Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review

Abstract

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use.

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer

“…The reason is that despite data indicating the correlation between high ki67 and pCR, most of these data are derived from retrospective studies other than clinical trials [6][7][8][9][10][11]. Furthermore, Ki67 cutpoints used in these studies were selected empirically (with thresholds associated with the mean of observed values in the study population) or were arbitrarily established at 10%-25% [14].…”

Ki67 Index in Breast Cancer: Correlation with Other Prognostic Markers and Potential in Pakistani Patients

“…It is not predictive for chemotherapy, but high Ki-67 was found to be associated with immediate complete response in the neoadjuvant setting (Luporsi et al, 2012).…”

Correlation of Microvessel Density with Nuclear Pleomorphism, Mitotic Count and Vascular Invasion in Breast and Prostate Cancers at Preclinical and Clinical Levels

“…Proliferation is often assessed by immunohistochemistry using Ki-67. This protein is present during all active phases of the cell cycle, including G1, S, G2, and mitosis (Luporsi et al, 2011), while in mitotic count, only those cells which are in the mitotic phase are counted. Since breast cancer has a prolonged doubling time (Medina et al, 2011), we can conclude that in the proliferation (mitotic activity index) method, the S phase is identified earlier than other phases, while the mitotic forms are identified later.…”