Abstract
The reproducibility of assessing potential biomarkers is crucial for their implementation. ONEST (Observers Needed to Evaluate Subjective Tests) has been recently introduced as a new additive evaluation method for the assessment of reliability, by demonstrating how the number of observers impact on interobserver agreement. Oestrogen receptor (ER), progesterone receptor (PR), and Ki67 proliferation marker immunohistochemical stainings were assessed on 50 core needle biopsy and 50 excision samples from breast cancers by 9 pathologists according to daily practice. ER and PR statuses based on the percentages of stained nuclei were the most consistently assessed parameters (intraclass correlation coefficients, ICC 0.918–0.996), whereas Ki67 with 5 different theoretical or St Gallen Consensus Conference–proposed cut-off values demonstrated moderate to good reproducibility (ICC: 0.625–0.760). ONEST highlighted that consistent tests like ER and PR assessment needed only 2 or 3 observers for optimal evaluation of reproducibility, and the width between plots of the best and worst overall percent agreement values for 100 randomly selected permutations of observers was narrow. In contrast, with less consistently evaluated tests of Ki67 categorization, ONEST suggested at least 5 observers required for more trustful assessment of reliability, and the bandwidth of the best and worst plots was wider (up to 34% difference between two observers). ONEST has additional value to traditional calculations of the interobserver agreement by not only highlighting the number of observers needed to trustfully evaluate reproducibility but also by highlighting the rate of agreement with an increasing number of observers and disagreement between the better and worse ratings.
Highlights
ER status is universally determined by immunohistochemistry (IHC) and the judgement of what constitutes an ER+ and ER- status is somewhat arbitrary and may depend on a number of pre-analytical and analytical issues, which are attempted to be minimalized by regularly updated guidelines such as the American Society of Clinical Oncology (ASCO) recommendations [1]
As the cases were continuous but with the exclusion of some ER- cases, the median scores for the markers are only characteristic for the cases assessed; but to some extent, they reflect breast cancer cases encountered in routine practice
The median percentage of ER+, progesterone receptor (PR)+, and Ki67+ cells as assessed by the 9 pathologists in biopsies vs excision specimens were 95 (30) vs 95 (15) (ER), 60 (89) vs 73 (95) (PR), and 20 (85) vs 10 (20) (Ki67), respectively. These values highlight that most nuclei stained for ER, less nuclei labelled with PR, and the least with Ki67
Summary
This heterogeneity is reflected in the classifications of the disease along several parameters, e.g., histological type, imaging features, and Hospital, Kecskemét, Hungary 3 Department of Pathology, University of Szeged, Szeged, Hungary 4 Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary several prognostic and/or predictive markers, some of which impact significantly on therapy. One of the most important is the segregation of carcinomas into oestrogen receptor (ER)–positive (ER+) and ER-negative (ER-) groups, of which only the first is likely to benefit from endocrine treatments. It is acknowledged that ER+ cancers with 1–10% ER expression may respond to endocrine treatment, but their response might be below expectations, and
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