Genomic analysis of circulating tumor DNA to predict endocrine resistance and clonal evolution in patients with prostate cancer: Clinical perspectives and research opportunities

Metastatic castration-resistant prostate cancer (mCRPC) is a multi-faceted disease and clinicians treating and managing the disease face several challenges. Progressive disease on androgen deprivation therapy (ADT) commonly occurs. With the approval of several survival-prolonging endocrine agents, the question of sequential treatment administration becomes increasingly important and new biomarkers beyond PSA should be identified to predict resistance and prognosis of mCRPC. A step forward has been made with the identification of splicing variants of androgen receptor (AR) associated with a resistance to ADT. The direct identification of AR mutants from patients’ serum, and the functional characterization of these mutants may provide personalized recommendations regarding the best future therapy. Genotyping circulating tumor DNA in blood samples can be used to identify the molecular profile of prostate cancer and to closely follow its evolution during therapy. This approach can also be used to detect minimal residual disease after surgery and to identify actionable therapeutic targets, and uncovering mechanisms of endocrine resistance ex-vivo. Importantly, by identifying mechanism of drug response by functional characterization of AR, novel compounds may be introduced in the treatment of mCRPC.