Gallbladder and Bile Duct Cancer Awareness Month: Improving Screening and Treatment Options With Waqas Haque, MD, MPH, and Matthew Hadfield, DO

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In honor of Gallbladder and Bile Duct Cancer Awareness Month this February, Fellows Forum members Dr. Waqas Haque and Dr. Matthew Hadfield sat down for a discussion on the challenges in diagnosis of gallbladder and bile duct cancers and the importance of genetic sequencing for making targeted treatments available for patients. 

Waqas Haque, MD, MPH: Hi everybody, thanks for joining our Oncology Data Advisor podcast today. My name is Waqas Haque. I’m a third-year Internal Medicine Resident at NYU, and I’ll be starting Oncology Fellowship at the University of Chicago this summer.

Today, we’ll be discussing Gallbladder and Bile Duct Cancer Awareness Month. This is a condition that affects 5,000 to 8,000 people annually, and even though it’s rare, it can be very devastating for patients. I recall in my inpatient oncology service having to take care of patients with late-stage complications of biliary cancer, both intrahepatic and extrahepatic, and also patients with gallbladder cancer—having to track the biliary labs every day, having difficult conversations about goals of care and code status, and really trying to find ways to promote comfort for people in their last moments.

I’ll let Dr. Hadfield introduce himself, and if you want to tell us a little about your experiences in treating these cancers, that would be great, Matt.

Matthew Hadfield, DO: Sure, I’m Matt Hatfield. I’m a third-year Medical Oncology Fellow at Brown University, Legoretta Cancer Center, in Providence, Rhode Island.

Cholangiocarcinoma is a very tough cancer to treat, and I’ve had multiple patients throughout my fellowship training who presented to the hospital. Waqas, I’m sure you’ve experienced this as well, patients who have cholangiocarcinoma can often present with hepatobiliary disease-like obstructive patterns. When they present, they can be very, very sick, and sometimes they can be so sick at presentation that they are difficult to treat with standard treatments.

Thankfully, over the last several years, we’ve had some advancements in treatment of cholangiocarcinoma, particularly the advent of using immune checkpoint inhibitors in combination with chemotherapy, which has improved overall survival. We’ve started to use more whole exome sequencing, identifying different driver mutations such as BRAF and NTRK and HER2. Immunohistochemistry (IHC) expression is something that’s become very relevant in recent years across a lot of solid tumors, but particularly cholangiocarcinoma. It’s a very difficult patient population to treat, unfortunately, and we really do need more novel therapeutic approaches to better prolong survival in this patient population.

Dr. Haque: Thanks for sharing that, Dr. Hadfield. One thing I want to talk about is that I know you recently published a study and review on cholangiocarcinoma in the International Journal of Molecular Sciences. Would you like to talk about some of the interesting points or things you learned that were surprising from your experience with that research?

Dr. Hadfield: I think some of the things that we’ve seen in cholangiocarcinoma haven’t matched up with other malignancies. For instance, there’s tissue-agnostic approval for BRAF inhibitors for BRAF, MET, and all solid tumors expressing BRAF V600E mutations. If you look at the prospective data in cholangiocarcinoma, there are very few patients who have BRAF V600E mutations, but of those that do, they don’t seem to respond as well as other tumors, particularly melanoma, where BRAF/MET inhibitors are second-line standard-of-care therapy with really high response rates and durable responses.

That’s an interesting part of the pathophysiology of how those mutations work in cholangiocarcinoma versus other cancers. I also think some of that may be, again, because people with hepatobiliary cancers tend to be very sick and very hard to treat. They have a lower performance status secondary to their malignancy, so treating them successfully and keeping them on therapy without having significant side effects and toxicities can be very challenging.

Another one of the more interesting things in cholangiocarcinoma that has been developed recently is ivosidenib for IDH1-mutated disease. Ivosidenib now has an FDA approval in the second-line setting, and it is a desperately needed biomarker driven-therapy for those patients who progress on frontline chemoimmunotherapy or immunotherapy alone depending on the performance status. Another interesting thing is MUC1, which is a surface protein that’s been shown to correlate with more aggressive cholangiocarcinoma. There have now been preclinical studies looking at MUC1 antibody-drug conjugates as well as adoptive cellular therapies, so we are developing more therapeutic targets.

I think the big thing that we need to think about with cholangiocarcinoma are, much like every other cancer, that we really need to get a whole exome sequencing on these patients at time of diagnosis. We really need to make sure that if we identify a driver mutation, we treat them with a targeted therapy. These are things that, outside of big academic medical centers, still prove to be very big logistical hurdles for community oncologists, so raising awareness around that issue is really important.

Dr. Haque: Thanks for sharing all of that. I definitely agree about the need for getting better testing for different types of cholangiocarcinoma. I do know that patients who test as HER2-positive by blood-based next-generation sequencing (NGS) may not necessarily be positive on central testing, so the fact that we have a lack of standard HER2 testing is a challenge for diagnosing patients and identifying other lines of therapy. I do think, as you mentioned, finding other biomarkers and finding further lines of treatment are definitely very exciting, because before, only 5% to 10% of patients with advanced disease would respond to second- or third-line therapies and they had a very low progression-free survival. Now we’re seeing improvements with HER2 therapies and the other things that you talked about.

For some of our listeners who might not be as familiar with biliary tract cancers, can you talk a little bit about the demographics of epidemiology for patients who present?

Dr. Hadfield: Typically, there seems to be a predilection for females over males with cholangiocarcinoma. There are about 10,000 to 12,000 cases diagnosed each year, and as I mentioned, these patients typically present at later stages of disease, typically beyond the point at which they can have a resection. Unfortunately, it’s more of a disease control, palliative-intense systemic therapy type of situation for a lot of patients. Patients who have previous predisposing factors include calcifications in the gallbladder, chronic inflammation in that tissue, things of that nature that can predispose you and contribute to the development of cholangiocarcinoma.

Dr. Haque: It definitely all makes sense, and I know that one of the frustrating things we see when it comes to screening is that a lot of the big cancers that we think about, like colon, breast, and lung, have screening guidelines that are set by the United States Preventive Services Task Force (USPSTF). Are there any universal guidelines for gallbladder and biliary cancers?

Dr. Hadfield: Unfortunately, no, there aren’t currently any guidelines. We don’t have good screening measures as we do for even things like low-dose computed tomography (CT) scans for lung cancer in at-risk populations who are smokers. We don’t have that for cholangiocarcinoma, unfortunately. It’s similar to pancreatic cancer, where you see a very insidious onset of disease. Patients can be fine for a long time and then they end up developing a pathology such as an obstructive pattern where they ultimately kind of tip over and end up needing inpatient care or workup. Only at that point do we realize that they have cholangiocarcinoma and how sick they are. Unfortunately, we don’t have good imaging or blood-based screening tests for catching it early.

Dr. Haque: I definitely agree. There’s really nothing right now that we can universally recommend to patients to get. Sometimes people ask, “Should I get my gallbladder removed if I have a family history?” Those things aren’t really settled in the literature either. There is some exciting news of a study recently published in Lancet where a team in India looked at abdominal ultrasound and used a machine learning artificial intelligence (AI)–based model to screen and detect gallbladder cancer. They’re actually able to get the same sensitivity as radiologists, so perhaps in the future we might be able to move the needle in that regard.

Are there any other points you’d like to make?

Dr. Hadfield: That’s very interesting. You and I were talking before this about the concept of AI and machine learning to help better augment radiological readings and try and bolster our sensitivity for screening and diagnosis. Certainly, those types of avenues will hopefully bring more advancements so we can catch disease earlier, because to be honest, catching it before someone progresses to the point beyond resection would be the goal. You don’t want to have to treat people with systemic therapies.

The big thing that I would reiterate is that I think it’s ingrained at large academic medical centers that whole exome sequencing really informs care, and it does make a huge difference in opening up treatment options—not just standard of care for more nuanced and rare mutations that could open up doors for targeted therapy, but also for clinical trials. There are lots of novel therapeutic approaches, to your point. There are a lot more HER2-directed antibody-drug conjugates that are in development. Testing for things like HER2 IHC expression is really important, and there have been lots of studies published over the last 10 years showing that as we get into more rural centers, patients aren’t getting whole exome sequencing as much. I think raising awareness around that and making sure that we really are sequencing our patients and opening up every treatment option, be it the standard of care or a trial, is the most important thing.

Dr. Haque: Thanks for sharing those insights, Dr. Hadfield. As I reflect on this month, there are just a couple of take-home points. One for the public, as we talked about—there are not really any universal screening guidelines for detecting gallbladder or biliary cancer, so I really emphasize the importance of having a healthy lifestyle, avoiding smoking, trying to cut down on drinking, having a healthy diet, and exercising. The second is for physicians and providers—the role of whole exome sequencing and the importance of making sure patients are getting sequenced and getting genetically tested so that we can open up different lines of therapy for patients who progress on what we have right now.

Thanks so much, Matt, for sharing your thoughts and answering those those questions, and thank you all for listening. Have a good rest of your day.

Dr. Hadfield: Thank you so much.

About Dr. Haque and Dr. Hadfield

Waqas Haque, MD, MPH, is a third-year Internal Medicine Resident at NYU in a Clinical Investigator Track. He is an incoming Oncology Fellow at the University of Chicago. Dr. Haque’s research interests include innovative clinical trial design, value-based care delivery to cancer patients, and becoming an early-stage clinical investigator.

Matthew Hadfield, DO, is a Hematology/Oncology Fellow at Brown University/Legoretta Cancer Center in Providence, Rhode Island. His research focuses on melanoma and early-phase clinical trials, including development, novel immunotherapeutic combinations to overcome therapeutic resistance, and predictive biomarkers for immunotherapy toxicities.

For More Information

American Association for Cancer Research (2024). February is gallbladder and bile duct cancer awareness month. Available at: https://www.aacr.org/patients-caregivers/awareness-months/gallbladder-cancer-and-bile-duct-cancer-awareness-month

Hadfield MJ, DeCarli K, Bash K, et al (2023). Current and emerging therapeutic targets for the treatment of cholangiocarcinoma: an updated review. In J Mol Sci, 25(1):543. DOI:10.3390/ijms25010543

Gupta P, Basu S, Rana P, et al (2024). Deep-learning enabled ultrasound based detection of gallbladder cancer in northern India: a prospective diagnostic study. Lancet Reg Health Southeast Asia, 100279. [Epub ahead of print] DOI:10.1016/j.lansea.2023.100279

Transcript edited for clarity. Any views expressed above are the speakers’ own and do not necessarily reflect those of Oncology Data Advisor. 

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