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Page 6 of 9 Tyerman et al. J Cancer Metastasis Treat 2022;8:29 https://dx.doi.org/10.20517/2394-4722.2022.20

blood test can be added to routine blood work during pre- and postoperative visits.

As its detection may identify patients who are at higher risk for recurrence, ctDNA is a potential tool for
neoadjuvant, surgical, and adjuvant therapy decision making. In Lee et al.’s study, all 13 patients with
[32]
postoperatively detectable ctDNA had disease recurrence, despite all receiving adjuvant therapy ,
suggesting that current adjuvant therapy regimens may not be as beneficial in patients who are ctDNA+
postoperatively, as they may be at higher risk for recurrence. However, it is still unclear if clearance of
ctDNA during adjuvant therapy portends a better outcome. Persistent ctDNA detectability during adjuvant
therapy may indicate the need for an alternative therapy. In line with this, 83% of patients in this study with
detectable ctDNA at diagnosis had disease recurrence, despite 81% undergoing standard adjuvant
[32]
therapy , suggesting that preoperative ctDNA detection may be a factor in determining who may benefit
from neoadjuvant therapy, rather than proceeding directly to surgery.

Groot and colleagues demonstrated that patients who underwent neoadjuvant therapy were significantly
[34]
less likely to have ctDNA detected preoperatively (21% vs. 69% P < 0.001) . Notably, the five patients with
persistent ctDNA after neoadjuvant therapy had a particularly poor prognosis, with 100% recurrence and a
[34]
median RFS of five months; two of whom had an overall survival shorter than 12 months . Although this is
a small sample size, these results favor avoiding surgery or prolonging therapy in patients with persistent
ctDNA after neoadjuvant chemotherapy. Current prospective clinical trials are underway to better define
the utility and predictive value of ctDNA to monitor for treatment response in pancreatic cancer. For
example, Chawla and colleagues are assessing ctDNA detectability in a phase II prospective observational
trial in patients undergoing neoadjuvant chemotherapy for potentially resectable pancreatic cancer. The
study aims to determine if clearance of ctDNA during treatment correlates with traditionally accepted
treatment response criteria like serum CA 19-9, histologic regression grade, and histologic margin
assessment. (NCT04616131). Several other studies examining longitudinal changes in ctDNA levels in
response to treatment modalities are ongoing. Heyd and colleagues are conducting a 3-year longitudinal
study of ctDNA in patients with resectable and potentially resectable pancreatic cancer to determine its
utility in monitoring treatment response and predicting RFS. Serum samples are analyzed at diagnosis, after
neoadjuvant chemotherapy, preoperatively, at the time of surgery, 1 month postoperatively, and 1 month
after the last round of adjuvant chemotherapy (NCT02818907). In a similar study, Woo and colleagues aim
to generate a ctDNA gene panel and collect longitudinal serum samples to verify the applicability of
predictive serum-based biomarkers for pancreatic cancer. Their patient population includes patients with
both resectable and metastatic pancreatic cancers, from whom they are collecting serum samples every 1-3
months for 24 months (NCT04241367).

Though ctDNA currently shows promise as a prognostic indicator and a tool to measure treatment
response, it also has potential as a diagnostic biomarker and screening test, especially when used alongside
other serum biomarkers and imaging. CA 19-9 has a sensitivity of 58%-87% and a specificity of 70%-80%,
which is inadequate in diagnosing early-stage tumors [36-38] . Dabritz and colleagues found that a combination
of testing CA 19-9 levels and KRAS ctDNA led to a sensitivity of 91% in detecting pancreatic cancer .
[36]
Similarly, Wang et al. found that testing CA 19-9 in combination with ctDNA led to an increased sensitivity
of 82% with an 81% specificity in their study of 100 pancreatic cancer patients . ctDNA, as a screening test
[39]
for pancreatic cancer, may have further utility in high-risk individuals. In a current prospective trial,
patients with a strong family history of pancreatic cancer are evaluated with MRIs and plasma ctDNA
assessment every 6 months for 3 years to correlate biomarker changes with radiological abnormalities as
they arise on imaging (NCT03250078). Ongoing prospective studies evaluating ctDNA in pancreatic cancer
are summarized in Table 2.