Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test

Abstract

Summary The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) differs from that of the primary tumor and is dynamic during tumor progression. The real-time and repeated characterization of this process via conventional solid tumor biopsies is challenging. Alternatively, circulating cell-free DNA (cfDNA) containing circulating tumor DNA (ctDNA) can be obtained from patient plasma using minimally disruptive blood draws and is amenable to sequential analysis. ctDNA has high overlap with the genomic sequences of biopsies from metastases and has the advantage of being representative of multiple metastases. The availability of techniques with high sensitivity and specificity, such as next-generation sequencing (NGS) and digital PCR, has greatly contributed to the development of the cfDNA field and enabled the detection of genomic alterations at low ctDNA fractions. In mCRPC, a number of clinically relevant genomic alterations have been tracked in ctDNA, including androgen receptor ( AR) aberrations, which have been shown to be associated with an adverse outcome to novel antiandrogen therapies, and alterations in homologous recombination repair (HRR) genes, which have been associated with a response to PARP inhibitors. Several clinical applications have been proposed for cfDNA analysis, including its use as a prognostic tool, as a predictive biomarker, to monitor tumor response and to identify novel mechanisms of resistance. To date, the cfDNA analysis has provided interesting results, but there is an urgent need for these findings to be confirmed in prospective clinical trials.

Multiplex Digital PCR to Detect Amplifications of Specific Androgen Receptor Loci in Cell-Free DNA for Prognosis of Metastatic Castration-Resistant Prostate Cancer

“…Circulating cell-free DNA (cfDNA) has become a promising tool in molecular oncology, allowing the detection of molecular alterations associated with cancer biology, treatment response [ 1 , 2 ] and overall survival (OS) [ 3 , 4 , 5 , 6 ]. However, cfDNA analysis is subject to relevant limitations [ 7 ]. There still remain technical challenges to analyze small amounts of highly fragmented (150–200 bp) and diluted (nanograms per 1 mL plasma) cfDNA fractions that are attributable to tumors (circulating tumor DNA-ctDNA) within cfDNA that are shed from cancer cells and which generally comprise 1–2% or less of cfDNA.…”

Advances in Prognostic Methylation Biomarkers for Prostate Cancer

“…Finally, we have discussed the advances in noninvasive DNA methylation prognostic biomarker research. Looking ahead, clinical translation of this research will be a priority as liquid biopsies offer a number of advantages over tissue-based methods, such as reducing side-effects like infection and surgical complications [ 17 , 18 ], and allowing serial collection of samples during the course of monitoring or therapy to provide opportunities for timely therapeutic interventions [ 177 ]. This should be paired with the utilisation of DNA methylation assays suitable for application in clinical settings (for example, Multiplex Bisulfite PCR Sequencing [ 178 , 179 ]) which are cost-effective, scalable, reproducible and capable of sensitively detecting methylated tumour DNA in limited clinical material such as liquid biopsies.…”

Advances in Prognostic Methylation Biomarkers for Prostate Cancer

“…Finally, we have discussed the advances in non-invasive DNA methylation prognostic biomarker research. Looking ahead, clinical translation of this research will be a priority as liquid biopsies offer a number of advantages over tissue-based methods, such as reducing side-effects like infection and surgical complications [17,18], and allowing serial collection of samples during the course of monitoring or therapy to provide opportunities for timely therapeutic interventions [176]. This should be paired with the utilisation of DNA methylation assays suitable for application in clinical settings (for example, Multiplex Bisulfite PCR Sequencing [177,178]) which are cost-effective, scalable, reproducible, and capable of sensitively detecting methylated tumour DNA in limited clinical material such as liquid biopsies.…”