Abstract PR006: A living biobank of patient-derived ductal carcinoma in situ (DCIS) Mouse-INtraDuctal (MIND) xenografts identifies multiple risk factors of invasive progression


 Ductal Carcinoma in Situ (DCIS) is a non-invasive non-obligate precursor of invasive breast cancer (IBC). DCIS is usually treated by surgery combined with radiotherapy, which can have a large impact on the life of patients. However, many of these DCIS lesions would never progress into IBC. To reduce the overtreatment of DCIS, but assure proper treatment for high risk DCIS, it is crucial to understand the biology underlying DCIS. To study the biology of DCIS we established Mouse INtraDuctal (MIND) patient-derived xenograft (PDX) models by intraductally injecting patient DCIS material into the mammary ducts of female immunocompromised mice. We engrafted 130 samples, which have been incubated in vivo for a period of 12 months. We obtain a take rate of 88% with 46% of our models showing invasive progression. Histology and molecular subtyping by PAM50 classification are well preserved in the MIND models compared to the primary counterpart, ensuring that our MIND models represent the patient disease well. For 102 primary samples we obtained RNAseq profiles as well as for 64 matched MIND-PDX models. In addition whole exome-/panel sequencing data is generated from the same primary DCIS samples together with 12 matched MIND-PDX WES profiles as well as 60 matched Copy Number Variation (CNV) MIND-PDX profiles. Together these data revealed multiple biomarkers related to invasive progression, including factors such as high grade, solid growth, a high copy number aberrations burden, HER2, PTK6 & MYC amplifications and a high Ki67. On top of this we used whole mount imaging of the injected mammary glands extracted from our MIND-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. We have also successfully passaged 42 MIND-PDX models which showed minimal changes in pheno- and genotype over time indicating invasive behavior is an intrinsic phenotype of DCIS with minimal evolution, supporting a multiclonal evolution model. Moreover, this provided a collection of 19 stable sequentially transplantable DCIS MIND models including Luminal A, Luminal B, ER+/HER2+ and ER-/HER2+ models. Ultimately these models can be used to validate the biomarkers found to be related to invasive progression, as an example we proved the direct role of HER2 overexpression in invasive progression by inhibiting the HER2 receptor or by overexpressing HER2. In conclusion all this data together enabled us to create a well-characterized biobank of DCIS models with the unique opportunity to follow the natural progression, sequentially transplant 42 models, find genomic and transcriptomic profiles related to high risk DCIS and manipulate gene expression to validate the role of genes in DCIS progression.
 Citation Format: Stefan J. Hutten, Roebi de Bruijn, Catrin Lutz, Madelon Badoux, Timo Eijkman, Xue Chao, Marta Ciwinska, Andrea Herencia-Ropero, Petra Kristel, Lennart Mulder, Joyce Sanders, Mathilde Almekinders, Alba Llop-Gueverra, Helen R. Davies, Fariba Behbod, Serena Nik-Zainal, Violeta Serra, Jacco van Rheenen, Esther H. Lips, Lodewyk F.A. Wessels, Jelle Wesseling, Colinda Scheele, Jos Jonkers. A living biobank of patient-derived ductal carcinoma in situ (DCIS) Mouse-INtraDuctal (MIND) xenografts identifies multiple risk factors of invasive progression [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR006.