Abstract P1-01-03: Variability of Ki67 labeling index depending on different measurements in luminal type breast cancers
Authors: Kim S , Moon B-I , Sung SH 
Published: May 2016

Background: Hormone receptor-positive and HER2-negative breast cancers are divided into luminal A (LA) and luminal B (LB) types using a cutoff of 14% Ki67 labeling index (LI). LB type breast cancer is associated with poor prognosis compared with LA, and considered as an indication of adjuvant chemotherapy. The main obstacles in classification of luminal type breast cancers are non-standardized measurement and Ki67 heterogeneity. We aimed to assess Ki67 variability depending on different methods of measurement and spot selection, and to assess Ki67 heterogeneity in luminal type breast cancers.

Design: We retrospectively retrieved 174 Ki67 stained slides of surgically excised invasive breast cancers with ER+ and/ or PR+, HER2-, and Ki67 LI of 10-20% range. On each slide, 3 spots of low, intermediate, and high Ki67 labeling densities were captured via camera snapshot. And then, Ki67 LI was measured by digital image analysis (DIA) and manual count (MC) on 3 captured spots. Each case was classified into LA and LB types based on Ki67 LI measured by 4 methods; hot spot index by DIA; average index by DIA; hot spot index by MC; average index by MC. Ki67 heterogeneity was defined by the tumor with Ki67 KI &lt;5% in low labeled spot, and ≥14% in high labeled spot by DIA. Correlation between the Ki67 heterogeneity and pathological parameters were analyzed.

Result: Ki67 LI measured by DIA was higher than by MC in 3 spots (low: 4.95 vs. 3.39, p&lt;0.001; intermediate: 10.07 vs.9.26, p=0.058; high: 14.88 vs. 14.03, p=0.025) with the biggest difference in low labeled spot. The 4 methods showed poor agreement on classification of LA/LB types. The proportion of LB type ranged from 3.4% to 60.9% depending on methods.

Classification of luminal A and luminal B types by different methods Luminal ALuminal BHot spot index-DIA68 (39.1%)106 (60.9%)Average index-DIA157 (90.2%)17 (9.8%)Hot spot index-MC82 (47.1%)92 (52.9%)Average index-MC168 (96.6%)6 (3.4%)

Forty two of 174 cases (24.1%) showed Ki67 heterogeneity. Ki67 heterogeneity was most frequent in T2 (p=0.001) and histologic grade 3 (p=0.023) tumors.

Comparison of pathological features according to Ki67 heterogeneityKi67 heterogeneityAbsentPresentp-valueNumber 132(75.9%)42 (24.1%) T stageT195(84.1%)18(15.9%)0.001 T232(58.2%)23(41.8%)  T35(83.3%)1(16.7%) Histologic grade130(90.9%)3(9.1%)0.023 293(74.4%)32(25.6%)  39(56.2%)7(43.8%) SubtypeInvasive ductal carcinoma, NOS114(74%)40(26%)0.475 Invasive lobular carcinoma8(88.9%)1(11.1%)  Mucinous carcinoma4(80%)1(20%)  Others (invasive micropapillary, tubular, etc.)6(100%)0(0%) 

Conclusion: Ki67 LI is markedly variable depending on different measurements and spot selections. Ki67 heterogeneity exists in 24.1% of luminal breast cancers in this series. Therefore, whole section slides should be preferred for Ki67 LI measurement, rather than tissue microarray or biopsy specimen which may not entirely reflect the proliferation index of the tumor.

Citation Format: Kim S, Moon B-I, Sung SH. Variability of Ki67 labeling index depending on different measurements in luminal type breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-03.