Introduction
Being already the third leading cause for cancer-related death in Europe and fourth leading in the world, pancreatic cancer remains one of the most challenging malignancies to treat, facing mere 5‑year survival rates of less than 32% (Ia) to 0.5% (IV) depending on the tumor stage [1, 2]. Although surgical removal is regarded the only curative approach, median overall survival from dissemination on does not exceed 1 year and 80% of patients will experience relapse within 2 years [1, 3]. The management of resectable pancreatic cancer, particularly the decision between upfront surgery versus neoadjuvant chemotherapy, is pivotal and can significantly impact outcomes [4]. Despite current gold standard staging (computed tomography, CA 19‑9 and tissue biopsy), some patients suffer from early recurrence or even initial metastatic stage of the disease explored during explorative laparotomy when intending curative resection (10–15% of patients, 21.3% in locally advanced stage) [5, 6]. The identification of those patients at high biological risk for recurrence or subclinical dissemination is of great interest for better stratification of either systemic or local therapy but is not sufficiently viable with current staging modalities.
Thus, circulating tumor DNA (ctDNA) has emerged as a promising marker indicating tumor burden with high sensitivity in several tumor entities but could be of special value for treatment decision-making in pancreatic cancer due to the relatively easy clinical implementation (small mutational spectrum, low cost) and high prognostic impact, especially in patients with potentially curative resectable pancreatic cancer.
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Circulating tumor DNA
Circulating tumor DNA (ctDNA), fragments of DNA shed by tumors into the bloodstream, has emerged as a promising biomarker in several cancers, offering a noninvasive means to provide information for treatment decisions via liquid biopsies. ctDNA represents a fraction of the free DNA found in blood and carries genetic and epigenetic alterations specific to tumors. Its detection and quantification can provide real-time insights into tumor genetics, burden, and heterogeneity, which are invaluable in the precision medicine landscape [7, 8].
ctDNA derivation, prognostic impact, and limitations of CA19-9
In pancreatic cancer, ctDNA is detectable in a significant proportion of patients (10–65% depending on the tumor stage) and correlates with disease burden and prognosis [9]. Studies have shown that higher levels of ctDNA are associated with advanced disease and worse outcomes, suggesting its potential role in staging and prognosis and even outperforms the current gold standard tumor marker CA19‑9 in doing so [4, 10‐12]. Moreover, several limitations regarding CA19‑9 have to be taken into account. First, its secretion is connected to Lewis antigen and, thus, CA19‑9 cannot be produced in 10–15% of patients (5–10% in Caucasians) [13]. Second, several nonmalignant conditions (e.g., chronic pancreatitis, liver cirrhosis, cholangitis or jaundice which is especially common in patients with pancreatic head tumors [the most common tumor location]) can lead to false elevated CA19-9 levels hampering exact diagnosis [13]. This is especially alarming when considering CA19‑9 as the only biomarker in pancreatic cancer care used for neoadjuvant chemotherapy recommendation when < 500 U/ml acknowledged by NCCN (National Comprehensive Cancer Network) [14, 15]. Generally, making such a fundamental treatment decision solely based on this threshold of < 500 U/ml in addition to the remaining ABC (anatomy: resectable, borderline resectable, locally advanced; biomarker: CA19‑9; C: performance status) factors for clinical staging makes no sense when considering the broad variety of values given for CA19‑9 in one and the same patient depending on the manufacturer (Abott Alinity/Architect +77%, Roche Cobas −48% compared to the consensus mean) [16, 17]. Ultimately, the use of CA19‑9 as screening tool is also hampered by its limited positive predictive value [2].
Neoadjuvant chemotherapy vs. upfront surgery
The traditional approach for resectable pancreatic cancer involves upfront surgery followed by adjuvant chemotherapy [2]. However, this strategy often leads to suboptimal outcomes due to undetected micrometastatic disease at the time of surgery [15]. Neoadjuvant chemotherapy (NACT), on the other hand, can treat micrometastatic disease early, potentially increasing resectability and survival rates. However, consistent data and guidelines (e.g., ESMO, NCCN) suggests NACT for borderline or locally advanced patients but improved outcome for primarily resectable patients undergoing upfront resection instead of NACT [18‐20].
Role of ctDNA in assessing tumor burden and metastatic potential:
ctDNA levels can serve as a proxy for tumor burden [9]. High preoperative ctDNA levels have been associated with poor surgical outcomes and higher recurrence rates [21]. Thus, detecting ctDNA preoperatively could help identify patients who may benefit more from initial systemic chemotherapy rather than immediate surgery [22]. This has not been proven yet.
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Predicting response to neoadjuvant chemotherapy:
Monitoring ctDNA levels during neoadjuvant treatment provides insights into the tumor’s response to therapy [22]. A decrease in ctDNA levels has been correlated with a better pathological response in nonmetastatic PDAC (pancreatic ductal adenocarcinoma) and dynamic changes of ctDNA levels during systemic treatment were associated with early evaluation of response to treatment at metastatic stage [10, 22]. Thus, ctDNA could identify patients who are responding well to chemotherapy before surgery.
Detection of minimal residual disease and early relapse:
Challenges and limitations
Despite its potential and advances in recent years, clinical implementation of ctDNA still faces several challenges:
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Sensitivity and specificity vary widely among assays, impacting reliability of the many different approaches available [24].
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Standardization of ctDNA sampling, processing, and analysis is needed [8].
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The cost and accessibility of ctDNA testing are concerns that must be addressed to make this a viable option across various healthcare settings [9]. Thus, NGS is neither cost effective nor necessary but used in many studies. Small spectrum ddPCR for the most common KRAS alterations should be sufficient [10].
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Despite its promising utility, ctDNA testing faces challenges such as variability in assay sensitivity and specificity, a lack of standardization in sample processing, and issues related to cost and accessibility [24]. Ongoing research and technological advancements are addressing these barriers, aiming to integrate ctDNA analysis more effectively into clinical practice [24].
Future directions
Conclusion
Although the current clinical application is purely experimental, ctDNA analysis bears promising potential to improve the management of resectable pancreatic cancer by providing a noninvasive tool to guide the choice between neoadjuvant chemotherapy and upfront surgery in the future by distinguishing between localized or systemic/advanced disease. This approach is currently subject of clinical trials, but as evidence accumulates, it becomes clear that integrating ctDNA into clinical workflows could enhance the precision of cancer care, offering patients tailored and potentially more effective treatment pathways.
Take-home message
The role of ctDNA in determining the optimal treatment strategies for resectable pancreatic cancer has not been definitively clarified yet but showed promising results in recent studies emphasizing its potential to tailor decisions between neoadjuvant chemotherapy and upfront surgery based on liquid biopsy results in the future.
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ctDNA displays the actual systemic tumor burden and is assessable with simple blood collection. No prior tissue testing is necessary for prognostic information in pancreatic cancer due to the small mutational spectrum. This allows fast decision making.
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Both preoperative and postoperative ctDNA detectability in localized pancreatic cancer is associated with worse overall survival and disease-free survival. However, there is no universal testing strategy or cut-off within the literature. Nevertheless, ddPCR at three positive droplets seems very suitable.
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Pretherapeutic ctDNA detectability could be used to identify patients at high biological risk for early recurrence despite insignificant CT and CA 19‑9 in the future.
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Prospective interventional trials are needed to establish the clinical applicability and impact of ctDNA-guided treatment in pancreatic cancer; to date, no such trials have been published. The LIQUIPANC trial (NCT06391892), initiated in January 2024 at the Ordensklinikum Linz, Austria, explores a pioneering approach using personalized ctDNA analysis to support treatment decisions for pancreatic cancer. This trial specifically assesses the feasibility of using preoperative ctDNA to guide the choice between chemotherapy and upfront surgery in resectable PDAC. Although data from previous observational studies at this and other centers suggest a potential shift towards more personalized treatment protocols, the broader impact on standard care practices remains to be confirmed. Ongoing research and multicentric validation by others are needed in the future. Additionally, the LIQUIPANC trial will be expanded to include several centers across Austria in 2025 as planned, trying to adopt an iterative approach to integrating ctDNA testing into clinical routines.Final results are expected in 2026/2027.
Conflict of interest
P. Kirchweger, B. Doleschal, H. Rumpold, H. Wundsam and M. Biebl declare that they have no competing interests.
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