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©The Author(s) 2022.
World J Gastroenterol. Dec 14, 2022; 28(46): 6478-6496
Published online Dec 14, 2022. doi: 10.3748/wjg.v28.i46.6478
Published online Dec 14, 2022. doi: 10.3748/wjg.v28.i46.6478
Table 1 Liquid biopsy in the early diagnosis of pancreatic cancer
Ref. | Journal | No. of patients | Biomarker | Method | Main findings |
Ankeny et al[76], 2016 | Br J Cancer | 72 | CTC | Microfluidic NanoVelcro CTC chip | Detection rate of PDAC: 54/72 (sensitivity = 75.0%, specificity = 96.4%) |
Rhim et al[77], 2014 | Gastroenterology | 51 | CTC | Microfluidic geometrically enhanced differential immunocapture | CTC (≥ 3) in 33% of patients with cystic lesions and no clinical diagnosis of cancer, 73% with PDAC, and 0% of controls |
Xu et al[78], 2017 | Int J Mol Sci | 40 | CTC | NE-iFISH | The positive rate of diagnosis of PDAC is nearly 97% in combination with CA19-9 |
Poruk et al[79], 2017 | Clin Cancer Res | 60 | CTC | ISET method & immunofluorescence | The positive rate is 12% in stageⅠPDAC |
Gao et al[80], 2016 | J Exp Clin Cancer Res | 25 | CTC | SE-iFISH platform | Sensitivity of 88 % and specificity of 90 % in PDAC |
Kulemann et al[81], 2015 | Pancreas | 11 | CTC | ScreenCell; Cyto kit | No difference in the rate of CTC detection between early-stage and advanced-stage diseases (P = 0.71) |
Melo et al[33], 2015 | Nature | 56 | Exosome | FACS analysis | The sensitivity and specificity of GPC1+ circulating exosomes in diagnosing PDAC were both 100% |
Buscail et al[82], 2019 | Cancers | 30 | Exosome and CTC | FACS, Cellsearch and RosetteSepTM | Combining quantification of GPC1-positive exosomes and CTC detection identified all the PDAC patients, showed a negative predictive value of 100%, and an overall diagnostic accuracy of 91% |
Lai et al[83], 2017 | Cancer Lett | 40 | Exosome and miRNA | LC-MS & RT-qPCR | High levels of exosomal miR-10b, miR-21, miR-30c, and miR-181a and low levels of miR-let7a differentiated PDAC from healthy and chronic pancreatitis samples |
Liang et al[84], 2017 | Nat Biomed Eng | 23 | EV | nPES assay | Pre-therapy EphA2-EV blood levels accurately distinguished stage I/II pancreatic cancer patients from NC (AUC = 0.96) and pancreatitis patients (AUC = 0.93) |
Que et al[85], 2013 | World J Surg Oncol | 49 | miRNA | RT-PCR | Serum exosomal miR-17-5p was higher in PDAC patients than in non–PDAC patients and healthy participants |
Cote et al[86], 2014 | Am J Gastroenterol | 215 | miRNA | RT-PCR | Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC |
Ouyang et al[87], 2015 | Oncogene | 42 | miRNA | RT-PCR | Plasma miR-10b levels significantly increased in comparison with normal controls |
Slater et al[88], 2014 | Transl Oncol | 59 | miRNA | Real-time PCR | A combination test of miRNA-196a and miRNA-196b, whose expression is upregulated from the PanIN state, can identify patients with PanIN 2/3 |
Madhavan et al[89], 2015 | Int J Cancer | 220 | Exosome and miRNA | miRNeasyMinikit, RT-PCR, qRT-PCR and flow cytometry | The selected miR-1246, miR-4644, miR-3976 and miR-4306 were significantly upregulated in 83% of PDAC serum-exosomes, but rarely in control groups |
Table 2 Liquid biopsy in the predicting prognosis of pancreatic cancer
Ref. | Journal | year | No. of patients | Biomarker | Method | Main findings |
Singh et al[91], 2015 | Cancer Invest | 2015 | cfDNA | Higher level of plasma DNA (> 62 ng/mL) was found to associate significantly with lower overall survival time (P = 0.002), presence of vascular encasement (P = 0.030) and metastasis (P = 0.001) | ||
Lapin et al[92], 2018 | J Transl Med | 2018 | 61 | cfDNA | 2100 Bioanalyzer | Pre-treatment cfDNA levels could independently predict prognosis for both PFS (HR = 3.049, P = 0.005) and OS (HR = 2.236, P = 0.028) |
Wang et al[93], 2021 | Pancreas | 2021 | 97 | cfDNA | PCR | The 1- and 5-year survivals for those with high cfDNA were poorer; 70.2% and 21.2%, respectively, as compared with 93.4% and 23.7% for those with low cfDNA level |
Castells et al[94], 1999 | J Clin Oncol | 1999 | 47 | ctDNA | PCR-RFLP and SSCP | Plasma KRAS mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95%CI: 1.02 to 2.23) |
Ako et al[95], 2017 | Pancreatology | 2017 | 40 | ctDNA | ddPCR | KRAS mutation at G12V in the plasma or serum conferred a significantly poorer prognosis than without the mutation (P < 0.01) |
Hadano et al[96], 2016 | Br J Cancer | 2016 | 105 | ctDNA | ddPCR | Patients who were preoperative ctDNA+ had a significantly poorer prognosis with respect to OS (P < 0.0001) |
Nakano et al[97], 2018 | Br J Cancer | 2018 | 45 | ctDNA | PNA directed, PCR clamping | There were no significant differences in DFS and OS between patients with and without KRAS mutations from preoperative serum |
Watanabe et al[98], 2019 | PLoS One | 2019 | 78 | ctDNA | ddPCR | No effect of the presence of KRAS-mutated ctDNA before surgery on RFS (median: 16.9 mo vs 32.4 mo) was observed |
Bernard et al[99], 2019 | Gastroenterology | 2019 | 34 | ctDNA and exosome DNA | ddPCR | Increased exosome DNA levels after neoadjuvant therapy were significantly associated with disease progression (P = 0.003) |
Kinugasa et al[100], 2015 | Cancer | 2015 | 75 | ctDNA | ddPCR | KRAS mutations in plasma correlated with poor OS (P = 0.002) |
Tjensvoll et al[101], 2016 | Mol Oncol | 2016 | 14 | ctDNA | PNA clamp PCR | Kaplan-Meier survival analyses indicated that patients with a positive ctDNA before or after initiation of chemotherapy had shorter PFS and OS |
Chen et al[102], 2010 | Eur J Surg Oncol | 2010 | 91 | ctDNA | Direct sequencing | KRAS codon 12 mutation from plasma DNA was an independent negative prognostic factor (HR, 7.39; 95%CI: 3.69-14.89) |
Sausen et al[103], 2015 | Nat Commun | 2015 | 101 | ctDNA | Next-generation sequencing and digital PCR | ctDNA was an independent prognostic marker of OS in advanced disease, with OS of 6.5 mo vs 19.0 mo for ctDNA-positive and negative patients, respectively |
Khoja et al[105], 2012 | Br J Cancer | 2012 | 54 | CTC | Cellsearch and ISET | The PFS and OS for patients without vs those with CTCswas 140 d vs 94 d (P = 0.13) and 164 d vs 127 d (P = 0.26), respectively |
Earl et al[106], 2015 | BMC Cancer | 2015 | 45 | CTC | Cellsearch | A Cox regression analysis showed a significant difference in OS for CTC positive vs negative patients with a HR of 3.0 (P = 0.023) |
Zhang et al[107], 2015 | Int J Cancer | 2015 | 61 | CTC | The EpCAM-independent method | CTCs positive pancreatic cancer patients exhibit a worse (P = 0.0458) survival rate |
Okubo et al[108], 2017 | Eur J Surg Oncol | 2017 | 65 | CTC | Cellsearch | A multivariate analysis identified the presence or absence of CTCs as an independent prognostic factor (P = 0.049) |
Ankeny et al[76], 2016 | Br J Cancer | 2016 | 100 | CTC | Microfluidic NanoVelcro CTC chip | A cut-off of 3 CTCs in 4 mL venous blood was able to discriminate between local/regional and metastatic disease (AUROC = 0.885; 95%CI: 0.800-0.969; and P < 0.001) |
Chang et al[109], 2016 | Clin Chem | 2016 | 63 | CTM | anti-EpCAM conjugated supported lipid bilayer-coated microfluidic chips | CTM was an independent prognostic factor of OS and PFS (P 0.0001 and P = 0.003, respectively) |
Bidard et al[110], 2013 | Ann Oncol | 2013 | 79 | CTC | Cellsearch | CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter OS in multivariable analysis (P = 0.01) |
Kurihara et al[111], 2008 | J Hepatobiliary Pancreat Surg | 2008 | 47 | CTC | Cellsearch | MST of the CTC-positive and -negative patients were 110.5 and 375.8 d (P < 0.001) |
de Albuquerque et al[112], 2008 | Oncology | 2012 | 74 | CTC | Median PFS time was 66.0 d for patients with baseline CTC positivity and 138.0 days for CTC-negative patients (P = 0.01) | |
Kulemann et al[81], 2015 | Pancreas | 2015 | 21 | CTC | ScreenCell | The presence of CTC did not adversely affect MST: 16 mo in CTC-positive (n = 18) vs 10 mo in CTC-negative (n = 3) patients |
Li et al[116], 2018 | Cell Physiol Biochem | 2018 | 73 | miRNA | Arraystar Human miRCURYTM LNA Array | Multivariate analyses showed that exosomal miR-222 was independent risk factors for PDAC survival (P = 0.046) |
Wang et al[117], 2018 | Cancer Res | 2018 | 50 | miRNA | qRT-PCR | Exosomal miR-301a-3p overexpression predicted late TNM stage and poor survival in human PDAC (P = 0.0182) |
Frampton et al[118], 2018 | Oncotarget | 2018 | 43 | GPC1+ circulating exosomes | ELISA | Patients with high crExos GPC1 levels have significantly larger PDACs (> 4 cm; P = 0.012) |
Costa-Silva et al[119], 2015 | Nat Cell Biol | 2015 | 55 | Exosome | ELISA | Increased levels of MIF in exosomes isolated from patients with PDAC with progression of disease post-diagnosis compared with PDAC patients with no evidence of disease five years post-diagnosis (P < 0.01) and with healthy controls (P < 0.01), but not patients with liver metastasis |
Table 3 Liquid biopsy in recurrence monitoring of pancreatic cancer
Ref. | Journal | No. of patients | Biomarker | Method | Main findings |
Nakano et al[97], 2018 | Br J Cancer | 45 | ctDNA | PNA-directed PCR clamping | Multivariate analysis revealed that KRAS mutations in postoperative serum are an independent prognostic factor for DFS (P = 0.027). Furthermore, the change from not detecting mutant KRAS in preoperative to mutant KRAS in postoperative cfDNA was an independent prognostic factor for OS (P = 0.004) |
Hussung et al[120], 2021 | BMC Cancer | 25 | ctDNA | ddPCR, PCR | An increased KRAS mutated ctDNA during adjuvant chemotherapy and follow-up was a highly predictive dynamic marker of early relapse and poor OS |
Watanabe et al[98], 2019 | PLoS One | 78 | ctDNA | ddPCR | Detection of mutant KRAS on postoperative ctDNA was associated with OS regardless of recurrence (P = 0.005) |
Groot et al[121], 2019 | Clin Cancer Res | 59 | ctDNA | ddPCR | ctDNA detected during follow-up predicted clinical recurrence (sensitivity 90%, specificity 88%) with a median lead time of 84 d |
Sausen et al[103], 2015 | Nat Commun | 20 (surgery group) | ctDNA | Next-generation sequencing and digital PCR | Patients with detectable ctDNA after surgical resection (n = 10) were more likely to relapse and die from disease compared with those with undetectable ctDNA (P = 0.0199) |
Jiang et al[122], 2020 | Front Oncol | 27 | ctDNA | Next-generation sequencing | Patients with ctDNA-positive status postoperatively had a markedly reduced DFS compared to those with ctDNA-negative status (P = 0.019) |
Kim et al[123], 2018 | Clin Chem | 106 | ctDNA | ddPCR | Patients who had increased KRAS MAF values at 6 mo had a shorter OS (P = 0.036) than those who had decreased values |
Yamaguchi et al[124], 2021 | Ann Surg Oncol | 97 | ctDNA | ddPCR | The multivariate analysis showed that the presence of preoperative ctDNA was associated with poorer OS (P = 0.008) and that postoperative ctDNA was not associated with either RFS or OS |
Guo et al[125], 2020 | Br J Cancer | 113 and 44 (discovery and validation cohorts) | ctDNA | ddPCR | Survival analysis showed that plasma KRAS mutations, especially KRAS G12D mutation, had significant association with OS and RFS of resectable PDAC. Plasma KRAS G12D mutation showed a strong correlation with early distant metastasis |
Lee et al[126], 2019 | Ann Oncol | 42 | ctDNA | PCR-based-SafeSeqS assays | Preoperative ctDNA detection was associated with inferior RFS (P = 0.002) and OS (P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (P < 0.0001) and OS (P = 0.003) |
Pietrasz et al[127], 2017 | Clin Cancer Res | 31 | ctDNA | Next-generation sequencing | The presence of ctDNA was associated with a shorter DFS (4.6 mo vs 17.6 mo; P = 0.03) and shorter OS (19.3 mo vs.32.2 mo; P = 0.027) |
Okada et al[128], 2020 | J Gastroenterol | 66 (surgery group) | ctDNA | Digital PCR | Patients with preoperative ctDNA MAF > 0.45% exhibited significantly shorter disease-free survival than those with lower MAF (HR 3.179, 95%CI: 1.025-9.859; P = 0.0452) |
Park et al[129], 2021 | Sci Rep | 40 | CTC | CD-PRIM kit | On multivariable logistic regression analysis, CTC positivity was an independent risk factor for early recurrence (P = 0.027) and systemic recurrence (P = 0.033) |
Allenson et al[130], 2017 | Ann Oncol | 142 and 121 (discovery and validation cohort) | Exosome and ctDNA | Electron microscopy, flow cytometry and particle analysis and ddPCR | Higher exosome KRAS MAFs were associated with decreased disease-free survival in patients with localized disease (P = 0.031) |
Takahasi et al[131], 2018 | J Hepatobiliary Pancreat Sci | 50 | miRNA | qRT-PCR | In cox proportional hazards model analysis, exosomal miR-451a showed significance to OS and DFS (P = 0.001, P = 0.004) |
Kawamura et al[132], 2019 | J Hepatobiliary Pancreat Sci | 55 | miRNA | qRT-PCR | miR-4525, miR-451a, and miR-21 from portal vein can be utilized for the evaluation of pancreatic cancer recurrence (P = 0.002, 0.001 and 0.002, respectively) |
Table 4 Liquid biopsy in the therapeutic effect monitoring of pancreatic cancer
Ref. | Journal | No. of patients | Biomarker | Method | Main findings |
Del Re et al[133], 2017 | Sci Rep | 27 | ctDNA | ddPCR | There was a statistically significant difference in PFS and OS in patients with increase vs stability/reduction of ctDNA in the sample collected at day 15 (P = 0.03 and P = 0.009, respectively) |
Kruger et al[134], 2018 | Ann Oncol | 54 | ctDNA | BEAMing | An increase in ctDNA at day 14 correlated with disease progression on subsequent imaging with a sensitivity of 83% and specificity of 100% |
Watanabe et al[98], 2019 | PLoS One | 39 | ctDNA | ddPCR | The emergence of KRAS ctDNA in longitudinal tests was associated with prognosis (P < 0.005) |
Wei et al[135], 2019 | Cancer Lett | 13 (chemotherapy group) | CTC | Vimentin or EpCAM immobilized microfluidic chip | In patients exhibiting a response, their CTC counts decreased or remained the same, except for one case |
Okubo et al[108], 2017 | Eur J Surg Oncol | 65 | CTC | Cellsearch | The overall survival rate was significantly lower in patients with than in those without CTCs even after chemotherapy and chemoradiotherapy (P = 0.045) |
Xu et al[78], 2017 | Int J Mol Sci | 83 | CTC | NE-iFISH | The proportion of triploid CTC detected by the NE-iFISH was significantly decreased after chemotherapy (P < 0.001) |
Tian et al[136], 2016 | Oncol Lett | 17 | microRNA | RT-qPCR | Significant upregulation of serum miRNAs (miR-21, miR-210, miR-221 and miR-7), at earlier time points (3-6 wk) was observed in non-responders of chemotherapy compared to responders |
Bernard et al[99], 2019 | Gastroenterology | 104 (chemotherapy group) | exosome and ctDNA | ddPCR | In the longitudinal analysis in chemotherapy group, a MAF peak above 1% in exosome DNA was significantly associated with radiologic progression (P = 0.0003) |
An et al[137], 2017 | J Proteome Res | 10 | exosome | iTRAQ | They analyzed exosomes before treatment, after one cycle of induction gemcitabine-based chemotherapy, and at 3 wk after starting chemoradiation therapy and compared these samples to serum derived from healthy volunteers. They identified eight proteins that changed during a course of therapy in all patients |
Liang et al[84], 2017 | Nat Biomed Eng | 23 (neoadjuvant chemotherapy group) | EV | nPES | EphA2-EVs were also informative in detecting early responses to neoadjuvant therapy (P < 0.05) |
Yin et al[138], 2021 | Clin Cancer Res | 36 | somatic mutations, CTCs, and ctDNA | Next-generation sequencing & ISET | Somatic mutations, CTCs, and ctDNA existed even in patients with PDAC with pathologic complete response to NAT, which could possibly predict early recurrence and reduced survival |
Poruk et al[140], 2016 | Ann Surg | 50 | CTC | ISET | The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01) |
Gemenetzis et al[139], 2018 | Ann Surg | 57 | CTC | ISET | Patients who received neoadjuvant chemotherapy had significantly lower total CTCs (tCTCs, P = 0.007), eCTCs (P = 0.007), and mCTCs (P = 0.034), compared with untreated patients eligible for upfront resection |
- Citation: Watanabe F, Suzuki K, Noda H, Rikiyama T. Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer. World J Gastroenterol 2022; 28(46): 6478-6496
- URL: https://www.wjgnet.com/1007-9327/full/v28/i46/6478.htm
- DOI: https://dx.doi.org/10.3748/wjg.v28.i46.6478