title: The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients.
abstract: BACKGROUND
  In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time "liquid biopsy" approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC.
  
  
  METHODS
  CTC-positive (five or more CTCs/7.5 mL blood; CellSearch®, Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch®). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan-Meier plots.
  
  
  RESULTS
  One hundred seven patients (median age (range) 57 (33-81) years) were included. 100/107 (93%) patients were followed-up for a median [95% confidence interval (CI)] of 28.5 [25.1-40.1] months. Of 37/107 (35%) CTC-HER2-positive patients only 10 (27%) were PRIM-HER2-positive. 6/46 (13%) patients were MET-HER2-positive; only 2/10 (20%) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69% and 74%, respectively. Kaplan-Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95% CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7-13.7] versus 4.34 [3.5-5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7-30.0] versus 8.7 [5.9-15.3] months; p = 0.287).
  
  
  CONCLUSIONS
  HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform "liquid biopsy" to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed.
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. markus.wallwiener@med.uni-heidelberg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Wallwiener
authors.affiliation: Department of Obstetrics and Gynecology, University of Tübingen, Calwerstraße 7, 72076, Tübingen, Germany. andreas.hartkopf@med.uni-tuebingen.de.
authors.forename: Andreas Daniel
authors.initials: AD
authors.lastname: Hartkopf
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. s.riethdorf@uke.uni-hamburg.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.affiliation: National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. juliane.nees@t-online.de.
authors.forename: Juliane
authors.initials: J
authors.lastname: Nees
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. martin.sprick@hi-stem.de.
authors.forename: Martin Ronald
authors.initials: MR
authors.lastname: Sprick
authors.affiliation: Department of Obstetrics and Gynecology, University of Tübingen, Calwerstraße 7, 72076, Tübingen, Germany. birgitt.schoenfisch@uni-tuebingen.de.
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schönfisch
authors.affiliation: Department of Obstetrics and Gynecology, University of Tübingen, Calwerstraße 7, 72076, Tübingen, Germany. florin-andrei.taran@med.uni-tuebingen.de.
authors.forename: Florin-Andrei
authors.initials: FA
authors.lastname: Taran
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. joerg.heil@med.uni-heidelberg.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heil
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. christof.sohn@med.uni-heidelberg.de.
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. pantel@uke.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.trumpp@dkfz.de.|Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.trumpp@dkfz.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany. andreas.schneeweiss@med.uni-heidelberg.de.|National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. andreas.schneeweiss@med.uni-heidelberg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human