Is the prognostic value of Ki-67 dependent on ER status and histological grade?.

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Abstract Abstract #1076 Purpose: Histological grade, tumor size, age, hormone receptor, and HER2 are established prognostic indicators for distant recurrences in node negative breast cancer. However, the role of the proliferation marker Ki-67 as a prognostic factor is still under debate. The aim of this study is to evaluate the additional prognostic value of Ki-67 in lymph node negative breast cancer.
 Patients and methods: In 200 consecutive premenopausal women with lymph node negative breast cancer, Ki-67 was determined using the monoclonal MIB-1 antibody on tissue microarray. High Ki-67 proliferation index was defined as >20% positive tumor cells. Cox proportional hazards regression was used to model the impact of the prognostic factors on distant disease-free survival (DDFS). Due to non-proportional hazards, the analysis was restricted to the first 5 years after diagnosis, a time period during which 38 patients developed distant recurrences.
 Results: Strong positive correlations were observed between Ki-67, histological grade, S-phase, and HER-2. In univariate analysis, Ki-67 was a prognostic factor for DDFS (HR 2.9 95%CI: 1.5-5.7, p=0.002), as well as HER2, histological grade, age and ER. Tumor size was not a significant factor. In multivariate analysis, Ki-67 was an independent prognostic factor for DDFS (HR 2.3 95% CI: 1.0-5.0, p=0.044) together with HER2 and age, whereas tumor size and ER were not significant factors. Models including both Ki-67 and histological grade were not fitted due to colinearity. When stratifying for ER status Ki-67 was a significant prognostic factor in the ER positive group only (HR 5.1 95% CI: 2.0-13, p=0.001, univariate analysis) and significant interaction between the two markers was found (p=0.02). When stratifying for histological grade, Ki-67 could divide the patients with histological grade 2 (n=69; 10 distant recurrences) into two separate groups with significant difference in DDFS (HR 15 95% CI: 3.7-57, p=0.0001). This remained significant after adjustment for age and HER2 status. In histological grade 1 and 3, Ki-67 provided no additional prognostic information.
 Conclusion: This study demonstrates that Ki-67 is an independent prognostic factor for premenopausal patients with lymph node negative breast cancer. It is noteworthy that Ki-67 adds prognostic information in ER positive patients, but not in ER negative, and in patients with histological grade 2, but not in patients with histological grade 1 and 3. Taken together, Ki-67 may be clinically helpful for prognostic considerations and for selection of adjuvant treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1076.