Targeting the Mutations Seen in Cholangiocarcinoma

Mutations in certain genes can lead to cancer

If you look close enough, you'll see that every part of your body is made up of cells.

Inside each cell is DNA that contains all of your genes. Genes provide instructions to make the proteins (sometimes called "molecules") that keep your cells and your whole body healthy and functioning.

While you go about your life, some cells in your body are multiplying and older cells are dying off. This is done through a very structured process, with lots of checkpoints along the way to make sure all of the DNA gets properly copied.

Sometimes, a mistake happens when the DNA is being copied. Other times, DNA may be damaged by things like smoking or ultraviolet rays from the sun.

When a gene within DNA is damaged, that's called a "mutation". Mutations can take many forms. Depending upon which gene is altered, the defective protein that results could affect how a cell functions.

If there is a mutation in any of the genes that controls when a cell multiplies or dies off, the cell could keep multiplying with the altered gene. This type of rogue, multiplying cell is called a cancer cell. As it continues to multiply, these cells can form a tumor. So cancer cells need specific proteins (sometimes called "molecules") in order to survive, multiply and spread.

Of course, it's all much more complicated than that and there are other ways in which cells can become cancerous. The important thing to understand is that some mutations in certain genes can lead to cancer.

Targeted therapies seek out cancer cells with a specific mutation

Mutations in certain genes can lead to cancer

Radiation and surgery target cancer in a particular location within the body.

Chemotherapy drugs affect cells in the body that are in the process of quickly multiplying. So in addition to cancer cells, they may affect healthy cells that quickly multiply, like hair follicles, nails, and the mucus membranes that line the mouth and stomach. This can cause some of the common side effects seen with chemo, like hair loss, nausea and mouth sores.

Targeted therapies are designed to interfere with, or target, cancer cells that have a certain molecule or feature. By going directly after cancer cells, one goal of targeted therapies is to reduce the effects of the therapy on healthy cells; however, it is important to note that these therapies don't just hit their target cells. There may be "off target" effects to healthy cells as well. Some doctors call targeted therapies "clean" or "dirty" inhibitors based on how accurately they hit their target.




Most targeted therapies work by preventing cancer cells from multiplying and
spreading to other parts of the body. Like many cancer therapies, targeted
therapies may:

  • Stop cancer cells from multiplying by disrupting the multiplication process
  • Help the body's immune system to find and destroy cancer cells
  • Stop signals that help tumors form new blood vessels that fuel their growth
  • Cause cancer cells to die off
  • Deliver substances that kill cancer cells directly to these cells

Examples of known mutations in cholangiocarcinoma

Even among people with the same type of cancer, not all cases of that cancer are the same. If we think about cholangiocarcinoma, people with a tumor in the same location—intrahepatic cholangiocarcinoma (iCCA), for instance—could have different mutations that are driving (causing) their cancer. Let’s look at a few…

HER2

Too much of a good thing isn't so good! Such is the case with HER2. The HER2 gene provides the instructions for making HER2, a protein involved in normal cell reproduction (growth).

In some cancer cells, the HER2 gene is "overexpressed", meaning the cell produces too much of the HER2 protein. Cancer cells may also have an "amplified" HER2 gene, where there are multiple copies of the gene within the DNA. This also leads to the production of too much HER2 protein.

HER2 overexpression and HER2 amplification can both instruct cancer cells to grow more quickly.

HER2 overexpression and amplification are seen in 5-11% of extrahepatic cholangiocarcinoma (eCCA) tumors. While the significance of HER2 in CCA isn't as well understood as it is in breast cancer, it is linked to more invasive cases of CCA and is associated with an increase in cell growth.

NTRK Fusions

NTRK genes provide instructions for producing TRK proteins. TRK proteins are receptors found on the surface of some cells. When certain molecules bind to these receptors, they trigger a series of signals inside a cell that controls cell survival.

Sometimes, a piece of the chromosome that contains the NTRK gene breaks off and gets stuck to a gene in another part of the DNA. This results in an "NTRK fusion" gene. This gene fusion then provides faulty instructions that produce abnormal TRK proteins. The gene fusion may lead the cell to produce too many of these faulty receptors. The faulty receptors can also trigger the cell into action, even without the molecules that typically need to bind to the receptors to activate them. This is just the sort of hyper-signaling that can drive the growth of cancer cells.

NTRK gene fusions are sometimes seen in cholangiocarcinoma, as well as a wide range of cancers, including brain, head and neck, thyroid, lung and colon cancer.

IDH1 and IDH2

The IDH1 and IDH2 genes provide instructions for producing the IDH1 and IDH2 enzymes. These are key enzymes involved in a cell's metabolism and help in repairing faulty DNA.

Mutations to IDH genes can lead to increased cell growth and aid the growth of
new blood vessels to feed a tumor. These mutations are seen in about 25% of intrahepatic cholangiocarcinoma (iCCA) tumors.

FGFR

There is a family of four fibroblast growth factor receptor (FGFR ) genes: FGFR 1, FGFR 2, FGFR 3, and FGFR 4. These four genes provide the blueprint for producing four fibroblast growth factor (FGF) receptors that are found on the surface of many types of cells.

In healthy cells, when an FGF molecule attaches to an FGF receptor, it triggers a series of signals that help tell the cell to perform a specific function. That's how cells know when to multiply or when it's time to die off.

In some cancer cells, one of the FGFR genes is mutated or fused to another gene, causing the cell to produce faulty FGF receptors. These receptors can then signal the cell to multiply—even without an FGF molecule.

FGFR mutations and gene fusions are found in many cholangiocarcinoma tumors. Most often, these are FGFR 2 fusions, which are seen in iCCA.

Targeting mutations to treat cholangiocarcinoma

As researchers come to better understand the role of various mutations in CCA, there has been great interest in studying targeted treatments for this cancer. Let’s look at three areas of interest that target mutations seen in cholangiocarcinoma: TRK inhibitors, mutant IDH inhibitors, and FGFR inhibitors…

Targeted therapies with the same target may have important differences

Even when targeted therapies are in the same “class”—that is, they are designed to go after the same targets, the individual drugs in that class are not identical. Their differences could be important for particular patients.

Talk with your doctor about which treatment option might be right for you.

Clinical trials can help identify new uses for targeted therapies

Many of the mutations seen in cholangiocarcinoma are also seen in other, more common cancers. This has given researchers more experience with these mutations. It has also led to the development of targeted therapies that address some of these mutations.

Researchers have found that sometimes a targeted therapy that works in one cancer may have potential in some of the other cancers that have the same mutation.

One way researchers learn which cancers a targeted therapy may affect is to conduct a basket trial. Basket trials study a drug in patients with different kinds of cancer who all have the same mutation.

Having your tumor tested may reveal mutations

Cholangiocarcinoma is associated with many different genetic mutations. In fact, about half the patients with CCA have at least one of these mutations. As we've discussed, some mutations associated with cholangiocarcinoma are also seen in other cancers.

Genetic Mutations and Other Changes Seen in CCA

Genetic mutations or changes Prevalence in CCA
CDKN2A mutation 47% (iCCA)
KRAS mutations 22% (iCCA)
42% (pCCA/dCCA)
TP53 mutation 27% (iCCA)
40% (pCCA/dCCA)
IDH1/IDH2 mutations 25% (iCCA)
HER2 amplification 11-20% (pCCA/dCCA)
EGFR overexpression 16% (iCCA)
FGFR2 mutations/fusions 10-16% (iCCA)
PIK3CA mutation 4-9%
BRAF mutation 1-5%
NTRK1 fusions Rare

iCCA = intrahepatic cholangiocarcinoma
pCCA = perihilar cholangiocarcinoma
dCCA = distal cholangiocarcinoma

Adapted from Pillino et al, Translational Gastroenterology and Hepatology, 2018; Amatu et al, ESMO Open, 2016.

Your doctor can send cells taken from your tumor to a laboratory to learn which mutations are at play in your own cancer. You might hear this called “biomarker testing”, “tumor profiling”, “molecular profiling” or “molecular testing”.

Having your tumor tested will tell you and your doctor more about your cancer and help to determine which treatment options might be right for you.

Learn more about biomarker testing.

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