To patients, families, and medical professionals

About Cholangiocarcinoma (Biliary Tract Cancer)

QWhat is Cholangiocarcinoma (Biliary Tract Cancer)?

AThe bile ducts are the tubes through which bile produced in the liver flows to the duodenum.
The bile ducts inside the liver are called intrahepatic bile ducts, those outside the liver are called extrahepatic bile ducts, the pouch that temporarily stores bile is called the gallbladder, and the outlet to the duodenum is called the vater papilla. Cancer arising from these sites are called intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and cancer of the papilla of Vater, respectively. Collectively, these cancers are referred to as biliary tract cancers.
Biliary tract cancer has a very poor prognosis, and therefore new treatments are required.
One promising approach to biliary tract cancer is molecular targeted therapy. The advent of molecularly targeted agents is expected to increase the treatment options for biliary tract cancer and improve the prognosis.

QWhat gene mutation is observed in biliary tract cancer, and what are the targets of molecular targeted therapy?

AOne of the target gene alterations is the FGFR2 fusion gene, a transmembrane receptor tyrosine kinase called the fibroblast growth factor receptor (FGFR). FGFR binds to the fibroblast growth factor FGF to form a dimer, which activates downstream signaling and triggers a variety of cellular responses.
Recently, clinical studies in Japan, Europe, and the United States have revealed that misregulation of FGFR signaling leads to cancer formation and progression.　FGFR2 fusion is one of the gene alterations responsible for this oncogenic activation, occurring in approximately 10% of intrahepatic cholangiocarcinoma, and clinical trials have proved that targeting this alteration contributes to patient’s clinical benefit.

QWhat is FGFR2 fusion gene?

AFGFR2 fusion gene is formed by recombination of the FGFR2 gene with another gene.
For example, when the FGFR2 fusion gene is formed by fusing the PPHLN1, AHCYL1, or BICC1 gene with the FGFR2 gene, an FGFR2 fusion protein is synthesized.
When expressed on the plasma membrane, this protein dimerizes and activates FGFR signaling in the absence of any protein that specifically binds to its receptor, the FGFR. Various cellular responses are then triggered in a homeostatic manner. Thus, cancer cell growth and proliferation are promoted.

QHow is the situation of the development of FGFR inhibitors in biliary tract cancer?

AAs of 2022, the development of FGFR inhibitors is in progress, and some agents are already on the market. Therefore, if FGFR2 fusion genes are detected in biliary tract cancer, treatment with these agents is expected to improve therapeutic outcomes.

About CHOICE study

QWhy are we conducting the CHOICE study?

AOne of the reasons for this study is to understand the characteristics and incidence rate of FGFR2 fusion gene positive cholangiocarcinoma patients in the Asian region. The expression of the FGFR2 fusion gene in intrahepatic cholangiocarcinoma was first reported by Yasuhiro Arai, a senior researcher in the Division of Cancer Genomics at the National Cancer Center. However, despite the reports from Japan, Europe, and the United States as described above, data about the frequency and distribution of patients eligible for these drugs in the Asian region remain limited.
The second reason is that it is foreseeable that FGFR inhibitors will not be available due to resistance or adverse events, and alternative treatments need to be developed. If data on the characteristics of FGFR2 fusion gene-positive biliary tract cancer patients in Asia become more available, the possibility of introducing clinical trials to these patients quickly and adequately will expand.
And the third reason is that by utilizing the NGS method for detecting genomic alterations, it is possible to find genomic alterations that has a potential of being a target for future drugs, other than the FGFR2 fusion gene.

About the testing for genomic alterations

QWhat are the methods for detecting genomic alterations?

AThe FISH method, currently one of the most widely used way to detect genomic fusions, is utilized to detect only a single gene alteration. The advantage of this test method is that results can be obtained in a short time and with a small sample volume. Therefore, we consider it an important test method to confirm the presence or absence of the FGFR2 fusion gene when administering FGFR inhibitors to biliary tract cancer.
On the other hand, the NGS method can comprehensively test not only for FGFR2 fusion gene but also for other genomic alterations all at once. In other words, it is an important test when considering various molecular targeted therapies. However, the NGS method requires a good amount of specimen. In addition, a certain level of equipment, technology, and experience is required to implement it.
The National Cancer Center Hospital Japan has these resources and a network within Asian countries. We believe that our leadership will enable this study to proceed efficiently. The CHOICE study will check for the presence or absence of the FGFR2 fusion gene using both two testing methods and will also examine how the results coincide or differ. Furthermore, we will accumulate data on the other genomic alterations obtained by NGS in all cases.
We believe that the CHOICE study will help us better understand the characteristics of FGFR2 fusion gene-positive cholangiocarcinoma patients and contribute to the improvement of treatment not only in the Asian region but also for patients worldwide.