DCIS genomic signatures define biology and clinical outcome: Human Tumor Atlas Network (HTAN) analysis of TBCRC 038 and RAHBT cohorts

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We identified 812 genes associated with ipsilateral recurrence within 5 years from treatment and developed a classifier that was predictive of 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 were 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. HIGHLIGHTS ### Competing Interest Statement CC serves on the Scientific Advisory Board and/or as a consultant for GRAIL, Deepcell, Ravel, Viosera, NanoString, Genentech and holds equity in GRAIL, Deepcell, Ravel. KP serves on the Scientific Advisory Board of Acrivon Therapeutics, Vividion Therapeutics, and Scorpion Therapeutics, holds equity in Scorpion Therapeutics and Vividion Therapeutics, is a consultant to Aria Pharmaceuticals, and received honorarium from Astra-Zeneca. RMA is an inventor on patent US20150287578A, and is a board member and shareholder in IonPath Inc. TR and RBW have consulted for IonPath Inc.