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Overexpression of HER-2/Neu in Uterine Serous Papillary Cancer¹

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology [A. S., S. B., M. P., D. D., T. O., G. P.], Departments of Pathology [M. G.], Medicine [J. A., L. H.], and Microbiology and Immunology [M. J. C.], University of Arkansas, Little Rock, Arkansas 72205-7199, and Division of Gynecologic Oncology, University of Brescia, 25123 Brescia, Italy [A. S., S. B., M. P., S. P.]

Purpose: Uterine serous papillary carcinoma (USPC) is a highly aggressive variant of endometrial cancer and histologically similar to high-grade ovarian cancer. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistology in 25% of ovarian cancers. In this study, we have evaluated the expression of HER-2/neu in several fresh, established, paraffin-embedded, fixed USPCs. In addition, we have tested the sensitivity of USPC cells to Herceptin treatment.

Experimental Design: Ten consecutive USPC specimens were assessed by immunohistochemistry for the intensity of expression of HER-2/neu. In addition, three USPC cell lines were analyzed for expression of HER-2/neu by flow cytometry as well as for sensitivity to Herceptin-mediated, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and inhibition of cell proliferation.

Results: Eight of 10 (80%) of the USPCs assessed immunohistochemically for the intensity of expression of HER-2/neu stained heavily for HER-2/neu (2+ to 3+). Fresh and established primary USPC cell lines were found to express significantly more HER-2/neu receptor by flow cytometry (on the average, 10-fold greater) when compared with HER-2/neu-positive primary or established breast and ovarian cancer cell lines (P < 0.001). Importantly, although these USPC cell lines were resistant to chemotherapy in vivo and to natural killer- and complement-mediated cytotoxicity in vitro, they were found to be highly sensitive to Herceptin-mediated ADCC. USPC cell proliferation was also inhibited by Herceptin. A significant enhancement of ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in vitro. Physiological concentrations of human serum IgG did not inhibit Herceptin-mediated ADCC against USPC.

Conclusions: On the basis of these findings and previous reports showing a positive in vivo correlation between efficacy of Herceptin therapy and the level of HER-2/neu overexpression by tumor cells, we propose that Herceptin might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic USPC.

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