San Antonio, Texas USA (UroToday.com) Our understanding of metastatic castration-resistant prostate cancer (mCRPC) has grown dramatically over the past decade. Gene sequencing has begun to identify tumor changes that cause some patients to develop more aggressive and resistant tumors in the setting of androgen-receptor (AR) inhibition resistance.
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One of the more pernicious forms of these changes involves the trans-differentiation of prostate cancer into the neuroendocrine phenotype (t-NEPC) that has extremely aggressive clinical features and poor survival. These tumors progress independent of AR activation, and a more thorough understanding of the biologic drivers of these tumors is needed.
Dr. Gleave and the researchers from the various centers comprising the West Coast Prostate Cancer Dream Team have sequenced and profiled many mCRPC tumors, and have now identified three distinct entities along the degenerative pathway: adenocarcinoma CRPC, small cell t-NEPC, and intermediate atypical carcinoma (IAC). This last entity is thought to be a likely intermediary between adeno and t-NEPC forms. From a survival standpoint, they have found a clear difference: IAC and t-NEPC have much poorer survival (11 mos) than adenocarcinoma CRPC (25 mos).
Beltran et al. have demonstrated that IAC and t-NEPC tumors express markers of NE lineage, but share enough genetic identity with adeno CRPC that they can be shown to be clones from a precursor adenocarcinoma cell type. IAC is, in fact, quite common among biopsies of men with mCRPC. Researchers estimate that 29% of biopsies of mCRPC men will have IAC, so it is important to understand these tumors more thoroughly.
One of the most intriguing and promising discoveries in the field of genomic profiling is the identification of circulating tumor DNA (ctDNA) derived from the plasma of patients with the disease. These “liquid biopsies” are ideal because one can identify the full milieu of genetic entities that are present within the patient. This reduces heterogeneity based on temporal and spatial differences from tissue samples obtained at different times and at different sites. For example, plasma ctDNA was used to track the AR genome in 62 patients with mCRPC treated with abiraterone or enzlutamide. The researchers confirmed that plasma samples identified and characterized prostate cancer genomes identical to the genomes expressed from actual prostate tissue. Thus, it is an easier and more homogenous way to characterize the tumor milieu in a patient by using just a plasma sample rather than various tissue samples. The Dream Team group has more recently found that plasma samples not only have good concordance with metastatic tissue samples, but can actually identify additional genetic alterations not previously identified from just tissue samples (full data to be presented at ASCO). This has already been used to treat patients with atypical agents not previously on the menu of available treatments for mCRPC.
The most pressing question is what drives the trans-differentiation of adeno CRPC to t-NEPC. The answer is complicated, but there are a growing number of genes and pathway alterations that are now being mechanistically associated with this process. This is exciting, as we are finding more targets for intervention with each new finding. An interesting takeaway from the early research in this process is that there is evidence that the baseline DNA sequence of trans-differentiated cells does not change. Instead, gene expression is radically changed by silencing adeno markers and upregulating NE markers. This means trans-differentiation occurs by manipulating phenotype from an identical genotype.
Dr. Gleave concluded by overviewing what we now know about the trans-differentiation process. A specific genome undergoes epigenetic changes, splicing, transcriptome manipulation, and further pathway derangements to ultimately form the t-NEPC phenotype. The intermediary forms comprising IAC are now being recognized as important for further understanding the genomic alterations responsible for trans-differentiation. Clearly, this will also open up more targets for future treatments.
Presented By: Martin E. Gleave, MD, FRCSC, FACS, Vancouver Prostate Center
Written By: Shreyas Joshi, M.D., Fox Chase Cancer Center
17th Annual Meeting of the Society of Urologic Oncology - November 30 -December 2, 2016 – San Antonio, Texas USA