Abstract P4-06-01: Patient derived DCIS mouse-intraductal (MIND) models recapitulate the full spectrum of human patient pathology and histologic features including progression to invasion in a subset of cases
Authors: F Behbod, D Limback, Y Hong, H Elsarraj, J Berger, E Heddens, K Valdez, WP Smith, M Inciardi, M Reddick, J Gatewood, J Darrah, O Winblad, R Meierotto, L Ricci, J Wagner, A Amin, L May, T Cusick, J Mammen, T Fields, AK Godwin, C Fabian, C Kaufman, O Tawfik, F Fan
Journal: Cancer Research (2017)

Abstract Introduction: The 20-year breast cancer mortality rate following a DCIS diagnosis is ∼3%. Radiation and anti-hormonal therapy of DCIS has not resulted in improved overall survival, which argues against the non-selective use of such therapies in DCIS management. However, some DCIS cases do progress to invasive cancer, and these patients may benefit from treatment. A study of 80 DCIS patients followed for up to 30 years reported a 43% progression rate. Notably, progression was not predicted by grade, as 39% of even low-grade DCIS ultimately progressed to invasive cancer. Clearly, there is a need to identify which DCIS lesions are likely to progress. We have developed a novel mouse xenograft model (mouse-intraductal; MIND) to study the molecular basis of DCIS progression and enable identification of suitable biomarkers that predict invasive progression. Methods: MIND involves injection of epithelial cells derived from patient breast lesions into the mammary ducts of immunocompromised mice. Serial sections of mouse mammary glands containing DCIS xenograft lesions were examined at time intervals of 3-14 months post-engraftment by histology using hematoxylin and eosin (H&amp;E) and immunohistochemistry using anti-human cytokeratin 5/19, smooth muscle actin, ER, PR, p53, Ki67 and HER-2. Results: Intraductal injection of cells derived from breast lesions of 28 patients into 133 mice resulted in a successful engraftment rate of 60%. Among these, 12 pure DCIS samples were injected into 35 different mice to create MIND xenografts. As early as three months post-engraftment, the DCIS xenograft cells showed multilayered in situ growth consisting of atypical neoplastic cells with prominent and vesicular nuclei. DCIS MIND xenografts exhibited the full spectrum of human DCIS histologic features, including similar biomarker expression (ER, PR, Ki67, HER-2 and p53) at long-term follow-up after engraftment (up to 12 months). Most remarkably, a subset of xenografts representing 5 patients (5/12; 42%) showed progression to invasion 6-12 months post-engraftment in the absence of any external genetic manipulations. This rate is very similar to that reported for human DCIS progression in untreated patients. MIND DCIS xenograft lesions that progressed showed disruption of basement membrane and myoepithelial layer by the invasive cells, retraction of basement membrane, and micro-invasion. MIND DCIS lesions were enriched in small capillaries, and in some cases clusters of invasive cells appeared inside nearby blood vessels. Conclusion: The MIND xenograft is a viable model for human DCIS progression that recapitulates histologic features of human DCIS, as well as reported rates of progression to invasion. The availability of this innovative model provides a valuable tool for the discovery of new biomarkers to identify DCIS with invasive potential. The identification of high risk DCIS will ultimately help patients and clinicians choose the best course of therapy and avoid the morbidity and costs associated with unnecessary treatment. Citation Format: Behbod F, Limback D, Hong Y, Elsarraj H, Berger J, Heddens E, Valdez K, Smith WP, Inciardi M, Reddick M, Gatewood J, Darrah J, Winblad O, Meierotto R, Ricci L, Wagner J, Amin A, May L, Cusick T, Mammen J, Fields T, Godwin AK, Fabian C, Kaufman C, Tawfik O, Fan F. Patient derived DCIS mouse-intraductal (MIND) models recapitulate the full spectrum of human patient pathology and histologic features including progression to invasion in a subset of cases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-01.