Munich, Germany (UroToday.com) In today’s thematic session on the changing landscape in the management of prostate cancer recurrence, Dr. G. Steven Bova delivered the State of the art lecture on the genomic picture of metastatic prostate cancer. He began by explaining his pilot test of a scalable basic science-clinical trial that describes the evolutionary history of lethal prostate cancer. Whole genome sequencing was performed on 51 tumor samples, and a high confidence set of substitutions, insertions/deletions, and copy number changes were identified in each sample. Integration of copy number and point mutation data allows for accurate estimates of clonal origin.
Moreover, it provides an understanding of the timing of events during metastatic progression. Mutations can be divided into 3 groups, including trunk mutations (those present in all metastatic sites), branch mutations (shared in 2 sites), and leaf mutations (present only in 1 site). It can also be divided into monoclonal seeding (all progeny are descendents of the “arriving” cell) and polyclonal seeding (multiple contributions to a metastatic site, some of which can be traced to other sites). A comparison of trunk vs. “off-trunk” events demonstrated that the androgen receptor was rarely modified on the truncal mutation; rather it was more commonly modified “off trunk.” The variability that is present between patients, combined the homogeneity within samples from the same patient, is useful to help us understand evolution of disease and the potential response to therapy.
A closer evaluation of one patient who ultimately died of disease helps to answer more questions about potential “precision therapy” targets. This patient had bone pain 3 years after undergoing radical prostatectomy and was started on ADT at that time. Examination of his X chromosome demonstrated 4 different patterns of copy number changes within metastatic sites (right rib, left iliac crest, left clavicle, left rib, left adrenal, multiple liver lesions). These changes in copy number were associated with the timing of his spread of disease, and ultimately his response to ADT.
This level of study allows us to identify opportunities for tailored therapy. Mutations that were identified that may be potentially “druggable” in this patient include FGFR 1, PIK3CG, ABCC4, ALDH9A1, and ASNA1.
Dr. Bova concluded that polyclonal seeding is a potential distinct phenotype. DNA changes associated with castration resistance are generally “off trunk” events, and that clonal truncal mutations are unique events with the potential for targeting. Finally, the tracing of metastatic feeder foci in primary cancers can provide context for discoveries distinguishing metastatic capacity at the pathology, radiology, immunology, and blood and body fluid marker levels.
Presented By: G. Bova, Tampere (FI)
Reported By: Nikhil Waingankar, MD, at the 31st Annual EAU Congress - March 12 - 15, 2016 – Munich, Germany Fox Chase Cancer Center