Ki67: A Time-Varying Biomarker of Risk of Breast Cancer in Atypical Hyperplasia.
Authors: Hartmann L. , Reynolds C. , Barr Fritcher E. , Frost M. , Vierkant R. , Anderson S. , Degnim A. , Visscher D. , Pankratz V. , Santisteban M. 
Published: December 2010

Abstract
Background: Uncontrolled proliferation is a defining feature of the malignant phenotype. Ki67 is a marker for proliferating cells and is overexpressed in many breast cancers. Atypical hyperplasia is a premalignant lesion of the breast (relative risk ∼ 4.0). Here we asked if Ki67 expression could stratify risk in women with atypia.Methods: Ki67 expression was assessed immunohistochemically by digital image analysis in archival sections from 192 women with atypia diagnosed at the Mayo Clinic 1/1/67-12/31/91. Risk factor and follow-up data were obtained via study questionnaire and medical records. Observed breast cancer events were compared to population expected rates (Iowa SEER) using standarized incidence ratios (SIRs). We examined both short-term (within 10 years) and long-term (after 10 years) risk of breast cancer (BC) following atypia biopsy.Results: The median value for percent positive cells for Ki67 was 1.0%; the 75th percentile value was 2.3%. Based on the empirical distribution of staining values in our cohort, we selected a cutoff of 2% cells positive to separate high from low staining. There were no differences in Ki67 levels by age at biopsy, type of atypia (ADH, ALH, or both), number of foci of atypia, or family history. 32 women developed BC over a median of 14.6 years. Among them, those with ≥2% Ki67 expression had a shorter time to breast cancer (median 5.5 years, IQR=3.2-7.2) than those with &lt;2% cells positive (median=13.8 years, IQR=11.6-20.3). There was a positive association between Ki67 overexpression (≥2% of cells positive) and risk of BC in the first 10 years of follow-up (SIR=4.42 [95% CI 2.21-8.84]). This excess risk resulted in a 10-year cumulative incidence of 14.1%. In contrast, in the women with low Ki67 expression, we found no increased risk of BC in the first 10 years, with SIR 1.01 (95% CI 0.38-2.70), which was significantly lower than the women with high expression (p=0.01). The 10-year cumulative incidence of BC was 3% for the low Ki67group, in line with population averages. After 10 years, risk increased significantly in the low Ki67 group [SIR 5.69 (3.63-8.92)] vs. no increased risk in the high Ki67 group [SIR 0.78 (0.11-5.55)]. We formally examined this apparent time-dependent difference in incidence patterns by Ki67 staining levels via Poisson regression analysis, and found a statistically significant interaction between pre- vs. post-10 years incidence and high vs. low staining levels (p&lt;0.001).Conclusions: Ki67 appears to be a time-varying biomarker of risk of breast cancer in women with atypical hyperplasia. Women whose atypias show higher proliferation rates have an increased risk for an earlier BC (within 10 years). Those with lower proliferation rates tend to develop BCs later, after 10 years. Ki67 levels may help to define the time period of greatest risk for women with atypia.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 909.