Circulating tumor cells in pancreatic cancer: The prognostic impact in surgical patients

Abstract

Pancreatic cancer is associated with a poor prognosis, even in the early stages, mainly due to metastatic progression. New diagnostic techniques that predict unfavorable outcomes are needed in order to improve treatment strategies. Circulating tumor cells (CTCs) are showing promising results as a predictive biomarker for various tumors. In this editorial we comment on the article by Zhang et al, who published the first systematic review and meta-analysis evaluating the prognostic value of CTCs as biomarkers in early-stage pancreatic cancer patients undergoing surgery. CTCs were detected in peripheral or central venous system blood, before or during surgery. Positive CTCs showed a correlation with decreased overall survival and decreased relapse-free, disease-free and progression-free survival in this meta-analysis. However, the heterogeneity was significant. The authors suggest that this result was related to the separation methods used between studies, but other differences such as the margin status or the neoadjuvant and adjuvant treatments used are also important to consider. CTCs may be a potential prognostic biomarker in pancreatic cancer patients, but it is necessary to compare and standardize the platforms used to isolate CTCs, to compare different biomarkers from liquid biopsy and to determine the impact on prognosis when therapeutic changes are made based on CTCs levels.

Introduction

Pancreatic cancer is an aggressive disease with a poor prognosis, estimated by the World Health Organization to be the seventh cancer-related cause of death in both sexes worldwide. The absence of specific symptoms in the initial stages makes early diagnosis difficult with half of patients having distant metastasis at presentation. Localized disease includes resectable pancreatic cancer, borderline resectable (involves major vascular structures but remains localized) and locally advanced (unresectable but without distant metastasis). Among these patients, only 10%-15% are surgical candidates at the time of diagnosis. Moreover, in surgical candidates, a high number of patients experience relapses after resection, frequently as metastatic progression. Computed tomography of the chest, abdomen and pelvis and abdominal magnetic resonance imaging are the main imaging tests for the diagnosis of pancreatic cancer. Endoscopic ultrasound (EUS) also plays an important role in selected cases as it provides information on venous involvement and allows confirmation of malignancy by EUS-guided fineneedle aspiration. However, diagnostic advances based on a deeper comprehension of the molecular biology of pancreatic cancer are needed to enhance early detection and treatment strategies, and identify poor prognosis factors in order to modify or intensify treatments in selected patients. Liquid biopsy is a minimally invasive technique that allows clinicians to isolate tumor-derived circulating biomarkers from blood or other fluid samples. Traditionally, carbohydrate antigen (CA) 19-9, carcinoembryonic antigen (CEA) and CA125 have been used in pancreatic cancer, but their sensitivity and specificity may be insufficient for diagnostic purposes. Recently, new biomarkers are emerging, such as cell-free DNA, circulating tumor DNA (ctDNA), tumorspecific RNA or circulating tumor cells (CTCs). CTCs are a small amount of cancer cells which originate in the primary tumor or metastasis that spread to the circulatory system. Although the majority of these cells die during the first 1 to 2.5 h, a small fraction survives and plays a significant role in the development of metastasis. The incorporation of CTCs in the diagnostic process can provide various advantages. Clinical studies have shown that CTCs are an independent predictor of progression-free survival (PFS) and overall survival (OS) in different tumors, including pancreatic cancer, but not only due to their presence. Analyzing the molecular characteristics of the CTCs, as the expression of certain genes or receptors, may also have a prognostic role.

Conclusion

CTCs are a promising biomarker in cancer patients. In a meta-analysis, Zhang et al demonstrated decreased DFS, RFS and PFS in early pancreatic cancer patients in which CTCs were isolated before or during surgery. These results are concordant with those in the literature for different tumors. However, with the rise of liquid biopsy, determining which biomarker is the most suitable for predicting distant metastasis and recurrence is still a challenge. As different platforms for CTCs detection are available, it is necessary to compare them in order to standardize their use. Also, clinical trials are needed to obtain higher levels of evidence. In conclusion, while CTCs hold promise for improving cancer diagnosis and monitoring, standardizing their isolation method and results interpretation are critical for incorporating this biomarker into clinical practice.

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