Liquid biopsy may assist in the management of cancer patients, which can be particularly applicable in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the utility of circulating cell-free DNA (cfDNA)-based markers as prognostic tools in metastatic PDAC. Plasma was obtained from 61 metastatic PDAC patients, and cfDNA levels and fragmentation were determined. BEAMing technique was used for quantitative determination of RAS mutation allele fraction (MAF) in cfDNA. We found that the prognosis was more accurately predicted by RAS mutation detection in plasma than in tissue. RAS mutation status in plasma was a strong independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). Moreover, RAS MAF in cfDNA was also an independent risk factor for poor OS, and was strongly associated with primary tumours in the body/tail of the pancreas and liver metastases. Higher cfDNA levels and fragmentation were also associated with poorer OS and shorter PFS, body/tail tumors, and hepatic metastases, whereas cfDNA fragmentation positively correlated with RAS MAF. Remarkably, the combination of CA19-9 with MAF, cfDNA levels and fragmentation improved the prognostic stratification of patients. Furthermore, dynamics of RAS MAF better correlated with patients’ outcome than standard CA19-9 marker. In conclusion, our study supports the use of cfDNA-based liquid biopsy markers as clinical tools for the non-invasive prognosis and monitoring of metastatic PDAC patients.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly inflammatory microenvironment and liquid biopsy has emerged as a promising tool for the noninvasive analysis of this tumor. In this study, plasma was obtained from 58 metastatic PDAC patients, and neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), circulating cell-free DNA (cfDNA) concentration, and circulating RAS mutation were determined. We found that NLR was significantly associated with both overall survival (OS) and progression-free survival. Remarkably, NLR was an independent risk factor for poor OS. Moreover, NLR and PLR positively correlated, and combination of both inflammatory markers significantly improved the prognostic stratification of metastatic PDAC patients. NLR also showed a positive correlation with cfDNA levels and RAS mutant allelic fraction (MAF). Besides, we found that neutrophil activation contributed to cfDNA content in the plasma of metastatic PDAC patients. Finally, a multi-parameter prognosis model was designed by combining NLR, PLR, cfDNA levels, RAS mutation, RAS MAF, and CA19-9, which performs as a promising tool to predict the prognosis of metastatic PDAC patients. In conclusion, our study supports the idea that the use of systemic inflammatory markers along with circulating tumor-specific markers may constitute a valuable tool for the clinical management of metastatic PDAC patients.

chemotherapy was 3 months. Chemotherapy regimens were FOLFOX in 45 patients (83%), Capecitabin in 6 patients (11%) and FLEX in 3 patients (6%). Only 34 patients had received all the planned adjuvant courses (63%). Thirteen patients (23%) relapsed with a mean time to relapse of 11 months. mean disease-free survival was 23 months and mean overall survival was 29.5 months All the analysed factors (histopathological type, differentiation degree, vascular embolisms, perineural neoplastic invasion, resection margins, lymph nodes number, chemotherapy delay, chemotherapy regimens, number of chemotherapy courses) had no impact on overall survival and relapse-free survival. In the metastatic subgroup, patients had liver metastasis in 29 cases (66%), lung metastasis in 11 cases (25%), and 4 patients had metastasis in other sites (9%). RAS testing was performed in only 19 cases and was wild in 12 cases (63%). Liver metastasis were resectable in 3%, potentially resectable in 37.5%, and non-resectable in 59.5%. First line chemotherapy was FOLFOX in most of cases (53%), FOLFOX or FOLFIRI in the second line and capecitabine in the third line. Response rates were 14% after the first and the second line. Only 4 patients had targeted therapy in the second line with a mean number of courses of 7. Overall survival was 16.3 months and progression-free survival was 11.9 months in this study. All the analysed factors (tumor location, RAS mutation status, metastasis location, liver metastasis resection status, treatment with targeted therapy ) had no impact on overall survival and progressionfree survival. Conclusion: Colon cancer management is still a challenge in Tunisia. Access to targeted therapy in metastatic colon cancer is still difficult for our patients.

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