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Targets for therapy in biliary tract cancers: the new horizon of personalized medicine.

ABSTRACT: Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repair, and HER2 pathways have demonstrated promising new therapeutic avenues, among others, and various studies have demonstrated clinical activity with targeted tyrosine kinase inhibitors and/or antibodies. In this review, we will discuss the currently identified targets for therapy in BTCs and review currently available data regarding clinical development of treatment options in these molecularly distinct subsets.

SUBMITTER: Iyer P

PROVIDER: S-EPMC8650725 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Targets for therapy in biliary tract cancers: the new horizon of personalized medicine.

Iyer Pritish P Chen Ming-Huang MH Goyal Lipika L Denlinger Crystal S CS

Chinese clinical oncology 20200201 1

Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repai ...[more]

PMID: 32146818

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Project description:Biliary tract cancer (BTC) represents a heterogeneous disease with dismal outcome. Herein, we examined genotype and angiogenesis features in BTC. We applied genotyping (Sanger, qPCR, 101-gene panel NGS), mRNA relative quantification methods, and β-catenin immunohistochemistry in 84 FFPE BTC (55 gallbladder [GBC], 14 intrahepatic [ICC], 15 extrahepatic [ECC] carcinomas). We identified 541 mutations in 68 (81%) tumors. Top mutated genes were CTNNB1 (36%); PTEN (33%); TP53 (31%); PIK3R1 (29%); PIK3CA (13%); BRCA2 and KRAS (12%); BRCA1 (11%). Six GBCs were hypermutated [hm] displaying a distinct mutational pattern. Mutations in TP53 and PI3K, Wnt and RAS components were prevalent among non-hypermutated tumors. All hmGBCs carried mutations in BRCA2 and other homologous recombination repair (HRR) genes, in PD1, but not in CTNNB1 and KRAS. None of the pathogenic BRCA2 p.D2723G and BRCA1 p.Q563* and c.5266dupC was present at frequencies expected for germline mutations. We observed copy gains (>6 copies) in EGFR (9% of informative tumors), PRKAR1A (7%), PIK3CA (6%), ERBB2 (5%) and MET (4%). TP53 mutations were prevalent in GBC (P<0.001) and PRKAR1A copy gains in ICC (P=0.007). PTEN was frequently co-mutated with CTNNB1 (P<0.001). Unrelated to CTNNB1 mutations, nuclear β-catenin was detected in 45% of tumors, among them in 5/6 hmGBC. We observed strong mRNA expression correlation of the two neuropilins (NRP1 and NRP2) with each other (Spearman's rho 0.59) and with the endothelin receptor (NRP2 rho 0.66; NRP2 rho 0.51), and between VEGFA and its receptors (FLT1 rho 0.49; KDR rho 0.45). All PIK3CA mutated tumors expressed endothelin 1 mRNA (P=0.010). Most tumors expressing nuclear β-catenin were negative for VEGFC (P=0.009) and FLT4 (P=0.002) mRNA expression. In conclusion, we confirmed the presence of known genomic aberrations in BTC and different genotypes between BTC subsets. Novel findings are the coexistence of PI3K and WNT pathway gene alterations in BTC, their association with angiogenesis, and the hypermutated GBCs with HRR gene mutations, all of which may be considered for new treatment options in this difficult to treat disease.

Dataset Information

Targets for therapy in biliary tract cancers: the new horizon of personalized medicine.

Publications

Targets for therapy in biliary tract cancers: the new horizon of personalized medicine.

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