Biliary Cancer: Current Management and Emerging Targeted Therapies

The Journal of Targeted Therapies in Cancer, December 2014, Volume 3, Issue 6

Biliary cancer includes gallbladder carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma.

Emmanuel Gabriel, MD

Roswell Park Cancer Institute,

Buffalo, NY

Renuka Iyer, MD

Roswell Park Cancer Institute,

Buffalo, NY

Abstract

Biliary cancer includes gallbladder carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. Each of these rare malignancies can be rapidly fatal due to the aggressive progression of disease and late stage at diagnosis. The various types of biliary cancer all have a different staging system, but they share common poor prognostic factors. Currently, effective treatment options are limited, but expanding. Surgery remains the only potential treatment for cure, but it is often not an option for advanced disease or in the setting of serious patient comorbidities. Chemotherapy with fluoropyrimidine-based or gemcitabine-based agents offers modest survival for patients with advanced disease. In recent years, molecular pathways have been increasingly identified to play a role in the carcinogenesis of biliary cancers. These include cell signaling pathways involving EGFR, VEGF, and MEK in the RAS/RAF/MEK/ERK cascade, as well as more recently characterized signals. Novel agents developed against key targets in these pathways have been investigated and show some promise in improving outcomes. In this review, we summarize the current treatment options for biliary cancer and highlight the studies involving novel targeted agents in early stages of clinical investigation.

Introduction

Cancers of the biliary tract include gallbladder carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. Of these, gallbladder cancer is the most common, accounting for 80% to 95% of biliary cancers.1Nearly 90% of gallbladder cancer is adenocarcinoma, with an incidence of 1.5 per 100,000 in the United States.2Aggressive biology, late stage at diagnosis, comorbidities, biliary obstruction, and chemorefractoriness make treatment of biliary cancer challenging. This is reflected in poor outcomes, with an overall median survival of 6 to 10 months.3Similarly, cholangiocarcinoma is an aggressive cancer with poor outcomes. The most common type of cholangiocarcinoma is also adenocarcinoma.4Intrahepatic cholangiocarcinoma has an incidence of 0.7 per 100,000,5with a mortality rate of 0.66 per 100,000.6Interestingly, intrahepatic cholangiocarcinoma has been increasing in incidence, whereas extrahepatic cholangiocarcinoma has been declining.7,8

There are demographic and environmental risk factors for gallbladder cancer and cholangiocarcinoma, including age, obesity, calculi within the gallbladder or common bile duct, and the presence of chronic inflammation.9-12Factors specific to gallbladder cancer include gallbladder polyps larger than 1 cm,10 whereas factors specific to cholangiocarcinoma include primary sclerosing cholangitis,13choledochal cysts,14and liver fluke infections.15

Role of Staging in Biliary Cancer

Within the last few years, investigators have characterized novel signaling pathways with the potential to be targets for innovative drug development. Cellular signaling proteins, including FGFR, PI3K/ mTor, HER-2, and BRAF, have all been the focus of intense investigation as targets for directed antitumor therapy in biliary cancer. Some of these targets are also being investigated in the treatment of hepatocellular cancer, which we discussed in a prior review.16Clearly, innovative treatments for these highly fatal diseases are needed. This review summarizes the current treatments of biliary cancer and their limitations, presents the emerging studies for targeted treatment, and highlights future directions in this exciting field of research.Unlike prior versions of the American Joint Commission on Cancer (AJCC) staging system, the 7th Edition has individual classifications specific for gallbladder carcinoma, intrahepatic and extrahepatic cholangiocarcinomas.17Poor prognostic factors for gallbladder cancer include advanced liver extension, nodal involvement, and incomplete resection.18This is reflected in the decreasing survival rate observed with increasing stage. Specifically, 5-year overall survival (OS) rates have been found to be 60%, 39%, and 15% for patients with stage 0, stage 1, and stage 3 disease, respectively.19

Table 1. Treatments for Biliary Cancer

Poor prognostic factors for intrahepatic cholangiocarcinoma include lymph node involvement, number of tumor foci, vascular involvement, and incomplete resection,20,21although tumor size has not been consistently shown to be associated with worse outcome. An analysis from the French Association Francophone de Chirurgie—Intrahepatic Cholangiocarcinoma (AFC-IHCC) study group showed worse outcomes with advanced stage, specifically a median survival of 53 months for stage 2 and 16 months for stage 3 disease.22

Tumor invasion, lymph node involvement, and incomplete resection after pancreaticoduodenectomy (Whipple procedure) are associated with worse outcomes in extrahepatic cholangiocarcinoma.23There are unique anatomically based classification systems for hilar cholangiocarcinomas (also known as Klatskin tumors, which occur at the junction of the right and left hepatic ducts), which include the Bismuth- Corlette and the Blumgart staging systems. Unlike the staging systems for gallbladder cancer and intrahepatic cholangiocarcinoma, outcomes have not been as well correlated with stage for extrahepatic cholangiocarcinoma.24

Current Management by Type of Biliary Cancer

Gallbladder Cancer

The different options for biliary cancer include surgery, adjuvant chemoradiation, transplant, and liverdirected therapies. Studies investigating systemic chemotherapy for advanced disease often include patients with each type of biliary cancer. Table 1 summarizes the key points for treatment for each type of biliary cancer. Table 2 summarizes the major clinical trials reporting on the systemic treatment for advanced biliary cancer. Palliative options are also important in the management of these cancers; these are discussed at the end of this section.The effectiveness of surgery correlates with intervention at an earlier stage, but is often difficult to obtain, given the frequently vague presentation of gallbladder cancer and delayed diagnosis, resulting in advanced stage. Surgical cure with cholecystectomy alone can be obtained for T1a gallbladder adenocarcinoma (limited to the inner layer lamina propria).25This is often an incidental finding after cholecystectomy performed for other indications, such as symptomatic cholelithiasis. Re-operation with extended cholecystectomy by resecting liver segments 4b and 5 can improve outcomes in patients with T2 tumors.26More radical liver surgery has not been shown to improve survival, and it is associated with increased morbidity.27Local recurrence rates following resection of advanced gallbladder tumors have been shown to be 15% and 20% for R0 and R1 margin status, respectively.28Recurrence rates in the form of distant disease were much worse, with 85% and 80% for R0 and R1 margin status, respectively.28

Table 2. Clinical Trials for Systemic Treatment of Biliary Cancer

Intrahepatic Cholangiocarcinoma

Adjuvant therapy to minimize local recurrence after resection includes fluoropyrimidine-based or gemcitabine-based chemotherapy (CT) with or without radiation therapy (RT). It should be noted that the evidence for adjuvant treatment is derived largely from retrospective studies, many of which have small sample sizes. In a meta-analysis of 22 studies by Horgan et al investigating adjuvant CT or chemoradiation (CRT), 6 of which investigated gallbladder cancer, adjuvant treatment in general was associated with improved outcomes compared with surgery alone, particularly for patients with lymph node involvement (test for overall effect: Z = 1.50,P=.13).29A phase III trial by Takada et al showed improved 5-year disease-free survival (DFS) for patients with gallbladder cancer treated with fluorouracil and mitomycin C compared with controls (20.3% vs 11.5%,P= .021).30Similar to gallbladder cancer, complete surgical resection offers the only potential cure for patients with intrahepatic cholangiocarcinoma. This is often difficult to achieve given advanced disease at presentation and potential limitations in patient comorbidities specific to liver dysfunction. When possible, R0 resection is sought as the surgical goal although the impact of margin width on OS is controversial, particularly in patients with nodal disease.31,32Recurrence rates can be as high as 53% after R0 resection, and 5-year OS is reported to be 33%.31

Similar to hepatocellular carcinoma, local regional therapies are options for patients with unresectable disease or for patients who are too frail to undergo surgery. These include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) with yttrium-90 spheres or selective internal radiation (SIR-spheres). These approaches are generally used on a case-by-case basis when chemotherapy is not an option.

Adjuvant treatments following surgery are similar to those for gallbladder carcinoma and include fluoropyrimidine- based and gemcitabine-based CT with or without RT. In the previously discussed meta-analysis by Horgan et al, 16 studies investigated the effects of CRT on cholangiocarcinoma. As was the case for gallbladder adenocarcinoma, the meta-analysis showed an overall improved effect with CRT compared with surgery alone (test for overall effect: Z = 1.91,P= .06).29Conversely, whereas the prospective study by Takada et al showed a survival benefit for gallbladder adenocarcinoma, this was not the case for cholangiocarcinoma (26.7% in the group treated with surgery followed by adjuvant mitomycin C and 5-FU vs 24.1% in patients treated with surgery alone).30This may be a consequence of chemorefractoriness or limited sample size.

Extrahepatic Cholangiocarcinoma

Surgical strategies for extrahepatic cholangiocarcinoma are dependent on tumor location. Proximal lesions, such as Klatskin tumors, may require partial hepatectomy with hepaticojejunostomy, whereas distal common bile duct tumors often require pancreatico- duodenctomy for R0 resection. Cancers of the middle common bile duct become more challenging in surgical approach, but require major bile duct resection with some sort of reconstruction such as choledochojejunostomy or hepaticojejunostomy. Following radical surgery, the 5-year OS for proximal and distal tumors has been found to be up to 42% and 52%, respectively.33Recommended adjuvant therapy also consists of fluoropyrimidine and gemcitabine-based CRT in an attempt to decrease the rate of recurrence, which has been shown to be as high as 59% for locoregional recurrence and 41% for distant-disease recurrence.28,34

Table 3. Genetic Mutations Associated With Biliary Cancer

Orthotopic liver transplantation (OLT) may be appropriate for select patients with hilar cholangiocarcinoma. The 5-year OS has been shown to be from 25% to 40%, and favorable prognostic factors include diagnosis prior to OLT and the implementation of perioperative chemoradiation around the time transplant.35-37DFS rates have been reported to be as high as 50%.38In a small series of patients undergoing a protocol developed at the Mayo Clinic involving neoadjuvant 5-FU, XRT, and brachytherapy with iridium, patients who were able to complete the Mayo regimen followed by OLT showed improved DFS (7/8 patients) albeit with a short follow-up time of 1 year.37In a larger multi-institutional study, patients who were able to tolerate neoadjuvant CRT followed by OLT experienced lower rates of disease recurrence of 20% and 5-year DFS of 65%.35However, the toxicity of this treatment regimen was high, resulting in some level of cholangitis and long-term structural complications such as biliary strictures (17%) and arterial compromise (7%).35

Treatments for Metastatic Disease

There have been several phase II and III trials supporting the use of CT in patients with advanced biliary disease. The phase II study ABC-01 conducted in the UK demonstrated that the combination of gemcitabine with cisplatin was superior to gemcitabine alone. The median time to progression (TTP) and 6-month PFS were 4 and 8 months and 45.5% and 57.1%, respectively in the gemcitabine alone and gemcitabine plus cisplatin groups.39The larger phase III study ABC-02 randomized 410 patients with biliary cancer to similar treatment arms in ABC-01 with the primary endpoint of OS. The investigators found an improved median OS of 11.7 months in the gemcitabine plus cisplatin group compared with the group that received gemcitabine alone (median OS of 8.1 months; HR = 0.64; 95% confidence interval [CI], 0.52-0.80; P <.001).40A phase II study from Japan showed similar results for gemcitabine and cisplatin (1-year OS 39.0% for gemcitabine/cisplatin compared with 31.0% gemcitabine alone; HR = 0.69; 95% CI, 0.42-1.13).41Based on this body of evidence, gemcitabine plus cisplatin is recognized as the current standard of care in patients with advanced biliary cancers.

Patients with advanced gallbladder cancer who were treated with gemcitabine and oxaliplatin (GEMOX) in a phase II trial experienced better OS compared with best supportive care (median OS of 9.5 months vs 4.5 months, respectively, P =.039).42A large meta-analysis of over 100 trials concluded that gemcitabine combined with oxaliplatin or cisplatin had an average response rate (RR) of 22.6% (85% CI, 21.0-24.2%).43

Palliative Care

Targeted Therapies for Biliary Cancer

Gemcitabine plus capecitabine is also a valid and well-tolerated first-line regimen for patients with advanced biliary cancer. In 2 separate studies, the median OS was 14 months, with stable disease and partial response seen in 58% to 72% of patients with improved quality of life.44,45There are no evidencebased guidelines to support any one second-line therapy and, given an OS of 10 to 14 months, it is reasonable to infer that better treatments are urgently needed to further improve outcomes for patients with metastatic disease.Jaundice and pruritus are typical clinical manifestations of biliary obstruction, and biliary stents or percutaneous drainage can alleviate these symptoms and improve quality of life.46Palliative options are important for patients with advanced biliary cancer complicated by biliary obstruction. These options include minimally invasive procedures as well as open surgery. Patients with biliary obstruction are considered for endoscopic or percutaneous drainage procedures (ERCP and PTC) or surgical bypass. In patients with very advanced cancers, the percutaneous approach may be the most successful compared with ERCP (92% vs 77%, P =.049).47Elevated bilirubin levels can be a relative contraindication to chemotherapy or require dose adjustment, and these palliative procedures can increase the ability to deliver systemic CT. Lastly, photodynamic therapy (PDT) is a new palliative treatment, which uses intravenous injections of photosensitizing agents that are selectively activated when exposed to external light radiation.48When used with biliary stenting, PDT has shown improved outcomes in the median OS in patients with advanced disease, specifically 21 months for the stented group compared with 7 months in the supportive care group (P = .0109).49Current targeted molecular therapies for biliary cancer can be categorized into agents against EGFR, VEGF, and MEK.50Table 3 outlines the different genetic mutations that are targeted with existing and developing agents. Table 4 summarizes the key points and outcomes of these targeted agents. In general, these agents have not yet been proven in large-scale trials to have clinically significant benefits. Challenges to the development and investigation of targeted therapies include the rarity of biliary cancers in general and the molecular heterogeneity across the different types. Other challenges include the presence of mutations within the targeted pathways, such as KRAS mutations, which may have various degrees of expression across different patient populations and further confound study results.51,52Nonetheless, there are several promising studies investigating the use these agents in the advanced setting.

Targets for EGFR

EGFR is overexpressed in all types of biliary cancers, with studies showing rates of increased expression in gallbladder carcinoma (12%),53intrahepatic cholangiocarcinoma (10%-32%),53,54and extrahepatic cholangiocarcinoma (5%-20%).53,55Targeted agents for advanced biliary cancer in this class include erlotinib, cetuximab, and panitumumab. As a group of agents, EGFR inhibitors have shown little benefit and do not have an established role in the treatment of biliary cancer.

Erlotinib is an oral small-molecule EGFR inhibitor that has been tested alone and in combination with CT. A single-arm study of erlotinib monotherapy showed a partial response rate of 8% with TTP of 2.6 months and OS of 7.5 months.56The addition of GEMOX to erlotinib has been shown to have improved outcomes. A multicenter phase III trial of GEMOX with or without erlotinib showed a trend toward improved progression-free survival (PFS), but no differences in OS. The median PFS was 4.2 months in the GEMOX group compared with 5.8 months in the GEMOX plus erlotinib group (HR 0.80; 95% CI, 0.61-1.03; P = .087), while OS was 9.5 months in each group (HR 0.93; 95% CI, 0.69-1.25; P = .611).57In contrast, a small phase II study of erlotinib plus docetaxel did not show any added benefit of docetaxel to erlotinib alone in terms of OS (only 6.7 months).58 Skin rash constituted the major grade 3-4 toxicity (7%).56

Cetuximab is a chimeric monoclonal antibody with activity against EGFR. A single-arm phase II study of GEMOX with cetuximab showed a CR of 10%, with median PFS and OS (8.8 months and 15.2 months, respectively) that were greater compared with the erlotinib studies.59In contrast, the phase II study BINGO very recently published less promising results on GEMOX plus cetuximab compared with GEMOX alone. The median PFS and OS were 6.1 months and 11.0 months in the GEMOX plus cetuximab group compared with 5.5 months and 12.4 in the GEMOX alone group.60 The authors concluded that there was no added benefit of cetuximab to standard CT. Grade 3-4 toxicities were low and included peripheral neuropathy (24%), neutropenia or thrombocytopenia (up to 22%), and increased liver function tests (LFTs) (22%).59,60

Lastly, panitumumab is a humanized monoclonal antibody against EGFR. This agent is being investigated in several active phase II trials testing panitumumab in combination with GEMOX, gemcitabine/ irinotecan, and gemcitabine/cisplatin. A previous single-arm phase II study showed that panitumumab in combination with GEMOX and capecitabine had a median PFS of 8.3 months and OS of 9.8 months.61In a second phase II trial of panitumumab in combination with gemcitabine and irinotecan, outcomes were improved, with a median PFS of 9.7 months and OS of 12.9 months.62

Targets for VEGF

VEGF is expressed in up to 50% to 60% of biliary cancers and has been associated with poor prognosis.55,63,64Among the targeted agents for advanced biliary cancer in this class are bevacizumab, sorafenib, and sunitinib. These agents are also being investigated in advanced hepatocellular cancer.16

Bevacizumab is a humanized monoclonal antibody against all isoforms of VEGF. A small single-arm phase II study investigated bevacizumab in combination with GEMOX. Results showed a RR of 40%, median PFS of 7.0 months and OS of 12.7 months.65 Treatment was well tolerated overall. Grade 3-4 toxicities included neutropenia, elevated LFT’s, peripheral neuropathy and hypertension.65Another phase II study investigated bevacizumab in combination with erlotinib.66While the treatment was well tolerated, with the most common grade 3-4 toxicity being rash, the median TTP was 4.4 months and OS was 9.9 months,66which are similar results to GEMOX with erlotinib. A current trial testing bevacizumab with gemcitabine/capecitabine has finished accrual of patients and results are awaited.67

Sorafenib is an oral multitargeted tyrosine kinase inhibitor with activity against VEGFR-2 and VEGFR-3. As a single agent, sorafenib has not shown activity against advanced biliary cancer.68Despite a phase II study of sorafenib and gemcitabine showing a RR of 7% and stable disease of 63% in patients with advanced biliary cancers,69a more recent published study did not show any significantly increased benefit compared with the ABC-02 trial.70This single-arm phase II study of sorafenib plus gemcitabine/cisplatin showed a median PFS of 6.5 months (95% CI, 3.5-8.3) and median OS of 14 months (95% CI, 11.6-19.2).70The major grade 3-4 toxicities included hematologic disturbances, elevations in LFT’s and pancreatic enzymes, and fatigue.

Sunitinib is a newer oral multitargeted tyrosine kinase inhibitor. In a single-arm phase II study of sunitinib monotherapy, marginal benefit was observed with a median TTP of 1.7 months (95% CI, 1.0-2.4).71Similar to sorafenib, major toxicities included hematologic disturbances, most commonly neutropenia and thrombocytopenia.

Table 4. Targeted Therapies for Advanced Biliary Cancer

Lastly, cediranib is another multitargeted tyrosine kinase inhibitor with activity against VEGFR-1, VEGFR- 2, and VEGFR-3. In the phase II ABC-03 study presented at the 2014 ASCO meeting, cediranib in combination with gemcitabine/cisplatin showed improved RECIST response rates compared with placebo (43% vs 19%, P = .01).72 However, with a median follow-up of 11.9 months, there were no statistically significant differences in PFS between the cediranib and placebo groups (7.7 months vs 7.4 months; HR 0.99; 80% CI, 0.78-1.26) or OS (14.1 months vs 11.9 months; HR 0.76; 95% CI, 0.50-1.14).72Thus, more studies will be needed to determine the effects of cediranib on longterm outcome.

Targets for MEK

Future Directions

Selumetinib is an oral small molecule inhibitor of MEK1/2. MEK plays a role in cellular proliferation through the RAS/RAF/MEK/ERK signaling pathway, which has been targeted in many cancers including biliary tract malignancies. In a small single-arm phase II study, patients treated with selumetinib showed no clinically significant improved outcomes compared with ABC-2 with a median PFS of 3.7 months (95% CI, 3.5-4.9) and OS of 9.8 months (95% CI, 5.97 to not yet available).73The most common grade 3-4 toxicities included gastrointestinal symptoms and fatigue.Advances in translational research have identified other potential targets in advanced biliary cancer in addition to those discussed for EGFR, VEGF, and MEK. Among these more novel targets are FGFR, PIK- 3CA (phosphatidylinsositol-3-kinase pathway), BRAF, c-MET, BAP1, and IDH 1/2. Additionally, further trials are actively investigating different combinations of newer agents targeted against the more established molecular pathways. Finally, patient-specific targeted immunotherapies are also being developed and tested for the treatment of biliary cancer.

Through genomic sequencing of patients with advanced cholangiocarcinoma, mutations have been characterized inFGFRandERRFI1, which is a direct negative regulator of EGFR activation.74BGJ398 is an oral pan-inhibitor of FGFR kinase and results in inhibition of tumor angiogenesis and proliferation.75It is currently being tested in a single-arm phase II trial in patients with advanced cholangiocarcinoma withFGFR2gene fusions or other mutations who have failed platinum-based CT.76Neratinib is an orally available, irreversible inhibitor of the HER-2/ERRB2 receptor tyrosine kinase. This drug is currently being tested in a phase II study in patients with solid tumors with EGFR gene amplification or mutations inEGFR,HER2, andHER3.76

PIK3CA is involved in the AKT/mTOR pathway and has been identified in patients with both gallbladder cancer and cholangiocarcinoma.77,78The agent BKM120 is an orally available PI3K inhibitor of all 4 class I PI3K isoforms.79A current multi-institutional phase II trial by Piha-Paul et al is investigating the effects of BKM120 on patients with PI3K-activated solid tumors with the primary endpoint of response rates based on RECIST criteria.80The trial is presently enrolling patients.

BRAF is involved in the RAS/RAF/MEK/ERK molecular signaling pathway. TheBRAF V600Emutation is most known in its role in malignant melanoma, but it has been identified in gallbladder carcinoma and cholangiocarcinoma.81,82There are currently no phase II or III trials in biliary cancer investigating BRAF-targeted therapies. However, vemurafenib is a kinase inhibitor against mutatedBRAFand is being investigated in combination with cetuximab and irinotecan in a phase I study for patients with advanced solid malignancies.83Most of the patients enrolled to date have advanced colorectal carcinoma, though the study is open to patients with advanced solid malignancies with theBRAFmutation. The estimated completion date projected for February 2016. Results from this study may have applications to biliary tract cancers.

Clinical Pearls

  • Biliary cancer comprises of 3 heterogeneously distinct, aggressive carcinomas with limited treatment options. Surgery offers the potential for cure if diagnosed at an early stage. Systemic chemotherapy with gemcitabine and cisplatin is the current standard as shown by the ABC-02 trial.
  • Differences exist in response and outcomes between gallbladder, extra and intrahepatic cholangiocarcinoma with better response, but worse survival in gallbladder, lesser response but improving survival in extra and the least response and higher survival in intrahepatic cholangiocarcinomas that may be explained by biological differences that may allow inclusion of enriched populations to biomarker-driven targeted agent trials in the future.29
  • Optimal adjuvant therapies still need to be defined for patients with resectable biliary cancers.
  • Pathways characterized in biliary carcinoma include EGFR, VEGF, and MEK. Agents targeted against EGFR include erlotinib, cetuximab, and panitumumab. Agents against VEGF include bevacizumab, sorafenib, sunitinib, and cediranib. Selumetinib is a small molecule inhibitor with activity against MEK, which plays a key role in the RAS/RAF/MEK/ERK signaling pathway. Although these drugs are well tolerated, several phase II clinical trials have not shown significantly improved benefit in outcomes compared with standard systemic chemotherapy
  • Other pathways have been identified as having potential roles in the carcinogenesis of biliary cancer. These include FGFR, BRAF, PIK3CA (phosphatidylinsositol-3-kinase pathway), c-MET (hepatocyte growth factor receptor), BAP 1 (BRCA associated protein 1), and IDH 1/2 (isocitrate dehydrogenase). Novel agents include BGJ398, neratinib, BKM120, cabozantinib, vemurafenib, and AG-120. Early-phase investigations are ongoing to determine the tolerability and potential efficacy of targeted therapies against these signals

c-MET is a proto-oncogene encoding HGFR (hepatocyte growth factor receptor) and is involved in multiple signal transduction pathways including MAPK and PIK3.84It has been identified in biliary cancers, mostly in cholangiocarcinoma compared with gallbladder carcinoma.53Cabozantinib is a small molecule inhibitor that blocks the activity of c-Met tyrosine kinase. In mouse xenograft models of hepatocellular carcinoma, cabozantinib was shown to block the MET pathway and result in decreased number of HCC metastases.85Although there are no clinical trials investigating c- MET inhibitors, this remains a potential target for biliary cancer.

BAP1(BRCA-associated protein 1) is a chromatin remodeling gene encoding a nuclear deubiquitinase.86While associated with many types of cancers, it has been recently found to be expressed in intrahepatic cholangiocarinomas.87,88There is emerging evidence thatBAP1may be integral to a cancer predisposition syndrome, resulting in melanoma, mesothelioma, and other cancers including biliary tumors.89,90There are currently no clinical trials investigating agents targetingBAP1.

Mutations ofisocitrate dehydrogenase,IDH1, andIDH2have been identified in intrahepatic cholangiocarcinoma at a frequency of 23%.91Involved in the conversion of isocitrate to α-ketoglutarate during Krebs cycle, mutations inIDH1/2result in the accumulation of the oncometabolite 2-hydroxyglutarate (2HG), which promotes tumorigenesis through cellular gain-of-function activity.92These mutations have also been shown to play a role in blocking hepatocyte differentiation through suppression of HNF-4α, which is a regulator of hepatocyte identity and quiescence.93The orally available, IDH1 inhibitor AG-120 is currently being investigated in a phase I multicenter trial in patients with advanced solid tumors including cholangiocarcinoma.94The estimated completion date is in early 2016.

Other studies have also explored novel agents in combination against the more established targeted pathways involving VEGF and MEK. Recently presented at the 2013 AACR meeting, a phase I study testing the combination of pazopanib and trametinib in advanced solid tumors including cholangiocarcinoma showed a tolerable side-effect profile.88Pazopanib is a multitargeted tyrosine kinase inhibitor with activity against VEGF and EGFR, and trametinib is an orally available inhibitor of MEK 1 and 2. In this phase I trial, grade 3 adverse events included diarrhea and elevated LFT’s (15%), hypertension (12%), and fatigue (8%).88 Preliminary results showed that 19/25 had stable disease or a partial response, though further testing of these agents is needed.

Lastly, applications for targeted antitumor immunotherapy are also being developed for patients with advanced cholangiocarinoma. The Rosenberg group recently showed that adoptive transfer of tumor-infiltrating lymphocytes (TIL) specific for HER-2/ERBB2 interacting protein (ERBB2IP) produced tumor responses in both the liver and lung of a specific patient.95Although these effects were reported for a single patient, adoptive immunotherapy holds promise in the treatment of advanced biliary cancers.

In summary, many molecular targets in biliary cancer have emerged in recent years. It is readily apparent from these new areas of research and novel drug development that treatment for biliary malignancies is becoming increasingly focused on the identification and targeting of genetic mutations specific to a particular patient. While this represents a different approach than existing treatment options including surgery and chemotherapy, which more broadly address the phenotypic characteristics of biliary cancer, new targeted therapies have the potential to strengthen the multimodality approach to biliary cancer treatment. As more and more targeted therapies are tested through the clinical trial pipeline, there remains enthusiasm in developing personalized treatments with tolerable side effects.

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