Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review

Abstract

Context: Multiple studies have reported on the genomic characteristics of metastatic hormone-sensitive prostate cancer (mHSPC). The impact of these findings on prognostication, treatment selection, and clinical trial design remains unclear.

Objective: To summarise genomic alteration prevalences in liquid and/or tissue biopsies, infer their clinical implications, and compare genomic alteration frequencies across different disease states and clinical phenotypes.

Evidence acquisition: The PubMed and Web of Knowledge databases were systematically searched up to January 2021. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal tools.

Evidence synthesis: In total, 11 studies encompassing 1682 mHSPC patients were included. High-volume disease was associated with more frequent alterations in TP53, DNA damage repair, and Wnt pathways. Tumours from patients with de novo mHSPC were enriched for alterations in TP53 and CDK12 compared with recurrent disease. Alterations in AR, TP53, cell cycle signalling, and MYC were associated with a poorer clinical outcome. A comparative analysis of gene alteration frequencies across disease states revealed a relative increase from localised to castration-resistant tumours, with noteworthy enrichment of CTNNB1 alterations in mHSPC (5%), which warrants further investigation. This study was limited by variability in methodology and definitions used among the eligible studies, including differences in sequencing methods, analytes (being either tissue or liquid), alteration calling thresholds, and target patient populations with a relative under-representation of recurrent metastatic disease.

Conclusions: Several genomic alterations are associated with differential prognosis and clinical phenotypes in mHSPC. We urge that emerging data on these potential predictive biomarkers must be validated in biomarker-driven randomised controlled trials before any clinical implementation. Alignment of the assay methodology and reporting will be critical for ensuring rapid scalability.

Patient summary: We reviewed current data on genomic alterations of metastatic hormone-sensitive prostate cancer, and summarised key genomic subtypes that associate with specific clinical phenotypes and treatment outcomes.

Keywords: Circulating tumour DNA; Genomics; Hormone sensitive; Liquid biopsy; Metastatic prostate cancer; Precision oncology; Sequencing; Tissue biopsy.