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Circulating HER-2/erbB-2/c-neu (HER-2) Extracellular Domain as a Prognostic Factor in Patients with Metastatic Breast Cancer

Cancer and Leukemia Group B Study 8662¹

Georgetown University Medical Center, Lombardi Cancer Center, Washington, DC 20007 [D. F. H., H. Y.]; CALGB Statistical Center, Durham, North Carolina 27710 [B. B., C. T. C.]; Down East Orthopedic Association, Bangor, Maine 04401 [S. P. R.]; University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77080 [D. A. B.]; Massachusetts General Hospital, Boston Massachusetts 02114 [J. Y.]; McGill Department of Oncology, Montreal, Quebec, Canada [L. L. P.]; Naval Hospital, San Diego, California 92134 [F. M.]; State University of New York, Upstate Medical Center, Syracuse New York 13210 [D. B. D.]; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [L. N.]; and University of California at San Francisco, San Francisco, California 94114 [I. C. H.]

Purpose: The HER-2/erbB-2/c-neu (HER-2) proto-oncogene is a M_r 185,000 transmembrane tyrosine kinase that is amplified and/or overexpressed by 20–40% of breast cancers. HER-2 has been associated with worse prognosis and resistance or sensitivity to specific treatment. We evaluated circulating levels of extracellular domain of HER-2 (ECD/HER-2) in metastatic breast cancer patients and investigated the prognostic and predictive significance of circulating HER-2 levels regarding endocrine therapy or chemotherapy.

Experimental Design: Plasma samples from 242 patients were assayed for circulating ECD/HER-2 levels, using a sandwich enzyme immunoassay. ECD/HER-2 was correlated with clinical data gathered from these patients while they were participating in prospective Cancer and Leukemia Group B (CALGB) therapeutic protocols for metastatic breast cancer.

Results: Eighty-nine (37%) of 242 patients had elevated ECD/HER-2 levels (10.5 ng/ml). ECD/HER-2 was significantly associated with tumor burden, progesterone receptor levels, and presence of visceral metastases. Patients with elevated pretreatment levels had a significantly shorter OS but not time-to-progression than did those with ECD/HER-2 levels <10.5ng/ml in univariate analysis. In univariate but not multivariate subset analyses, among patients treated with endocrine therapy (megestrol acetate), elevated initial ECD/HER-2 was associated with worse OS compared with nonelevated patients. However, among patients treated with chemotherapy (mainly anthracycline-containing regimens), OS did not differ significantly. Rates of response to either endocrine therapy or chemotherapy were similar for patients with elevated and nonelevated ECD/HER-2 levels.

Conclusions: ECD/HER-2 levels are elevated in 35–40% of patients with metastatic breast cancer. Elevated ECD/HER-2 levels are associated with a poorer prognosis in these patients. However, no predictive role for ECD/HER-2 was identified, either for endocrine therapy or for anthracycline-based chemotherapy in the metastatic setting.

Commentaries

The Prognostic and Predictive Values of ECD-HER-2

William N. Hait
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