Bile-Biopsy: Biliary mutational analysis in patients affected by biliopancreatic maliganancies. A prospective observational study

Cholangiocarcinoma and pancreatic ductal adenocarcinoma are two dangerous and often fatal neoplasms, with a 10-year survival rate around 3%. Currently, surgical resection is the only curative option for these neoplasms, although only 20% of patients are eligible for surgical treatment at the time of diagnosis. In addition, available chemotherapies do not have specific molecular targets, making it necessary to identify precision therapies based on the biological and molecular characteristics of neoplasms.
Understanding the mutational cascade underlying the natural history of neoplasms is crucial for the development of effective targeted therapies. According to the pancreatic adenocarcinoma progression model, the main molecular alterations tcan be classified as early (telomere shortening and activating KRAS mutations), intermediate (inactivating mutations or epigenetic silencing of CDKN2A), and late (inactivating mutations of TP53 and SMAD4).
Early diagnosis of CCA and PDAC is still very difficult, due to intrinsic biological aggressiveness and late onset of symptoms. However, genetic studies can help identify risk factors and discover biomarkers that can be used for early diagnosis. Furthermore, microbiome analysis can provide additional information on neoplasm development since it has been demonstrated that intestinal bacteria can influence tumor cell growth and spreading through the activation of specific cellular signaling pathways.
There are several potential therapies for patients with CCA and PDAC, including targeted molecular therapies, immunotherapy, and gene therapy. Targeted molecular therapies are based on knowledge of specific molecular alterations in the neoplasm and utilize drugs that act on these molecular targets. Immunotherapy exploits the patient's immune system to attack tumor cells, while gene therapy uses genetic engineering techniques to modify patient cells to attack tumor cells. Additionally, it is important to develop new ways to identify patients who can benefit from surgical therapy, as well as to identify new target molecules for the creation of new targeted therapies.
The identification of early biomarkers and understanding of molecular mechanisms underlying CCA and PDAC are crucial. The purpose of this study is to conduct a prospective observational assessment of molecular mutations in the bile of patients with biliary-pancreatic malignancies who undergo biliary drainage. This is done in order to improve the diagnostic approach for these patients, as well as define prognosis and therapeutic strategies.
Primary objective of our study is:

• Qualitative and quantitative evaluation of molecular mutations present in circulating tumor DNA in the bile of patients with biliary-pancreatic tumors, and comparison with plasma and tissue mutation profiles, in order to improve the diagnostic and staging approach of the disease.

Secondary objectives are:

• Correlation between type of mutation and disease stage in PDAC
• Identification of actionable mutations in bile in CCA
• Overall survival, disease-free progression, time to progression, complication rate, access to oncological care -Rate of re-intervention
• Identification of biomarkers in bile, peripheral blood, and tissue in relation to patient clinical characteristics and prognosis -Analysis of bile microbiota and correlation with molecular expression and staging