Driver Mutations in Advanced Cholangiocarcinoma

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Saeed Sadeghi, MD: Next-generation sequencing has identified a variety of mutations and genetic changes that occur in cholangiocarcinoma. Of the very common ones is the fibroblast growth factor receptor 2 [FGFR2] aberrations and rearrangements, as well as mutations that tend to occur in about 10% to 16% of intrahepatic cholangiocarcinomas. Additional mutations include IDH1 and IDH2. ROS1 rearrangements occur in about 8% to 9% of patients. IDH1 and IDH2 mutations occur in about 25% of cases. EGFR amplification has been reported in 16% of cases. HER2 [human epidermal growth factor receptor 2] amplification has been reported in 11% to 20% of cases. Finally, a very small subset of patients has the BRAF V600E mutation, and that tends to occur in about 5% of patients.

The targets that have been identified may be predictive of response if you have the appropriate therapeutic available. There is not a lot of information about the prognostic benefit of the various subtypes of cholangiocarcinoma, perhaps with the exception of the FGFR2 aberrations and rearrangements. Recently presented data at ASCO [the American Society of Clinical Oncology Annual Meeting] retrospectively looked at a group of patients who had the FGFR2 rearrangement. That study identified this in younger women. These patients tend to have a normal CA [cancer antigen] 19-9 level. They have a higher propensity for bone metastases. Interestingly enough, their response to first-line chemotherapy with cisplatin and gemcitabine is usually short—about 6 months. However, taken as a whole, these patients tend to do a lot better, with a median survival around 36 months.

As we have come to the realization that there are actionable mutations that occur in this disease, it’s more important to do next-generation sequencing in all patients who have metastatic cholangiocarcinoma. I am in favor of testing patients who have locally advanced disease as well. It’s important to identify these mutations early, because then there is an opportunity to enroll these patients in clinical trials or, perhaps, give them a targeted therapy for their specific aberration.

Testing for next-generation sequencing should be done at diagnosis in patients who have metastatic or locally advanced disease. In select cases, it is reasonable to actually consider repeat testing at time of progression, based on emerging data that show that by identifying new mutations in patients, you can selectively tailor their future therapies to allow them to have a better response.

Transcript edited for clarity.


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