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HER2-Positive Circulating Tumor Cells Indicate Poor Clinical Outcome in Stage I to III Breast Cancer Patients

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology, ² Gerhard-Domagk Institute of Pathology, and ³ Institute of Clinical Chemistry and Laboratory Medicine, University of Münster, Münster, Germany; ⁴ Institute of Immunology, University of Witten/Herdecke, Witten, Germany; and ⁵ Institute of Tumor Biology, University Medical Centre, Hamburg, Germany

Requests for reprints: Pia Wülfing, Department of Obstetrics and Gynecology, University of Münster, Albert-Schweitzer-Str. 33, 48149 Münster, Germany. Phone: 49-251-834-8202; Fax: 49-251-834-8267; E-mail: wuelfip{at}uni-muenster.de.

Purpose: Early metastasis in node-negative breast cancer indicates that breast cancer cells obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs. For this purpose, we evaluated the prognostic value of blood-borne, HER2-positive circulating tumor cells (CTC) in the peripheral blood from 42 breast cancer patients with a median follow-up of 95 months.

Experimental Design: Cells were isolated by the patented combined buoyant density gradient and immunomagnetic separation procedure and analyzed by immunocytochemistry.

Results: We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis. As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive. Healthy persons and patients (n = 32) operated for nonmalignant diseases presented negative for CTCs. The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05). Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization.

Conclusions: This study provides some evidence of a prognostic effect of HER2-positive CTCs in stage I to III breast cancer. Future studies have to determine the outcome of patients treated with HER2-targeting therapies with respect to HER2-positive CTC levels because it is not unlikely that high levels of HER2-positive CTCs reflect the activity of the tumor and may predict response to trastuzumab.

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