Abstract P5-10-15: Empowering the Nottingham Grading System: An integrated Ki67-mitosis classifier yields a better patient stratification tool
Authors: Pannu Vaishali , Rida Padmashree CG , Klimov Sergey , Wright Nikita , Cantuaria Guilherme , Reid Michelle , Aneja Ritu 
Published: May 2015

Abstract
Therapeutic decision-making for personalized management of breast cancer relies on patient stratification based on the risk conferred by clinicopathologic factors, such as stage, Ki67 Index (KI) and tumor histological grade. The most widely used histologic grading system for breast cancer, the Nottingham Grading System (NGS) provides prognostic information about breast tumor samples by combining analysis of the extent of glandular differentiation, nuclear pleomorphism and mitotic activity present in the tumor sample. In the NGS, the mitotic Index (MI) is defined as the number of mitotic cells per ten high-power fields. KI is a universal prognostic indicator but is not part of the NGS. Although the NGS has been widely used owing to its reproducibility and significant prognostic value, its accuracy in predicting disease prognosis and aggressiveness is limited. Our earlier work has demonstrated that by rationally integrating KI and MI into a new metric called the Ki67-Adjusted Mitotic Score (KAMS), which is a measure of the proportion of mitotic cells amongst Ki67-positive cells, we are able to glean a new layer of prognostic information about metastatic risk. We found that for Nottingham Grade II and III patients, high KAMS values predicted relatively better overall survival (OS) than low KAMS values.
We therefore asked if the incorporation of a KAMS-based classifier subsequent to conventional Nottingham classification, would improve patient stratification to enable their funneling towards more optimal treatment choices. Ideal KAMS thresholds were established by analyzing the KAMS-stratified survival groups and selecting the thresholds which created the widest survival stratification that was additionally confirmed to be statistically significant via a Log-Rank test. For Nottingham Grade II and III patients, an above-threshold KAMS value was deemed as low-risk and a below-threshold KAMS value was deemed as high-risk for the purpose of grade adjustment. Grade adjustments were based solely on the patients’ KAMS values. Thus the adjusted Nottingham Grade I consisted of the original Nottingham Grade I patients along with KAMS determined low-risk original Nottingham Grade II patients. Adjusted Nottingham Grade II patients were composed of KAMS determined high-risk patients originally in Nottingham Grade II along with KAMS determined low-risk original Nottingham Grade III patients. Finally, the adjusted Nottingham Grade III was made up exclusively of high-risk patients from the original Nottingham Grade III.
We found that the adjusted system represents a wider separation between OS curves with adjusted Grade I (n = 774) OS being 95.48%, adjusted grade II (n = 727) OS at 87.62%, and adjusted Grade III (n = 110) having an OS of 78.18%. Overall survival groups between adjusted grade I and II and I and III (p &lt; 0.001) showed statistical significance. We also found that the hazard ratios for all Nottingham grades are significantly better after adjustment (2.875 versus 2.034 for Grade II and 5.115 versus 3.456 for Grade III) indicating that the KAMS can function as an effective risk-stratification biomarker and that incorporation of a KAMS-based classifier enhances patient stratification.
Citation Format: Vaishali Pannu, Padmashree CG Rida, Sergey Klimov, Nikita Wright, Guilherme Cantuaria, Michelle Reid, Ritu Aneja. Empowering the Nottingham Grading System: An integrated Ki67-mitosis classifier yields a better patient stratification tool [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-15.