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The Search for Targetable Alterations in Pancreatic Cancer

Insights From: Tony Saab, MD, Mayo Clinic; Davendra Sohal, MD, MPH, Cleveland Clinic
Published: Tuesday, Feb 19, 2019



Transcript: 

Tanios Bekaii-Saab, MD:
There were 3 very interesting presentations at ASCO GI [Gastrointestinal Cancers Symposium] that all were consistent in terms of thematic value. All 3 presentations focused on the capacity to find alterable, so alterations that would be targetable in pancreatic cancer, a disease where we thought there was very little to go after. So we have 1 presentation by Mike Pishvaian and colleagues and another by Michael Lee focusing on tissue testing. And those studies suggest that there is a richness of targets in pancreatic cancer, up to 20% that are at least targetable.

The Pishvaian presentation was very interesting because it focused on DDR [DNA damage repair], on the targets that we tend to go after with PARP [poly (ADP-ribose) polymerase] inhibition, or with platinum agents, or with other similar agents like the topo [topoisomerase]. And in fact, they did an analysis and saw that those are the patients who may actually benefit the most from platinum agents and perhaps PARP inhibitors in the future.

So we know that there are lots of groups of patients where we can identify alterations or genomic variations that could lead us down the pathway of a specific treatment like platinum agents, so PARP inhibitors or the likes. There are also other alterations that seem to be predictive for other treatment options that should be explored in the future. And that’s almost 1 out every 5 patients with pancreatic cancer. So it’s a big deal.

A third presentation, by Kabir Mody from Mayo Clinic and colleagues, essentially showed that we could also find some of these targets in liquid biopsies. So by capturing circulating free DNA, and in fact they had a cohort of patients who had both the circulating free DNA test available as well as the tissue testing, and they found a large coloration in some of the major mutations in both. So there is validity to it.

Now, why is this important? Tissue is important. Tissue remains the golden standard if we can get it. And what I would suggest from these studies is 1 of the oldest things in the year of MSI [microsatellite instable]–high and the year of NTRK fusions, where in pancreatic cancer MSI-high is 0.5%, and NTRK fusions are about 0.3% to 0.5%. That’s 1 out of every 100 patients, who you know would have these alterations, where agents targeting specifically NTRK and PD-1 [programmed cell death protein 1] inhibitions in MSI-high, can produce some of the best responses I’ve ever seen in pancreatic cancer. But add to that now BRCA mutations, plus somatic and germline, and add to that DDRs. So other alterations that fall in that same category. Add the rare BRAF mutations and others, and suddenly we’re talking about 20% to 30% of patients with pancreatic cancer where we can have a target or where we can have a specific chemotherapeutic regimen that makes more sense.

So I think that at this point in time, when I take all this together, I say, every patient with pancreatic cancer needs to have a genomic testing, genomic analysis, or NGS [next-generation sequencing] platform. I don’t care which one you use, but you have to do it. The second thing, I understand that for some pancreatic cancer patients, their first diagnosis is an EUS-FNA [endoscopic ultrasound-guided fine needle aspiration], and we have cells. So we cannot get tissue analysis. I encourage always to try to get a biopsy if we can. But if we can’t, then mediate all suggests we can use circulating free DNA to get closer to an answer. It’s not yet the full answer, but it gets us closer.

Interestingly, they can even do MSI-high correlative testing with liquid biopsies today. Again, cold standard remains tissue, and I’ll turn it, now we know from this study that you can do circulating free DNA.

Davendra Sohal, MD, MPH: The role of a diagnostic biopsy is certainly evolving in pancreatic cancer. Initially we used to do, and still we do, fine needle aspirations, some pancreatic tumors to just establish a diagnosis. But at least in clinical trials we are moving toward a strategy where we take more tissue; for example, core biopsies from pancreatic tumors, to be able to study the biology better. Now, for example, we are treating patients with neoadjuvant therapy in clinical trials and sometimes off study as well. And that gives us the opportunity to study the biology of the tumor from the initial core biopsy to determine treatment strategies moving forward.

In metastatic disease, for example, we certainly always require a core biopsy to study the genomics to define treatment options in the future based on microsatellite instability, etc. And so the biopsies from primary pancreatic tumors, as well as metastatic sites, are moving from fine needle aspirations to core biopsies.

The molecular targets that should be tested for in pancreatic cancer, especially on microsatellite instability and actionable fusions such as NTRK, are those for which there are now FDA-approved drugs—pembrolizumab and larotrectinib namely, respectively. ASCO [American Society of Clinical Oncology] guidelines recommend clearly that if we are starting second-line therapy, we should test microsatellite instability. Less than 1% of patients may have that, but again, if they do, they have access to pembrolizumab, an excellent choice for treatment of such patients. Should we recommend testing all patients? Certainly.


Transcript Edited for Clarity
 
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Transcript: 

Tanios Bekaii-Saab, MD:
There were 3 very interesting presentations at ASCO GI [Gastrointestinal Cancers Symposium] that all were consistent in terms of thematic value. All 3 presentations focused on the capacity to find alterable, so alterations that would be targetable in pancreatic cancer, a disease where we thought there was very little to go after. So we have 1 presentation by Mike Pishvaian and colleagues and another by Michael Lee focusing on tissue testing. And those studies suggest that there is a richness of targets in pancreatic cancer, up to 20% that are at least targetable.

The Pishvaian presentation was very interesting because it focused on DDR [DNA damage repair], on the targets that we tend to go after with PARP [poly (ADP-ribose) polymerase] inhibition, or with platinum agents, or with other similar agents like the topo [topoisomerase]. And in fact, they did an analysis and saw that those are the patients who may actually benefit the most from platinum agents and perhaps PARP inhibitors in the future.

So we know that there are lots of groups of patients where we can identify alterations or genomic variations that could lead us down the pathway of a specific treatment like platinum agents, so PARP inhibitors or the likes. There are also other alterations that seem to be predictive for other treatment options that should be explored in the future. And that’s almost 1 out every 5 patients with pancreatic cancer. So it’s a big deal.

A third presentation, by Kabir Mody from Mayo Clinic and colleagues, essentially showed that we could also find some of these targets in liquid biopsies. So by capturing circulating free DNA, and in fact they had a cohort of patients who had both the circulating free DNA test available as well as the tissue testing, and they found a large coloration in some of the major mutations in both. So there is validity to it.

Now, why is this important? Tissue is important. Tissue remains the golden standard if we can get it. And what I would suggest from these studies is 1 of the oldest things in the year of MSI [microsatellite instable]–high and the year of NTRK fusions, where in pancreatic cancer MSI-high is 0.5%, and NTRK fusions are about 0.3% to 0.5%. That’s 1 out of every 100 patients, who you know would have these alterations, where agents targeting specifically NTRK and PD-1 [programmed cell death protein 1] inhibitions in MSI-high, can produce some of the best responses I’ve ever seen in pancreatic cancer. But add to that now BRCA mutations, plus somatic and germline, and add to that DDRs. So other alterations that fall in that same category. Add the rare BRAF mutations and others, and suddenly we’re talking about 20% to 30% of patients with pancreatic cancer where we can have a target or where we can have a specific chemotherapeutic regimen that makes more sense.

So I think that at this point in time, when I take all this together, I say, every patient with pancreatic cancer needs to have a genomic testing, genomic analysis, or NGS [next-generation sequencing] platform. I don’t care which one you use, but you have to do it. The second thing, I understand that for some pancreatic cancer patients, their first diagnosis is an EUS-FNA [endoscopic ultrasound-guided fine needle aspiration], and we have cells. So we cannot get tissue analysis. I encourage always to try to get a biopsy if we can. But if we can’t, then mediate all suggests we can use circulating free DNA to get closer to an answer. It’s not yet the full answer, but it gets us closer.

Interestingly, they can even do MSI-high correlative testing with liquid biopsies today. Again, cold standard remains tissue, and I’ll turn it, now we know from this study that you can do circulating free DNA.

Davendra Sohal, MD, MPH: The role of a diagnostic biopsy is certainly evolving in pancreatic cancer. Initially we used to do, and still we do, fine needle aspirations, some pancreatic tumors to just establish a diagnosis. But at least in clinical trials we are moving toward a strategy where we take more tissue; for example, core biopsies from pancreatic tumors, to be able to study the biology better. Now, for example, we are treating patients with neoadjuvant therapy in clinical trials and sometimes off study as well. And that gives us the opportunity to study the biology of the tumor from the initial core biopsy to determine treatment strategies moving forward.

In metastatic disease, for example, we certainly always require a core biopsy to study the genomics to define treatment options in the future based on microsatellite instability, etc. And so the biopsies from primary pancreatic tumors, as well as metastatic sites, are moving from fine needle aspirations to core biopsies.

The molecular targets that should be tested for in pancreatic cancer, especially on microsatellite instability and actionable fusions such as NTRK, are those for which there are now FDA-approved drugs—pembrolizumab and larotrectinib namely, respectively. ASCO [American Society of Clinical Oncology] guidelines recommend clearly that if we are starting second-line therapy, we should test microsatellite instability. Less than 1% of patients may have that, but again, if they do, they have access to pembrolizumab, an excellent choice for treatment of such patients. Should we recommend testing all patients? Certainly.


Transcript Edited for Clarity
 
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