Evaluation of an Optimal Cut-Off Point for the Ki-67 Index as a Prognostic Factor in Primary Breast Cancer: A Retrospective Study.

Rumiko Tashima,Masahiro Nakano,Yasuyuki Nishiyama,Tomofumi Osako,Yasuhiro Okumura,Reiki Nishimura,Yasuo Toyozumi,Nobuyuki Arima,Mamiko Fujisue,Anthony W.I Lo

doi:10.1371/journal.pone.0119565

Abstract

The Ki-67 index is an important biomarker for indicating the proliferation of cancer cells and is considered to be an effective prognostic factor for breast cancer. However, a standard cut-off point for the Ki-67 index has not yet been established. Therefore, the aim of this retrospective study was to determine an optimal cut-off point in order to establish it as a more accurate prognostic factor. Immunohistochemical analysis of the Ki-67 index was performed on 4329 patients with primary breast cancer from August 1987 to March 2012. Out of this sample, there were 3186 consecutive cases from September 1997 with simultaneous evaluations of ER, PgR and HER2 status. Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors related to OS. The hazard ratios (HR) and the p values were then compared to determine the optimal cut-off point for the Ki-67 index. The median Ki-67 index value was 20.5% (mean value 26.2%). The univariate analysis revealed that there was a statistically significant negative correlation with DFS and OS and the multivariate analysis revealed that the Ki-67 index value was a significant factor for DFS and OS. The top seven cut-off points were then carefully chosen based on the results of the univariate analysis using the lowest p-values and the highest HR as the main selection criteria. The multivariate analysis of the factors for OS showed that the cut-off point of 20% had the highest HR in all of the cases. However, the cutoff point of 20% was only a significant factor for OS in the Luminal/HER2- subtype. There was no correlation between the Ki-67 index value and OS in any of the other subtypes. These data indicate that the optimal cut-off point of 20% is the most effective prognostic factor for Luminal/HER2- breast cancer.

Highlights

Multi-gene assays, primarily derived from proliferation genes [1], provide valuable prognostic information for medical professionals and cancer patients
A multivariate analysis was conducted using the Ki-67 index values as continuous variables to investigate the prognostic significance of this index in primary breast cancer
The multivariate analysis revealed that the Ki-67 index value, tumor size, p53 overexpression and lymph node status were significant factors (Table 3)

Summary

Introduction

Multi-gene assays, primarily derived from proliferation genes [1], provide valuable prognostic information for medical professionals and cancer patients. Within cell proliferation the biomarkers in particular have proven to be effective in the formulation of a more accurate prognosis and further research in this area is warranted. The 2011 St. Gallen’s International Expert Consensus found that the Ki-67 index is effective in discriminating between Luminal A and B type tumors and recommended a cut-off point of 14% [10]. Gallen’s International Expert Consensus found that the Ki-67 index is effective in discriminating between Luminal A and B type tumors and recommended a cut-off point of 14% [10] This was the first time that any attempt was made at trying to establish a standard international cut-off point for the Ki-67 index as a prognostic factor for breast cancer [11]

Methods

Results

Discussion

Conclusion