Breast Cancer Research and Treatment 86: 9–18, 2004. © 2004 Kluwer Academic Publishers. Printed in the Netherlands. Report Prognostic and predictive impact of the HER-2/neu extracellular domain (ECD) in the serum of patients treated with chemotherapy for metastatic breast cancer Volkmar Müller 1,∗ , Isabell Witzel 1,∗ , Hans Joachim Lück 4 , Günter Köhler 4 , Gunther von Minckwitz 4 , Volker Möbus 4 , Daniel Sattler 4 , Waldemar Wilczak 2 , Thomas Löning 2 , Fritz Jänicke 1 , Klaus Pantel 3 , and Christoph Thomssen 1 1 Department of Gynecology, 2 Department of Gynecopathology, 3 Institute of Tumor Biology, University Hospital Hamburg-Eppendorf; 4 AGO Study Group, Germany Key words: chemotherapy, HER-2/neu serum, metastatic breast cancer, paclitaxel, predictive factors Summary Background. The extracellular domain of the HER-2/neu-receptor (ECD) is shed from the receptor protein and can be detected in serum. However, the clinical implication of HER-2/neu ECD measurement must be further evaluated. Methods. In patients with metastatic breast cancer participating in a trial on first-line chemotherapy, the as- sociation of serum HER-2/neu ECD with progression-free interval, survival, and response was studied. Blood samples of patients receiving epirubicin and either cyclophosphamide (EC) or paclitaxel (ET) were collected before (n = 103) and in addition, after three courses of therapy (n = 46). Results. HER-2/neu ECD levels correlate with HER-2/neu overexpression of corresponding primary tumors de- termined by immunohistochemistry (antibody CB11, p = 0.018) with an optimized cut-off at 15 ng/mL. Elevated serum levels of HER-2/neu ECD before chemotherapy were correlated with shorter overall survival (p = 0.0097), but not with reduced progression-free survival and response to chemotherapy. In subgroup analyses, patients with elevated pretherapeutic HER-2/neu ECD levels treated with EC showed shorter overall survival (p = 0.0092); no difference was seen in the ET group. With regard to progression-free survival, patients with elevated HER-2/neu ECD levels tended to benefit from ET (p = 0.0341), in patients with low levels no difference was observed between EC and ET. A decrease of HER-2/neu ECD levels after three courses of therapy was associated with response to therapy (p = 0.006). Conclusion. In our group of metastatic breast cancer patients, elevated HER-2/neu ECD levels are associated with decreased overall survival. With regard to progression-free survival, particularly patients with high HER-2/neu ECD levels seem to benefit from taxane-containing chemotherapy. Abbreviations: ECD: extracellular domain; ELISA: enzyme-linked immunosorbant assay; kDa: kiloDalton; mL: milliliter; ng: nanogram Introduction The HER-2/neu protooncogene encodes a 185 kDa transmembrane receptor with tyrosine kinase activity. Amplification of the HER-2/neu gene and/or overex- pression of the protein correlates with poor prognosis ∗ These authors contributed equally to this paper. of patients with breast cancer in most studies. HER- 2/neu overexpression might influence a number of aspects in breast cancer phenotype. These include reduced endocrine responsiveness, increased meta- static ability and drug resistance. The extracellular domain of the HER-2/neu-protein (HER-2/neu ECD)