Towards clinical implementation of circulating tumor DNA in metastatic prostate cancer: Opportunities for integration and pitfalls to interpretation

Abstract

Plasma circulating tumor DNA (ctDNA) represents short fragments of tumor-derived DNA released into the bloodstream primarily from cancer cells undergoing apoptosis. In metastatic castration-resistant prostate cancer (mCRPC), characterizing genomic alterations in ctDNA identifies mutations, copy number alterations, and structural rearrangements with predictive and prognostic biomarker utility. These associations with clinical outcomes have resulted in ctDNA increasingly incorporated into routine clinical care. In this review, we summarize current and emerging applications for ctDNA analysis in metastatic prostate cancer, including outcome prediction, treatment selection, and characterization of treatment resistance. We also discuss potential pitfalls with interpreting ctDNA findings, namely false negatives arising from low tumor content and optimal assay design, including correction for clonal hematopoiesis of indeterminate potential and germline variants. Understanding the influence of these limitations on interpretation of ctDNA results is necessary to overcome barriers to clinical implementation. Nevertheless, as assay availability and technology continue to improve, recognizing both opportunities and shortcomings of ctDNA analysis will retain relevance with informing the implementation of precision-oncology initiatives for metastatic prostate cancer.

Genome-wide studies in prostate cancer poised liquid biopsy as a molecular discovery tool

“…ctDNA monitoring is currently in transition towards potential clinical implementation. ctDNA percent levels do not necessarily reflect the same tumour characteristics as current evaluation methods, which as previously mentioned, can provide more information alongside current popular markers ( 60 ). For AR-directed therapy regimens, the changes in monitored ctDNA levels may act as indicators for early cancer progression, thus warranting therapy alterations ( 61 , 62 ).…”

The Current State and Future of Plasma Cell-Free DNA Analysis in Urologic Malignancies

“…3). However, the detection of copy number loss is difficult unless the ctDNA fraction is high (at least 20%) [17]. For example, in normal cells, there are 2 copies of PTEN, a gene often lost in prostate cancer.…”

Perspective Chapter: Clinical Application of Exosome Components

“…Circulating tumor DNA (ctDNA) fragments are released by tumor cells into the bloodstream. The information on genomic alterations identified in tumors, including point mutations, rearrangements, amplifications, and even gene copy variations, could be identified by analyzing ctDNA molecules [119]. Although cancer detection by monitoring ctDNA is an area of active investigation, identifying very low amounts of ctDNA in blood samples with variable amounts of free DNA (cfDNA) remains challenging.…”