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Key Takeaway 8: MSI-High Status and HER2 Amplification

Insights From: Tanios S. Bekaii-Saab, MD, Mayo Clinic
Published: Monday, Sep 16, 2019



Transcript:

Tanios S. Bekaii-Saab, MD: Microsatellite status testing is done in different ways. We primarily rely on IHC [immunohistochemistry]. We can do it through PCR [polymerase chain reaction], but IHC is simple and quick. Within a couple of days you’ll have your answer. More and more it is being reported as part of the next genomic sequencing panel. We recently heard that Guardant360, through its liquid biopsy test, is able to report very accurately the presence of microsatellite instability [MSI]. So any of those are used at this point of time. If you don’t have tissue, get the blood. If you have the tissue accessible and you can run it very quickly, most pathology labs—including in smaller community hospitals—can run an IHC test for patients who are MSI-high. If not, it’s part of your next-generation sequencing [NGS], and it’s reported out. It’s a good surrogate for MSI-high. In fact, as we said, MSI-high is only a surrogate marker for a large mutational burden.

Tumor mutational burden [TMB] is really what drives response to immuno-therapy. For that purpose, TMB could be more than enough. MSI-high would be good for us for genetic stratifying. TMB would be more than enough to decide whether we want to treat patients with immuno-therapy agents or not. That also links to not only MSI-high but also POLE, POLD, and CHEK. So you have a lot of different ways to identify MSI status and lots of different ways to decide who is that patient who would be optimal for treatment with immuno-therapy agents.
One of the emerging targets in colorectal cancer, which I think is also going to transform how we care for about another 4% of patients with metastatic colorectal cancer, is a subgroup of patients with HER2 amplifications. We know from a couple of studies with trastuzumab and pertuzumab, as well as trastuzumab and lapatinib, that these patients can exhibit 20% to 30% response rate. These responses can be quite durable. In fact, the NCCN [National Comprehensive Cancer Network] Guidelines just included those doublets or doublet therapies into the guidelines. They’re there, and these are published facts.

There are a number of studies that are ongoing, both nationally and internationally, trying to confirm the role of these HER2-targeted strategies. There’s a SWOG study looking at the combo versus cetuximab plus irinotecan. There is another study that will be presented at ESMO [European Society for Medical Oncology] 2019 Congress. Actually, 2 of them will be presented at ESMO, 1 from Japan with trastuzumab and pertuzumab, the other 1 from our research network with tucatinib, which is an oral tyrosine kinase inhibitor, and trastuzumab.
The sum of all these studies continues to point in the same direction, that these are agents that work incredibly well in patients with metastatic colorectal cancer who have HER2 amplification. The other important aspect about HER2 amplifications or HER2-amplified colorectal tumors, those patients do not seem to respond well to EGFR inhibitors. And that has mostly been validated retrospectively, hoping for more prospective validation. But it makes sense that those patients probably should be excluded from EGFR inhibitors.

Transcript Edited for Clarity
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Transcript:

Tanios S. Bekaii-Saab, MD: Microsatellite status testing is done in different ways. We primarily rely on IHC [immunohistochemistry]. We can do it through PCR [polymerase chain reaction], but IHC is simple and quick. Within a couple of days you’ll have your answer. More and more it is being reported as part of the next genomic sequencing panel. We recently heard that Guardant360, through its liquid biopsy test, is able to report very accurately the presence of microsatellite instability [MSI]. So any of those are used at this point of time. If you don’t have tissue, get the blood. If you have the tissue accessible and you can run it very quickly, most pathology labs—including in smaller community hospitals—can run an IHC test for patients who are MSI-high. If not, it’s part of your next-generation sequencing [NGS], and it’s reported out. It’s a good surrogate for MSI-high. In fact, as we said, MSI-high is only a surrogate marker for a large mutational burden.

Tumor mutational burden [TMB] is really what drives response to immuno-therapy. For that purpose, TMB could be more than enough. MSI-high would be good for us for genetic stratifying. TMB would be more than enough to decide whether we want to treat patients with immuno-therapy agents or not. That also links to not only MSI-high but also POLE, POLD, and CHEK. So you have a lot of different ways to identify MSI status and lots of different ways to decide who is that patient who would be optimal for treatment with immuno-therapy agents.
One of the emerging targets in colorectal cancer, which I think is also going to transform how we care for about another 4% of patients with metastatic colorectal cancer, is a subgroup of patients with HER2 amplifications. We know from a couple of studies with trastuzumab and pertuzumab, as well as trastuzumab and lapatinib, that these patients can exhibit 20% to 30% response rate. These responses can be quite durable. In fact, the NCCN [National Comprehensive Cancer Network] Guidelines just included those doublets or doublet therapies into the guidelines. They’re there, and these are published facts.

There are a number of studies that are ongoing, both nationally and internationally, trying to confirm the role of these HER2-targeted strategies. There’s a SWOG study looking at the combo versus cetuximab plus irinotecan. There is another study that will be presented at ESMO [European Society for Medical Oncology] 2019 Congress. Actually, 2 of them will be presented at ESMO, 1 from Japan with trastuzumab and pertuzumab, the other 1 from our research network with tucatinib, which is an oral tyrosine kinase inhibitor, and trastuzumab.
The sum of all these studies continues to point in the same direction, that these are agents that work incredibly well in patients with metastatic colorectal cancer who have HER2 amplification. The other important aspect about HER2 amplifications or HER2-amplified colorectal tumors, those patients do not seem to respond well to EGFR inhibitors. And that has mostly been validated retrospectively, hoping for more prospective validation. But it makes sense that those patients probably should be excluded from EGFR inhibitors.

Transcript Edited for Clarity
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