Correlation of Ki67 working group prognostic risk categories with oncotype DX recurrence score (RS) in early breast cancer (EBC).
Authors: Patel Rima , Hovstadius Malin , Kier Melanie Wain , Moshier Erin , Zimmerman Brittney Shulman , Cascetta Krystal Pauline , Jaffer Shabnam , Sparano Joseph A. , Tiersten Amy 
Published: June 2022

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Background: The 21-gene RS (Oncotype DX) provides prognostic information for distant recurrence risk and is predictive of adjuvant chemotherapy benefit in hormone receptor (HR)-positive, HER-2 negative EBC. Ki67 protein expression is a proliferation marker that is determined by immunohistochemistry (IHC). The International Ki67 Working Group (IKWG) has provided guidelines for clinical use of Ki67 for prognostic classification (PMID: 33369635). The objectives of this study were to determine the correlation between IHC-measured Ki67 with the 21-gene RS, and evaluate their association with other anatomic and biologic tumor features. Methods: We performed a retrospective chart review of women with HR-positive, HER-2 negative EBC with 0-3 positive lymph nodes who had both Ki67 (via IHC using MIB-1 antibody on surgical specimen at our institutional pathology CLIA laboratory) and 21-gene RS between 2013 to 2021. Patients were categorized into Ki67 low (≤ 5%), intermediate (6-29%), and high (≥30%) based on IKWG recommendations. Overall and risk stratified agreement between Ki67 and RS were assessed using the proportion of agreement and Kappa statistic. Linear regression was used to test for associations between tumor features of ER%, PR%, and tumor size and log transformed Ki67 and RS. A t-test was used to compare average log transformed Ki67 and RS by tumor differentiation and nodal status. Results: We identified 461 patients with HR-positive BC of whom 26.7% were ≤ 50 years at diagnosis, 30% pre-menopausal and 10% node-positive. Overall, 29% (n = 137) of patients had low Ki67, 49% (n = 227) intermediate, and 21% (n = 97) high Ki67. 18% (n = 85) had RS 0-10, 67% (n = 311) had RS 11-25 and 14% (n = 65) had RS ≥ 26. There was no significant agreement (kappa < 0) between Ki67 and RS (Kappa = -0.0035, p = 0.5406) in the overall population and fair agreement (kappa 0.21-0.40) between high Ki67 and RS (Kappa = 0.2510, p < 0.0001). Higher ER% was significantly associated with lower RS (p < 0.0001) and lower Ki67 (p = 0.0042). High tumor grade was associated with higher RS and higher Ki67 (p < 0.0001). Higher PR% was associated with lower RS (p > 0.0001) but not lower Ki67. Positive nodal status and larger tumor size were associated with higher Ki67 (p = 0.0081, p < 0.0001) but not RS. Among the 49% of patients with intermediate Ki67 of 6-29%, the distribution of low, intermediate, and high RS was 24%, 65%, and 11%, respectively. Conclusions: In this group of patients selected to have a 21-gene RS, there was no correlation between Ki67 and RS in the overall population, and fair agreement between high Ki67 and high RS. Among the approximately one-half with an intermediate Ki67 of 6-29%, 89% would be spared chemotherapy based on a low-intermediate RS. In patients with high Ki67, 68% might be spared chemotherapy based on the RS. In the low Ki67 group, 6% had a high RS. Ki67 has limited utility in identifying patients with high or low RS.