Select Topic:
Browse by Series:

Molecular Testing in Pancreatic Adenocarcinoma

Panelists: John L. Marshall, MD, Georgetown University; George Kim, MD, 21st Century Oncology; Kabir Mody, MD, Mayo Clinic Cancer Center; Eileen M. O
Published: Friday, Jul 27, 2018



Transcript: 

John L. Marshall, MD: Toni, we have a lot of trouble with this disease. One of our barriers to success is access to tissue. We don’t have big biobanks of big biopsies that we can do this with. So, what’s the strategy for getting this molecular testing done in your practice? As a corollary to that, is there any role for circulating markers in this patient population?

Tanios S. Bekaii-Saab, MD: That’s a great question. I think that tissue is always important. One of the limiting factors with circulating DNA with this disease, is that it’s a hit or miss. There’s actually a lot of miss than hit, unfortunately, unlike say, colorectal cancer or other cancers where the tumor burden tends to be higher and that environment around the tumor is not as protective from releasing those cells out and breaking the DNA, etcetera. So, there is a challenge.

John L. Marshall, MD: So, not yet on circulating marker?

Tanios S. Bekaii-Saab, MD: I think if you do not have tissue or access to tissue, you should consider circulating DNA.

John L. Marshall, MD: Can you get BRCA on blood?

Tanios S. Bekaii-Saab, MD: No. Well. Germline versus somatic.

Eileen M. O’Reilly, MD: Germline, yes.

Tanios S. Bekaii-Saab, MD: I’m sorry, germline, yes. We agree on germline. Somatic, not quite yet.

Kabir Mody, MD: But, there is an issue in terms of assays reporting BRCA in tumors for the reasons that it’s not always reported.

Tanios S. Bekaii-Saab, MD: It’s not a reliable test, and so, with this disease, you have to try everything possible to get adequate tissue.

John L. Marshall, MD: You need a bigger piece, right?

Tanios S. Bekaii-Saab, MD: A bigger piece.

John L. Marshall, MD: They’re getting better at getting us some tissue, but it’s still not a core biopsy.

Tanios S. Bekaii-Saab, MD: They’re getting better.

Eileen M. O’Reilly, MD: So, I think that’s a very important point to make, that there's been a transition in terms of how we approach acquisition of tissue in people with pancreas cancer. The older days where the FNA was sufficient, we made our diagnosis, and moved on. But now, we really want this core biopsy, either from the metastatic site, or from the primary tumor to facilitate these next-generation approaches in terms of learning. That’s a big message for our community colleagues in terms of recommendations to their surgeons, their international radiologists, or their gastroenterologists.

John L. Marshall, MD: It’s easy for us to say, “But I have a patient right now who’s trying to enroll in a trial and it’s required that he has tissue on a biopsy”. We’re at biopsy number 3 right now because every time they go, they’re right in the tumor, and what they get is a lot of stroma. They don’t get enough tumor cells to do molecular testing, and, of course, we’re all frustrated with that. What about the stroma, Toni? What’s going on there? Is this part of our problem fundamentally?

Tanios S. Bekaii-Saab, MD: It’s both part of our problem, and perhaps part of our solution, at the same time. The whole issue of the stroma and the microenvironment in pancreas cancer has gone both ways. In fact, we think about it both as a friend and a foe. As a friend, it essentially keeps those cancer cells from metastasizing and also, it somewhat protects the cancer from spreading. On the other hand, it’s also a foe because it keeps the good macrophages out, it keeps the bad macrophages in, it keeps the NK cells which are beneficial, it keeps the T-reg cells confined into it; so it creates an incredibly immunosuppressive environment. We’ve had a hit or miss with targeting the stroma. The whole story with the hedgehog inhibitors was very confusing. It looked very promising and then ended up being, in one study, detrimental; in the study, nonbeneficial. In going back to the basics, the realization was, if you destruct the stroma, you actually increase the risk of metastases. We’re seeing some of those signals, and I know we’ll discuss later with that agent PEGPH20. Again, this is both a friend and a foe, and how we handle it more as a friend, rather than a foe is likely to make a big difference in outcomes in this disease.

John L. Marshall, MD: George, I was walking down the conference center yesterday with another GI oncologist friend of ours, and this person was really expressing how frustrated they were in that all of these other cancers have these driving mutations, and these targets, and we in GI cancer are still figuring out our chemotherapy regimens. Do you share the same frustration? Do you see some light ahead in the genomic world?

George P. Kim, MD: Yes. Just getting back to the stroma real quick; I don’t think stroma is a friend, I think it’s a foe. I think we have to target the stroma, and, if you look at the drugs that are now being approved, nab-paclitaxel (Abraxane), and nal-IRI (nanoliposomal irinotecan), and hopefully PEGPH20; they do impact the stroma in a meaningful way. I think we have to go after it.

With new metastases, we don’t see that in the trials; you would see that in failure. So, we don’t see that people aren’t coming off of a drug because they’re having new lesions. We’re not necessarily seeing that, but I think hitting stroma is important. In terms of the mutations, we have a lot of work to do. I’m getting very frustrated with targeting signal transduction pathways. I really think we have to hit it in a multiple TKI manner, or with drugs like regorafenib (Stivarga), which hit multiple receptors at once. I think that’s the way we need to perceive. Look where we are; we’re using chemotherapy, we’re using multi-drug therapies that are having some impact, and we need to do a little more work in terms of the molecular aspects because there are so many mutations that are potentially going to cause resistance, and then need to be targeted.

John L. Marshall, MD: Yes, I think we are all jealous of the other gang.

Eileen M. O’Reilly, MD: Yes, but I would echo your thoughts, John, we’re not getting away from chemotherapy soon in pancreas cancer and much at all, as we would like to think otherwise. Having said that, I think it’s a platform for how some of these other agents may be developed in this disease and with lots of examples of trials; building anti-stromal agents on chemotherapy, building immune agents on chemotherapy. This may prove at least, a path forward to debulking disease, and then perhaps a strategy for some of these less intense agents being used as a maintenance approach.

Transcript Edited for Clarity 

Slider Left
Slider Right


Transcript: 

John L. Marshall, MD: Toni, we have a lot of trouble with this disease. One of our barriers to success is access to tissue. We don’t have big biobanks of big biopsies that we can do this with. So, what’s the strategy for getting this molecular testing done in your practice? As a corollary to that, is there any role for circulating markers in this patient population?

Tanios S. Bekaii-Saab, MD: That’s a great question. I think that tissue is always important. One of the limiting factors with circulating DNA with this disease, is that it’s a hit or miss. There’s actually a lot of miss than hit, unfortunately, unlike say, colorectal cancer or other cancers where the tumor burden tends to be higher and that environment around the tumor is not as protective from releasing those cells out and breaking the DNA, etcetera. So, there is a challenge.

John L. Marshall, MD: So, not yet on circulating marker?

Tanios S. Bekaii-Saab, MD: I think if you do not have tissue or access to tissue, you should consider circulating DNA.

John L. Marshall, MD: Can you get BRCA on blood?

Tanios S. Bekaii-Saab, MD: No. Well. Germline versus somatic.

Eileen M. O’Reilly, MD: Germline, yes.

Tanios S. Bekaii-Saab, MD: I’m sorry, germline, yes. We agree on germline. Somatic, not quite yet.

Kabir Mody, MD: But, there is an issue in terms of assays reporting BRCA in tumors for the reasons that it’s not always reported.

Tanios S. Bekaii-Saab, MD: It’s not a reliable test, and so, with this disease, you have to try everything possible to get adequate tissue.

John L. Marshall, MD: You need a bigger piece, right?

Tanios S. Bekaii-Saab, MD: A bigger piece.

John L. Marshall, MD: They’re getting better at getting us some tissue, but it’s still not a core biopsy.

Tanios S. Bekaii-Saab, MD: They’re getting better.

Eileen M. O’Reilly, MD: So, I think that’s a very important point to make, that there's been a transition in terms of how we approach acquisition of tissue in people with pancreas cancer. The older days where the FNA was sufficient, we made our diagnosis, and moved on. But now, we really want this core biopsy, either from the metastatic site, or from the primary tumor to facilitate these next-generation approaches in terms of learning. That’s a big message for our community colleagues in terms of recommendations to their surgeons, their international radiologists, or their gastroenterologists.

John L. Marshall, MD: It’s easy for us to say, “But I have a patient right now who’s trying to enroll in a trial and it’s required that he has tissue on a biopsy”. We’re at biopsy number 3 right now because every time they go, they’re right in the tumor, and what they get is a lot of stroma. They don’t get enough tumor cells to do molecular testing, and, of course, we’re all frustrated with that. What about the stroma, Toni? What’s going on there? Is this part of our problem fundamentally?

Tanios S. Bekaii-Saab, MD: It’s both part of our problem, and perhaps part of our solution, at the same time. The whole issue of the stroma and the microenvironment in pancreas cancer has gone both ways. In fact, we think about it both as a friend and a foe. As a friend, it essentially keeps those cancer cells from metastasizing and also, it somewhat protects the cancer from spreading. On the other hand, it’s also a foe because it keeps the good macrophages out, it keeps the bad macrophages in, it keeps the NK cells which are beneficial, it keeps the T-reg cells confined into it; so it creates an incredibly immunosuppressive environment. We’ve had a hit or miss with targeting the stroma. The whole story with the hedgehog inhibitors was very confusing. It looked very promising and then ended up being, in one study, detrimental; in the study, nonbeneficial. In going back to the basics, the realization was, if you destruct the stroma, you actually increase the risk of metastases. We’re seeing some of those signals, and I know we’ll discuss later with that agent PEGPH20. Again, this is both a friend and a foe, and how we handle it more as a friend, rather than a foe is likely to make a big difference in outcomes in this disease.

John L. Marshall, MD: George, I was walking down the conference center yesterday with another GI oncologist friend of ours, and this person was really expressing how frustrated they were in that all of these other cancers have these driving mutations, and these targets, and we in GI cancer are still figuring out our chemotherapy regimens. Do you share the same frustration? Do you see some light ahead in the genomic world?

George P. Kim, MD: Yes. Just getting back to the stroma real quick; I don’t think stroma is a friend, I think it’s a foe. I think we have to target the stroma, and, if you look at the drugs that are now being approved, nab-paclitaxel (Abraxane), and nal-IRI (nanoliposomal irinotecan), and hopefully PEGPH20; they do impact the stroma in a meaningful way. I think we have to go after it.

With new metastases, we don’t see that in the trials; you would see that in failure. So, we don’t see that people aren’t coming off of a drug because they’re having new lesions. We’re not necessarily seeing that, but I think hitting stroma is important. In terms of the mutations, we have a lot of work to do. I’m getting very frustrated with targeting signal transduction pathways. I really think we have to hit it in a multiple TKI manner, or with drugs like regorafenib (Stivarga), which hit multiple receptors at once. I think that’s the way we need to perceive. Look where we are; we’re using chemotherapy, we’re using multi-drug therapies that are having some impact, and we need to do a little more work in terms of the molecular aspects because there are so many mutations that are potentially going to cause resistance, and then need to be targeted.

John L. Marshall, MD: Yes, I think we are all jealous of the other gang.

Eileen M. O’Reilly, MD: Yes, but I would echo your thoughts, John, we’re not getting away from chemotherapy soon in pancreas cancer and much at all, as we would like to think otherwise. Having said that, I think it’s a platform for how some of these other agents may be developed in this disease and with lots of examples of trials; building anti-stromal agents on chemotherapy, building immune agents on chemotherapy. This may prove at least, a path forward to debulking disease, and then perhaps a strategy for some of these less intense agents being used as a maintenance approach.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
Publication Bottom Border
Border Publication
x