Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts

Ductal carcinoma in situ; Tumor microenvironment; Whole genome sequencingCarcinoma ductal in situ; Microambiente tumoral; Secuenciación del genoma completoCarcinoma ductal in situ; Microambient tumoral; Seqüenciació del genoma completDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors/. R01 CA185138-01 (E.S.H.); U2C CA-17-035 Pre-Cancer Atlas (PCA) Research Centers (E.S.H., R.B.W., C.M., K.P., G.A.C., K.O.); UO1 CA214183 (J.R.M.); DOD BC132057 (E.S.H., C.M.); BCRF 19-074 (E.S.H.); BCRF 19-028 (G.A.C.); PRECISION CRUK Grand Challenge (E.S.H.); R01CA193694 (R.B.W., G.A.C.), BCRF PPI-18-006 (R.B.W.). AEI RYC2019- 026576-I, "LaCaixa" Foundation LCF/PR/PR17/51120011 (J.A.S.). S.H.S. was supported by the Lundbeck Foundation (R288-2018-35) and the Danish Cancer Society (R229-A13616). K.E.H. was supported by a CIHR Banting Postdoctoral Fellowship. TBCRC 038 was conducted by the TBCRC, which receives major funding support from The Breast Cancer Research Foundation and Susan G. Komen. Some results in this paper are based upon data generated by the TCGA Research Network