Abstract 1124: Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals annually in the US, with almost 90% lethality even when diagnosed prior to metastasis. There is an urgent unmet medical need both for new therapies as well as better matching of existing therapies to patients. To address this emergency, we are assessing the feasibility of implementing a strategy of using HRD (Homologous Recombination Deficiency) scores for better therapy matching in PDAC patients. Using a panel of 77 patient-derived xenograft (PDX) models that were developed from fresh surgical PDAC tumor samples, HRD scores were generated based on analysis of three biomarkers (LOH, TAI and LST) and mutational data for 45 genes. All 77 samples met inclusion criteria, 75 FFPE specimens generated mutation data. HRD analysis was successful for 71 specimens (range= 1 - 63 (median=22)), with the primary cause of failure identified as high non-tumor content. 53 PDX models had mutations in KRAS gene and 45 in TP53. We have also identified 4 PDX models with mutations in BRCA2, 3 models with mutations in ATM, 4 models with mutations in RAD51. We have also found frequent mutations in several other DNA repair genes (ATR, PALB2, MLH1, MSH2, MSH3, MSH6, FANCM), but most of these models retained one functional allele and were not associated with a high HRD score. Using this genomic analysis, all 71 PDX models were stratified into three clusters with high, medium and low HRD scores. Three PDX models with the highest and lowest HRD scores each were selected for an in vivo study with DNA-damaging platinum-based chemotherapeutic agents Cisplatin and Carboplatin, as well as with a clinically relevant PARP inhibitor Niraparib. The results of the PDX study will be reported and compared with responses to chemotherapy using RECIST V1.1 in patients. Note: This abstract was not presented at the meeting. Citation Format: Vladimir Khazak, Natalia Skobeleva, Anastasiia Vetkina, Ilya Serebriiskii, Kirsten M. Timms, Angela Davies, Igor Astsaturov. Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1124. doi:10.1158/1538-7445.AM2017-1124