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Lisa Garvin: Welcome to Cancer Newsline, a podcast series from the University of Texas MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention providing the latest information on reducing your family's cancer risk. I'm your host Lisa Garvin. Today we're going to be talking about bile duct cancer, also known as cholangiocarcinoma and our guest today to speak on that is Professor and Dr. Milind Javle who is in the Gastrointestinal Medical Oncology Department here at MD Anderson. Dr. Javle we talked about this disease a year ago but it seems that there are some advances and we will definitely get to that but bile duct cancer is a pretty aggressive type of cancer, is it not?Dr. Milind Javle: Most of the time it is diagnosed at an advanced and inoperable stage, this cancer is one of the most rapidly rising cancers, it's still not very common, however it is one of the most rapidly rising cancers in the Western world. So clearly we need innovative approaches to cure this cancer.Lisa Garvin: And typically in the past they were often times discovered pretty late in stages. I mean I had a personal experience with that with a friend who basically came to MD Anderson and she was gone within a couple of weeks at stage 3, so is this a disease that presents pretty late?Dr. Milind Javle: Yes, unfortunately it present quite late, so there's two kinds of bile duct cancers, one that occurs within the liver, I'll call it intrahepatic bile duct cancers and those cancers can grow quite substantially without really having any symptoms because the liver has a great capacity for regeneration. There's the other kind that's called extrahepatic that arises in the bile ducts outside the liver that causes jaundice and that is detected relatively early.Lisa Garvin: So which is cholangiocarcinoma specifically?Dr. Milind Javle: So both are cholangiocarcinoma is a term used for bile duct cancer and it has to be distinguished from liver cancer which it is not because it is not involving liver cells or gall bladder cancer which is by the bile duct but it is a completely different entity.Lisa Garvin: So what was the standard of care say about five years ago for bile duct cancers?Dr. Milind Javle: So the standard of care is surgery, the patient is diagnosed at an advanced stage of disease. Sorry, the standard of care is surgery if the patient is diagnosed at a localized stage of disease, unfortunately most patients present in advanced disease stage and for them the only option available was chemotherapy and five years ago it was gemcitabine or 5FU. These are the old traditional chemotherapies that have been around now for now over 20 years.Lisa Garvin: And with high toxicities as well.Dr. Milind Javle: That's right with high toxicity and low efficacy.Lisa Garvin: So you said that you were working on...well, let's talk about immunotherapy that is definitely a big push here at MD Anderson as a whole, how is immunotherapy working to treat bile duct cancers?Dr. Milind Javle: So immunotherapy as you know has made very impressive strides in diseases like melanoma, kidney cancer, lung cancer and it seems like this maybe another disease where we might see some impressive responses with immunotherapy. The goal of immunotherapy is that we administer agents so that the tumor itself is recognized as foreign, within the body and the T cells which are responsible for eliminating any extraneous objects, infections, etc. are then likely to attack the tumor. So there are several agents that are investigational and a couple that have been approved particularly in melanoma. We have found that these immunotherapeutic agents in early studies have shown impressive responses in cholangiocarcinoma, so it's an active area of development in this disease.Lisa Garvin: Is that dasatinib or...Dr. Milind Javle: So one of the first studies that was conducted in cholangiocarcinoma was with this agent called pembrolizumab which is known by the brand name Keytruda and is now approved for melanoma. In a pilot study about 20 patients with cholangiocarcinoma were also enrolled and were treated with Keytruda and I know that there was stability seen in some of these patients and an impressive response in at least one of those patients who was treated in California. So the final data are yet to be out, there is another approach to immunotherapy which is T cell related therapy where a patient was treated in NCI, this woman with very advanced disease and had a very impressive, almost complete response with the T cell therapy. And this article was featured in the New York Times several months ago. At our own center we are doing a trial with a drug called IL10 and this IL10 is a subcutaneous injection, it is an investigational trial. The side effects of this therapy are mild to very modest at the most and we have found that at least in a couple of patients we have seen stability in one patient who also receives chemotherapy and has had a good response that has lasted for over five months. So It's clearly and area of development and I feel like we are going to see some impressive results in the near future.Lisa Garvin: IL meaning interleukin?Dr. Milind Javle: That's right, interleukin 10, interleukin 10 is an anti-inflammatory agent which has been in investigation for other autoimmune diseases, Crohn's, rheumatoid arthritis and so on and it seems to be quite an active anticancer agent, at least in the lab and in mice bearing cancers so there are several trials with this drug in lung cancer, renal cell cancer, melanoma and fortunately for us also in cholangiocarcinoma.Lisa Garvin: You said another area you were looking at it was mutation profiling which is basically you're assessing and discovering the mutations that may be responsible for this cancer. It sounds like you've been able to identify enough mutations to craft targeted therapies.Dr. Milind Javle: That's right Lisa we recently had a study with 75 patients and this paper is going to be published just in a few weeks in [inaudible]. We found that in 75 patients that there are some distinct subgroups that have genetic profiles that we can target with targeted therapies. For instance there is a group of patients who have mutations in their gene called FGFR, we found first of all that these mutations seem to predict a relatively indolent prognosis that is patients who have this kind of mutations have a much better natural history of the cancer and people seem to live for a long time even in the presence of advanced disease. Secondly, it seems like this mutation can be targeted by specific targeted inhibitors that are in development. So we have a clinical trial with an FGFR inhibitor which is [inaudible] this particular mutation. On the other hand we found some other mutations, for instance there was another mutation called BAP1 which was described in a kind of lung cancer called mesothelioma which predicts a very aggressive prognosis and we found that a few patients who had BAP1 mutation and had undergone surgery had a very rapid recurrence of the tumor which occurred within weeks. So when you see data of this nature I think this is going to inform our decisions regarding therapy, whether these patients should be offered clinical trials, investigational therapies rather than be put on very aggressive surgical resections which may perhaps not be useful for this type of mutation. So really we have several such mutations identified in studies done here at MD Anderson and it has helped us to identify subgroups that have really good prognosis as well as subgroups that can be targeted with specific inhibitors that are either approved or in clinical trials. I think a time will come like in breast cancer where therapy choices will be determined by the underlying mutation profile of the patient. For instance in breast cancer we treat HER2 mutation with Herceptin or we would treat a hormone receptive positive breast cancer with tamoxifen. This sort of guided therapy doesn't occur...does not exist for most solid tumors but I think in this particular disease type I see this happening in the not too distant future where we will have distinct therapy subgroups.Lisa Garvin: You were saying it would also help you with prognosis; it would more easily help you to determine who would benefit from surgery, who would benefit from not having surgery, correct?Dr. Milind Javle: That's right for instance KRAS mutation which is a very commonly occurring mutation in solid tumors occurs in about 30% of cholangiocarcinomas, we found that those patients who have a KRAS mutation have a pretty aggressive prognosis, on the other hand those who do not have the mutation and those tumors that are [inaudible] KRAS type have a relatively much better prognosis and those patients may perhaps be benefitted by aggressive surgical resections. Patients for instance with the FGFR mutation who have a good prognosis might perhaps be benefitted by even consideration of liver transplantation because the disease is not terribly aggressive. On the other hand KRAS mutated patients like I described earlier, BAP1 mutated patients you know maybe we need to give them chemotherapy first or investigational therapies first to assess the course of the disease and the base of their tumor before we offer them an aggressive surgical resection.Lisa Garvin: Well, it sound like immunotherapy and mutation profiling has allowed you to take major steps forward in this disease in a very short time.Dr. Milind Javle: That's right, in fact February of this year we have a meeting in Salt Lake city which is the Cholangiocarcinoma Foundation which I happen to be chairing and we are going to have a large session on how we can refine therapy of this disease using immunotherapeutic approaches as well as target therapies based on mutation profiling. So I look forward to learning in that meeting.Lisa Garvin: It sounds like you've got your work cut out for you.Dr. Milind Javle: Thank you, I do.Lisa Garvin: If you have questions about anything you've heard today on Cancer Newsline contact ask MD Anderson at 1 877 MDA-6789 or online at ask. Thank you for listening to this episode or Cancer Newsline, tune in for the next podcast in the series. ................
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