Comprehensive insight on staging biliary tract cancers followed by an overview of molecular testing and targetable clinicopathologic features.
Milind Javle, MD: While we are on the topic of cancer and the extent, surgeons stage them better than anyone else, Flavio. We often see them in the locally advanced in metastatic stage. Could you briefly touch on the staging of these different cancers from a high level?
Flavio G. Rocha, MD, FACS, FSSO: Thank you, Milind. I’ll echo what Mark was saying. Colon cancer metastatic to the liver, which is something else that I treat, is much more common than intrahepatic cholangiocarcinoma, so we do have to do our due diligence to exclude a GI [gastrointestinal] source. As far as staging, surgeons are very visual people. Cross-sexual imaging is key for staging and preoperative planning. Typically, a high-quality multiphase CT is what we rely on because we want to see what the extent in the liver is and what the relationship to vascular structures might be. Of course, for preoperative planning purposes, how much liver can we leave behind? The other important piece for hilar cholangiocarcinoma specifically is looking at the extent of biliary involvement, because these tumors tend to be at the confluence. We must make a decision as a surgeon whether we’re going to go to the right or left, or to take out the liver. We want to have high-quality imaging via MRCP [magnetic resonance cholangiopancreatography] if possible. If that’s not conclusive, then that’s when we rely on direct cholangiography to get a good image.
Those are the things we probably use most frequently. There are some preoperative classification systems, so the bismuth chelate is probably the 1 that most people are familiar with. It looks at the up-and-down extent. Think about the bile duct, but that’s only 1 dimension. We know cancers don’t grow in 1 dimension; they grow in 3 dimensions. More recently, we adopted the Blumgart staging system for hilar cholangiocarcinoma, so we look at both the biliary involvement as well as the extent of vascular involvement to determine resectability. That’s how we determine the staging. Certainly, once the pathology is out, then we tend to follow the AJCC [American Joint Committee on Cancer] guidelines. Those have been recently updated in the eighth edition [of the Cancer Staging Manual]. It was nice to see that intrahepatic cholangiocarcinoma was split out from paracellular carcinoma, and we have some guidelines about the lymph nodes and their significance as well.
Milind Javle, MD: Mark, there’s been so much excitement about targeted therapy in cholangiocarcinoma. There’s so much focus on immunotherapy in biliary tract cancer. Could you highlight a little about the various pathways that are of interest? Then is this a hot tumor or a cold tumor? Is this tumor immuno-responsive or is it not immuno-responsive? How do you judge all these things in the clinic?
Mark Yarchoan, MD: This is such an important topic, so thanks for giving me the chance to answer. My recommendation for medical oncologists who don’t treat this cancer all day is that all these patients should absolutely get molecular testing done. In particular, molecular testing that includes not just DNA but also RNA is very helpful because these tumors often have rearrangements or other alterations that happen at the RNA level that can be missed with DNA sequencing. The joke that I tell our oncology fellows is that cholangiocarcinoma is the lung cancer of the GI oncologist, and a huge percentage of these patients have something actionable that you find if you order molecular subtyping. How often is it? About a third of patients have some alterations, some pathway that can be targeted as standard of care. I’m not talking about something on a clinical trial. I mean standard pathway with an FDA-approved or NCCN [National Comprehensive Cancer Network]–recommended agent.
What pathways are we talking about? For the first time, we have drugs approved for cholangiocarcinoma that target FGFR2 fusions or rearrangements. Milind was instrumental in developing some of these drugs. This is found in about 15% of patients with intrahepatic cholangiocarcinoma, so it’s not extrahepatic. It’s intrahepatic cholangiocarcinoma. We have 3 drugs—pemigatinib, infigratinib, and likely futibatinib very soon—that can be used to target this. IDH1 mutations are also common in intrahepatic cholangiocarcinoma. We have itacitinib, which can prolong PFS [progression-free survival] in the subgroup of patients. You never know what you’re going to find. You find mismatch repair deficiency, high TMB [tumor mutational burden], and NTRK or BRAF V600E mutations. HER2 [human epidermal growth factor receptor 2] is quite common, particularly in extrahepatic cholangiocarcinoma and gallbladder cancer. You never know what you’re going to find until you order the testing, and it’s critical that patients get this done.
I think there was a second part to your question, about immunotherapy for cholangiocarcinoma. I’m sure we’ll be talking about this in more detail, but in general, unfortunately, biliary tract cancers tend to be relatively immune resistant. The response rate to anti–PD-1 or anti–PD-L1 therapy in unselected populations of biliary tract cancer is in a range of 5% to 10% if you look at the totality of all the data. Some studies are a little higher, some a little lower. If you were to subtract the patients who have mismatch repair deficiency or high TMB, the response rate would likely be even lower than that. This is an immune-resistant tumor type. Part of the reason why the interest in immunotherapy is in combination with other agents is because the activity isn’t high enough as a single agent.
Transcript edited for clarity.