Absence of c-KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer.
BACKGROUND
Germ 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.


METHODS
We 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.


RESULTS
The 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.


CONCLUSIONS
The 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.
Department of Internal Medicine, University of Tuebingen Medical Center, Tuebingen, Germany.
C
C
Kollmannsberger
F
F
Mayer
H
H
Pressler
S
S
Koch
L
L
Kanz
J W
JW
Oosterhuis
L H J
LH
Looijenga
C
C
Bokemeyer
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis*; D018734:Genes, erbB-2; D018237:Germinoma / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D020893:Receptor, ErbB-3 / Q000032:analysis; D066247:Receptor, ErbB-4
D000970:Antineoplastic Agents; D002945:Cisplatin; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human