title: The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence.
abstract: OBJECTIVE
  The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required.
  
  
  OBJECTIVE
  To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation.
  
  
  METHODS
  This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log2-transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value.
  
  
  METHODS
  Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67.
  
  
  METHODS
  Distant recurrence-free interval (DRFI).
  
  
  RESULTS
  Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic information to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94% (95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%).
  
  
  CONCLUSIONS
  Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade, the GG assay can identify a higher proportion of endocrine-only treated patients with very low risk of distant recurrence at 10 years.
  
  
  BACKGROUND
  clinicaltrials.gov Identifiers: NCT00004205 and NCT00004205.
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium2Medical Oncology Clinic, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Michail
authors.initials: M
authors.lastname: Ignatiadis
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Azim
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: Department of Breast and Gynecological Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Veys
authors.affiliation: Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark6Danish Breast Cancer Cooperative Group, Copenhagen, Denmark.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Lyng
authors.affiliation: Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Avera Cancer Institute, Sioux Falls, South Dakota.
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.affiliation: International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.affiliation: International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Bern, Switzerland.
authors.forename: Rosita
authors.initials: R
authors.lastname: Kammler
authors.affiliation: Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dell'Orto
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rothé
authors.affiliation: Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Laïos
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark6Danish Breast Cancer Cooperative Group, Copenhagen, Denmark11Department of Oncology, Odense University Hospital, Odense, Denmark12AgeCare, Odense University Hospital, Odense.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
authors.affiliation: International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.affiliation: Medical Oncology Clinic, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.affiliation: Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France14INSERM U1018, CESP, Université Paris-Sud, Villejuif France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium2Medical Oncology Clinic, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016612:Paraffin Embedding; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016707:Tissue Fixation / Q000379:methods; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D005404:Fixatives; D019394:Ki-67 Antigen; D005557:Formaldehyde