Abstract P5-01-01: Intraductal patient-derived xenograft models of ductal carcinoma in situ (DCIS) to distinguish indolent DCIS from aggressive DCIS

Abstract 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 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. In order to study the biology of DCIS we established patient-derived xenograft (PDX) models by intraductally injecting fresh patient DCIS material into the mammary ducts of female immunocompromised mice (Mouse Mammary Intraductal(MIND)). To date, 150 primary DCIS patient samples were engrafted and >100 have been incubated in vivo for a period of 12 months. Using this method we obtain a take rate of 89% with 36% of our models showing progression. 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. For >80 primary samples we obtained RNAseq as well as >50 matched PDX profiles. In addition WES or WGS data is generated from the same primary DCIS samples together with 10 matched PDX WES profiles as well as >40 matched CNV PDX profiles. On top of this we used whole mount imaging, in order to create 3D sections of the injected mammary glands extracted from our PDX models, showing two distinct growth patterns correlated with invasion. And as this is all done in the context of the PRECISION consortium this allows us to confirm and validate our findings in larger sequencing and imaging efforts of human samples. Besides collecting large amounts of data which we can now link to DCIS progression we have successfully sequentially transplanted >25 of our PDX models in order to create models that can be shared with the scientific community and can be manipulated to validate the role of genes in DCIS progression. As an example we took HER2 overexpression, which in our models was found to be associated to progressive disease. On the one hand we treated three progressive HER2 overexpressing DCIS PDX models with a HER2-antibody Herceptin showing a massive decline in growth, while on the other hand we infected two indolent HER2 negative DCIS PDX models with a HER2-GFP lentivirus showing a transformation to HER2 positive progressive growth. In conclusion all this data together enables us to create a well-characterized biobank of DCIS models of which we can follow the progression, sequentially transplant >25 models, find mutational and expression profiles related to high risk DCIS and manipulate gene expression to validate the role of genes in DCIS progression. Citation Format: Jelle Wesseling, Stefan Hutten, Catrin Lutz, Colinda Scheele, Madelon Badoux, Timo Eijkman, Roebi de Bruijn, Mathilde Almekinders, Joyce Sanders, Esther Lips, Jacco van Rheenen, Jos Jonkers, Grand challenge PRECISION consortium. Intraductal patient-derived xenograft models of ductal carcinoma in situ (DCIS) to distinguish indolent DCIS from aggressive DCIS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-01.