Cholangiocarcinoma: One Size Does Not Fit All

In the ever-changing landscape of cancer, targeted therapies and precision medicine are altering the way the disease is treated, and cholangiocarcinoma, a rare liver cancer, is no exception.

Cholangiocarcinoma, which starts in the bile duct — a thin tube that runs from the liver to the small intestine — can be treated with surgery when found early enough. However, the disease is usually diagnosed after it has advanced and is then likely treated with chemotherapy. Recent advances in molecular profiling and targeted therapies may change that approach. For example, the phase 3 PROOF trial is currently evaluating the safety and efficacy of infigratinib, an orally bioavailable FGFR 1-3 inhibitor of human fibroblast growth factor receptors (FGFRs), compared with standard of care chemotherapy for the frontline treatment of patients with unresectable or metastatic, FGFR-positive cholangiocarcinoma.

CURE® spoke with Sameek Roychowdhury, M.D., Ph.D., an associate professor in the department of internal medicine at the Ohio State University Comprehensive Cancer Center, about cholangiocarcinoma and the importance of molecular testing in determining treatment options.

CURE®: In what ways is cholangiocarcinoma not a one-size-fits-all disease when it comes to treatment?

Roychowdhury: Cholangiocarcinoma involves parts of the liver and bile duct, and the patients who have such a cancer may have different treatment needs. We are starting to learn that different subtypes exist, and not all cholangiocarcinoma is the same. One of the most important things we have found out is that we must complete molecular characterization or genetic testing in patients. That helps us choose different types of therapies for patients based on subtype.

Why should patients ask about molecular profiling?

Without tumor molecular profiling information, it will be hard to match a patient to the therapy that might be best suited to them. Otherwise, we may be taking shots in the dark. Beyond chemotherapy, there are new, emerging targeted therapies (and) immune therapies, which might be a fit for one patient but not for another. That profiling will help make that choice to match patients to the therapy that will benefit them. Once we have identified a molecular driver or gene in someone’s cancer, there is no guarantee that therapy is going to work with certainty, but it is much more likely than choosing a random therapy without knowing that information.

What role does the FGFR gene mutation play in the disease?

Fibroblast growth factor receptors are genes that we have seen altered in patients with cholangiocarcinoma. These alterations seem to be more common in patients who are younger or female, but that is not an absolute finding. Being able to detect these genes could help match patients to an FGFR inhibitor (a targeted drug). The mutation or fusion is thought to activate the receptor and provide the cancer the ability to grow and travel to other parts of the body. New drugs that inhibit these receptors , called kinase inhibitors, can, hopefully, shut down the receptor encoded by the altered gene and decrease its ability to grow and invade these other organs, benefiting the patient.

What is the typical course of treatment for this type of disease?

The standard treatment is a combination of chemotherapy, which can be very effective for some patients. In some instances, it is not effective, and today most of our patients undergo this molecular testing to identify these genetic changes and help us choose the next therapy. So far, we have seen some success with FGFR inhibitors. These have been studied in patients who have already had chemotherapy, and now findings are emerging that suggest offering these drugs earlier. In new studies coming out, patients with FGFR-positive cholangiocarcinoma are being randomized to receive either chemotherapy or FGFR inhibitors. Right now, we don’t know which one is going to be better upfront, and that is why these studies are being done.

What is your advice for patients with cholangiocarcinoma?

The most important thing is that patients are aware that they should undergo molecular testing of their tumor. Also, it is very important that they travel to local comprehensive cancer centers, where they have access to new clinical trials for cholangiocarcinoma. There are many therapies emerging, such as targeted therapies and combinations, and some are being introduced at the beginning of treatment. So, before patients have even had standard chemotherapy, many of these trials will offer these novel therapies.

This content is sponsored by QED Therapeutics.