Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer

Table 2 Diagnostic and prognostic outcomes methods of studies investigating circulating tumor ribonucleic acid in prostate cancer by liquid biopsy

Ref.	Methods and patients	Prognostic or predictive outcomes
Joncas et al[48], 2019	Plasma dPCR, AR-7 mRNA, PCa patients (n = 35)	AR-V7 mRNA expression was associated with shorter time to progression (median, 16.0 vs 28.0 mo; P = 0.0499)
Mohammadi Torbati et al[49], 2019	Serum qPCR, miR-20A, miR-26A, PCa patients (n = 40), healthy controls (n = 40)	In PCa samples miR-20A was significantly upregulated compared to healthy controls. On the other hand, there was no significant difference in the levels of pre- and post-operation miR-26A compared to controls
Ishiba et al[50], 2018	Plasma dPCR, PDL-1 mRNA, PCa patients (n = 88)	PD-L1 mRNA was detected and quantified in ctRNA of cancer patients. Interestingly, there was a comparison between expression of PD-L1 protein in tumor tissues and PD-L1 gene expression in plasma of cancer patients
Wang et al[51], 2018	Plasma qPCR, SAP30L-AS1 and SChLAP1 lncRNAs, PCa patients (n = 34), BPH patients (n = 46), Healthy controls (n = 30)	SAP30L-AS1 lncRNAs levels were upregulated in BPH and SChLAP1 lncRNAs levels were significantly higher in PCa than in BPH and healthy controls. The area under the ROC curve indicated that SAP30L-AS1 and SChLAP1 lncRNA had an adequate diagnostic value different from PCa and controls
Zedan et al[52], 2018	Plasma qPCR, miR-93, miR-221, miR-125b, miR-93, PCa patients (n = 149)	Significantly lower levels of miRNA-93 and miRNA-221 in the follow-up of patients vs baseline z = −2.738, P = 0.006, and z = −4.498, P < 0.001, respectively. Similarly, miRNA-125b was significantly lower in the observational cohort (z = −2.656, P = 0.008). There was a correlation between both miRNA-125b and miRNA-221 with risk assessment r = 0.23, P = 0.015 and r = 0.203, P = 0.016, respectively. However, miRNA-93 was significantly correlated with prostatectomy Gleason score (r = 0.276, P = 0.0576)
Farran et al[53], 2018	Plasma qPCR, miRNA signature, PCa patients (n = 114)	Aggressiveness of PCa could be segregated based on circulating miRNA signature consisting of an interaction between a combination of two miRNAs (miR-17/miR-192) and an independent miRNA (miR-181a)
Liu et al[54], 2018	Plasma qPCR, miR-223, miR-24, miR-375, PCa patients (n = 329)	Patients could be significantly reclassified using a 3-miR (miRNA-223, miRNA-24 and miRNA-375) score (training OR 2.72, 95%CI 1.50e 4.94 and validation OR 3.70, 95%CI 1.29e 10.6)
Adalsteinsson et al[37], 2017	Plasma WES, Metastatic PCa patients (n = 520)	There is a concordance between clonal somatic mutations (88%), copy number alterations (80%), mutational signatures and neoantigens between tumor biopsies and cfDNA form 41 patients with ≥ 10% cfDNA
Albitar et al[55], 2017	Urine and plasma qPCR, mRNAs panel, PCa patients (n = 306)	The urine/plasma biomarker test, evaluating the mRNA levels of PCa-specific gene such as PDLIM5, HSPD1, PSA, IMPDH2, PCA3,TMPRSS2, ERG, UAP1, PTEN, AR, the housekeeping B2M and GAPDH genes, accurately predicted high-grade cancer with sensitivity at 92%-97%, while core-biopsy sensitivity was 78%
Endzeliņš et al[56], 2017	Plasma qPCR, miR-375, miR-200-3p, miR-21-5p, miRNA Let-7a-5p, PCa patients (n = 50), BPH patients (n = 22)	miR-375 could be used to differentiate between PCa and BPH patients when analyzed in whole plasma, while miR-200-3p and miR-21-5p performed better in EVs. Let-7a-5p could be used to differentiate PCa patients, with Gleason score ≥ 8 vs ≤ 6
McDonald et al[57], 2017	Plasma qPCR, miRNA panel, PCa patients (n = 134)	miR-381, miR-34a, miR-523, miR-365, miR-122, miR-375, miR-1255b, miR-34b, miR-450b-5p, and miR-639 were the most statistically significant miRNA after adjusting for age (P values ≤ 0.05)
Alhasan et al[58], 2016	Plasma Scano-miR, miRNA panel, very high risk, PCa patients (n = 9), Low risk, PCa patients (n = 9), and healthy controls (n = 10)	miR-200c, miR-605, miR-135a, miR-433, and miR-106a were identified as useful for differentiating indolent and aggressive forms of PCa
Yan et al[59], 2015	Urinary qPCR, TSPAN13 and S100A9 mRNAs, PCa patients (n = 129), BPH patients (n = 105)	qPCR was used to measure urinary nucleic acid levels and tissue mRNA expression. The TSPAN13 and S100A9 mRNA ratio was selected to determine the diagnostic value of urinary nucleic acids in PCa (P = 0.037). It was significantly higher in PCA than in BPH in the mRNA and nucleic acid cohort analyses (P < 0.001 and P = 0.013, respectively). ROC analysis showed that the area under the ROC curve was 0.898 and 0.676 in tissue mRNA cohort and urinary nucleic acid cohort, respectively. This ratio could have a strong potential as a diagnostic PCa marker
Antonarakis et al[60], 2014	Serum qPCR, AR-V7 mRNA, PCa enzalutamide-treated patients (n = 31), PCa abiraterone-treated patients (n = 31)	AR-V7 mRNA detectable (positive) patients receiving enzalutamide had lower PSA response rates compared to AR-V7 mRNA not detectable (negative) patients (0% vs 53%, P = 0.004) and shorter PSA PFS (median, 1.4 mo vs 6.0 mo; P < 0.001), clinical or radiological PFS (median, 2.1 mo vs 6.1 mo; P < 0.001), and OS (median, 5.5 mo vs not reached; P = 0.002). Similarly, AR-V7 mRNA positive patients, receiving abiraterone had lower PSA response rates compared to AR-V7 mRNA negative patients (0% vs 68%, P = 0.004) and shorter PSA PFS (median, 1.3 mo vs not reached; P < 0.001), clinical or radiological PFS (median, 2.3 mo vs not reached; P < 0.001), and OS (median, 10.6 mo vs not reached, P = 0.006)
Korzeniewski et al[61], 2014	Urine qPCR, miR-483-5p, PCa patients (n = 71), healthy controls (n = 18)	miR-483-5p was expressed at higher levels in PCa than in control
Deligezer et al[42], 2010	Plasma qPCR, cBMP6 mRNA, Local PCa patients (n = 22), local advanced PCa patients (n = 11) or mCRPC patients (n = 28)	The levels of cBMP6 mRNA in patients with metastatic disease were higher than those in patients with localized disease (P = 0.001) or in patients with local advanced disease (P = 0.05)
Papadopoulou et al[62], 2006	PBMC and plasma qPCR, PSMA mRNA, newly diagnosed PCa patients (n = 12), under therapy PCa patients (n = 4)	Among the newly diagnosed patients 4/12 (33.3%) had positive mRNA for PSMA in plasma, whereas only 2/12 (16.7%) had positive PSMA mRNA in PBMC. Among under therapy PCa patients, three (15.8%) were positive for PSMA mRNA in plasma, while only one (5.3%) was positive in PBMC. Furthermore, > 60% of PCa had elevated levels of cfDNA

AR: Androgen receptor; AR-V7: Androgen-receptor splice variant 7; BPH: Benign prostatic hyperplasia; cfDNA: Cell free DNA; dPCR: Digital polymerase chain reaction; lncRNAs: Exosomal circulating long non-coding RNAs; mCRPC: Metastatic castrate-resistant prostate cancer; PSA: Prostate specific antigen; WES: Whole exome sequencing; PFS: Progression-free survival; OS: Overall survival; PBMC: Peripheral blood mononuclear cells; PCa: Prostate cancer; qPCR: Quantitative polymerase chain reaction; lncRNA: long non-coding RNA; PSMA: Prostate specific membrane antigen; BMP-6: Bone morphogenetic protein-6.