Caracterización molecular de los tumores de vías biliares avanzados e identificación de biomarcadores potenciales predictivos de respuesta a nuevas dianas terapéuticas.

Abstract

Biliary tract cancer (BTC) has a poor prognosis and treatment with systemic chemotherapy provides a modest benefit. In the present Doctoral Thesis, it is proposed whether genomic comprehensive profiling (GCP) of the BTC would reveal clinically relevant genomic alterations (CRGA), which may be different depending on the tumor location in the biliary tree. We also examined the benefits provided by patient’s participation in a clinical trial (CT) with or without targeted therapy. Methods: Tumor samples embedded in paraffin blocks from 154 patients were analyzed; intrahepatic cholangiocarcinoma 101 cases, extrahepatic cholangiocarcinoma 28, and gallbladder 25. The complete genomic analysis of mutations, amplifications, and fusions was performed using the Sequenom, Amplicon-MiSeq, immunohistochemistry, Nanostring or FoundationONE technique. CRGA were analyzed in the different tumor samples. Likewise, we assessed the benefit of participation in CT of patients with BTC by survival from the date of progression to the first-line of treatment (OS1ºT) until death or the last follow-up and with clinical benefit defined as partial responses or stabilizations more than 4 months. Results: The characteristics of the patients were similar in the three tumor types. We observed different CRGA according to the site of tumor. CRGA in intrahepatic cholangiocarcinoma were characterized by FGFR fusions, IDH1/2 mutations, ARID1A mutations, and MET amplification. CRGA in extrahepatic cholangiocarcinoma and gallbladder presented amplifications in ERBB2. Also, extrahepatic cholangiocarcinoma was further characterized by a high frequency KRAS mutation. Clinical benefit was observed with TM (n = 19), one partial response and eight stabilizations. OS1ºT was 6,17 months in patients who did not participate in a CT and 14.1 months in the group of patients who did participate in a CT. The difference was statistically significant, P = 0,003. However, SP1ºT was 12,8 months in patients who participated in a CT with TM and 14,1 months in the group of patients who participated in a CT without TM. No statistically significant differences were observed (P = 0,7). Conclusions: A high frequency of CRGA in different types of BTC was detected by GCP. Some of these molecular alterations may be potential therapeutic targets for the development of new drugs in CT. In our series, patients with a BTC who participated in a CT presented a higher OS1ºT compared to those who did not participate in a CT. Although there was no statistically significant increase in OS1ºT according to the participation in a CT with TM, clinical benefits were observed.

Date of Award	11 Jun 2019
Original language	Spanish
Supervisor	Josep Maria Tabernero Caturla (Director), Teresa Macarulla Mercadé (Director) & Albert Selva O Callaghan (Tutor)