Plasma Androgen Receptor in Prostate Cancer

Abstract

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as ¹⁷⁷Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.

Keywords: androgen receptor; biomarkers; plasma DNA; prostate cancer.

Figure 1

The role of biomarker tools and plasma AR status in different clinical states of prostate cancer. A clinical states framework for clinical practice, clinical research, and biomarker tools in prostate cancer with a graphical representation of tumor burden, plasma DNA levels, clonal heterogeneity, and utility of plasma AR status over time and in response to therapy. Abbreviations: ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castration-resistant prostate cancer; ctDNA, circulating tumor DNA; HSPC, hormone-sensitive prostate cancer; RT, radiotherapy.

Figure 2

Biology of circulating free DNA. Circulating free DNA (plasma DNA) is released from the cells of healthy, inflamed, or tumor tissue undergoing apoptosis or necrosis, or, more rarely, from living cancer cells that actively release DNA into the circulation because of oncogenic properties. Certainly, levels of plasma DNA are also under the control of the activity of infiltrating phagocytes that usually clear apoptotic and necrotic debris and pro-apoptotic cytokines released by inflammatory cells (e.g., lymphocytes) or cancer cells. Circulating DNA may also be released by CTCs shed by the tumor and by DTC into bone marrow. The analysis of plasma DNA, together with other circulating nucleic acids in the bloodstream, such as miRNA and exosomes, has led to the identification of several genetic and epigenetic alterations of tumor, including circulating aberrations of androgen receptor such as copy number variation, mutations and splice variants. Abbreviations: AR, androgen receptor; BPH, benign prostatic hyperplasia; ctDNA, circulating tumor DNA; CTC, circulating tumor cell; DTC, disseminated tumor cell; miRNA, microRNA; PC, prostate cancer; PIN: prostatic intraepithelial neoplasia.