A Biological Framework for the Development of Therapy in Prostate Cancer

Abstract

Because of the inherent heterogeneous nature of clinically evident prostate cancer and its long and unpredictable natural history, the potential benefits of therapy are obscured. Traditionally, the therapy decision has been based on the clinically determined anatomic stage of the disease. When truly confined to the prostate, the disease can be eradicated by local therapeutic modalities. Unfortunately, clinical staging — derived from available diagnostic tools such as prostate-specific antigen (PSA), transrectal ultrasonograpy (TRUS), and TRUS-guided biopsies — does not correlate well with pathological staging. Androgen ablation, the standard therapy for metastatic disease, is limited in its efficacy. Although approximately 85% of patients achieve tumor response, the vast majority of these relapse, with a median time to progression of 12 to 18 months, and such patients have a median survival of 3 years. This fatal progression of prostate cancer occurs coincident with androgen-independent growth of the tumor. Until recently, nonhormonal therapeutic approaches have been applied during this androgen-independent progression, when the salutary effect from the therapy is often minimal. The increasing understanding of the sequential and concurrent cellular and molecular events that occur during the development and progression of prostate cancer necessitates, a new clinico- biological classification based on tumor-specific biology, one that will classify patients into relevant clinical categories for development of target-based therapies.