Circulating Tumor DNA Testing for Homology Recombination Repair Genes in Prostate Cancer: From the Lab to the Clinic

Abstract

Approximately 23% of metastatic castration-resistant prostate cancers (mCRPC) harbor deleterious aberrations in DNA repair genes. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) therapy has shown improvements in overall survival in patients with mCRPC who harbor somatic and/or germline alterations of homology recombination repair (HRR) genes. Peripheral blood samples are typically used for the germline mutation analysis test using the DNA extracted from peripheral blood leucocytes. Somatic alterations can be assessed by extracting DNA from a tumor tissue sample or using circulating tumor DNA (ctDNA) extracted from a plasma sample. Each of these genetic tests has its own benefits and limitations. The main advantages compared to the tissue test are that liquid biopsy is a non-invasive and easily repeatable test with the value of better representing tumor heterogeneity than primary biopsy and of capturing changes and/or resistance mutations in the genetic tumor profile during disease progression. Furthermore, ctDNA can inform about mutation status and guide treatment options in patients with mCRPC. Clinical validation and test implementation into routine clinical practice are currently very limited. In this review, we discuss the state of the art of the ctDNA test in prostate cancer compared to blood and tissue testing. We also illustrate the ctDNA testing workflow, the available techniques for ctDNA extraction, sequencing, and analysis, describing advantages and limits of each techniques.

Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients

“…Recently, the analysis of ctDNA for alterations in homologous recombination (HR) repair genes in PCa has been reviewed [ 40 ]. However, the DDR comprises more repair genes and pathways.…”

Molecular Characterization of Prostate Cancers in the Precision Medicine Era

“…Several studies have also investigated the role of circulating tumor DNA (ctDNA) in metastatic PCa patients. The analysis of ctDNA represents an additional low invasive and easily repeatable approach useful to monitor tumor progression and able to provide information on tumor molecular status and prognosis, complementing clinical data [ 150 , 151 ]. Moreover, quantitative studies on the changes in tumor fraction in serial samples treated with PARP inhibitors and taxanes have been associated with patients’ outcome and treatment responses [ 152 ].…”

DNA repair deficiency as circulating biomarker in prostate cancer

“…Some authors have evaluated the false positive rate linked to specific ctDNA tests in healthy controls, recording a rate of 0.82% in unique short variants. These false positive results may derive from somatic non-tumor changes in genes derived from clonal hematopoiesis indeterminate potential (CHIP), including ASXL1, ATM, CBL, CHEK2, DNMT3A, JAK2, KMT2D, MLL2, MPL, MYD88, SF3B1, TET2, TP53 and U2AF1 (109)(110)(111)(112)(113). Despite tumor biopsy represents the reference tissue for the determination of MSI, clinically it has several limitations mainly related to the complexity of the procedure and to the spatial heterogeneity of the disease (114).…”