Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 3

Pan-Tumor Biomarker Testing in Oncology

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A panel of oncology experts in lung, thyroid, and sarcomatous tumors discuss the role and impact of pan-tumor biomarker testing.

Mark Socinski, MD: I am going to ask Jonathan here to give us his thoughts on, we’ve had a couple of indications recently over the past year or so for a pan-tumor biomarker; NTRK comes to mind, and RET comes to mind. How has that played out in molecular testing and oncology? What is the impact of these pan-tumor biomarkers in solid tumors?

Jonathan Trent, MD, PhD: This is a great question and a great topic. I am a sarcoma medical oncologist. For patients with GI [gastrointestinal] stromal tumors, we have been doing and requiring molecular testing for close to 12 years. It has been a very active part of our practice. We were early embracers of this because we noticed that although there are 175 different types of sarcoma, GI stromal tumors are probably the most common. There are 6 different molecular subtypes of GI stromal tumors: KIT mutations make up about 70%, PDGF receptor mutations make up 10%. Another 10% is attributed to loss of succinate dehydrogenase.

Then there is the more rare subset, which is seen in about 10% of patients, and is divided among NTRK translocations, RAF mutations, and NF1 deletion. So we have those 6 drivers. In order to treat our patients with systemic therapy, we have to know the molecular subtype, so we essentially examine 100% of our patients with GI stromal tumors up front for metastatic disease, as well as adjuvant therapy. We have imatinib, a KIT inhibitor, approved for 3 years of adjuvant therapy. Then there is the other bucket of sarcomas, the other 174 different subtypes. There are a few that are molecularly driven, inflammatory myofibroblastic tumors driven by ALK, and then we have dermatofibrosarcoma driven by the PDGF receptor. We have CSF1 driving tenosynovial giant cell tumors, and then we have NTRK. As we are going to hear a little more about today, we have patients with spindle cell sarcomas or even other specific histologies like angiosarcoma, that may be driven by an NTRK translocation.

Mark Socinski, MD: NTRK has been one of the ones, again, not very common in lung cancer, it is probably more common in sarcoma. But there are some pediatric sarcomas that are driven by NTRK, and I wonder, could you comment on that aspect of it, the fusion being a true driver?

Jonathan Trent, MD, PhD: Yes, the fusion is absolutely a driver. We have found the point mutations do not seem to be effective or targetable, at least in the experience that we’ve had so far. You are exactly right, though: infantile fibrosarcoma represents about 20% of the patients in some of the original studies that have been published with NTRK inhibitors, and the response rates to this targeted therapy are in the 90% range.

Lori Wirth, MD: Can I jump in here while we are talking about kids? NTRK fusions and RET fusions, as well as other oncogenic fusions, are concentrated in pediatric and young adult patients with thyroid cancer. It is really important to recognize that fact, so when we are treating young patients with thyroid cancer, we absolutely want to go looking for oncogenic fusions. About 30% of pediatric and young adult patients with thyroid cancer will have RET fusions, and overall, in that patient population, about 50% of them will have driver fusions.

Benjamin Levy, MD: Can I add one thing, Mark, that Jonathan said, that I think is so important, a quick point about point mutations for NTRK? We see these, and they are not predictive of response to targeted therapies. I know all of us, at least on the lung side here, are recipients of the phone a friend, “Will you help me interpret this NGS [next-generation sequencing] report?” Often we see these NTRK point mutations, and we know that these are not relevant in terms of being predictive of targeted therapy. It is the fusion, and that is a really important point to make.

Mark Socinski, MD: I think that is. We have actually seen a couple of patients who have been started on an NTRK inhibitor with an NTRK mutation, specifically to that point. Obviously, that is not the role, and it is not the molecular lesion that is the driver; it is really the fusions, and I think to point that out is important.

I wanted to ask both Lori and Jonathan, you heard the community of people who treat and study lung cancer endorsing both liquid and tissue testing. I wonder if you could comment on the role of this when examining sarcomas as well as the role this takes in treating thyroid disease? I am under the impression that, at least at presentation, many of those are much more localized than we tend to see in lung cancer, so there may be an issue of tumor DNA shedding. I am curious how you see that in your world.

Jonathan Trent, MD, PhD: I can speak to sarcoma, especially GI stromal tumors. We generally test the tissue. If we do not find that the tissue has a mutation, then we do a blood-based circulating tumor DNA [ctDNA] test. We use circulating tumor DNA in all patients [with GI stromal tumors] who progress because our second-line therapy can be selected based on the resistance mutations. Resistance mutations that we find in ctDNA in exon 13 respond to sunitinib but not to other agents. In exon 17, resistance mutations in the KIT gene respond to regorafenib, ripretinib, other agents, but not to sunitinib. We are actually guiding our therapy based on ctDNA results at Sylvester [Comprehensive Cancer Center].

Mark Socinski, MD: Lori?

Lori Wirth, MD: In thyroid cancer, generally we have plenty of tissue to test. Sometimes, that tissue might be very old or lost, and then that is a problem. We have not been as desperate to use ctDNA to identify driver alterations because we almost always have plenty of tissue. We do not have a great experience with these assays across all different thyroid cancer histologies. We have seen that you can have circulating tumor DNA positivity in some patients with RET-mutated medullary thyroid cancer, but not in all patients. We have seen positivity in patients with BRAF V600E-mutated thyroid cancers as well, but we do not have a lot of data yet.