Author reply
2003-05-19

Moroni et al. and our own group studied the presence of members of the epidermal growth factor receptor (EGFR) family in germ cell tumors; the goal was to obtain prognostic information and potentially new treatment targets for patients with this disease. In their correspondence, Moroni et al. approve of the data described in our article but disagree with the conclusions. Both studies report expression of EGFR restricted to trophoblastic giant cells and syncytiotrophoblastic components of nonseminomatous germ cell tumors.1, 2 Although the results of Moroni et al. encouraged them to initiate a Phase II study testing an EGFR-targeted regimen in patients with germ cell tumors, we do not consider such an approach promising for the majority of patients with germ cell tumors. This notion is based on the reasoning that follows. We agree that—unlike the situation in HER-2/neu–positive breast carcinoma—there is no strict correlation between response to EGFR-interacting agents and the extent of EGFR expression in EGFR-positive tumors. This finding recently was demonstrated in a study of patients with colorectal carcinoma.3 However, to date, there are no data indicating the antitumor activity of EGFR-interacting agents against tumors that lack EGFR expression. In normal placenta, EGFR is physiologically expressed predominantly in the cytotrophoblast during the first 5 gestational weeks and in the syncytiotrophoblast afterward. In the last trimester, EGFR expression is down-regulated. Increased EGFR expression has been linked to the development of gestational trophoblastic disease.4, 5 Accordingly, its expression probably is linked to placental differentation rather than to the neoplastic phenotype of germ cell tumors in general. An expression level below the detection threshold of immunohistochemistry in the other histologic subtypes cannot be assumed without formal proof—even if EGFR is present at such a low level, its significance with respect to favorable response to EGFR-interacting agents remains doubtful. Moroni et al. confirmed their immunohistochemical results on the mRNA level by performing the reverse transcriptase–polymerase chain reaction on a choriocarcinoma cell line. Subsequently, ZD1839, an inhibitor of the tyrosine kinase activity of EGFR, was applied to 2 EGFR-expressing choriocarcinoma cell lines. Treatment of these cell lines with ZD1839 resulted in inhibition of proliferation and clonogenicity. These results are encouraging with regard to the treatment of patients with pure choriocarcinoma, but it remains to be seen whether they can be transferred to patients with germ cell tumors that contain components of different histology. In vitro efficacy data on cell lines of yolk sac or embryonal carcinoma differentiation would be informative in this respect. There is a high probability that treatment targeted at EGFR will be active in germ cell malignancies only against components expressing the receptor (i.e., choriocarcinoma). Although the level of human chorionic gonadotropin (HCG) has an unequivocal prognostic value, high HCG levels most likely reflect high tumor burden rather than a correlation with the histologic component of the choriocarcinoma itself. In addition, patients who experience recurrence after chemotherapy do not exhibit a predominance of this histologic subtype. Nonetheless, refractory patients are the only cohort of patients with germ cell malignancies for whom it currently is possible to study new biologic agents. If the Phase II trial implemented by Moroni et al. to test the efficacy of ZD1839 in combination with cisplatin in truly refractory patients shows a reversal of platinum sensitivity or any other meaningful clinical response, this will be very valuable information. Frank Mayer M.D.*, Christian Kollmannsberger M.D.*, Carsten Bokemeyer M.D.*, Leendert Looijenga Ph.D. , * Department of Hematology/Oncology, University of Tuebingen, Tuebingen, Germany, Pathology/Laboratory for Experimental Patho-Oncology, Josephine Nefkens Institute, Erasmus University, Rotterdam, The Netherlands.