Cancer-cell-derived cell-free DNA can predict distant metastasis earlier in pancreatic cancer: a prospective cohort study

Abstract

Background: Carbohydrate antigen 19-9 (CA19-9) is the only biomarker for monitoring responses during treatments of pancreatic cancer, but its accuracy for disease outcome is controversial. Fluid biopsy is a new method for diagnosis and monitoring treatment response. In this study, we investigate the usefulness of cell-free DNA (cfDNA) in predicting disease progression during the treatment of pancreatic cancer. Methods: Biopsy-proved advanced pancreatic cancer patients who received systemic chemotherapy were enrolled after signed informed consent. CA19-9 and cfDNA in blood were measured before and after every two cycles of treatments, and the disease progression was monitored by computed tomography (CT) with 3-month interval. Results: In total, 74 patients and 148 blood samples were enrolled in this study. Patients whose average blood cfDNA concentration of >9.71 ng/mL before and after first two courses of chemotherapy would subsequently show new distant metastasis (NDM) on CT scans 3 months later. The accuracy was 94.37% (AUC 0.9705, p < 0.0001) and the progression-free survival (PFS) and overall survival (OS) of patients with cfDNA concentration of >9.71 ng/mL were worse than those patients with cfDNA concentration of <9.71 ng/mL (median PFS: 95 days versus 322 days, p < 0.0001; median OS: 150 days versus 431 days, p < 0.0001). The cfDNA concentration of >9.71 ng/mL is a predictor for PFS, OS, and distant metastasis-free survival by multivariate analysis. Comparison of KRAS G12 variants detected by next-generation sequencing from tumor tissue issue and remnant DNA of cfDNA showed that increased cfDNA was primarily derived from cancer cells. Conclusion: The cancer-cell-derived cfDNA levels could be served as a powerful biomarker for prediction of NDM in patients with advanced/metastatic pancreatic cancer.

Cell-Free Tumor DNA Detection-Based Liquid Biopsy of Plasma and Bile in Patients with Various Pancreatic Neoplasms

“…According to our results, this type of liquid biopsy is even more informative regarding overall survival if a certain cftDNA level/MAF cutoff value is implemented in contrast to the basic qualitative approach. The association of cftDNA with negative prognosis might be, in part, explained by its ability to reflect the ongoing metastasis (which is known to be a major cause of death in PDAC patients [43,44]), as it was demonstrated in our cohort as well as in several other studies [45][46][47]. Moreover, potential clinical applications of liquid biopsy in PDAC might go way beyond survival prediction, as this method is proving to be useful in the monitoring of response to chemotherapy and post-treatment recurrence of the disease [48,49].…”

Prognostic Value of Circulating Cell-Free DNA Concentration and Neutrophil-to-Lymphocyte Ratio in Patients with Pancreatic Ductal Adenocarcinoma: A Prospective Cohort Study

“…In a prospective cohort study including 74 patients with advanced or metastatic pancreatic cancer, high levels of total ccfDNA were associated with new distant metastasis (91% sensitivity, 95% specificity). Additionally, the researchers discovered a negative correlation between total ccfDNA concentration and OS and progression-free survival (PFS) [ 32 ].…”

Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer

“…For example, in early stages of cancer the VAF is often less than 1%, whereas in the metastatic setting this is often much higher, with reports ranging from 5–80% depending on extent and location of disease [ 16 , 17 ]. Notably, many studies including patients with metastatic disease will report cfDNA levels as a surrogate for ctDNA when prognosticating or evaluating response to treatment [ 18 ].…”

“…There are a growing number of studies showing that liquid biopsy can accurately predict tumor response and that sensitivity and specificity are increased when combined with CA19-9 [ 18 , 50 , 58 , 62 , 64 ]. However, there is limited data indicating that incorporation of liquid biopsy into clinical practice improves clinical outcomes or reduces unnecessary chemotherapy administration.…”

“… Patients enrolled onto clinical trials assessing the role of liquid biopsy in PDAC. Grouped per 2-year increments [ 13 , 17 , 18 , 26 , 36 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 65 , 66 , 67 , 68 , 69 , 77 , 78 , 79 , 100 , 101 , 116 , 117 , 164 ]. …”