Abstract B13: A novel metric illuminates disparities in cell cycling kinetics between ethnically-distinct breast tumors and enhances prediction of metastatic risk

Breast tumors in African-Americans (AAs) exhibit higher recurrence rates and faster kinetic progression to metastasis than those in European-Americans (EAs). This results in a stark ethnic disparity in breast cancer outcomes. Hence, enhancing understanding of cell cycle kinetics within breast tumors may illuminate hitherto overlooked and fundamental tumor biological characteristics of breast tumors underpinning racial differences in metastatic propensities. Current clinico-pathological prognostic markers that evaluate cell proliferation in breast carcinomas include mitotic index (MI) and Ki67 proliferation index (KI). However, as autonomous prognosticators measured on distinct scales, MI and KI lack the ability to capture information about the cycling kinetics of proliferating tumor cells-a key driver of intratumoral heterogeneity; this diminishes and undermines their prognostic accuracy. We performed a three-color immunofluorescence staining on paraffin-embedded AA (n=83) and EA (n=151) breast tumor tissue specimens from Northside Hospital to integrate mitotic cells and cycling cells into the same measurement scale. Phospho histone H3 was used as a mitotic marker and Ki-67 as a cell proliferation marker. Stained samples were examined in confocal microscopy to determine the proportion of mitotic cells among Ki-67 positive proliferative cells to yield the Mitosis:Proliferation (M:P) Ratio, a measure of the turnover rate of proliferating tumor cells. We observed higher M:P ratio in AA compared to grade-matched and stage-matched EA tumor tissue specimens. AA displayed significantly higher M:P ratio than EA among early stage tumors (p=0.015). Furthermore, among the clinico-pathological parameters, age, race, grade, stage, and receptor status, a multivariate analysis revealed that race was the only variable that exhibited a significant confounding influence on M:P ratio (p=0.042). A higher M:P Ratio likely reflects an increased mitotic propensity and higher risk of developing intratumoral heterogeneity and producing aggressive clones; thus, a higher M:P ratio may underlie the observed greater metastatic propensity exhibited in AA compared to EA patients. Thus, our novel metric provides new insights into the KI-MI relationship in tumors, exposes previously unrecognized differences in cycling kinetics among early stage AA and EA breast tumors, and proffers additional metastatic risk predictive information currently unavailable in the clinic. Citation Format: Nikita Wright, Sergey Klimov, Mildred Jones, Guilherme H. Cantuaria, Padmashree C. G. Rida, Ritu Aneja. A novel metric illuminates disparities in cell cycling kinetics between ethnically-distinct breast tumors and enhances prediction of metastatic risk. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B13.