Major Advances in RET Inhibition for NSCLC and MTC - Episode 3

Optimal Detection of RET Fusions


Jared Weiss, MD: As wonderful as these drugs are, we can’t take action with these drugs unless we find RET. This is true of RET because it’s been historically an EGFR, ALK, RAS1 and most recently a spate of others in lung cancer. It’s natural to turn our conversation toward testing. Perhaps I can start by asking you how do you find RET?

Benjamin P. Levy, MD: It depends on when you ask this question. If you would have asked maybe 5 years ago, you could say that, you know, picking up rearrangements may be optimally done by FISH [fluorescence in situ hybridization], dare I say. I think that the needle is certainly moving in the right direction. Historically—you can probably explain this a little better based on the biological platform—testing for fusions like ALK, RAS, NTRK, and RET, FISH has been 1 of the ways we’ve been able to do that. Another way ALK has been done is with IHC [immunohistochemistry], looking at the protein product. I think we’ve got newer diagnostic, more sensitive platforms that do a deeper interrogation called next-generation sequencing [NGS].

If we look at next-generation sequencing—that’s a buzzword, but there are different platforms for next-generation sequencing. There are certainly DNA-based platforms commercially available, also in-house, and there are RNA-based platforms as well. What we’re beginning to learn is that RET fusions can be detected by DNA in NGS-based platforms, but the sensitivity increases dramatically when you layer in an RNA, NGS platform. I will give you my anecdotal experience because we participated in some of the trials with selpercatinib. FISH is not an ideal way to pick these up. It often misses them, and even DNA-based NGS platforms may miss these fusions.

Jared Weiss, MD: It may be worth noting that FISH is highly operator dependent, particularly for RET. I mean, to do RET FISH right, you need to do a lot of RET FISH. If someone is doing a lot of RET FISH you probably have a good next-gen platform.

Benjamin P. Levy, MD: Yes, I will tell you that, given all the things you just said, even at Hopkins [Johns Hopkins Sidney Kimmel Comprehensive Cancer Center], we had an internal platform that we use religiously on all our patients. We’ve shared stories about this before. We were using FISH for our ALK, RAS, RET, and NTRK until about 3 months ago when we realized how many of these alterations and fusions we were missing. Given all the reasons you just stated, and we have now moved to a DNA and an RNA panel in parallel, so we can optimize our genetic interrogation and do comprehensive genomic profiling. Because as you mentioned, if you can’t find the mutation or the fusion, you can’t give the drug. There is an educational gap on optimal platforms that need to be used or utilized to identify all these mutations. Jared, you and I have spoken before. Not all commercially available assays are the same. Some may be better than others in detecting fusions, and if 1 of the more important components of this whole discussion is testing. I don’t know what your thoughts are on this and what you guys are doing at Carolina Lineberger Comprehensive Cancer Center. Is it any different in how you view this changing over time?

Jared Weiss, MD: I strongly agree that the testing modality matters. We’ve never had RET FISH, but we’ve always been heavily invested since the next-generation sequencing. As you’ve outlined very nicely, it’s more comprehensive. It is more sensitive to multiple changes, including some changes older than RET. Critically there’s also a tissue stewardship issue, where if you’re doing lots of serial testing, you’re using up the tissue and using up a lot of time too, which can matter for patients.

There is also an issue of complexity. If you think about our community partners, they don’t have the privilege that you and I have to nerd out on 1 narrow area all day, right? My wife makes fun of us that we we’re left-little-toe doctors. You know, if all you study is the left little toe, you don’t know how to treat, I don’t know, a fracture of the arm. It’s not as hard to be an expert in the left little toe. Even the most brilliant of our community partners, I have no idea how they keep up with a new change that 2% of lung cancer, while they’re also keeping up with breast cancer and benign heme disorders. I’m impressed by it, but if you translate that to the practicality of the busyness of these people, even with their extraordinary intelligence and diligence, this needs to be simplified for them. What I like about a good next-gen panel is that instead of having to order EGFR, then ALK, RAS1, RET, and so forth, you can just press the easy button and order 1 broad comprehensive path.

Benjamin P. Levy, MD: That’s very well stated. For all of us, I think you would agree that all of us are trying, even as left-toe doctors, to educate others. The left little toe. That up-front NGS testing should be done on all advanced-stage patients and some new data are suggesting even for adjuvant TKIs. It’s not the topic here, that maybe earlier stage is important too, but at least for advanced adenocarcinoma of the lung up front, NGS testing should be done, and we can’t give drugs unless we identify the target.

Transcript Edited for Clarity