Abstract P4-06-04: Triple negative breast cancer patient-derived xenografts: Molecular characteristics and sensitivity to emerging therapies

Abstract

Abstract Background: Patients with triple negative breast cancer (TNBC) that have significant residual disease following neoadjuvant therapy have a poorer prognosis. The difficulty in developing improved treatment strategies for these patients is compounded by the molecular diversity of this pathology. Thus, preclinical efficacy testing with models representing the molecular heterogeneity of TNBC may not only improve efficacy testing but also has the potential to facilitate biomarker discovery to inform patient selection. Methods: We generated 28 hormone receptor-low/HER2- patient-derived xenografts (PDXs) from 26 patients; the majority from residual disease following neoadjuvant chemotherapy. We characterized the tumors from the patients and the matched PDXs by targeted exome sequencing, RNA sequencing, and Reverse Phase Protein Arrays. We established single agent sensitivity for a set of PDXs to standard TNBC therapies as well as emerging targeted therapies targeting PARP, mTOR, PI3K and MEK1/2. Results: PDXs maintained DNA/RNA profiles similar to the patients' tumors. Our PDX set exhibits a diverse set of potential driver alterations and is comprised of PDXs representative of all TNBC molecular subtypes. The PDXs varied in their sensitivity to standard chemotherapeutics. PI3K, mTOR and MEK inhibition caused tumor growth inhibition in several PDX models but were unable to cause tumor regression as single agent. In contrast, talazoparib caused dramatic regression in 5 out of 12 PDXs tested, including 3 PDXs from patients whose tumors had progressed on neoadjuvant anthracyclines and/or paclitaxel. Four of these talazoparib sensitive PDXs were derived from patients not harboring BRCA1/2 germline alterations; three had somatic alterations in genes linked to DNA damage repair (ATM, BRCA2, PTEN). The comparison of PARP sensitivity with molecular profiles will be presented. Conclusions: TNBC PDXs represent molecular tumor heterogeneity as well as heterogeneity in response to targeted therapeutics. PDXs represent an opportunity for biomarker discovery as well as for rationale combination therapies to enhance the efficacy targeted therapies. Citation Format: Evans KW, Yuca E, Akcakanat A, Scott SM, Paez Arango N, Zheng X, Chen K, Tapia C, Tarco E, Eterovic AK, Black DM, Jennifer LK, Tripathy D, Mills GB, Meric-Bernstam F. Triple negative breast cancer patient-derived xenografts: Molecular characteristics and sensitivity to emerging therapies [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 P4-06-04.