Evolution of Clinical States and the Castration Resistant Clinical Paradigm

Abstract

Progressive disease burden in the face of castrate levels of testosterone defines the castration resistant disease state in prostate cancer. The mechanisms of disease progression into this state are numerous and include novel endocrine/paracrine androgen synthesis, androgen receptor mutations, amplification, and splice variants, and non-androgen axis oncogenic programs, all in the context of host and tumor microenvironment interactions. The clinical progression of castration resistant prostate cancer (CRPC) is currently classified according to a number of clinical phenotypes defined by the presence or absence of metastatic disease, exposure to prior therapies, symptoms, and patterns of spread. At each point of the evolution of clinical states in CRPC, patients must be evaluated based on previous lines and types of therapy and their potential susceptibility or resistance to further treatment options. A number of additional validated prognostic factors also define clinical states, and may assist in identifying men at high or low risk of rapid disease progression. These include performance status, anemia, elevated alkaline phosphatase, type of progression, Gleason sum at diagnosis, lactate dehydrogenase, circulating tumor cell burden, and histologic subtype. The current challenge facing clinical research is to define a molecular taxonomy that merges with the current clinical taxonomy that identifies men with CRPC most likely to benefit from specific systemic therapies and minimizes harms and costs.