Abstract 1186: Patient-derived breast cancer xenografts demonstrate molecular evolution in the phosphatidylinositol 3-kinase pathway upon engraftment
Authors: McAuliffe Priscilla F. , Akcakanat Argun , Evans Kurt , Eterovic Agda Karina , Zhao Hao , Chen Ken , Sangai Takafumi , Chen Huiqin , Do Kim-Anh , Holder Ashley M. , Sharma Chandeshwar , Symmans William Fraser , Gagea Mihai , Naff Katherine A. , Sahin Aysegul , Multani Asha S. , Mills Gordon B. , Gonzalez-Angulo Ana Maria , Meric-Bernstam Funda 
Published: May 2015

Abstract
Introduction: Patients with breast cancer who do not respond to standard systemic therapy have a poor prognosis. There is a pressing need to develop in vivo models of breast cancer to test novel therapeutics. Directly implanting tumors into immunodeficient mice may more accurately recapitulate human tumor characteristics compared to cell line xenografts. We tested the feasibility of generating breast cancer xenografts (BCXs) and the effect of serial passage on tumor characteristics.
Methods: Tumors from 48 patients with breast cancer were implanted. Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, and a series of BCXs were characterized with next generation sequencing, molecular inversion probe arrays and reverse phase protein arrays. Results: BCXs were established in 15 (31%) of 48 patients and 13 have been serially passaged. BCX engraftment was higher in patients with triple negative compared to ER or PR+ breast cancer (11 of 18, 61% vs. 4 of 30, 13%, p=0.001), and in patients who received neoadjuvant chemotherapy (13 of 25, 52% vs. 2 of 23, 9%, p=0.002). 7 patients developed metastases after surgery; in 5, BCXs developed before distant relapse. Compared to patient tumors, BCXs demonstrated genomic instability. Although mutation status, copy numbers and proteomic profiles were often maintained, an activating PIK3CA mutation was acquired in one BCX lineage and loss of PTEN in another. Proteomics demonstrated activation in PI3K/mTOR signaling in BCXs compared with patient tumors. Notably, 2 of 48 models demonstrated a transformation to induce mouse tumors.
Conclusions: BCXs can be established prior to relapse from breast cancer, especially in patients with poor response to neoadjuvant chemotherapy. Although molecular profiles of BCX are mostly similar to the patient tumor that was implanted, differences such as aberrations in PI3K signaling can occur. Future studies will determine whether molecular evolution in BCXs reflect that seen upon progression/relapse and the potential of in vivo models for individualization of treatment.
Citation Format: Priscilla F. McAuliffe, Argun Akcakanat, Kurt Evans, Agda Karina Eterovic, Hao Zhao, Ken Chen, Takafumi Sangai, Huiqin Chen, Kim-Anh Do, Ashley M. Holder, Chandeshwar Sharma, William Fraser Symmans, Mihai Gagea, Katherine A. Naff, Aysegul Sahin, Asha S. Multani, Gordon B. Mills, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam. Patient-derived breast cancer xenografts demonstrate molecular evolution in the phosphatidylinositol 3-kinase pathway upon engraftment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1186. doi:10.1158/1538-7445.AM2014-1186