title: Circulating tumor cells in HER-2 positive metastatic breast cancer patients treated with trastuzumab and chemotherapy.
abstract: The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2 positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response.
authors.affiliation: Department of Cancer Biology/Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Nunes
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Soonmo Peter
authors.initials: SP
authors.lastname: Kang
authors.forename: Harold
authors.initials: H
authors.lastname: Burstein
authors.forename: Lisa
authors.initials: L
authors.lastname: Roberts
authors.forename: Walter
authors.initials: W
authors.lastname: Carney
authors.forename: Kimberly
authors.initials: K
authors.lastname: Blackwell
authors.forename: Paula
authors.initials: P
authors.lastname: Ryan
authors.forename: Virginia
authors.initials: V
authors.lastname: Borges
authors.forename: J Dirk
authors.initials: JD
authors.lastname: Iglehart
authors.forename: Paula
authors.initials: P
authors.lastname: Friedman
authors.forename: Lyndsay N
authors.initials: LN
authors.lastname: Harris
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods / Q000706:statistics & numerical data; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use; D011379:Prognosis; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D012680:Sensitivity and Specificity; D000068878:Trastuzumab; D014747:Vinblastine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017931:DNA Primers; D005419:Flavonoids; D053539:Keratin-19; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine; C077990:alvocidib; C508053:ERBB2 protein, human