Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies

Abstract

Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies.Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy.Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease.A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease.

Advanced biliary tract cancer: clinical outcomes with ABC-02 regimen and analysis of prognostic factors in a tertiary care center in the United States

“…Metastatic cholangiocarcinoma is often combined with unresectable locally advanced disease in clinical trials and registries (2,4). The results of these studies should be interpreted with caution as patients with metastatic disease have a worse survival compared to regional disease (2) as metastatic diseases may have a more aggressive biology (2,3,12). This is suggested by a genomic analysis study of cholangiocarcinoma in which it was shown EHC with mutations in BAP1 and PBRM1 are more likely to be associated with bone metastases and worse survival (13).…”

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.…”

“…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.…”

“…Due to the dismal prognosis with conventional chemotherapy, attention has been shifting to the potential role of molecularly targeted agents in advanced CCA. Several clinical trials had been carried out, where targeted agents were applied alone or in combination with chemotherapy with only modest or no proven benefit at all (5)(6)(7)(8). One main limitation of most trial design was subject heterogeneity with regards to the anatomical and molecular characteristics of the cholangiocellular malignancies.…”

Emerging therapies for the treatment of cholangiocarcinoma

“…Intrahepatic CCA exists as a range of genetic subtypes [98] with varying sensitivity to chemotherapeutics and molecular targeted agents [99]. Genetic studies of biliary tumors have identified known growth factor gene mutations [100,101] and signaling pathways [102] that control tumor growth and survival.…”