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

Abstract

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.

Fig 1.

Patients from the Breast International Group 1-98 trial included and excluded in this study according to treatment group and availability of tumor material. L, letrozole; T, tamoxifen; ER, estrogen receptor.

Fig 2.

Kaplan-Meier estimates of disease-free survival according to (A) level of Ki-67 labeling index (high > 11% v low ≤ 11%) and (B) treatment assignment.

Fig 3.

Kaplan-Meier estimates of disease-free survival according to level of Ki-67 labeling index (LI) (high > 11% v low ≤ 11%) and treatment assignment, separately for patients (A) with lymph node–negative disease and (B) node-positive disease, and with tumors that are (C) estrogen receptor expressing (1% to 79%) and (D) strongly estrogen receptor expressing (≥ 80%).

Fig 4.

Subpopulation Treatment Effect Pattern Plot analysis of the treatment effect of letrozole versus tamoxifen as measured by 4-year disease-free survival according to overlapping subpopulations defined by percentages of Ki-67 labeling index (LI). The x-axis indicates the median percentage of Ki-67 LI for patients in each of the overlapping subpopulations.

Fig 5.

Proportional hazards model results of disease-free survival in subgroups. The size of each box is inversely proportional to the SE of the hazard ratio (HR). The solid vertical line is placed at HR = 0.63, which is the HR estimate for the overall analysis of letrozole compared with tamoxifen in this analytic cohort. HER-2, human epidermal growth factor receptor 2; LI, labeling index; ER, estrogen receptor.