Understanding DCIS initiation and progression using PDX and genetically engineered mouse and rat models

Ductal carcinoma in situ (DCIS) is a starting lesion in the milk duct of the breast, which accounts for 25% of all “breast cancers” detected. DCIS is usually treated by surgery combined with radiotherapy, which can have a large impact on the life of patients. However, there is little to no evidence that treatment of low- and intermediate-grade DCIS reduces mortality, while women diagnosed with DCIS do perceive their risk of dying to be the same as patients with invasive disease. To reduce the negative perception and the overtreatment of DCIS, but assure proper treatment for high-risk DCIS, it is crucial to understand the biology underlying DCIS. To model DCIS and the progression to invasive ductal carcinoma (IDC), we took two approaches. 1) We established patient-derived xenograft (PDX) models by intraductally injecting fresh patient DCIS material into the mammary ducts of female immunocompromised mice. To date, 100 human patient DCIS samples were engrafted and incubated in vivo for a period of 12 months. The first 25 of these PDX models had a 72% take rate and show both indolent and invasive tumor growth. Histology and molecular subtyping by PAM50 classification are well preserved in the outgrown PDX lesions compared to the original human counterpart, ensuring that our models are a good representation of the patient disease. On top of this, we profiled copy numbers for both PDX and original patient lesions. Finally, using whole mount imaging, we were able to create 3D sections of the injected mammary glands extracted from our PDX models, showing two distinct growth patterns correlated with invasion. 2) We generated genetically engineered mouse and rat models by intraductal injection of lentiviral vectors (over)expressing known breast cancer driver genes and mutations, or combinations thereof, which are suspected to play a role in DCIS initiation and/or its progression. We were able to successfully and selectively transduce the mammary epithelial cell layer in both mice and rats and are therefore able to somatically engineer the mammary gland in vivo. DCIS formation presented in mice with overexpression of Ccnd1 and Myc only. However, the in situ stage could be observed in rat models with overexpression of the latter genes, as well as oncogenic point mutations in Pik3ca and p53 and all combinations of the tested genetic perturbations. These models will eventually allow us to study the biologic processes underlying DCIS progression. This knowledge could then be used to predict DCIS evolution and distinguish patients with high-risk DCIS from those with low-risk DCIS, which will aid in better care. Citation Format: Stefan Hutten, Catrin Lutz, Colinda Scheele, Madelon Badoux, Timo Eijkman, Stefano Annunziatio, Jelle Wesseling, Jos Jonkers. Understanding DCIS initiation and progression using PDX and genetically engineered mouse and rat models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B37.