Abstract PR003: Convergent evolution in DNA repair-deficient mCRPC in response to targeted therapy
Authors: Moreno Thaidy , Zhang Meng , Lundberg Arian , Shrestha Raunak , Sjöström Martin , Pasam Anu , Foye Adam , Trigos Anna , Feng Felix , Sandhu Shahneen , Quigley David A. 
Published: June 2023

Abstract
BACKGROUND: Distinct metastatic prostate cancer lesions within the same patient can show a range of responses to targeted therapy. These variations in response present a challenge for the interpretation of predictive biomarkers derived from a single lesion. The influence of tumor evolution on how lesions respond to Androgen Signaling Inhibitor (ASI) or PARP inhibitor therapy has been difficulty to study, because few autopsy studies have been performed in heavily treated patients with DNA repair defects. METHODS: In this study, we analyzed an autopsy cohort of 54 tumors from six men with DNA repair-deficient metastatic prostate cancer using whole genome, exome, and targeted DNA sequencing as well as RNA-sequencing. Observations were validated in an independent cohort of 135 mCRPC biopsies with whole genome and transcriptome sequencing. To automate the analysis of mutations conferring resistance to PARP inhibitor therapy, we developed a tool (AARDVARK) that detects and annotates PARP inhibitor resistance mutations. RESULTS: Patients harboring germline inactivation of the DNA repair gene BRCA2 showed consistent BRCA2 biallelic inactivation, while somatic BRCA2 inactivation was not always associated with biallelic deletion and genomic scars of DNA repair inactivation. AARDVARK identified numerous identical resistance mutations in physically distinct tumors in the same individual, consistent with dissemination of these mutations prior to later targeted therapy. We identified DNA structural variations linked to extra-chromosomal DNA (ecDNA) in 52% of mCRPC biopsies, and ecDNA amplified an oncogene 28% of the time. Extensive heterogeneity of structural variants was present at the Androgen Receptor locus, which was the most frequent target of ecDNA amplification (15% of tumors). Cyclins CCND1 and CCNE1 were amplified in 3% of cases, and a long tail of oncogenes were also targeted. Phylogenetic analysis was consistent with AR amplification by ecDNA in response to both androgen deprivation therapy and second-generation ASI. The presence of ecDNA was significantly associated with overall genomic instability, aneuploidy, whole genome doubling, chromothripsis, and with inactivating PTEN alterations. CONCLUSIONS: This study demonstrated that mCRPC lesions continue to evolve on therapy, and their varied responses can be influenced by shared genetic backgrounds. Oncogene amplification by ecDNA is common in mCRPC, particularly at the AR locus, and is linked to genomic instability. Alterations conferring resistance to ASI and PARP inhibitor therapy can be present in individual lesions before metastatic dissemination, and the evolutionary history of tumors plays an important role in their tumor response to targeted therapy.
Citation Format: Thaidy Moreno, Meng Zhang, Arian Lundberg, Raunak Shrestha, Martin Sjöström, Anu Pasam, Adam Foye, Anna Trigos, Felix Feng, Shahneen Sandhu, David A. Quigley. Convergent evolution in DNA repair-deficient mCRPC in response to targeted therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR003.