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Page 2 of 9 Tyerman et al. J Cancer Metastasis Treat 2022;8:29 https://dx.doi.org/10.20517/2394-4722.2022.20

[1,2]
States, with a 5-year survival rate of approximately 10% . While surgical resection is the only curative
treatment for pancreatic cancer, up to 80% of diagnosed patients are not candidates for resection due to
[3]
aggressive spread and advanced-stage diagnosis . For the 20% who undergo curative resection, recurrence
[4]
occurs in up to 80% of cases , likely due to micro-metastatic disease present at the time of diagnosis .
[5,6]
Current methods for diagnosis, treatment planning, and surveillance of pancreatic cancer are insufficient.
The only serum biomarker recommended by the National Comprehensive Cancer Network guidelines is
serum carbohydrate antigen 19-9 (CA 19-9), which can be used as an adjunct to guide treatment plans for
patients, informing the diagnosis, resectability, response to therapy, recurrence, and overall prognosis of the
disease . However, testing CA 19-9 levels can result in false positives due to the presence of certain medical
[7]
[12]
conditions [8-11] , and false negatives in those who are Lewis genotype negative and do not express CA 19-9 .
More accurate biomarkers like circulating tumor DNA (ctDNA) could be valuable for recurrence risk
stratification, therapeutic decision making, and detecting and monitoring disease burden in pancreatic
cancer.

In 1946, Mandel and Metais described DNA in noncellular blood, which was referred to as cell-free DNA
(cfDNA) . Further studies demonstrated that patients with cancer had higher circulating levels of
[13]
cfDNA . In patients with cancer, DNA released from tumor cells, ctDNA, makes up a fraction of the
[14]
overall cfDNA. Detection of tumor-specific ctDNA is a highly specialized process [15,16] . There are two main
methods of ctDNA detection and quantification, digital droplet polymerase chain reaction (ddPCR), and
next-generation sequencing (NGS). ddPCR involves the detection of preselected genes (usually KRAS for
pancreatic cancer) in each sample. Compared to traditional PCR, a single sample is partitioned into tens of
thousands of nanoliter-sized droplets, allowing the measurement of thousands of independent amplification
[17]
events in a single sample . However, for multiple gene targets, the use of ddPCR can be cumbersome,
which is where NGS demonstrates its utility. With NGS, mutated gene sequences do not need to be
preselected. NGS platforms perform sequencing of millions of small fragments of DNA in parallel and
compare them against a human reference genome. This allows NGS to sequence entire exomes or genomes
and identify novel sequences at an extremely high resolution. However, because the sequencing is more
extensive, it is more time-consuming and expensive than ddPCR, especially for low numbers of desired gene
[18]
targets . Though ctDNA levels often parallel tumor burden within individual patients, variability has been
observed in patients with the same form of cancer, possibly reflecting individual tumor biology and rate of
cell turnover [19,20] . Unlike currently utilized serological biomarkers such as carcinoembryonic antigen (CEA)
and cancer antigen 125 (CA-125), ctDNA has a short half-life (approximately 1 h) [11,21] . Because of this,
ctDNA may be used to more accurately monitor the time-related response of an individual patient to
[22]
therapy . There is also potential for improved surveillance after treatment, where, in some studies,
increased ctDNA can precede radiographic disease progression by months [22-25] .

ctDNA has gained traction in gastrointestinal malignancies [26-28] ; however, its use in pancreatic cancer
remains investigational. Measuring ctDNA in pancreatic cancer has shown promise in monitoring locally
advanced and metastatic tumors [29-31] , but less is known about how ctDNA can inform the management of
localized, non-metastatic pancreatic cancer. This report reviews the literature on the prognostic value of
ctDNA in resectable pancreatic cancer and the potential value of assessment during treatment.

METHODS
A computerized search was completed up to July 2020 on PubMed with no date restrictions. The search
strategy included (pancreatic cancer OR PDAC OR pancreatic ductal adenocarcinoma) AND (cell-free
DNA OR cfDNA OR circulating tumor DNA OR ctDNA) AND (resect OR local OR surgical OR operative