Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance

Okada, Tetsuhiro; Mizukami, Yusuke; Ono, Yoshio; Sato, Hiroki; Hayashi, Akira; Kawabata, Hidemasa; Koizumi, Kazuya; Masuda, Sakue; Teshima, Shin‐ichi; Takahashi, Kuniyuki; Katanuma, Akio; Omori, Yuko; Iwano, Hirotoshi; Yamada, Masataka; Yokochi, Tomoki; Asahara, Shingo; Kawakubo, Kazumichi; Kuwatani, Masaki; Sakamoto, Naoya; Enomoto, Katsuro; Goto, Takuma; Sasajima, Junpei; Fujiya, Mikihiro; Ueda, Junji; Matsumoto, Seiji; Taniue, Kenzui; Sugitani, Ayumu; Karasaki, Hidenori; Okumura, Toshikatsu

doi:10.1007/s00535-020-01724-5

Cited by 25 publications

(15 citation statements)

References 28 publications

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“…The UICC/AJCC TNM classification was given by an exact number of patients in each stage in 18 of the studies [ 23 , 25 , 28 , 30 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], while the UICC/AJCC TNM classification was not reported for a subgroup of patients for which the ctDNA was measured, but was instead given for a total number of patients included in the study in four studies [ 20 , 49 , 50 , 51 ]. In total, 42 studies measured the cfDNA in plasma [ 9 , 13 , 21 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 ...…”

Section: Resultsmentioning

confidence: 99%

“…In total, 42 studies measured the cfDNA in plasma [ 9 , 13 , 21 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ], three studies measured it from serum [ 37 , 47 , 67 ], two studies measured it from blood [ 20 , 22 ] and one study examined the cfDNA both in serum and plasma [ 23 ]. The time of the sampling was pre-treatment in 29 studies [ 9 , 13 , 23 , 24 , …”

Section: Resultsmentioning

confidence: 99%

“…The time of the sampling was pre-treatment in 29 studies [ 9 , 13 , 23 , 24 , 26 , 29 , 34 , 36 , 37 , 38 , 39 , 40 , 43 , 44 , 46 , 49 , 52 , 53 , 54 , 55 , 57 , 58 , 60 , 62 , 63 , 64 , 65 , 66 , 67 ], pre/post-treatment in 10 studies [ 25 , 27 , 28 , 30 , 35 , 41 , 42 , 45 , 47 , 59 ], post-treatment only in two studies [ 48 , 50 ], pre/post and during treatment in one study [ 22 ], and six studies did not report the time of sampling [ 20 , 21 , 31 , 51 , 56 , 61 ]. KRAS was explicitly measured in 41 studies [ 9 , 20 , 21 , 22 ,…”

Section: Resultsmentioning

confidence: 99%

“…The HR was than estimated using a calculator formulated by Tierney et al [ 19 ]. The number of patients at risk was extracted when available; if not, the numbers were calculated taking into account the total number of patients included in the survival analysis and selected time points accounting for the censored data [ 6 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. In addition, if the HR data were not available, but were presented in the individual-level data, the HR with corresponding 95% CI were calculated by IBM SPSS, version 25 [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

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Meta-Analysis of Circulating Cell-Free DNA’s Role in the Prognosis of Pancreatic Cancer

Milin-Lazović

Madzarevic

Rajović

et al. 2021

Cancers

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Introduction: The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. Material and Methods: We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients’ survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I2 statistic. Results: In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95–2.99 and HR = 2.46, 95% CI: 2.01–3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90–3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I2 = 87% and I2 = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I2 = 24% and I2 = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02–27.63). Conclusion: The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Meta-Analysis of Circulating Cell-Free DNA’s Role in the Prognosis of Pancreatic Cancer

Milin-Lazović

Madzarevic

Rajović

et al. 2021

Cancers

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“…Plasma ctDNA quantification of hot-spot mutations in KRAS and GNAS has also been reported to be useful in predicting tumor burden in patients diagnosed with PC. In addition to this, digital PCR (dPCR) provided accurate tumor-derived mutant KRAS detection in plasma in resectable PC and improved post-resection recurrence prediction compared to CA19-9[ 332 ].…”

Section: Serological Biomarkers Of Pcmentioning

confidence: 99%

Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket?

O’Neill

Stoita

2021

WJG

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Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).

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Current status of molecular diagnostic approaches using liquid biopsy

et al. 2023

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, and developing an efficient and reliable approach for its early-stage diagnosis is urgently needed. Precancerous lesions of PDAC, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN), arise through multiple steps of driver gene alterations in KRAS, TP53, CDKN2A, SMAD4, or GNAS. Hallmark mutations play a role in tumor initiation and progression, and their detection in bodily fluids is crucial for diagnosis. Recently, liquid biopsy has gained attention as an approach to complement pathological diagnosis, and in addition to mutation signatures in cell-free DNA, cell-free RNA, and extracellular vesicles have been investigated as potential diagnostic and prognostic markers. Integrating such molecular information to revise the diagnostic criteria for pancreatic cancer can enable a better understanding of the pathogenesis underlying inter-patient heterogeneity, such as sensitivity to chemotherapy and disease outcomes. This review discusses the current diagnostic approaches and clinical applications of genetic analysis in pancreatic cancer and diagnostic attempts by liquid biopsy and molecular analyses using pancreatic juice, duodenal fluid, and blood samples. Emerging knowledge in the rapidly advancing liquid biopsy field is promising for molecular profiling and diagnosing pancreatic diseases with significant diversity.

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Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance

Cited by 25 publications

References 28 publications

Meta-Analysis of Circulating Cell-Free DNA’s Role in the Prognosis of Pancreatic Cancer

Meta-Analysis of Circulating Cell-Free DNA’s Role in the Prognosis of Pancreatic Cancer

Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket?

Current status of molecular diagnostic approaches using liquid biopsy

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