Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

Simple Summary Metastatic prostate cancer is traditionally treated with androgen deprivation therapy. The introduction of second-generation antiandrogens into clinical practice elicits prolonged responses but also gives rise to mechanisms of resistance that do not rely on androgens. The emergent phenotype of androgen-indifferent prostate cancer is associated with an aggressive, atypical clinical course. The term "aggressive variant prostate cancer" (AVPC) has been coined in order to separate this phenotype from hormone-responsive tumors. Unfortunately, morphology alone cannot reliably predict virulent behavior. The development of prognostic and predictive biomarkers is therefore crucial. In line with this, research has been focusing on unraveling the biological identity of AVPC. Drawing from the current knowledge about AVPC molecular pathogenesis and evolution, we attempt to identify candidate tissue-based AVPC biomarkers.Abstract Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice.