Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer

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)

ctDNA: Circulating tumor DNA; cfDNA: Cell-free survival; CTC: Circulating tumor cell; DFS: Disease-free survival; ddPCR: Droplet digital polymerase chain reaction; HR: Hazard ratio; MAF: Mutant allele frequency; miRNA: microRNA; OS: Overall survival; PNA: Peptide nucleic acid; PCR: Polymerase chain reaction; PDAC: Pancreatic ductal adenocarcinoma; qRT-PCR: Quantitative reverse transcription polymerase chain reaction; RFS: Recurrence-free survival; SafeSeqS: Safe-sequencing system.