Tumor-associated Stromal Cellular Density as a Predictor of Recurrence and Mortality in Breast Cancer: Results from Ethnically-diverse Study Populations.

Background Tumor-associated stroma is comprised of fibroblasts, tumor infiltrating lymphocytes (TILs), macrophages, endothelial, and other cells, that interactively influence tumor progression through inflammation and wound repair. Although gene expression signatures reflecting wound repair predict breast cancer survival, it is unclear whether combined density of tumor-associated stromal cells, a morphological proxy for inflammation and wound repair signatures on routine hematoxylin and eosin (HE 24-55years), Poland (n=810; 31-75years), and the United States (n=678; 55-78years), we characterized tumor-associated stromal cellular density (SCD) as the percentage of tumor-stroma that is occupied by nucleated cells. Hazard ratios (HR) and 95% confidence intervals (CI) for associations between SCD and clinical outcomes (recurrence (China); mortality (Poland and United States)) were estimated using Cox proportional hazard regression, adjusted for clinical variables. Results SCD was independently predictive of poor clinical outcomes in hormone receptor-positive (luminal) tumors from China (multivariable HR(95%CI)fourth(Q4) vs first(Q1) quartile=1.86(1.06-3.26);Ptrend=0.03), Poland (HR(95%CI)Q4 vs Q1=1.80(1.12-2.89);Ptrend=0.01), and United States (HR(95%CI)Q4 vs Q1=2.42(1.33-4.42);Ptrend=0.002). In general, SCD provided more prognostic information than most classical clinicopathologic factors, including grade, size, PR, HER2, IHC4, and TILs, predicting clinical outcomes irrespective of menopausal or lymph nodal status. SCD was not predictive of outcomes in hormone receptor-negative tumors. Conclusions Our findings support the independent prognostic value of tumor-associated SCD among ethnically-diverse luminal breast cancer patients. Impact Assessment of tumor-associated SCD on standard H&E could help refine prognostic assessment and therapeutic decision-making in luminal breast cancer.