Prognostic value of different cut-off levels of Ki-67 in breast cancer: a systematic review and meta-analysis of 64,196 patients

Abstract

A proliferative marker, expressed as the percentage of cells in a cell cycle, has been developed and used as a discriminant of more aggressive malignant phenotypes in early breast cancer (BC). The marker is usually expressed by the immunohistochemical staining of the cell cycle antigen Ki-67. It has not, however, yet been definitely evaluated, due to methodological concerns, which specific Ki-67 cut-off provide the strongest prognostic information in resected BC. We conducted a meta-analysis to explore the prognostic value of different cut-off levels of Ki-67 in terms of overall survival (OS) and disease-free survival (DFS) in early BC. The databases of PubMed, the ISI Web of Science, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, and CINHAL were used to identify the relevant literature. Data from studies reporting a hazard ratio (HR) and a 95 % confidence interval (CI) calculated as a multivariate analysis were pooled in a meta-analysis, with metaregression used to test for trends in predefined subgroups. All the statistical tests were 2-sided. Forty-one studies encompassing 64,196 BC patients were included in the analysis. Overall, n = 25 studies were available for the OS analysis. The pooled HR for high versus low Ki-67 was 1.57 (95 % CI 1.33-1.87, P < 0.00001). Twenty-nine studies were available for the DFS analysis. The pooled HR for high versus low Ki-67 was 1.50 (95 % CI 1.34-1.69, P < 0.00001). When a cut-off of Ki-67 staining ≥ 25 % was used, the pooled HR for OS was 2.05 (95 % CI 1.66-2.53, P < 0.00001), which was significantly different to studies where the cut-offs chosen were <25 %. In ER+ tumors, the HR for high versus low Ki-67 was similar and significant (HR = 1.51, 95 % CI 1.25-1.81, P < 0.0001). We conclude that Ki-67 has an independent prognostic value in terms of OS in BC patients. The Ki-67 threshold with the greatest prognostic significance is as yet unknown, but a cut-off >25 % is associated with a greater risk of death compared with lower expression rates.

Prognostic and clinicopathological role of high Ki-67 expression in patients with renal cell carcinoma: a systematic review and meta-analysis

“…Recently, Ki-67 has drawn increasing attention as an attractive prognostic prediction marker and potential therapeutic target in malignant neoplasms. Several studies suggested that Ki-67 is significantly associated with the prognosis of bladder cancer, breast cancer, lung cancer, upper urinary tract urothelial carcinomas, cervical cancer, and lymphoma6933343536. However, the prognostic and clinicopathological values of Ki-67 remain ambiguous in RCC.…”

Dynamic contrast-enhanced and diffusion-weighted MRI of estrogen receptor-positive invasive breast cancers: Associations between quantitative MR parameters and Ki-67 proliferation status

“…Accordingly, the Ki‐67 status could be a potential prognostic marker for determining management of patients with ER‐positive breast cancer. Currently, although the National Comprehensive Cancer Network (NCCN) guidelines do not recommend Ki‐67‐based assessment, increasing evidence shows that the Ki‐67 proliferation index is associated with treatment efficacy and survival . A recent meta‐analysis of data from over 6000 patients showed that a high Ki‐67 index is associated with a >50% risk of death and a 64% greater risk of recurrence in patients with early‐stage breast cancer, after adjustment for stage, histological grade, and ER status.…”

“…A recent meta‐analysis of data from over 6000 patients showed that a high Ki‐67 index is associated with a >50% risk of death and a 64% greater risk of recurrence in patients with early‐stage breast cancer, after adjustment for stage, histological grade, and ER status. Therefore, routine assessment of the Ki‐67 is recommended …”

Hypoxia‐related carbonic anhydrase IX expression is associated with unfavourable response to first‐line therapy in classical Hodgkin's lymphoma

“…The Ki‐67 nuclear protein is a key factor of cell cycle progression, which can be demonstrated with high affinity by the antibody clone Mib‐1 . The Ki‐67 labelling index is widely used to estimate proliferative activity, and as such it is an established prognostic factor in different malignant conditions . including lymphoid neoplasias .…”