Interlaboratory variability of Ki67 staining in breast cancer

Focke, CM; Bürger, Horst; Diest, Paul J. van; Finsterbusch, K; Gläser, Doreen; Korsching, Eberhard; Decker, Thomas; Anders, MW; Bollmann, R.; Eiting, Fr.; Friedrich, Katrin; Habeck, Jörg-Olaf; Haroske, G.; Hinrichs, Bernd; Behrens, Alice; Krause, U; Lang, Ulrich; Lorenzen, Johann; Minew, N.; Mlynek-Kersjes, Maria L.; Nenning, H; Packeisen, J; Vos, F. Poche-de; Reyher–Klein, S.; Rothacker, D; Schultz, Marcela; Sturm, U; Tawfik, M.; Berghäuser, K. H.; Böcker, W.; Cserni, Gábor; Habedank, S; Lax, Sigurd; Moinfar, Farid; Regitnig, Peter; Reiner-Concin, Angelika; Rüschoff, J.; Varga, Zsuzsanna; Woziwodski, J.

doi:10.1016/j.ejca.2017.07.041

Cited by 82 publications

(75 citation statements)

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“…Excellent intra ‐ observer reproducibility under controlled pre‐analytical and staining conditions has contributed to the body of evidence showing the potential of Ki67 immunohistochemistry assay to be implemented in hospital laboratories as a cost‐effective part of clinical management . However, poor interobserver reproducibility and variability due to technical aspects of the assay has limited its adoption in clinical practice …”

Section: Introductionmentioning

confidence: 99%

“…[22][23][24] However, poor interobserver reproducibility and variability due to technical aspects of the assay has limited its adoption in clinical practice. 4,9,[25][26][27][28] The International Ki67 Working Group (IKWG) has undertaken a systematic multiphase programme to determine whether Ki67 scoring can be standardised and analytically validated throughout laboratories. 9,21,29,30 In Phase I, as assessed by the intraclass correlation coefficient (ICC) estimate of interobserver reproducibility, differences in pathologists' visual interpretation were the main source of variability (ICC = 0.71, 95% credible interval (CI) = 0.47-0.78).…”

Section: Introductionmentioning

confidence: 99%

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Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

et al. 2019

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Aims The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot‐spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot‐spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot‐spots varies between cases. The median times for scoring were 9 and 6 min for global and hot‐spot methods, respectively. Conclusions The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

et al. 2019

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“…However, the consensus conferences in 2013, 2015 and 2017 raised the issues of standardised assessment and definition of a useful cut‐off for the Ki67‐LI with which to make clinical decisions 2‐4 . Other expert panels, such as the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP), explicitly do not recommend the Ki67‐LI for making therapy decisions for BC patients, 5 as its assessment is compromised by variability between laboratories, 6 methods, 7 and observers 8,9 . To date, other established proliferation markers have not been considered as alternatives to the Ki67‐LI in intrinsic BC subtyping, 4 probably because of the lack of available data concerning their potential to reproduce molecular test results.…”

Section: Introductionmentioning

confidence: 99%

Luminal A versus luminal B breast cancer: MammaTyper mRNA versus immunohistochemical subtyping with an emphasis on standardised Ki67 labelling‐based or mitotic activity index‐based proliferation assessment

et al. 2020

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Aims: Proliferation assessment by the use of Ki67 is a crucial component in intrinsic subtyping of luminal breast cancers (BCs), but suffers from variability between laboratories, observers, and methods. Mam-maTyper is a quantitative molecular tool that measures mRNA levels of ERBB2, ESR1, PGR and MKI67 in BC, and interprets the results according to the St Gallen 2013 consensus recommendations. We compared MammaTyper with immunohistochemistry (IHC)-based subtypes, with a focus on standardised proliferation assessment. Methods and results: We analysed the agreement in assigning subtypes between MammaTyper and receptor IHC in 101 unifocal luminal HER2-negative early BCs of no special type. Two Ki67 counting protocols, Ki67-Global (Ki67-G) and Ki67-HotSpot (Ki67-H), recommended by the International Ki67 in BC Working Group, and the mitotic activity index (MAI) were used for proliferation assessment. The proportions of BCs identified as luminal A and as luminal B were 55% and 45% for MammaTyper, 55% and 45% for IHC + Ki67-G, 36% and 64% for IHC + Ki67-H, and 56% and 44% for IHC + MAI. The levels of agreement between MammaTyper-based and IHC-based subtyping were 84% (j = 0.679) for IHC + Ki67-G, 72% (j = 0.462) for IHC + Ki67-H, and 89% (j = 0.779) for IHC + MAI. Conclusions: High rates of agreement between mRNA-based and IHC-based intrinsic subtyping of luminal HER2-negative BC can be achieved. However, the agreement between IHC-based and MammaTyperbased luminal subtypes depends on the proliferation assessment method, and was highest when the MAI was used. Further comparative clinical studies are needed to determine which method is to be preferred, including analysis of cost-effectiveness.

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“…Currently, Ki-67 is principally used to evaluate prognosis, guide adjuvant treatment and predict the response to neoadjuvant treatment in ER+/ HER2− BC. The Ki-67 cutoff at 14% is an important parameter in subclassifying luminal BC into the luminal A subtype with good prognosis and the luminal B subtype with worse prognosis [6][7][8] .…”

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confidence: 99%

The prognostic and predictive potential of Ki-67 in triple-negative breast cancer

Zhu

Chen

Huang

et al. 2020

Sci Rep

127

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As a cell proliferation biomarker, Ki-67 is principally used in ER+/HER2− breast cancer. However, the importance and the best cutoff point of Ki-67 in triple-negative breast cancer (TNBC) remains unclear and was evaluated in this study.A total of 1800 patients with early invasive TNBC between 2011 and 2016 at Fudan University Shanghai Cancer Center were consecutively recruited for this study. The optimal cutoff for Ki-67 was assessed by Cutoff Finder. Propensity score matching (PSM, ratio = 1:2) was performed to match the Ki-67 low group with the Ki-67 high group. Overall survival (OS) and diseasefree survival (DFS) were compared between the two groups using the Kaplan-Meier method and Cox regression model. The most relevant cutoff value for Ki-67 for prognosis was 30% (p = 0.008). At the cutoff point of 30%, worse DFS and OS were observed in the Ki-67 high group. In multivariate analyses, N-stage (p < 0.001), T-stage (p = 0.038), and Ki-67 at the 30% threshold (p = 0.020) were independently linked to OS. In subgroup analysis, Ki-67 cutoff at 30% had prognostic and predictive potential for DFS with either tumor size ≤2 cm (p = 0.008) or lymph node-negative (N−) (p = 0.038) and especially with t 1 n 0 M 0 (stage I) TNBCs. For 945 N− TNBC patients, adjuvant chemotherapy (CT) was associated with better OS in the Ki-67 high group (p = 0.017) than in the Ki-67 low group (p = 0.875). For stage I/Ki-67 low patients, adjuvant CT did not affect DFS (p = 0.248). Thus, Ki-67 cutoff at 30% had early independent prognostic and predictive potential for OS and DFS in TNBCs, and Ki-67 > 30% was significantly associated with worse prognosis, especially for stage I patients. For stage I/Ki-67 low TNBC patients, the advantage of CT is unclear, providing the basis for future de-escalation therapy.

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Interlaboratory variability of Ki67 staining in breast cancer

Cited by 82 publications

References 30 publications

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

Luminal A versus luminal B breast cancer: MammaTyper mRNA versus immunohistochemical subtyping with an emphasis on standardised Ki67 labelling‐based or mitotic activity index‐based proliferation assessment

The prognostic and predictive potential of Ki-67 in triple-negative breast cancer

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