Ki67 expression in invasive breast cancer: the use of tissue microarrays compared with whole tissue sections

Abstract

BackgroundAlthough the prognostic value of Ki67 in breast cancer is well documented, using optimal cut-points for patient stratification, reproducibility of the scoring and interpretation of the results remains a matter of debate particularly when using tissue microarrays (TMAs). This study aims to assess Ki67 expression assessed on TMAs and their matched whole tissue sections (WTS). Moreover, whether the cut-off used for WTS is reproducible on TMA in BC molecular classes and the association between Ki67 expression cut-off, assessed on TMAs and WTS, and clinicopathological parameters and patient outcome were tested.MethodA large series (n = 707) of primary invasive breast tumours were immunostained for Ki67 using both TMA and WTS and assessed as percentage staining and correlated with each other, clinicopathological parameters and patient outcome. In addition, MKI67 mRNA expression was correlated with Ki67 protein levels on WTS and TMAs in a subset of cases included in the METABRIC study.ResultsThere was moderate concordance in Ki67 expression between WTS and TMA when analysed as a continuous variable (Intraclass correlation coefficient = 0.61) and low concordance when dichotomised (kappa value = 0.3). TMA showed low levels of Ki67 with mean percentage of expression of 35 and 22% on WTS and TMA, respectively. MKI67 mRNA expression was significantly correlated with protein expression determined on WTS (Spearman Correlation, r = 0.52) and to a lesser extent on TMA (r = 0.34) (p < 0.001). Regarding prediction of patient outcome, statistically significant differences were detected upon stratification of patients with tumours expressing Ki67 at 10, 15, 20, 25 or 30% in TMA. Using TMA, ≥20% Ki67 provided the best prognostic cut-off particularly in triple-negative and HER2-positive classes.ConclusionKi67 expression in breast cancer can be evaluated using TMA although different cut-points are required to emulate results from WTS. A cut-off of ≥20% for Ki67 expression in BC provides the best prognostic correlations when TMAs are used.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4270-0) contains supplementary material, which is available to authorized users.

Influence of intra-tumoral heterogeneity on the evaluation of BCL2, E-cadherin, EGFR, EMMPRIN, and Ki-67 expression in tissue microarrays from breast cancer

“…For Ki-67, intra-tumoral heterogeneity was found to affect the interpretation, which is in accordance with the current knowledge that Ki-67 harbors both spatial and temporal heterogeneity [22,25]. Muftah et al [26] have examined the concordance between a WS and a single peripheral core, and found a low concordance, when dichotomized (j ¼ 0.30), and a moderate concordance when using Ki-67 as a continuous variable (Intraclass coefficient ¼ 0.61). On the contrary, Batistatou et al [27] found a very high correlation between TMA cores and WS (j ¼ 0.95), using a 14% cut off, and only a single core from a non-specified area.…”

Diffusion Kurtosis at 3.0T as an in vivo Imaging Marker for Breast Cancer Characterization: Correlation With Prognostic Factors

“…23,33 As a biomarker of cell proliferation, the Ki-67 expression is a good predictive and prognostic marker widely used in clinical practice of breast cancer. 34,35 Its high expression is associated with a high risk of metastasis or recurrence, poor clinical or pathological response, and decreased survival. 36 Increased Ki-67 expression tends to indicate enhanced cellularity, vascular hyperplasia and necrosis, and high-grade breast cancer are depicted by the absence of normal glandular architecture, marked nuclear pleomorphism, and active mitosis.…”

Etiology of hormone receptor positive breast cancer differs by levels of histologic grade and proliferation

“…KI67 scores were obtained from TMAs that are generally lower than those obtained on whole sections. 49 In addition, we used an automated system to generate KI67 scores that are usually lower than visual scores, regardless of whether measurement was made on TMAs or whole sections. 26,50 Thus, our scores for proliferation were lower than what is typically obtained for whole sections or following visual scoring on TMAs.…”