Abstract
Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81–0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999–0.93) and hot-spot methods (0.84; 95% CI: 0.77–0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.
Highlights
Assessment of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers,1,2 either in standard clinical practice as a prognostic3–11 and predictive5,7,10,12 marker or in clinical trials as an eligibility criterion or as a primary end point in early-phase neoadjuvant studies.10 Perhaps the most critical use for standard clinical care would be to determine prognosis in the context of other factors, such as nodal status, tumor size, and estrogen receptor, progesterone receptor, and HER2 status
The different-section intraclass correlation coefficient (ICC) estimate for the unweighted global score was 0.87 (95%credible interval (CI): 0.81–0.93), and met the prespecified and the corresponding selected fields and scores can be viewed at http://www.gpec.ubc.ca/papers/ki67p3)
The different-section ICCs for the weighted global score and hot-spot score were 0.87 (95%CI: 0.7999–0.93) and 0.84, respectively, and both methods had ICC credible intervals that extended below the success criterion
Summary
Assessment of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers, either in standard clinical practice as a prognostic and predictive marker or in clinical trials as an eligibility criterion or as a primary end point in early-phase neoadjuvant studies. Perhaps the most critical use for standard clinical care would be to determine prognosis in the context of other factors, such as nodal status, tumor size, and estrogen receptor, progesterone receptor, and HER2 status. Assessment of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers, either in standard clinical practice as a prognostic and predictive marker or in clinical trials as an eligibility criterion or as a primary end point in early-phase neoadjuvant studies.. Perhaps the most critical use for standard clinical care would be to determine prognosis in the context of other factors, such as nodal status, tumor size, and estrogen receptor, progesterone receptor, and HER2 status. Gene expression multiparameter molecular assays have gained widespread use in the United States and other countries, these assays may not be an option in many clinical settings owing to availability or economic considerations. Received 23 December 2015; revised 22 February 2016; accepted 1 April 2016 cancer deaths occur in less developed regions of the world, accentuating the need for low cost, widely accessible biomarkers
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