Radiogenomic analysis of cellular tumor-stroma heterogeneity as a prognostic predictor in breast cancer

Abstract Background The tumor microenvironment and intercellular communication between solid tumors and the surrounding stroma play crucial roles in cancer initiation, progression, and prognosis. Radiomics provides clinically relevant information from radiological images; however, its biological implications in uncovering tumor pathophysiology driven by cellular heterogeneity between the tumor and stroma are largely unknown. We aimed to identify radiogenomic signatures of cellular tumor-stroma heterogeneity (TSH) to improve breast cancer management and prognosis analysis. Methods This retrospective multicohort study included five datasets. Cell subpopulations were estimated using bulk gene expression data, and the relative difference in cell subpopulations between the tumor and stroma was used as a biomarker to categorize patients into good- and poor-survival groups. A radiogenomic signature-based model utilizing dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was developed to target TSH, and its clinical significance in relation to survival outcomes was independently validated. Results The final cohorts of 1330 women were included for cellular TSH biomarker identification (n = 112, mean age, 57.3 years ± 14.6) and validation (n = 886, mean age, 58.9 years ± 13.1), radiogenomic signature of TSH identification (n = 91, mean age, 55.5 years ± 11.4), and prognostic (n = 241) assessments. The cytotoxic lymphocyte biomarker differentiated patients into good- and poor-survival groups ( p < 0.0001) and was independently validated ( p = 0.014). The good survival group exhibited denser cell interconnections. The radiogenomic signature of TSH was identified and showed a positive association with overall survival ( p = 0.038) and recurrence-free survival ( p = 3 × 10 –4 ). Conclusion Radiogenomic signatures provide insights into prognostic factors that reflect the imbalanced tumor-stroma environment, thereby presenting breast cancer-specific biological implications and prognostic significance.