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ONCAlert | Upfront Therapy for mRCC

Identifying TRK-Driven Disease Amid Tumor Types

Targeted Oncology
Published Online:1:31 PM, Wed January 30, 2019

Shubham Pant, MD: Tell me a little bit about how this is not found, this is not a garden variety, you don’t find this in all cancers. In which solid tumors and what frequency do you really find NTRK fusions for which these drugs can be useful?

David S. Hong, MD: We don’t fully understand the full prevalence of NTRK fusions in cancer at this point. I think that as more and more patients undergo next-generation sequencing (NGS), we will have a better sense of what that prevalence is across all solid tumors. I think many, many people who are investigators in this space believe that NTRK fusions occur probably at a certain percentage across most tumors, as low as 0.1% to maybe even being pathognomonic.

Shubham Pant, MD: Where it could be one of the main drivers of some of these cancers.

David S. Hong, MD: Right, right. What we’ve seen now is that there are certain subsets of rare tumors such as mammary analog secretory carcinoma, or MASC tumors.

Shubham Pant, MD: I can never say that. Say that again.

David S. Hong, MD: Mammary analog secretory carcinoma, which is a variant of a salivary type tumor that almost 100% of the time carries TRK fusions. There are other subsets of very rare tumors, pediatric tumors, such as infantile fibrosarcoma. There are other subsets of tumors, such as secretory breast. But common tumors such as lung, colorectal, even pancreatic cancers may have a subset of these patients who who have these NTRK fusions.

Shubham Pant, MD: What you’re saying is some of the cancers, which are these rare cancers in a way, can have a higher percentage, and then there are some cancers that are very common, and they have a lower-percentage expression of this, but this therapy or these types of therapies—this targeted therapy—may work. We’ve discussed fusion, but tell me what’s different really among amplification, fusion, mutation. Sometimes you hear all these words now with NGS testing, and these have become very prevalent.

David S. Hong, MD: Correct.

Shubham Pant, MD: Right. So people are sometimes saying, “This is over amplified,” versus, “This is a fusion.” What’s the difference when people look at it? It’s not all the same.

David S. Hong, MD: It’s not all the same, that’s very true. Mutations are just, as most people are familiar with that terminology, an alteration in a codon that leads to a specific change in the amino acid, which may lead to change in the proteins.

Shubham Pant, MD: Proteins. So something happens in the gene. It’s a mutation in the gene somewhere.

David S. Hong, MD: Right, correct. Amplification means a natural increase in the expression of that gene or ultimately the protein.

Shubham Pant, MD: Which is like HER2 amplification.

David S. Hong, MD: Correct.

Shubham Pant, MD: That we use in breast cancer.

David S. Hong, MD: And fusion is different in the sense that you’re taking 2 genes and fusing them together leading to an alteration of both of those genes and both of those proteins, causing either an increase in expression or a turning on of that construct.

Shubham Pant, MD: Now, one of the terms is fusion. We look for fusion in the NGS there. Do you ever do something like immunohistochemistry to see whether the TRK protein is overexpressed?

David S. Hong, MD: Yes.

Shubham Pant, MD: Does that make sense to do in these patients?

David S. Hong, MD: So I think we are trying to identify whether or not IHC [immunohistochemistry] may be an easier way to identify these patients. There have been some studies to suggest that there may be good sensitivity and specificity. There are issues with whether that specificity actually is really reproducible. And so that is still in development at this time.

Shubham Pant, MD: So that’s an experiment right now.

David S. Hong, MD: An experiment.

Shubham Pant, MD: But right now if you wanted to treat with other TRK inhibitors, you would probably do next-generation sequencing looking for fusions in the NTRK.

David S. Hong, MD: Correct, correct. At this point, that is probably the best way to identify these fusion patients. Another way would be FISH [fluorescence in situ hybridization]. The only problem with FISH is that the NTRK genes—1, 2, and 3—can partner with a number of different other genes. To try to create a FISH assay with multiple different genes would be cost prohibitive and would not be practical in a way. And so at this time, the most accurate way to identify these patients is really by the next-generation sequencing.

Transcript edited for clarity.

Shubham Pant, MD: Tell me a little bit about how this is not found, this is not a garden variety, you don’t find this in all cancers. In which solid tumors and what frequency do you really find NTRK fusions for which these drugs can be useful?

David S. Hong, MD: We don’t fully understand the full prevalence of NTRK fusions in cancer at this point. I think that as more and more patients undergo next-generation sequencing (NGS), we will have a better sense of what that prevalence is across all solid tumors. I think many, many people who are investigators in this space believe that NTRK fusions occur probably at a certain percentage across most tumors, as low as 0.1% to maybe even being pathognomonic.

Shubham Pant, MD: Where it could be one of the main drivers of some of these cancers.

David S. Hong, MD: Right, right. What we’ve seen now is that there are certain subsets of rare tumors such as mammary analog secretory carcinoma, or MASC tumors.

Shubham Pant, MD: I can never say that. Say that again.

David S. Hong, MD: Mammary analog secretory carcinoma, which is a variant of a salivary type tumor that almost 100% of the time carries TRK fusions. There are other subsets of very rare tumors, pediatric tumors, such as infantile fibrosarcoma. There are other subsets of tumors, such as secretory breast. But common tumors such as lung, colorectal, even pancreatic cancers may have a subset of these patients who who have these NTRK fusions.

Shubham Pant, MD: What you’re saying is some of the cancers, which are these rare cancers in a way, can have a higher percentage, and then there are some cancers that are very common, and they have a lower-percentage expression of this, but this therapy or these types of therapies—this targeted therapy—may work. We’ve discussed fusion, but tell me what’s different really among amplification, fusion, mutation. Sometimes you hear all these words now with NGS testing, and these have become very prevalent.

David S. Hong, MD: Correct.

Shubham Pant, MD: Right. So people are sometimes saying, “This is over amplified,” versus, “This is a fusion.” What’s the difference when people look at it? It’s not all the same.

David S. Hong, MD: It’s not all the same, that’s very true. Mutations are just, as most people are familiar with that terminology, an alteration in a codon that leads to a specific change in the amino acid, which may lead to change in the proteins.

Shubham Pant, MD: Proteins. So something happens in the gene. It’s a mutation in the gene somewhere.

David S. Hong, MD: Right, correct. Amplification means a natural increase in the expression of that gene or ultimately the protein.

Shubham Pant, MD: Which is like HER2 amplification.

David S. Hong, MD: Correct.

Shubham Pant, MD: That we use in breast cancer.

David S. Hong, MD: And fusion is different in the sense that you’re taking 2 genes and fusing them together leading to an alteration of both of those genes and both of those proteins, causing either an increase in expression or a turning on of that construct.

Shubham Pant, MD: Now, one of the terms is fusion. We look for fusion in the NGS there. Do you ever do something like immunohistochemistry to see whether the TRK protein is overexpressed?

David S. Hong, MD: Yes.

Shubham Pant, MD: Does that make sense to do in these patients?

David S. Hong, MD: So I think we are trying to identify whether or not IHC [immunohistochemistry] may be an easier way to identify these patients. There have been some studies to suggest that there may be good sensitivity and specificity. There are issues with whether that specificity actually is really reproducible. And so that is still in development at this time.

Shubham Pant, MD: So that’s an experiment right now.

David S. Hong, MD: An experiment.

Shubham Pant, MD: But right now if you wanted to treat with other TRK inhibitors, you would probably do next-generation sequencing looking for fusions in the NTRK.

David S. Hong, MD: Correct, correct. At this point, that is probably the best way to identify these fusion patients. Another way would be FISH [fluorescence in situ hybridization]. The only problem with FISH is that the NTRK genes—1, 2, and 3—can partner with a number of different other genes. To try to create a FISH assay with multiple different genes would be cost prohibitive and would not be practical in a way. And so at this time, the most accurate way to identify these patients is really by the next-generation sequencing.

Transcript edited for clarity.
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