ASCO GU 2017: Genomic Evolution in Primary and Therapy-Resistant Prostate Cancer - Session Highlights

Orlando, Florida USA ( Dr. Eliezer M. Van Allen described the current understanding of genomic evolution from primary to therapy-resistant prostate cancer (PC). Background work from several groups has elucidated tumor heterogeneity in primary PCs with multiple divergent phylogenies within one primary tumor. These diverse phylogenies have also been shown in metastatic tumors, making the determination of how tumors evolve over time (and in the context of therapy) quite challenging.

Fortunately, work from The Cancer Genome Atlas (TCGA) group and the Prostate Cancer Foundation/Stand Up to Cancer Dream Team has emerged to help improve the understanding of these challenges. The TCGA group has analyzed 333 PCs and redefined the molecular taxonomy of primary untreated PC. Virtually simultaneously, the Prostate Cancer Foundation/Stand Up to Cancer Dream Team identified 150 castration-resistant prostate cancer (CRPC) tumor exomes and transcriptomes. Combined, these data offer the opportunity to compare changes at the genomic level between primary PC and CRPC. Using computational analyses, one can characterize the modifications in the genomic evolution as primary-enriched (i.e. associated with primary cancers) vs. CRPC-enriched (i.e. associated with CRPC). As expected, p53 and androgen-receptor changes are profoundly enriched in CRPC. However, variations in other genes were also found to be associated with a trend toward CRPC (e.g. BRCA2, GNAS, an MLL2).

Dr. Van Allen closed by describing three ways by which the genomic evolution from primary to therapy-resistant PC may occur. Firstly, expanded sample size analysis offers more power to determine movement from a primary-enriched genotype to a CRPC-enriched genotype. Secondly, individual serial biopsy strategies are currently being employed. In this setting, a patient undergoes interventional radiology-guided biopsy of a metastatic site prior to systemic therapy. The patient is then given second-generation, androgen-targeted therapy until CRPC arises. Serial biopsies throughout this clinical course are taken, and the genomic evolution over the treatment course can be compared within patients.

Finally, a patient-driven (designed by patients for patients) strategy will be getting underway shortly and is modeled after previously successful programs developed by breast cancer patients. A patient-designed website can be accessed to recruit patients from wherever they are, with consent obtained over the website. A saliva kit can be mailed for germline DNA assessment, and a liquid biopsy kit will be mailed throughout an individual’s treatment course. These exciting novel programs will ideally give us a better comprehension of how tumors change over time in the context of systemic therapies.
Presented By: Eliezer M. Van Allen, MD, Dana-Farber Cancer Institute

Written By: Benjamin T. Ristau, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center

at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA