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HER 2-Positive CirculatingTumor Cells Indicate Poor Clinical Outcome in Stage I to III Breast Cancer Patients

Purpose: Early metastasis innode-negative breast cancer indicates that breast cancer cells obviously can bypass the lymphnodes 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 withmetastatic 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, in12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization. Conclusions:This studyprovides someevidenceofaprognostic effectofHER2-positiveCTCs 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. Breast cancer, even in stage I and II, obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs, consequently adjuvant therapy is given to lower the risk of metastasis (1, 2). These cells have been referred to as ‘‘micrometastases’’ (disseminated tumor cells; ref. 3). Clinical studies consistently report an independent negative prognostic value of disseminated tumor cells in the bone marrow of breast cancer patients at primary diagnosis (4–6). In many cancer patients, circulating tumor cells (CTC) have been identified in the peripheral blood. Because CTCs are present not only in patients with metastatic disease but also in those at stage I to III cancer, these cells may represent an undetected spread of the tumor and serve also as a prognostic marker (7). In addition, CTCs have been reported to reflect the outcome of systemic treatment (8, 9). Therefore, detection of CTCs in these patients using prognostic markers, such as HER2 expression, may help to understand their biology and clinical relevance. The objective of the present study was to evaluate the prognostic value of HER2-positive CTCs in the peripheral blood of stage I to III breast cancer patients. The presence and frequency of HER2-positive CTCs has been correlated with clinicopathologic variables and with patients’ follow-up. To the best of our knowledge, this is the first study to analyze the prognostic value of HER2-positive CTCs from the peripheral blood of breast cancer patients. Because HER2 overexpression indicates a poor prognosis in breast cancer, analysis of HER2positive CTCs in the peripheral blood of breast cancer patients may also help to identify high-risk patients who could benefit from targeting HER2.