DNA repair deficiency as circulating biomarker in prostate cancer

Abstract

Deleterious aberrations in DNA repair genes are actionable in approximately 25% of metastatic castration-resistant prostate cancers (mCRPC) patients. Homology recombination repair (HRR) is the DNA damage repair (DDR) mechanism most frequently altered in prostate cancer; of note BRCA2 is the most frequently altered DDR gene in this tumor. Poly ADP-ribose polymerase inhibitors showed antitumor activity with a improvement in overall survival in mCRPC carrying somatic and/or germline alterations of HHR. Germline mutations are tested on peripheral blood samples using DNA extracted from peripheral blood leukocytes, while the somatic alterations are assessed by extracting DNA from a tumor tissue sample. However, each of these genetic tests have some limitations: the somatic tests are related to the sample availability and tumor heterogeneity, while the germline testing are mainly related to the inability to detect somatic HRR mutations. Therefore, the liquid biopsy, a non-invasive and easily repeatable test compared to tissue test, could identified somatic mutation detected on the circulating tumor DNA (ctDNA) extracted from a plasma. This approach should better represent the heterogeneity of the tumor compared to the primary biopsy and maybe helpful in monitoring the onset of potential mutations involved in treatment resistance. Furthermore, ctDNA may inform about timing and potential cooperation of multiple driver genes aberration guiding the treatment options in patients with mCRPC. However, the clinical use of ctDNA test in prostate cancer compared to blood and tissue testing are currently very limited. In this review, we summarize the current therapeutic indications in prostate cancer patients with DDR deficiency, the recommendation for germline and somatic-genomic testing in advanced PC and the advantages of the use liquid biopsy in clinical routine for mCRPC.

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

“…The use of liquid biopsy achieves 93% concordance between BRCA 1/2 mutations detected in tissue biopsy and those identified by ctDNA, 100% concordance for germline variants, and the detection of alterations in Tp53, RA, BRCA2/1, PI3K/AKT/mTOR, WNT/β-catenin pathway genes, RAS/RAF/MEK, and MSI-H is also possible [170]. In addition to their predictive value, ctDNA, PacBioScience, and Oxford Nanopore may have a predictive value for patients in active surveillance and salvage therapy; however, the cost and wide availability of genomic profiling tools continue to limit the development of this technology [171,172].…”

Mutational spectrum of DNA damage and mismatch repair genes in prostate cancer

“…Authors have recently reported a breakthrough in PCa treatment that uses the DDR gene mutation to target the tumor only while protecting healthy cells with intact DDR pathways. This discovery has led to numerous clinical trials that take advantage of these defects, and numerous PARP inhibitors, such as olaparib, rucaparib, niraparib, talazoparib, and veliparib, have been successfully tested in patients with a variety of DDR gene mutations, including BRCA1 , BRCA2 , ATR , ATM , CHEK1/2 , and PALB2 ( Catalano et al, 2023 ).…”

“…In recent years, the PCa treatment PARPi—poly (ADP-ribose) polymerase inhibitors—has been approved by the FDA ( Catalano et al, 2023 ). Patients with mutations in the DDR response genes BRCA2, ATM , and BRCA1 reported significantly greater response rates to olaparib than noncarriers in one of the earliest trials of PARPi in patients with advanced PCa ( Gurley and Kemp, 2001 ).…”

Cytokine and soluble programmed death-ligand 1 levels in serum and plasma of cancer patients treated with immunotherapy: Preanalytical and analytical considerations

“…However, robust evidence is still lacking to support the clinical utility of circulating cytokines and other soluble proteins measurements to predict immunotherapy response in the real world. 6 This uncertain scenario may not only reflect the complex biology of an inflammation signaling cascade, but also could be due—at least in part—to the unattained standardization of assay methods and inaccurate choice or preparation of biological samples.…”