Understanding The Biology Of High-Risk Ductal Carcinoma In Situ (Dcis) Through Genomics And The Tumor Immune Microenvironment: The Defense Study

Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology and risk. While many patients with DCIS undergo surgical resection with no survival benefit given the indolent nature of their disease, others do possess biologically aggressive DCIS that has the potential to evolve into invasive cancer if left untreated. Yet even among those patients with biologically aggressive DCIS, their risk of dying from metastatic breast cancer is only 3.3% compared to 30-40% among patients with biologically aggressive invasive cancer.1 We are interested in identifying molecular and tumor immune microenvironment factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer. Methods: We are conducting a retrospective pilot study (DEFENSE) of 10 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile to 10 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (\u003e5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients will be divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunohistochemistry (mIHC) using three immune panels, and stromal profiling. Each profiling modality will be performed by a different institution included in the NIH Molecular Characterization of Screen-Detected Lesions (MCL) consortium. This pilot study will inform our decision to expand our study to a full-scale review of 200 patients (100 DCIS, 100 invasive cancer) among our institutions. Results: We have thus far demonstrated the feasibility of our pilot study with 10 blocks in total sent to and received by each institution. Whole exome DNA sequencing, SMART-3SEQ, mIHC, and stromal profiling work has begun and will be available for presentation, and we plan to make pathology, clinical and genomic data available through the MCL9s collaborative partnership with the NASA Jet Propulsion Lab (JPL) cloud-based platform. Conclusions: We have successfully shown that a multi-institution collaborative can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that our data will allow us to differentiate the underlying biology of high-risk DCIS from invasive breast cancer, identifying mechanistic opportunities for future intervention. References: 1 Narod SA et al (2015). Breast Cancer Mortality After a Diagnosis of Ductal Carcinoma in Situ. JAMA Oncol. 1(7): 888-96. Citation Format: Alexa Glencer, Olivier Harismendy, Alexander Borowsky, Gillian L. Hirst, Janet Stein, Mark Evans, Donald Weaver, Robert West, Case Brabham, Hidetoshi Mori, Laura J. Esserman. Understanding the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and the tumor immune microenvironment: The DEFENSE study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5440.