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Original Investigation
February 2016

The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence

Author Affiliations
  • 1Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
  • 2Medical Oncology Clinic, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
  • 3Department of Breast and Gynecological Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
  • 4Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
  • 5Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
  • 6Danish Breast Cancer Cooperative Group, Copenhagen, Denmark
  • 7Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy
  • 8Avera Cancer Institute, Sioux Falls, South Dakota
  • 9International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 10International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Bern, Switzerland
  • 11Department of Oncology, Odense University Hospital, Odense, Denmark
  • 12AgeCare, Odense University Hospital, Odense, Denmark
  • 13Service de Biostatistique et d’Epidémiologie, Gustave Roussy, Villejuif, France
  • 14INSERM U1018, CESP, Université Paris-Sud, Villejuif France
JAMA Oncol. 2016;2(2):217-224. doi:10.1001/jamaoncol.2015.4377

Importance  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.

Design, Setting, and Participants  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.

Interventions  Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifiers: NCT00004205 and NCT00004205