Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer

Abstract

Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.

Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics

“…As a result of the relative rarity, difficulties in obtaining preneoplastic cells and benign background epithelial cells for study, and other reasons, there is little scientific knowledge on gallbladder precursor lesions compared to lesions in other organs [ 70 , 71 ]. We hope recent new technologies will provide precision data regarding precursor neoplastic lesions of the gallbladder in the near future.…”

Trends in Primary Gallbladder Cancer Incidence and Incidence-based Mortality in the United States, 1973 to 2015

“…54 Recently, the FUGA-BT (JCOG1113) phase III randomized clinical trial in 354 Japanese patients with advanced/recurrent biliary tract cancer (including 137 patients with GBC; 38.7% of the population) showed that a combination of gemcitabine and an oral fluoropyrimidine (S1) was noninferior to the gemcitabine/cisplatin combination (median overall survival 15.1 vs. 13.4 months, respectively; HR: 0.945; 90% CI: 0.78-1.15; P = 0.046). 74,75 Similarly, another Japanese phase III trial (KHBO1401-MITSUBA) showed a slight benefit of the gemcitabine/cisplatin/S-1 combination over gemcitabine/ cisplatin) in advanced biliary tract cancer, including GBC. 76 Lastly, adjuvant chemotherapy before recurrence has been shown to improve the overall survival in patients with recurrent GBC after curative intent surgery (HR = 0.56, P = 0.027).…”

“…In patients diagnosed with resectable GBC with curative intent, adjuvant capecitabine is indicated based on the BILCAP trial that showed an improvement of overall survival by 17 months in patients with resectable biliary tract malignancies, including a 17.7% of the population diagnosed with GBC 54. Recently, the FUGA-BT (JCOG1113) phase III randomized clinical trial in 354 Japanese patients with advanced/recurrent biliary tract cancer (including 137 patients with GBC; 38.7% of the population) showed that a combination of gemcitabine and an oral fluoropyrimidine (S1) was noninferior to the gemcitabine/cisplatin combination (median overall survival 15.1 vs. 13.4 months, respectively; HR: 0.945; 90% CI: 0.78-1.15; P =0.046) 74,75. Similarly, another Japanese phase III trial (KHBO1401-MITSUBA) showed a slight benefit of the gemcitabine/cisplatin/S-1 combination over gemcitabine/cisplatin) in advanced biliary tract cancer, including GBC 76.…”

MiR-4733-5p promotes gallbladder carcinoma progression via directly targeting kruppel like factor 7

“…GBC is an extremely aggressive cancer with 5-year survival rate no more than 5%, especially for those advanced-stage patients. There still no curable treatment methods for advanced GBC patients [ 23 , 24 ]. It is critical to clarify the underlying mechanisms of GBC progression.…”