Detecting and targeting NTRK gene fusions in cholangiocarcinoma: news and perspectives

Cholangiocarcinomas (CCAs) are rare and aggressive tumors accounting for less than 1% of all malignancies worldwide and approximately the 10–15% of all primary liver cancers [1]. Unfortunately, advanced CCA carries a poor prognosis and the benefit provided from systemic treatments is modest [2]. In the last decade, CCA has emerged as a disease entity presenting several potentially druggable mutations, and the advent of next-generation sequencing (NGS) has led to a new era in CCA management [3]. In fact, a number of potential therapeutic targets have been described, including fibroblast growth factor receptor (FGFR) fusions, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and BRAF mutations [4]. In particular, some molecularly targeted treatments have been shown to improve progression-free survival (PFS) and overall survival (OS), with these therapies that add to the armamentarium of therapeutic options currently available for CCA patients [5]. Few data are available on the putative role of other molecular aberrations which have already provided interesting results in other solid tumors, including neurotrophic tropomyosin receptor kinase (NTRK) fusions. Several genes have been suggested to represent fusions partner of NTRK, including the transcription factor ETV6 and BCAN. Notably enough, NTRK1, NTRK2, and NTRK3 gene fusions have been suggested to act as oncogenic drivers in a range of solid tumors, including gastrointestinal cancers such as CCA [6]; these fusions have been highlighted in around 1% of all pediatric and adult malignancies, with recent studies suggesting their role as promising therapeutic targets for anticancer treatment [7]. In particular, the frequency of these fusions seems to vary from less than 1% in cancer types such as colorectal, lung, pancreatic, breast cancers, melanoma and other hematological and solid tumors, up to 25% in tumors including thyroid, spitzoid, and gastrointestinal stromal tumors, to more than 90% in rare cancer types such as secretory breast carcinoma, mammary analogue secretory carcinoma, congenital infantile fibrosarcoma, and congenital mesoblastic nephroma [6–8]. Typically, these molecular aberrations occur following the fusion of the C-terminal tyrosine kinase with a N-terminal fusion partner, leading to ligand-independent phosphorylation. Consequently, several pathways are activated, resulting in cellular growth and increase proliferation [8]. In recent years, several methods have been used to diagnose NTRK fusions. Among these, fluorescent in situ hybridization reverse-transcriptase PCR, and NGS; in addition, beyond tumor-based approaches, NTRK fusions can be potentially detected also through plasma-based cell-free DNA testing. As regards biliopancreatic malignancies, in a report presented at ESMO World Congress on Gastrointestinal Cancer 2020, Demols and colleagues explored the prevalence of NTRK gene fusions in 149 CCAs and pancreatic adenocarcinomas through the use of different techniques [9]. More specifically, the authors used a two-step diagnostic method providing for immunohistochemistry and RNA-based NGS. Interestingly, according to the results of this study, NTRK gene fusion was observed in only 1 out of 149 CCA patients, with a prevalence in this population of 0.67% [9]. Similarly, another recent report conducted by Solomon and colleagues identified only 2 NTRK gene fusions among 787 CCA patients, with an even lower prevalence of 0.25% [10]. Two potent TRK inhibitors have recently emerged as novel therapeutic options in NTRK fusion-positive malignancies, entrectinib (RXDX-101) and larotrectinib (LOXO-101). Interestingly, these two agents reported a broad range of action, since entrectinib and larotrectinib have also shown antitumor efficacy against malignancies harboring ROS1 and ALK fusions, molecular aberrations that have been observed in approximately the 3% of CCAs – according to previous studies [11]. As regards the former agent, recent reports have highlighted that entrectinib treatment could provide clinically meaningful and durable responses in patients with NTRK fusion-positive tumors [12]. In fact, impressive response rates have been observed in basket trials assessing tumor-agnostic therapeutic approaches, with overall response rates (ORRs) ranging from 55% to 75% in previously treated patients with advanced malignancies. Thus, we are witnessing a growing interest toward this molecule, with entrectinib who is candidate for becoming an important treatment option in NTRK fusion-positive cancers [13].