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Prognostic Value of the Molecular Detection of Circulating Tumor Cells Using a Multimarker Reverse Transcription-PCR Assay for Cytokeratin 19, Mammaglobin A, and HER2 in Early Breast Cancer

Authors' Affiliations: Departments of ¹ Medical Oncology and ² Pathology, University General Hospital of Heraklion; ³ Laboratory of Tumor Cell Biology and ⁴ Department of Biostatistics, School of Medicine, University of Crete, Crete, Greece and ⁵ Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece

Requests for reprints: Dimitris Mavroudis, Department of Medical Oncology, University General Hospital of Heraklion, P. O. Box 1352, Heraklion 711 10, Crete, Greece. Phone: 30-2810-392823; Fax: 30-2810-392802; E-mail: mavrudis{at}med.uoc.gr.

Purpose: To investigate the prognostic value of the molecular detection of circulating tumor cells (CTCs) using three markers [cytokeratin 19 (CK19), mammaglobin A (MGB1), and HER2] in early breast cancer.

Experimental Design: CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells were detected using real-time (CK19) and nested (MGB1 and HER2) reverse transcription-PCR in the peripheral blood of 175 women with stage I to III breast cancer before the initiation of adjuvant chemotherapy. The detection of CTCs was correlated with clinical outcome. In 10 patients, immunofluorescence staining experiments were done to investigate the coexpression of cytokeratin, MGB1, and HER2 in CTCs.

Results: CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells were detected in 41.1%, 8%, and 28.6% of the 175 patients, respectively. Patients had one of the following molecular profiles: CK19mRNA+/MGB1mRNA+/HER2mRNA+ (n = 8), CK19mRNA+/MGB1mRNA+/HER2mRNA– (n = 1), CK19mRNA+/MGB1mRNA–/HER2mRNA+ (n = 42), CK19mRNA+/MGB1mRNA–/HER2mRNA– (n = 21), CK19mRNA–/MGB1mRNA+/HER2mRNA– (n = 5), and CK19mRNA–/MGB1mRNA–/HER2mRNA– (n = 98). Double-immunofluorescence experiments confirmed the following CTC phenotypes: CK+/MGB1+, CK+/MGB1–, CK–/MGB1+, CK+/HER2+, CK+/HER2–, MGB1+/HER2–, and MGB1+/HER2+. In univariate analysis, the detection of CK19mRNA+, MGB1mRNA+, and HER2mRNA+ cells was associated with shorter disease-free survival (DFS; P < 0.001, P = 0.001, and P < 0.001, respectively), whereas the detection of CK19mRNA+ and MGB1mRNA+ cells was associated with worse overall survival (P = 0.044 and 0.034, respectively). In multivariate analysis, estrogen receptor–negative tumors and the detection of CK19mRNA+ and MGB1mRNA+ cells were independently associated with worse DFS.

Conclusion: The detection of peripheral blood CK19mRNA+ and MGB1mRNA+ cells before adjuvant chemotherapy predicts poor DFS in women with early breast cancer.