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

Knutsvik, Gøril; Stefansson, Ingunn M.; Aziz, Sura; Arnes, Jarle B.; Eide, Johan; Collett, Karin; Akslen, Lars A.

doi:10.1371/journal.pone.0112121

Cited by 60 publications

(67 citation statements)

References 55 publications

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“…Similar findings were reported by Marrelli et al ,41 although a lower cut-off for high proliferation (≥10%) was used 41. High proliferation by Ki67 evaluated on whole sections and tissue microarrays has been associated with lymph node metastasis 40. Ki67 was an independent prognostic factor in patients with breast cancer with ≥4 lymph node metastasis42 and showed increased proliferation in node-positive patients 43.…”

Section: Discussionsupporting

confidence: 59%

Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer

et al. 2018

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AimsThe accuracy of biomarker assessment in breast pathology is vital for therapy decisions. The therapy predictive and prognostic biomarkers oestrogen receptor (ER), progesterone receptor, HER2 and Ki67 may act as surrogates to gene expression profiling of breast cancer. The aims of this study were to investigate the concordance of consecutive biomarker assessment by immunocytochemistry on preoperative fine-needle aspiration cytology versus immunohistochemistry (IHC) on the corresponding resected breast tumours. Further, to investigate the concordance with molecular subtype and correlation to stage and outcome.MethodsTwo retrospective cohorts comprising 385 breast tumours with clinicopathological data including gene expression-based subtype and up to 10-year overall survival data were evaluated.ResultsIn both cohorts, we identified a substantial variation in Ki67 index between cytology and histology and a switch between low and high proliferation within the same tumour in 121/360 cases. ER evaluations were discordant in only 1.5% of the tumours. From cohort 2, gene expression data with PAM50 subtype were used to correlate surrogate subtypes. IHC-based surrogate classification could identify the correct molecular subtype in 60% and 64% of patients by cytology (n=63) and surgical resections (n=73), respectively. Furthermore, high Ki67 in surgical resections but not in cytology was associated with poor overall survival and higher probability for axillary lymph node metastasis.ConclusionsThis study shows considerable differences in the prognostic value of Ki67 but not ER in breast cancer depending on the diagnostic method. Furthermore, our findings show that both methods are insufficient in predicting true molecular subtypes.

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Section: Discussionsupporting

confidence: 59%

Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer

et al. 2018

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“…Although TMAs are primarily a research tool conducted on large number of patients in population-based studies, this sampling error is usually balanced for by the large number of study population giving an overall prognostic significance [36,37]. However, generalising cutoffs demarcating low from highly proliferative cases generated in studies using TMA carries the potential of misclassification of some patients from high to low proliferative subgroups [38]. However, at an individual patient level, which is the case in clinical decision making for neoadjuvant therapy using core needle biopsy (CNB), again sampling bias or error could influence the final status of the case, as shown in our study.…”

Section: Discussionmentioning

confidence: 99%

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer

Aleskandarany

Green

Ashankyty

et al. 2016

Breast Cancer Res Treat

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In breast cancer (BC), the prognostic value of Ki67 expression is well-documented.Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour quadrants and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression (hot) spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), coefficient of variation and correlation coefficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (p<0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r=0.98, p <0.001). In summary, assessment of Ki67 expression using HS scoring method on a fullface BC tissue section can represent the primary tumour growth fraction that likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.3

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“…Then, 4-8 tissue cores (Ø 0.8 mm) per patient were punched and mounted into a tissue microarray using a semiautomated instrument (Minicore 3, Tissue Arrayer, Alphelys, France). After exclusions of patients with incomplete PAM50 gene assay data and/or clinical immunohistochemical data, tissue microarray cores with o 100 tumor cells, 22,23 failed digital scanning, and errors in software operation, 195 patients remained for analysis (Table 1).…”

Section: Patients and Samplesmentioning

confidence: 99%

Digital image analysis outperforms manual biomarker assessment in breast cancer

Stålhammar

Martínez

Lippert³

et al. 2016

Modern Pathology

146

128

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In the spectrum of breast cancers, categorization according to the four gene expression-based subtypes 'Luminal A,' 'Luminal B,' 'HER2-enriched,' and 'Basal-like' is the method of choice for prognostic and predictive value. As gene expression assays are not yet universally available, routine immunohistochemical stains act as surrogate markers for these subtypes. Thus, congruence of surrogate markers and gene expression tests is of utmost importance. In this study, 3 cohorts of primary breast cancer specimens (total n = 436) with up to 28 years of survival data were scored for Ki67, ER, PR, and HER2 status manually and by digital image analysis (DIA). The results were then compared for sensitivity and specificity for the Luminal B subtype, concordance to PAM50 assays in subtype classification and prognostic power. The DIA system used was the Visiopharm Integrator System. DIA outperformed manual scoring in terms of sensitivity and specificity for the Luminal B subtype, widely considered the most challenging distinction in surrogate subclassification, and produced slightly better concordance and Cohen's κ agreement with PAM50 gene expression assays. Manual biomarker scores and DIA essentially matched each other for Cox regression hazard ratios for all-cause mortality. When the Nottingham combined histologic grade (Elston-Ellis) was used as a prognostic surrogate, stronger Spearman's rank-order correlations were produced by DIA. Prognostic value of Ki67 scores in terms of likelihood ratio χ 2 (LR χ 2 ) was higher for DIA that also added significantly more prognostic information to the manual scores (LR− Δχ 2 ). In conclusion, the system for DIA evaluated here was in most aspects a superior alternative to manual biomarker scoring. It also has the potential to reduce time consumption for pathologists, as many of the steps in the workflow are either automatic or feasible to manage without pathological expertise.

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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

Cited by 60 publications

References 55 publications

Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer

Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer

Digital image analysis outperforms manual biomarker assessment in breast cancer

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