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Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity

Authors' Affiliations: ¹ Institute of Tumor Biology, ² Clinic of Gynecology, ³ Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, and ⁴ Greiner Bio-One GmbH, Frickenhausen, Germany

Requests for reprints: Klaus Pantel, Institut für Tumorbiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. Phone: 49-40-42803-3503; Fax: 49-40-42803-5379; E-mail: pantel{at}uke.uni-hamburg.de.

Purpose: The incidence and biological characteristics of circulating tumor cells in the blood of patients with breast cancer were examined and subgroups were evaluated in the context of systemic treatment and the presence of disseminated tumor cells in bone marrow.

Experimental Design: Circulating tumor cells were isolated from the peripheral blood of patients with breast cancer using a gradient system designed for the enrichment of circulating tumor cells (OncoQuick). Circulating tumor cells were identified with the anti-cytokeratin antibody, A45-B/B3. In subsets of patients, expression of the proliferation-associated Ki-67 antigen in circulating tumor cells and the concomitant presence of micrometastases in bone marrow were examined.

Results: In patients with primary breast cancer (stage M₀), circulating tumor cells were detected in 5 of 60 patients (8.3%) after surgery and before initiation of adjuvant chemotherapy; a positive correlation to the presence of disseminated tumor cells in bone marrow was observed (P = 0.030, n = 53). During the course of adjuvant chemotherapy, repeated analysis of 20 M₀ patients revealed the occurrence of circulating tumor cells in 7 of 16 patients that were initially negative. Patients with metastatic disease (stage M₁) showed circulating tumor cells in 25 of 63 cases (39.7%, P < 0.0001 as compared with M₀ patients), and a positive finding was correlated with elevated concentrations of the serum tumor marker CA15.3 (P = 0.0093). Performing repeated analysis in a subgroup of 25 M₁ patients, circulating tumor cells were found more frequently in patients with progressive disease than in patients with stable disease or remission (87.5% versus 43.8% of patients with circulating tumor cells, respectively; P = 0.047). Independent of the disease-stage, none of the 47 patients examined for the proliferative status of their circulating tumor cells showed coexpression of Ki-67.

Conclusions: Circulating tumor cells seem to be nonproliferating cells that persist during chemotherapy. Circulating tumor cell detection is linked to disease progression and elevated tumor marker concentrations in patients with metastatic breast cancer.

Key Words: Breast cancer • circulating tumor cells • disseminated tumor cells blood • micrometastases bone marrow • systemic therapy

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