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 The DEFENSE study, supported with funding from the NCI Molecular Characterization of Screen-Detected Lesions (MCL) consortium, was designed to identify molecular, immunological, and stromal-related factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer.

Methods: The overall objective of the DEFENSE study is to compare 100 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile (Mammaprint) to 100 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (>5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients are divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunofluoresence (mIF) for immune cell infiltrates, and stromal profiling by IHC. Each profiling modality is performed by a different institution included in the MCL consortium (UCSF, UCD, UCSD, Stanford, and UVM). In order to evaluate the logistic and financial feasibility of our multi-institution protocol prior to expanding to our proposed full-scale study, we are conducting a pilot study of 11 high-risk DCIS specimens.

Results: The 11 pilot specimens have been successfully sent and received by each institution. H&E images from the sectioned specimens have been uploaded to the NASA Jet Propulsion Lab (JPL) cloud-based platform and shared for pathologic annotation among institutions. mIF of the pilot cohort has been completed, but interpretation of associations between tumor subtype and immune cell infiltrate is limited by the small sample size. Whole exome DNA sequencing, SMART-3SEQ RNA sequencing, and stromal profiling of the pilot cohort are each ongoing. We anticipate being able to provide full results from each profiling modality performed from the pilot cohort, as well as results from an expanded cohort of 40 additional specimens, by December 2020.

Conclusions: We have successfully shown that a multi-institution collaboration can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that data from our expanded cohort 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. JAMAOncol. 1(7): 888-96.

Citation Format: Alexa Glencer, Olivier Harismendy, Alexander Borowsky, Hidetoshi Mori, Michael Campbell, Gillian Hirst, Janet Stein, Mark Evans, Prachi Ghule, Robert West, Laura J. Esserman. Elucidating the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and immunohistochemical profiling of the tumor microenvironment: The DEFENSE study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-14.