Endoscopic ultrasound-guided portal vein sampling and circulating tumor cells: the next frontier in pancreatic cancer, or a step too far?

Liquid biopsy has emerged as a pivotal tool in oncology. Unlike with tissue biopsies, the possibility of analyzing circulating tumor-derived material in bodily fluids offers the potential for real-time monitoring of cancer dynamics and prognosis. These advantages might be of paramount importance for pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers. Despite some progress in the field of its early detection and the therapeutic armamentarium, the prognosis of PDAC remains poor, with 5-year survival rates of about 10% [1].

“… future research can unlock the full potential of liquid biopsy in PDAC, ultimately contributing to more accurate diagnostics, better prognostication, and personalized treatment strategies.”

The main determinants of this prognosis are: (i) PDAC often being diagnosed at an advanced stage, when therapeutic options are limited; (ii) there being few opportunities for disease prognostication and treatment personalization; (iii) actual follow-up strategies offering a low sensitivity in anticipating or detecting chemotherapy resistance and disease progression.

The only available biomarker, CA19.9, is limited by its sensitivity (many patients with PDAC have normal CA19.9) and specificity (it is elevated in benign conditions such as cholangitis). Therefore, the traditional approach to assessing disease progression relies heavily on radiological imaging, which fails to capture early metastatic events or assess tumor biology in real-time.

Liquid biopsy, especially through the detection of circulating tumor cells (CTCs), could overcome some of these challenges, offering a potential means of assessing micrometastasis, predicting disease progression, and tailoring treatments to individual patients; however, liquid biopsy has been extremely underpowered in PDAC. For CTCs in particular, one of the main reasons for this is the scarce information provided from the systemic circulation, owing to the liver acting as a filter for most of the events [2]. For this reason, the portal circulation has raised many more expectations; however, this anatomical area has primarily been accessible during surgery, which is an option for only a minority of PDAC patients. This limitation has driven efforts to develop alternative, minimally invasive approaches to access this potentially informative area.

The study by Prasoppokakorn et al. [3] provides valuable insights into the role of portal vein CTCs in predicting survival and tumor aggressiveness in PDAC patients. The authors were able to demonstrate that endoscopic ultrasound (EUS) could be “easily” used to access this area, with 100% feasibility and no adverse events. Their study confirmed previous findings of a higher CTC detection rate and concentration in the portal rather than peripheral circulation. By matching CTC concentrations and oncological outcomes, they were also able to demonstrate that CTC concentration correlated with both the progression-free and overall survival rates.

The study overcame some of the limitations of the previous literature [4] [5] [6], being one of the larger experiences with this technique, and further enrolling a homogeneous cohort of patients with early stage PDAC only, who were naïve to oncological treatments.

While this study presents compelling findings, it also paves the way for further research and refinement, highlighting key aspects that warrant deeper investigation in future. The integration of semiautomated methods for CTC analysis in the future could help minimize the potential for human error associated with manual enrichment and enumeration, particularly with low numbers of cells. Additionally, while the immunosorting approach – based on the positive selection of epithelial antigens and the negative selection of hematopoietic antigens – represents a valuable strategy, it overlooks a potentially significant number of epithelial-to-mesenchymal transition events. Given the pivotal role of this process in the metastatization of PDAC, its under-representation has been suggested as a key factor contributing to the limited accuracy of liquid biopsy in PDAC so far. Furthermore, future studies may explore ways to mitigate the potential capture of contaminant epithelial cells from the gastric mucosa or hepatic parenchyma during EUS-guided sampling.

Ultimately, the ideal platform for CTC enrichment and enumeration has yet to be established. A method that balances high sensitivity – ensuring no significant loss of mesenchymal events – while maintaining specificity by integrating immunostaining markers with physical characteristics, such as cell size or morphology, remains an unmet need. Additionally, for widespread clinical application, any future platform must offer a streamlined and cost-effective processing workflow, ensuring accessibility beyond highly specialized research settings. Identifying and validating such a system would represent a critical step toward making CTC analysis a practical and reliable tool in oncology.

Despite portal CTCs being more informative, even peripheral CTCs significantly predicted progression-free and overall survival, thereby bringing into question the advantages of EUS-guided portal vein sampling. A crucial challenge for future research is determining whether the clinical implementation of this technique is truly feasible. While the concept holds great promise, practical limitations must be considered. The sampling technique is invasive and technically demanding, requiring advanced endoscopic expertise, while CTC enrichment remains costly and methodologically complex. This raises the question of whether portal CTC analysis will ever become a routine clinical tool or if its value will remain primarily in the realm of research. Even if widespread clinical adoption proves difficult, future studies could still offer invaluable insights into PDAC biology, potentially uncovering novel mechanisms of metastasis and resistance that could inform future therapeutic strategies.

Future studies should ideally explore the broader potential of CTCs beyond simple enumeration. For example, molecular characterization of CTCs could help confirm their tumor origin, ensuring they are not confounded by non-tumor cells circulating in the bloodstream. Furthermore, incorporating the identification of mutations within these CTCs could enhance their prognostic value, and/or unlock personalized treatment strategies if actionable mutations are found. Another intriguing possibility for the future is to potentially cultivate CTCs for chemosensitivity testing, creating "tumor avatars" that allow for more precise, patient-specific drug testing. This could revolutionize how we assess treatment responses, ultimately improving therapeutic outcomes for PDAC patients.

By exploring these additional avenues, future research can unlock the full potential of liquid biopsy in PDAC, ultimately contributing to more accurate diagnostics, better prognostication, and personalized treatment strategies. This kind of bench-to-bedside research can position the endoscopist as a crucial player in risk stratification and treatment planning. Ultimately, incorporating bench discoveries into clinical practice could enable oncologists to tailor treatment strategies on the basis of a more precise understanding of disease behavior, potentially improving survival outcomes for patients.

Publication History

Article published online:
08 April 2025

• References

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