriptase-polymerase chain reaction (RT-PCR) was performed in a choriocarcinoma cell line, because a quantitative RT-PCR assay is not applicable to specimens from mixed tumors.…”

Absence of c‐Kit and members of the epidermal growth factor receptor family in refractory germ cell cancer

“…2,3 Furthermore, our recent in vitro experiments showed the inhibitory effect of ZD1839, a smallmolecule EGFR tyrosine kinase inhibitor, on the proliferation and clonogenicity of 2 EGFR-positive choriocarcinoma cell lines (Schiavo R, Moroni M, Siera S, 2002; unpublished data). Based on these data, a Phase II clinical trial evaluating the efficacy of ZD1839 in combination with cisplatin for patients with platinum-refractory or relapsed NSGCTs with EGFR expression is underway at our institution.…”