Abstract 2905: Clinical and genomic resistance to second generation androgen blockade in paired biopsies of metastatic castration-resistant prostate cancer
Authors: Han G. Celine , Hwang Justin , Mullane Stephanie A. , Cibulskis Carrie , Zhang Zhenwei , McKay Rana R. ,   PCF-SU2C Dream Team, Carter Scott L. , Hahn William C. , Taplin Mary-Ellen , Allen Eliezer M. Van 
Published: July 2017

Abstract
Background
Recent “next generation” androgen deprivation therapies (ADT), such as abiraterone and enzalutamide, have improved survival in patients with castrate-resistant prostate cancer (CRPC). Despite therapy, most patients develop resistance to these agents. We investigated the genetic basis of tumor evolution and clinical resistance to next generation ADT in CRPC by using whole exome sequencing (WES) on paired pretreatment and post-resistance biopsies from CRPC patients.
Methods
Matched “trios” of germline, pre-treatment and post-resistant tumor samples were obtained from 7 patients treated with abiraterone (n=4) and enzalutamide (n=3) and WES was performed. Clinical data, including PSA and radiographic measurements, was used to classify patients as intrinsically resistant or initially responsive to treatment. Quality control, mutation and indel calling, copy number variation identification were performed using analytical pipelines at the Broad Institute. Tumor purity and ploidy were inferred, and phylogenetic analysis was performed using ABSOLUTE and Phylogic, respectively to identify resistance associated alterations in the context of clinical phenotypes.
Results
We identified multiple putative mechanisms and genetic categories of resistance to next generation ADT in CRPC. One abiraterone patient acquired an AR mutation (L702H) in the post-treatment sample, previously reported to be associated with poor outcomes and to confer resistance to this therapy. Amplification of MYC was associated with resistance in two other abiraterone patients with pre-existing AR gain: one patient with initial response to therapy acquired a focal gain of MYC in the resistant sample, and the other harbored a pre-existing MYC amplification, but had no response to therapy. In three enzalutamide patients, all acquired alterations in cell cycle genes (CDKN2A mutation, focal amplifications in regions spanning CDK4/6, and CCND3 focal amplification) at the time of resistance that were absent in pre-treatment tumors. In parallel, we confirm CDK4/6 overexpression was sufficient to promote enzalutamide resistance in prostate cancer cell models. Additional candidate genomic events associated with CRPC were also implicated with this approach, such as RSPO3 amplification.
Conclusion
This study outlines an approach to identify clinical genetic resistance mechanisms of next generation ADT in CRPC through integration of genomic data from serial biopsies, clinical patient outcomes, and preclinical functional screening. These findings confirm previously known potential resistance mechanisms, such as AR and MYC activation, and suggest putative mechanisms
linked to therapeutic agents, which may inform novel targets for treating CRPC patients.
Citation Format: G. Celine Han, Justin Hwang, Stephanie A. Mullane, Carrie Cibulskis, Zhenwei Zhang, Rana R. McKay, PCF-SU2C Dream Team, Scott L. Carter, William C. Hahn, Mary-Ellen Taplin, Eliezer M. Van Allen. Clinical and genomic resistance to second generation androgen blockade in paired biopsies of metastatic castration-resistant prostate cancer [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 2905. doi:10.1158/1538-7445.AM2017-2905