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

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.