Abstract
Although Ki67 labeling index is a potential predictive marker for chemotherapy benefit, its clinical utility has been limited by the lack of a standard scoring method resulting in poor interobserver reproducibility. Especially, there is no consensus on the use of average versus hotspot score for reporting. In order to determine the best method for Ki67 scoring and validate manual scoring method proposed by the International Ki67 Working Group (IKWG), we systematically compared average versus hotspot score in 240 cases with a public domain image analysis program QuPath. We used OncotypeDx Recurrence Score (RS) as a benchmark to compare the potential clinical utility of each scoring methods. Both average and hotspot scores showed statistically significant but only modest correlation with OncotypeDx RS. Only hotspot score could meaningfully distinguish RS low-risk versus high-risk patients. However, hotspot score was less reproducible limiting its clinical utility. In summary, our data demonstrate that utility of the Ki67 labeling index is influenced by the choice of scoring method.
Highlights
OncotypeDx (Genomic Health, Redwood City, CA, USA), a 21-gene breast cancer recurrence score (RS) assay, has both prognostic and predictive value for estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−)/lymph node negative breast cancer patients[1,2]
NSABP B-20 trial demonstrated a statistically significant benefit from adjuvant chemotherapy added to 5 years of tamoxifen in estrogen receptor positive axillary node negative breast cancer, post hoc analyses suggested that the benefit is limited to a subset of patients with high OncotypeDx 21-gene RS1,2
In order to avoid subjectivity in selection of the microscopic fields to score and achieve unbiased objective scoring results, we examined the whole Ki67-stained slides from a cohort with available OncotypeDx results from National Cancer Center
Summary
OncotypeDx (Genomic Health, Redwood City, CA, USA), a 21-gene breast cancer recurrence score (RS) assay, has both prognostic and predictive value for estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−)/lymph node negative breast cancer patients[1,2]. Despite the level I evidence for its clinical utility, high cost has been an impediment to its adoption in developing countries resulting in a significant global health care disparity. This strongly indicates that further development of a low cost, accessible surrogate for OncotypeDx is necessary. Hotspot score did not meet the predefined success criterion with ICC of 0.83 (95% CI = 0.74–0.90)[9] Based on these results, IKWG concluded to move forward with evaluation of clinical utility of average score. Utilization of image analysis programs achieved the same degree of ICC for average score (0.89, 95% CI = 0.81–0.96) as manual scoring by rigorously trained scorers when applied to core biopsy specimens from 30 patients[10]. (15.0%), and 30 (12.5%) patients had OncotypeDx RS below 15, 16–20, 21–25, and over 25, respectively (Tables 1 and 2)
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