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Tyerman et al. J Cancer Metastasis Treat 2022;8:29 https://dx.doi.org/10.20517/2394-4722.2022.20 Page 3 of 9

OR early-stage OR early). This search generated 316 articles.

Titles and abstracts were screened by three authors, and all articles not pertaining to ctDNA in patients with
pancreatic cancer were excluded, as were reviews and meta-analyses. Disagreements between the first two
authors were decided by a third author. A full-text analysis of the remaining articles was then completed
with a focus on overall survival (OS) and disease-free survival. Articles with a study population containing
only unresectable or metastatic pancreatic cancer cases or a sample size of fewer than five patients were
excluded, as were retrospective studies. The study selection process resulted in the collection of four studies
meeting our eligibility criteria, including prospective nature and pancreatic cancer patients that had
undergone surgical resection [Figure 1].

RESULTS
ctDNA may be useful as a prognostic biomarker in patients with resectable pancreatic cancer. Baseline
and/or postoperative ctDNA has been associated with decreased OS and recurrence-free survival (RFS) in
several prospective studies, as summarized in Table 1.

In a prospective multi-institutional study, Lee et al. evaluated 81 pancreatic cancer patients undergoing
[32]
curative resection . Plasma was tested for ctDNA pre- and postoperatively. Preoperative ctDNA detection
(ctDNA positive disease [ctDNA+]) was associated with inferior RFS compared with ctDNA negative
(ctDNA-) patients who had undetectable ctDNA levels. (ctDNA+: 10.3 months vs. ctDNA-: median not
reached [NR]; HR 4.1; 95%CI: 1.8-9.0, P = 0.002]. OS was also significantly lower [OS 13.6 months vs. NR
(HR 4.1, 95%CI: 1.6-10.5; P = 0.015)]. Based on multivariate analysis adjusted for preoperative and
pathologic factors, preoperative detection of ctDNA had a statistically significant association with
recurrence (HR 4.1; 95%CI: 1.4-12.1; P = 0.018) and OS (HR 4.1; 95%CI: 1.0-16.6; P = 0.049).

After curative intent surgical resection, patients with persistent ctDNA detection postoperatively had a
shorter interval of recurrence compared to those who remained undetectable (5.4 vs. 17.1 months; HR 5.4,
CI 1.9-15.2; P < 0.001) and shorter OS (10.6 months vs. NR; HR 4.0, CI 1.2-13.6; P = 0.003). Of note, in the
13 patients who were ctDNA+ postoperatively, 100% had cancer recurrence during the median follow-up
period of 38.4 months from the time of diagnosis. In comparison, in the 22 patients who were ctDNA-
postoperatively, 10 (45%) had disease recurrence during the study period. Detectable ctDNA following
curative resection was independently associated with recurrence, with a 100% positive predictive value, with
a specificity and sensitivity of 100% and 57%, respectively. The authors concluded that postoperative ctDNA
detection has the best prognostic value in predicting recurrence compared with preoperative ctDNA and
[32]
other clinical and pathologic factors .

In a similar study, Pietrasz et al. found postoperative ctDNA detection was prognostic of OS and RFS . In
[33]
the subgroup of 31 patients who underwent curative intent resection for pancreatic cancer, patients with
detectable ctDNA postoperatively had a median OS of 19.3 months, compared to 32.3 months for patients
with undetectable ctDNA (P = 0.027). Similarly, ctDNA+ patients had an RFS of 4.6 months vs. 17.6 months
in ctDNA- patients. Of note, in the subgroup of patients who underwent resection, preoperative ctDNA
studies were not collected .
[33]

In a prospective study of 59 patients with resectable PDAC, Groot and colleagues collected preoperative and
[34]
longitudinal postoperative plasma samples for the detection of ctDNA . Subjects had a median follow-up
of 16 months from the time of surgical resection. Patients with detectable preoperative ctDNA had a
decreased median RFS and incidence of recurrence (8 months; 26 out of 29 [90%] recurred), compared with