title: Standardized Ki67 Diagnostics Using Automated Scoring--Clinical Validation in the GeparTrio Breast Cancer Study.
abstract: OBJECTIVE
  Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies.
  
  
  METHODS
  We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring.
  
  
  RESULTS
  The three groups of autoKi67 as defined by low (≤ 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P(OS) < 0.0001 and P(PFS) < 0.0002, compared with P(OS) < 0.0005 and P(PFS) < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P(OS) = 0.002, P(PFS) = 0.009 (autoKi67) versus P(OS) = 0.007, PPFS = 0.004 (manual Ki67).
  
  
  CONCLUSIONS
  The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics.
authors.affiliation: Institute of Pathology, Charité University Hospital Berlin, Charitéplatz 1, Berlin, Germany. frederick.klauschen@charite.de.
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.affiliation: Institute of Pathology, Charité University Hospital Berlin, Charitéplatz 1, Berlin, Germany. VMscope GmbH, Charitéplatz 1, Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wienert
authors.affiliation: Institute of Pathology, Charité University Hospital Berlin, Charitéplatz 1, Berlin, Germany.
authors.forename: Wolfgang D
authors.initials: WD
authors.lastname: Schmitt
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: University Women's Hospital Rostock, Rostock, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.affiliation: Department of Gynecology and Breast Center, Charité University Hospital Berlin, Charitéplatz 1, Berlin, Germany.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.affiliation: University Women's Hospital Ulm, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Klinikum Karlsruhe, Karlsruhe, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rüdiger
authors.affiliation: AMEOS Klinikum Halberstadt, Halberstadt, Germany.
authors.forename: Erhard
authors.initials: E
authors.lastname: Erbstößer
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: Keyur
authors.initials: K
authors.lastname: Mehta
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Lederer
authors.affiliation: Institute of Pathology, Charité University Hospital Berlin, Charitéplatz 1, Berlin, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: Institute of Pathology, Charité University Hospital Berlin, Charitéplatz 1, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: German Breast Group, Neu-Isenburg, Germany. University Women's Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D043823:Taxoids; D004317:Doxorubicin; D003520:Cyclophosphamide