Abstract A39: Patient-derived xenografts to test emerging therapies for triple negative breast cancer
Authors: Evans Kurt W. , Yuca Erkan , Scott Stephen M. , Paez Natalia Arango , Zheng Xiaofeng , Chen Ken , Gonzales Laura , Tapia Coya , Tarco Emily , Black Dalliah M. , Mills Gordon B. , Meric-Bernstam Funda 
Published: March 2017

Introduction: Patients with triple negative breast cancer (TNBC) that do not respond to cytotoxic neoadjuvant therapy have a poor prognosis, thus there is a pressing need to develop pre-clinical models of chemoresistant TNBC and identify optimal therapeutic targets. Patient-derived xenografts (PDX) are a simple, expandable approach to model TNBC in vivo. We have generated a collection of triple negative PDXs that have undergone molecular characterization at the DNA, RNA and protein levels and have initiated characterization of their therapeutic sensitivity to standard chemotherapeutics regimens as well as targeted therapies.

Methods: Tumors from patients and matching PDXs have been characterized by cancer-specific targeted exome sequencing, RNA sequencing, and Reverse Phase Protein Arrays. We have established single agent sensitivities for a set of PDXs to standard TNBC therapies (paclitaxel, carboplatin, doxorubicin, eribulin, gemcitabine) and the following targeted therapies: talazoparib (PARP), MLN0128 (mTOR), buparlisib (PI3K), and trametinib (MEK1/2).

Results: We have generated 25 hormone receptor-low/HER2- PDXs from 24 patients (1 primary-local recurrence pair) with an overall engraftment rate of 49% for this patient population. Exome sequencing found that the PDXs mostly maintain the somatic mutation profile of the originating tumor and exhibit alterations common to TNBC: 16 (73%) with TP53 mutations, 2 (9%) with PI3KCA mutations and 4 (18%) with PTEN deletions. RNA sequencing demonstrated that the PDXs maintain gene expression profiles similar to the originating tumor and that our panel is comprised of PDXs representative of five TNBC molecular subtypes. Treatment with standard therapies established differential sensitivity to paclitaxel and carboplatin between PDXs. The two models with PI3KCA alterations were responsive to mTOR/PI3K inhibition and unresponsive to trametinib and talazoparib, supporting heightened reliance on mTOR/PI3K signaling in PI3KCA mutant TNBC. Talazoparib was the only targeted agent tested that caused regression as a single agent in any model. All three models that regressed with talazoparib treatment had genetic alterations linked to DNA damage pathways (BRCA1 germline alteration, ATM deletion; PTEN deletion); these models also had low BRCA1 mRNA expression and were the only PDXs to regress when treated with carboplatin.

Conclusions: PDXs of all TNBC subtypes can be generated from TNBC patients that are resistant to neoadjuvant chemotherapy. These PDXs maintain molecular alterations of TNBC, retain patient-specific gene expression, and display differential response to therapies enabling identification of associations between responses and molecular traits.

Citation Format: Kurt W. Evans, Erkan Yuca, Stephen M. Scott, Natalia Arango Paez, Xiaofeng Zheng, Ken Chen, Laura Gonzales, Coya Tapia, Emily Tarco, Dalliah M. Black, Gordon B. Mills, Funda Meric-Bernstam. Patient-derived xenografts to test emerging therapies for triple negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A39.