As shown in the clinical case the landscape for the treatment of castrate resistant metastatic prostate cancer (mCRPCP) has changed dramatically over the last 10 years with several new therapies being added the to the treatment armamentarium. The focus of research is now in the risk stratification of patients with castrate resistant prostate cancer with hope that care can be individualized to improve cancer outcomes. In a report by Halabi et al, patients with castrate resistant prostate cancer were stratified based on metastatic disease sites and this was then correlated with survival outcomes. The authors performed a meta-analysis of 9 Phase III clinical trials showing that the site of metastatic disease did have an effect in overall survival (OS) with nodal metastasis patients faring better than those with liver metastatasis (OS 31.6 months vs. 13.5 months).
Although site of metastatic disease provides us with some form of patient stratification not all patients within the same site behave the same way. For example, a retrospective review of the AFFIRM trial by Dr. Sharer, showed that while visceral metastasis do have a poorer response to enzalutamide compared to pulmonary metastasis response to enzalutamide remains active in a small cohort of patients which may benefit from the therapy. In order, to further characterize mCRPC patients molecular evaluation of the metastatic disease foci needs to be performed. Several articles were published this past year assessing molecular divers in mCRPC, the most important being the publication by Robinson et al in Cell. The authors performed a thorough evaluation of the different genetic alterations present in patients with metastatic disease previously treated with enzalutamide or abiraterone. The genetic analysis noted alterations in the androgen receptor (AR) pathway in 63% of the samples, with 49% showing alternations in the PI3K pathway. Further evaluation of the AR mutations showed intricate splice variants, such as AR-V7 variant, which may allow for further patient stratification and future treatment allocation. In a study by Beltran and colleagues, the genomic and epigenomic signatures of histological classified adenocarcinoma and neuro-endocrine prostate cancer where evaluated. AR signaling activity was noted to be dramatically distinct between the two histologies giving some insight into the AR indifference seen in neuroendocrine tumors.
Additional studies have given insight into germline mutation in DNA repair gene are commonly seen in patient with mCRPC. This altered pathways were further evaluated by Pritchard and colleagues, who hoped to assess the incidence of this alterations in 16 DNA repair genes. The study showed that in average 11% of patients harbor a germline mutation in one or multiple of this DNA repair gene pathways. Interestingly germline alternations did not differ significantly according to age at diagnosis or family history of prostate cancer. There is now a movement of creating high risk prostate cancer clinics in which this germline mutations will be tested and followed with the hope they may provide some insight into patient stratification.
Although the several advancements have been made over the last year in regards to the genetic characterization of mCRPC, several questions remain such as the appropriate timing and frequency in which metastatic biopsies should be performed and genetic evaluation completed.
Speaker: Joshua M. Lang, MD, MS, University of Wisconsin Carbone Cancer Center
Written By: Andres F. Correa, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center
at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA