Mouse-INtraDuctal (MIND): An In Vivo Model for Studying the Underlying Mechanisms of DCIS Malignancy

Journal of Pathology Manuscript
Authors Yan Hong, Darlene Limback, Hanan S. Elsarraj, Haleigh Harper, Haley Haines, Hayley Hansford, Michael Ricci, Carolyn Kaufman, Emily Wedlock, Mingchu Xu, Jianhua Zhang, Lisa May, Therese Cusick, Marc Inciardi, Mark Redick, Jason Gatewood, Onalisa Winblad, Allison Aripoli, Ashley Huppe, Christa Balanoff, Jamie L. Wagner, Amanda L. Amin, Kelsey E. Larson, Lawrence Ricci, Ossama Tawfik, Hana Razek, Ruby Obaldo Meierotto, Rashna Madan, Andrew K. Godwin, Jeffrey Thompson, Susan G. Hilsenbeck, Andy Futreal, Alastair Thompson, E. Shelley Hwang, Fang Fan, Fariba Behbod

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similarly to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression while 17 (46%) samples injected into 107 xenografts remained noninvasive. Among the 20 samples that showed invasive progression, 9 samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained noninvasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS FFPE sections including 8 DCIS that showed invasive progression, 5 DCIS that remained non-invasive and 3 DCIS that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer related pathogenic mutations among the groups showed no significant differences (KW: P >0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; P >0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease.