Selection of HER-2/neu-positive tumor cells in early stage cervical cancer: implications for Herceptin-mediated therapy.
OBJECTIVE
The purpose of this study was to compare HER-2/neu expression on biopsies obtained from early stage cervical cancer, primary cell lines established therefrom, established cervical cancer cell lines, and metastatic or recurrent sites of disease; and to evaluate the sensitivity of primary cervical cancer cell lines to treatment with a humanized MAb against HER-2/neu (Herceptin).


METHODS
Surface HER-2/neu expression on 18 cervical cancer cell lines was compared to HER-2/neu detection by immunohistochemistry on biopsies obtained from the original tumors (10 patients) and sites of recurrence (2 patients). Primary cell lines were tested for sensitivity to Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC) and sensitivity to Herceptin-mediated inhibition of proliferation.


RESULTS
Nine out of 10 primary (90%) and 8 out of 8 (100%) established cervical cancer cell lines expressed HER-2/neu by flow cytometry. Surprisingly, all HER-2/neu-positive primary cell lines were derived from tumor biopsies that scored negative (i.e., 0 to 1+) for HER-2/neu expression by immunohistochemistry. Heavy staining for HER-2/neu (i.e., 3+) was found in the recurrent/metastatic lesions of the two relapsed patients. Importantly, all HER-2/neu-positive primary cell lines were highly sensitive to Herceptin-mediated ADCC, and their proliferation was also significantly inhibited by Herceptin. A significant enhancement of Herceptin-mediated ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in vitro.


CONCLUSIONS
Early stage cervical cancer may develop a population of HER-2/neu-positive cells with a selective growth advantage over HER-2/neu-negative cells. Therapy which targets HER-2/neu may be more effective in patients with cervical cancer than indicated by the commonly low expression of HER-2/neu in tumors removed at the time of primary treatment.
Bellone
Stefania
S
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
Palmieri
Michela
M
Gokden
Murat
M
Joshua
Jabbar
J
Roman
Juan J
JJ
Pecorelli
Sergio
S
Cannon
Martin J
MJ
Santin
Alessandro D
AD
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000494:pharmacology; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000276:immunology; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab