Contemporary Tailored Oncology Treatment of Biliary Tract Cancers

Abstract

Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.

Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer

“…The PI3K/AKT/mTOR pathway activated by ERBB receptors is responsible for stimulating cell proliferation and survival. Most of the molecular alterations affect PI3KCA mutations and amplifications or aberrant expression of AKT and mTOR, as well as somatic mutations affecting the phosphatase tumor suppressor PTEN [37,38]. Molecular alterations affecting this pathway have been found in 4-16% of GBC patients [37,39], while PTEN mutations were found in 4-51% of GBC patients [37,38].…”

“…Most of the molecular alterations affect PI3KCA mutations and amplifications or aberrant expression of AKT and mTOR, as well as somatic mutations affecting the phosphatase tumor suppressor PTEN [37,38]. Molecular alterations affecting this pathway have been found in 4-16% of GBC patients [37,39], while PTEN mutations were found in 4-51% of GBC patients [37,38]. Alterations affecting this pathway have been associated with poorer prognosis in GBC patients [40].…”

Development of Possible Next Line of Systemic Therapies for Gemcitabine-Resistant Biliary Tract Cancers: A Perspective from Clinical Trials

“…The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, proliferation and survival, and is involved in BTC carcinogenesis and progression [ 94 ]. The aberrations in PI3K/AKT/mTOR signaling mainly consist of PI3KCA mutations/amplifications, PTEN loss, phosphorylated AKT or mTOR over-expression in BTC [ 95 , 96 , 97 ]. Several trials have applied to test the efficacy of PI3K/AKT/mTOR inhibitors in first- and second-line settings, but the results showed limited activity [ 98 , 99 ].…”

Second-line Treatment in Advanced Biliary Tract Cancer: Today and Tomorrow

“…Aberrations involving the PI3K/AKT/mTOR pathway are common in eCCA (40%), iCCA (25%) and GBC (4-16%) patients (110,111); these aberrations mainly include PI3KCA amplifications, PI3K mutations, phosphorylated AKT overexpression and phosphorylated mTOR overexpression (112)(113)(114)(115). Several trials have investigated the role of PI3K, AKT and mTOR inhibitors in first-and second-line setting in BTC, with limited tumor responses and disappointing results (116).…”