Originally published as JCO Early Release 10.1200/JCO.2007.11.7762 on October 22 2007

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Different Prognostic Value of Cytokeratin-19 mRNA–Positive Circulating Tumor Cells According to Estrogen Receptor and HER2 Status in Early-Stage Breast Cancer

Michail Ignatiadis, Nikos Xenidis, Maria Perraki, Stella Apostolaki, Eleni Politaki, Maria Kafousi, Efstathios N. Stathopoulos, Aliki Stathopoulou, Evi Lianidou, Grigorios Chlouverakis, Christos Sotiriou, Vassilis Georgoulias, Dimitris Mavroudis

From the Department of Medical Oncology and Pathology, University General Hospital of Heraklion; Laboratory of Tumor Cell Biology and Department of Biostatistics, School of Medicine, University of Crete, Crete; Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, Greece; and the Functional Genomics and Translational Research Unit, Jules Bordet Institut, Brussels, Belgium

Address reprint requests to Dimitris Mavroudis, MD, PhD, Department of Medical Oncology, University General Hospital of Heraklion, PO Box 1352, Heraklion 711 10, Crete, Greece; e-mail: mavrudis{at}med.uoc.gr

Purpose To examine the prognostic value of cytokeratin-19 (CK-19) mRNA–positive circulating tumor cells (CTCs) in early-stage breast cancer patients focusing on clinically relevant subgroups based on estrogen receptor (ER) and HER2 expression.

Patients and Methods CK-19 mRNA–positive CTCs were detected by real-time reverse transcriptase polymerase chain reaction in the blood of 444 consecutive, stage I-III, breast cancer patients before initiation of adjuvant chemotherapy. The association between detection of CK-19 mRNA–positive CTCs and clinical outcome was analyzed for patients with ER-positive, ER-negative, triple-negative, HER2-positive, and ER-positive/HER2-negative tumors.

Results CK-19 mRNA–positive CTCs were detected in 181 (40.8%) of 444 patients; 109 (41.9%) of 260 patients with ER-positive tumors; 71 (40.6%) of 175 patients with ER-negative tumors; 27 (35%) of 77 patients with triple-negative tumors; 35 (39.8%) of 88 patients with HER2-positive tumors; and 82 (44.1%) of 186 patients with ER-positive/HER2-negative tumors. After a median follow-up of 53.5 months, patients with CK-19 mRNA–positive CTCs experienced reduced disease-free survival (DFS; P < .001) and overall survival (OS; P < .001); this was mainly observed in patients with ER-negative (P < .001 and P < .001, respectively) but not ER-positive tumors (P = .172 and P = .425, respectively) and in patients with triple-negative (P = .008 and P = .001, respectively) and HER2-positive (P = .023 and P = .040, respectively) but not ER-positive/HER2-negative tumors (P = .210 and P = .578, respectively). In multivariate analysis, the interaction between CK-19 mRNA–positive CTCs and ER status was the strongest independent prognostic factor for reduced DFS (hazard ratio [HR], 3.808; 95% CI, 2.415 to 6.003; P < .001) and OS (HR, 4.172; 95% CI, 2.477 to 9.161; P < .001).

Conclusion Detection of CK-19 mRNA–positive CTCs before adjuvant chemotherapy predicts poor clinical outcome mainly in patients with ER-negative, triple-negative, and HER2-positive early-stage breast cancer.

published online ahead of print at www.jco.org on October 22, 2007.

M.I. and N.X. have contributed equally to this article.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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