Originally published as JCO Early Release 10.1200/JCO.2008.17.0829 on November 3 2008

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Prognostic and Predictive Value of Centrally Reviewed Ki-67 Labeling Index in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Results From Breast International Group Trial 1-98 Comparing Adjuvant Tamoxifen With Letrozole

Giuseppe Viale, Anita Giobbie-Hurder, Meredith M. Regan, Alan S. Coates, Mauro G. Mastropasqua, Patrizia Dell'Orto, Eugenio Maiorano, Gaëtan MacGrogan, Stephen G. Braye, Christian Öhlschlegel, Patrick Neven, Zsolt Orosz, Wojciech P. Olszewski, Fiona Knox, Beat Thürlimann, Karen N. Price, Monica Castiglione-Gertsch, Richard D. Gelber, Barry A. Gusterson, Aron Goldhirsch

From the Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan; Department of Pathological Anatomy, University of Bari, Bari, Italy; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health; Frontier Science and Technology Research Foundation, Boston, MA; IBCSG Coordinating Center; Swiss Group for Clinical Cancer Research (SAKK), Bern; Senology Center of Eastern Switzerland, Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; University of Sydney, Sydney; Australian New Zealand Breast Cancer Trials Group, University of Newcastle and Anatomical Pathology, Hunter Area Pathology Service, John Hunter Hospital, New South Wales, Australia; Department of Pathology, Institut Bergonié, Bordeaux, France; Department of Gynecologic Oncology and Multidisciplinary Breast Centre, UZ-KU Leuven, Leuven, Belgium; Department of Pathology, National Institute of Oncology, Budapest, Hungary; Center of Oncology-Institute, Warsaw, Poland; Department of Pathology, South Manchester University Hospital, Manchester; and the Division of Cancer Sciences and Molecular Pathology, Glasgow University, United Kingdom

Corresponding author: Giuseppe Viale, MD, FRCPath, Department of Pathology, European Institute of Oncology, Via Ripamonti 435-20141 Milan, Italy; e-mail: giuseppe.viale{at}ieo.it

Purpose To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer.

Patients and Methods Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%.

Results Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09).

Conclusion Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

published online ahead of print at www.jco.org on November 3, 2008

Supported by Novartis, Swedish Cancer Society, Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), National Cancer Institute Grant No. CA-75362, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK).

Presented in part at the 30th Annual San Antonio Breast Cancer Symposium, December 13-16, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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