Molecular profiling of biliary tract cancer: a target rich disease

Abstract

Biliary tract cancers (BTCs) are relatively uncommon orphan tumors that have an aggressive disease course and a poor clinical outcome. Surgery is the only curative treatment, but most patients present with advanced disease and therefore have a limited survival. Gemcitabine and cisplatin based chemotherapy has been the only widely accepted standard systemic therapy regimen in these patients but these tumors can be chemoresistant, further complicating their management. In recent times, there has been considerable research in the genetics of BTC and with the advent of new, advanced technologies like next-generation sequencing (NGS) we are achieving a greater understanding of its disease biology. With the help of NGS, we have now been able to identify actionable mutations such as in the isocitrate dehydrogenase 1 (), and genes for targeted therapeutics and correlate the genetic variations with distinct clinical prognoses. This recent genetic information has the potential to make precision medicine a part of routine clinical practice for the management of BTC patients.

Current biologics for treatment of biliary tract cancers

“…Performing randomized control trials (RCT) for advanced BTCs has proven challenging due to the rarity of these malignancies, lack of effective agents, potential high heterogeneity within this diagnostic entity, and possibly fundamental differences among the three BTC subtypes (IHCC, EHCC, and GBC). In fact, next generation sequencing (NGS) and transcriptomic analyses have revealed that these BTC subtypes are molecularly distinct from one another, and therefore may respond differently to the same treatment strategy and should not be approached as a single entity for clinical trial design (13,14). To improve patient outcome, future clinical trial design must better stratify patients based on considerations of histologic and molecular subtypes, and allocate patients to the appropriate targeted agents driven by biomarkers that could predict treatment response.…”

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

“…Since the prognosis of CCA remains poor with traditional chemotherapy, in the era of personalized medicine several research teams have been working on the molecular and genetic characterization of CCA to identify molecular targets (5)(6)(7)(8)14). Landscape of signalling pathways offers multiple therapeutic targets including growth factor receptors (GFRs) like epidermal (EGFR), vascular (VEGFR), human epidermal growth factor receptor 2 (HER2), the ligand of VEGFR (VEGF) and their downstreaming signal molecules of RAS-RAF-MEK-ERK and PI3K-ACT-mTOR (5)(6)(7)(8)14). Targetspecific monoclonal antibodies and tyrosine kinase inhibitors are able to block selectively the over-expressed or over-activated signal molecules potentiating the growth and invasion of CCA cells.…”

“…Based on the success of targeted therapy in colorectal, breast, lung cancer and melanoma, targeted treatment could be effective in advanced CCA, as well. However as frequency and distribution of the potentially actionable targets are exceptionally variable in CCA, comprehensive genomic testing seems to be a reasonable option before initiation of a targeted treatment (14).…”

“…In CCA the frequency of BRAF V600E has been reported to range 0-12% in EH and 0-22% in IH subtypes (5)(6)(7)(8)14). Although BRAF V600 can serve as a potential molecular target in CCA, until now there was no evidence of benefit using BRAF inhibitor therapy.…”

HER2-Neu Gene Testing in Gastric Cancer by Immunohistochemistry in Tunisian Patient’ Samples

“…This recent genetic information has the potential to make precision medicine a part of routine clinical practice for the management of BTC patients [28].…”