Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays

Abstract

Introduction: Tumor cell proliferation in breast cancer is strongly prognostic and may also predict response to chemotherapy. However, there is no consensus on counting areas or cut-off values for patient stratification. Our aim was to assess the matched level of proliferation by Ki67 when using different tissue categories (whole sections, WS; core needle biopsies, CNB; tissue microarrays, TMA), and the corresponding prognostic value.

Methods: We examined a retrospective, population-based series of breast cancer (n = 534) from the Norwegian Breast Cancer Screening Program. The percentage of Ki67 positive nuclei was evaluated by visual counting on WS (n = 534), CNB (n = 154) and TMA (n = 459).

Results: The median percentage of Ki67 expression was 18% on WS (hot-spot areas), 13% on CNB, and 7% on TMA, and this difference was statistically significant in paired cases. Increased Ki67 expression by all evaluation methods was associated with aggressive tumor features (large tumor diameter, high histologic grade, ER negativity) and reduced patient survival.

Conclusion: There is a significant difference in tumor cell proliferation by Ki67 across different sample categories. Ki67 is prognostic over a wide range of cut-off points and for different sample types, although Ki67 results derived from TMA sections are lower compared with those obtained using specimens from a clinical setting. Our findings indicate that specimen specific cut-off values should be applied for practical use.

Figure 1. Box plots of tumor cell proliferation by Ki67 expression according to breast cancer molecular subgroups in different specimen categories.

Horizontal lines inside the boxes represent the median value; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles.

Figure 2. Frequency of cases in the Luminal/HER2- subgroup showing high proliferation when applying a Ki67 cutoff-point of 14% to different specimen categories.

WS (n = 415), CNB (n = 125), TMA (n = 350).

Figure 3. Breast cancer specific survival according to Ki67 expression.

Survival curves (Kaplan-Meier) are shown for Ki67 expression on WS (A); TMA (B) and CNB (C). Cut-off points at the median were applied for all specimen categories. The number of events and total number of patients in each group are shown beside the description of each curve. Numbers at risk are presented below each curve.

Figure 4. Breast cancer prognosis by molecular subtype.

Survival curves (Kaplan-Meier) for breast carcinomas showing an association between molecular subtype and breast cancer specific survival. The Luminal B subgroup includes Luminal/HER2+ cases. For each category, the number of events is given followed by the number of patients.