DEPTH2 score was associated with cell proliferation and immune cell infiltrations but not with systemic treatment response in breast cancer

Abstract Intratumoral genomic heterogeneity (ITGH), the existence of genotypic and phenotypic variation within an individual tumor, is known to be a key mechanism in treatment resistance. Deviating gene Expression Profiling Tumor Heterogeneity 2 (DEPTH2) algorithm was developed to estimate ITGH using solely RNA expression data unlike the others that require both DNA- and RNA-expression data. Total of 6,500 breast cancer patients from multiple independent cohorts were analyzed using DEPTH2. High DEPTH2 score patients were associated with worse overall survival consistently across all subtypes in METABRIC, but not in TCGA and SCAN-B cohort. Higher DEPTH2 score was linked to increased cell proliferation, as evidenced by elevated Nottingham histological grades and Ki67 gene expression, as well as enrichment of the cell proliferation-related gene sets, and immune cell infiltrations. DEPTH2 score was significantly higher in triple negative breast cancer among the subtypes but did not reflect with lymph node and distal metastasis. DEPTH2 scores decreased in two but showed no change in another two cohorts after neoadjuvant chemotherapy (NAC). DEPTH2 score was not associated with pathologic complete response after NAC in any subtypes across 3 cohorts. DEPTH2 score may not capture the entire biological aspects of ITGH in breast cancer patients.