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Precision Medicine for Pancreatic Cancer

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Winson Y. Cheung, MD, MPH, University of Calgary and CancerControl Alberta; Manuel Hidalgo, MD, PhD, Harvard Medical School and Beth Israel Deaconess Medical Center; Ramesh K. Ramanathan, MD, Mayo Clinic; Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Thomas Seufferlein, MD, University of Ulm
Published Online: Wednesday, Oct 11, 2017



Transcript: 

Johanna C. Bendell, MD: It’s fascinating. As we’re breaking down, more and more, the biology of how pancreatic cancer works, we’re going to see (later on, when we talk about new and emerging therapies), that it gives us more targets. We don’t just think, again, about the cell itself, but we think about what’s around it. We’re also looking toward precision medicine, right? That was the 2017 ASCO Annual Meeting theme. We’re seeing more of this at The European Society for Medical Oncology (ESMO) 2017 Congress, now, about how we, from the limited things that we know, translate and try to find biomarkers or molecular components of pancreas cancer where we could potentially individualize treatment for patients. Winson, when you first see a patient with advanced pancreas cancer, do you order molecular profiling? What do you think about the biopsy? Tell us about your approach in Canada?

Winson Y. Cheung, MD, MPH: Sure. I do want to start off by echoing what I’m hearing. I think things have really advanced along in the last 8 years that I’ve been in practice. As you alluded to, I think we’re learning more about the biology and the potential utility of biomarkers in terms of individualizing therapy. To that point, I think all of us are well aware that a fraction of pancreatic cancer patients express a mutation. The BRCA mutation is one example. In Canada, it’s not universal, but we are starting to test more routinely in certain demographics. In a young female, for example, with a family history of other cancers, we would routinely test. And as you mentioned already, I think it also has implication, in terms of therapeutic decision making, down the road.

Johanna C. Bendell, MD: Yes. We’ll be talking a little bit more about some of the specific drugs that we might think about for patients with BRCA mutations. There’s this code word, especially among gastrointestinal oncology, about microsatellite instability (MSI). Do we see microsatellite instability in pancreas cancer, Dr. Saab?

Tanios Bekaii-Saab, MD, FACP: We do, although rarely. It’s probably about 0.5%, but now that we do understand that these PD-1 inhibitors have tremendous activity in MSI-high tumors, regardless of the origin, I think it’s almost a mandate for us, where feasible, to test every adenocarcinoma for MSI.

We’re doing that. From personal experience, I’ve had at least a couple of patients in whom MSI-high was found in their adenocarcinoma. One patient was MSI-high in the setting of Lynch syndrome and failed a couple lines of chemotherapy. That patient was placed on, back then, a clinical trial with pembrolizumab, and had a CR—something that you rarely see in pancreas cancer. And that patient continues to have a CR, 2.5 years after. So, a pretty significant response. You have to see that to be convinced about the value, even at a rate of 0.5%, to do that more universally.

Johanna C. Bendell, MD: Manuel, you were one of the pioneers of looking at tumor tissue samples and biopsies and noting the importance of having an adequate biopsy for patients. In pancreas cancer, I’ll often see patients come to me who have had fine needle aspirations (FNAs) for diagnosis. Can you tell us a little bit more about what your recommendations would be in this modern era of tissue acquisition and what you look for?

Manuel Hidalgo, MD, PhD: That’s very true. Patients continue to be mainly diagnosed by fine needle aspirates. The reality is, now you can do fine needle biopsies very safely. And that, at least in our institution, is now the preferred method for 2 reasons. You, of course, acquire more tissue that then allows you to do a more detailed pathological evaluation. But also, there is an opportunity to do genomics. Otherwise, fine needle aspirates are very hard to do. Even in the fine needle biopsies, we sometimes get very, very little tissue and the genomics come back negative. We use it, also, to develop living models, like organoids and PDX. You can grow them very nicely from the biopsies, but not so much from the aspirates. So, I think that if we want to really make progress, we will need to do more biopsies and less FNAs.

Johanna C. Bendell, MD: Yes, that’s a big real-world initiative—the education of, “Don’t do FNAs unless you absolutely have to. The core needle biopsy is the thing to do.” It’s back to the old ‘tissue is the issue.’ Thomas, you’ve been doing some work looking at liquid biopsies. Tell us a little bit about that?

Thomas Seufferlein, MD: This comes back to what Manuel was saying. Sometimes we actually fail in taking biopsies, even FNAs. We are running a neoadjuvant trial in Germany. This is up to 30%, even in experienced centers, using the new needles which are more flexible. You can bend them, but you still can get a tissue core. And so, of course, there is a need or a desire for having an alternative means of a simpler, precise method (particularly when you want neoadjuvant treatment). You can’t do that without any diagnosis. You can operate on patients, but you cannot really give chemotherapy.

We’ve done some studies on liquid biopsies, and there were some posters, also, at the ASCO Annual Meeting and in this program, here. But one has to say, in the critical tumors (the smaller tumors where it’s very hard to get tissue), 50% of cases fail to give you a signal with circulating tumor DNA. Also, if you are very sensitive and do a digital droplet PCR, not NGS, or you’re using the most sensitive method, in 50%, you do not get a signal.

So, we are not really there yet. Maybe by refining these methods, looking, for example, for tumor secreted exosomes instead of ctDNA, we’re getting a little bit better. But there is still some research to do. There probably will be more coming. In particular, markers that may not be standalone markers, but in combination, let’s say, with CA 19-9—novel markers that have just been reported, like thrombospondin-2. This could be a very interesting way of diagnosing and differentiating tumors, also, from chronic pancreatitis, which sometimes is not easy to do.

Johanna C. Bendell, MD: Right now, we’re trying to move more toward the liquid biopsy—the liquid evaluation of the tumor and how this applies to treatment options. Winson, we all know that the best way to treat pancreas cancer is to take it out, and that means early detection. That’s such a key piece. As Thomas just alluded to, we’ve recently seen some data looking at some markers in the blood that might help us detect pancreas cancers, earlier.

Winson Y. Cheung, MD, MPH: Right. It’s quite exciting work. I think we’re all familiar in using CA 19-9. When we monitor a patient, as you’re all kind of aware or familiar with, it’s not a perfect marker. The question, now, is, how do we advance things further and perhaps perfect that kind of methodology? So, there were a couple abstracts, presented in the last year, that looked at thrombospondin and other biomarkers. However, I would say that they’re still kind of in their early days, yet. It’s not ready for prime time, but I think the results are very promising in terms of how we can best fine-tune things.

Johanna C. Bendell, MD: Absolutely. We’ve talked a lot about the future and the science that’s emerging and ways that we’re going to translate that science into potential treatment options. I guess the takeaway for our audience is knowing that the future is bright. There’s a lot that’s coming. But with your patients, it’s important to understand the importance of getting that proper biopsy. To try to get the core, if possible. To consider whether or not, in certain patient populations, you might want to do profiling. You might want to check MSI. You might want to look into BRCA. Does everybody agree that, for the practicing oncologist, there’s a lot to come, but to make sure we get adequate tissue?

Tanios Bekaii-Saab, MD, FACP: Absolutely.

Ramesh K. Ramanathan, MD: And also, I think, obviously, for the patient who presents with metastatic disease, you would biopsy the liver. You can get high-quality core tissue from there.

Thomas Seufferlein, MD: Also, it might be worthwhile, if you fail at your center, to refer the patient to an endoscopy center of excellence. Why? Because otherwise you drag things on and people are having 3 or 4 biopsies taken and there’s still no diagnosis. Then, if the patient has pancreatic cancer, it just delays all the sensible, novel next approaches. Therefore, it might be sensible, if you fail at your center, that you maybe try another one (for, at least, the diagnosis).

Johanna C. Bendell, MD: Yes, that’s a very good point.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: It’s fascinating. As we’re breaking down, more and more, the biology of how pancreatic cancer works, we’re going to see (later on, when we talk about new and emerging therapies), that it gives us more targets. We don’t just think, again, about the cell itself, but we think about what’s around it. We’re also looking toward precision medicine, right? That was the 2017 ASCO Annual Meeting theme. We’re seeing more of this at The European Society for Medical Oncology (ESMO) 2017 Congress, now, about how we, from the limited things that we know, translate and try to find biomarkers or molecular components of pancreas cancer where we could potentially individualize treatment for patients. Winson, when you first see a patient with advanced pancreas cancer, do you order molecular profiling? What do you think about the biopsy? Tell us about your approach in Canada?

Winson Y. Cheung, MD, MPH: Sure. I do want to start off by echoing what I’m hearing. I think things have really advanced along in the last 8 years that I’ve been in practice. As you alluded to, I think we’re learning more about the biology and the potential utility of biomarkers in terms of individualizing therapy. To that point, I think all of us are well aware that a fraction of pancreatic cancer patients express a mutation. The BRCA mutation is one example. In Canada, it’s not universal, but we are starting to test more routinely in certain demographics. In a young female, for example, with a family history of other cancers, we would routinely test. And as you mentioned already, I think it also has implication, in terms of therapeutic decision making, down the road.

Johanna C. Bendell, MD: Yes. We’ll be talking a little bit more about some of the specific drugs that we might think about for patients with BRCA mutations. There’s this code word, especially among gastrointestinal oncology, about microsatellite instability (MSI). Do we see microsatellite instability in pancreas cancer, Dr. Saab?

Tanios Bekaii-Saab, MD, FACP: We do, although rarely. It’s probably about 0.5%, but now that we do understand that these PD-1 inhibitors have tremendous activity in MSI-high tumors, regardless of the origin, I think it’s almost a mandate for us, where feasible, to test every adenocarcinoma for MSI.

We’re doing that. From personal experience, I’ve had at least a couple of patients in whom MSI-high was found in their adenocarcinoma. One patient was MSI-high in the setting of Lynch syndrome and failed a couple lines of chemotherapy. That patient was placed on, back then, a clinical trial with pembrolizumab, and had a CR—something that you rarely see in pancreas cancer. And that patient continues to have a CR, 2.5 years after. So, a pretty significant response. You have to see that to be convinced about the value, even at a rate of 0.5%, to do that more universally.

Johanna C. Bendell, MD: Manuel, you were one of the pioneers of looking at tumor tissue samples and biopsies and noting the importance of having an adequate biopsy for patients. In pancreas cancer, I’ll often see patients come to me who have had fine needle aspirations (FNAs) for diagnosis. Can you tell us a little bit more about what your recommendations would be in this modern era of tissue acquisition and what you look for?

Manuel Hidalgo, MD, PhD: That’s very true. Patients continue to be mainly diagnosed by fine needle aspirates. The reality is, now you can do fine needle biopsies very safely. And that, at least in our institution, is now the preferred method for 2 reasons. You, of course, acquire more tissue that then allows you to do a more detailed pathological evaluation. But also, there is an opportunity to do genomics. Otherwise, fine needle aspirates are very hard to do. Even in the fine needle biopsies, we sometimes get very, very little tissue and the genomics come back negative. We use it, also, to develop living models, like organoids and PDX. You can grow them very nicely from the biopsies, but not so much from the aspirates. So, I think that if we want to really make progress, we will need to do more biopsies and less FNAs.

Johanna C. Bendell, MD: Yes, that’s a big real-world initiative—the education of, “Don’t do FNAs unless you absolutely have to. The core needle biopsy is the thing to do.” It’s back to the old ‘tissue is the issue.’ Thomas, you’ve been doing some work looking at liquid biopsies. Tell us a little bit about that?

Thomas Seufferlein, MD: This comes back to what Manuel was saying. Sometimes we actually fail in taking biopsies, even FNAs. We are running a neoadjuvant trial in Germany. This is up to 30%, even in experienced centers, using the new needles which are more flexible. You can bend them, but you still can get a tissue core. And so, of course, there is a need or a desire for having an alternative means of a simpler, precise method (particularly when you want neoadjuvant treatment). You can’t do that without any diagnosis. You can operate on patients, but you cannot really give chemotherapy.

We’ve done some studies on liquid biopsies, and there were some posters, also, at the ASCO Annual Meeting and in this program, here. But one has to say, in the critical tumors (the smaller tumors where it’s very hard to get tissue), 50% of cases fail to give you a signal with circulating tumor DNA. Also, if you are very sensitive and do a digital droplet PCR, not NGS, or you’re using the most sensitive method, in 50%, you do not get a signal.

So, we are not really there yet. Maybe by refining these methods, looking, for example, for tumor secreted exosomes instead of ctDNA, we’re getting a little bit better. But there is still some research to do. There probably will be more coming. In particular, markers that may not be standalone markers, but in combination, let’s say, with CA 19-9—novel markers that have just been reported, like thrombospondin-2. This could be a very interesting way of diagnosing and differentiating tumors, also, from chronic pancreatitis, which sometimes is not easy to do.

Johanna C. Bendell, MD: Right now, we’re trying to move more toward the liquid biopsy—the liquid evaluation of the tumor and how this applies to treatment options. Winson, we all know that the best way to treat pancreas cancer is to take it out, and that means early detection. That’s such a key piece. As Thomas just alluded to, we’ve recently seen some data looking at some markers in the blood that might help us detect pancreas cancers, earlier.

Winson Y. Cheung, MD, MPH: Right. It’s quite exciting work. I think we’re all familiar in using CA 19-9. When we monitor a patient, as you’re all kind of aware or familiar with, it’s not a perfect marker. The question, now, is, how do we advance things further and perhaps perfect that kind of methodology? So, there were a couple abstracts, presented in the last year, that looked at thrombospondin and other biomarkers. However, I would say that they’re still kind of in their early days, yet. It’s not ready for prime time, but I think the results are very promising in terms of how we can best fine-tune things.

Johanna C. Bendell, MD: Absolutely. We’ve talked a lot about the future and the science that’s emerging and ways that we’re going to translate that science into potential treatment options. I guess the takeaway for our audience is knowing that the future is bright. There’s a lot that’s coming. But with your patients, it’s important to understand the importance of getting that proper biopsy. To try to get the core, if possible. To consider whether or not, in certain patient populations, you might want to do profiling. You might want to check MSI. You might want to look into BRCA. Does everybody agree that, for the practicing oncologist, there’s a lot to come, but to make sure we get adequate tissue?

Tanios Bekaii-Saab, MD, FACP: Absolutely.

Ramesh K. Ramanathan, MD: And also, I think, obviously, for the patient who presents with metastatic disease, you would biopsy the liver. You can get high-quality core tissue from there.

Thomas Seufferlein, MD: Also, it might be worthwhile, if you fail at your center, to refer the patient to an endoscopy center of excellence. Why? Because otherwise you drag things on and people are having 3 or 4 biopsies taken and there’s still no diagnosis. Then, if the patient has pancreatic cancer, it just delays all the sensible, novel next approaches. Therefore, it might be sensible, if you fail at your center, that you maybe try another one (for, at least, the diagnosis).

Johanna C. Bendell, MD: Yes, that’s a very good point.

Transcript Edited for Clarity 
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