Benjamin Levy, MD: We have all these wonderful drugs. It’s exciting, but it’s confusing. Probably just as confusing is testing. There are certainly a lot of competing testing strategies—tissue, NGS [next-generation sequencing], DNA based, RNA based, liquid. Where does that fit in? Josh, I’ll start with you. Give us your best practices for testing at Penn Medicine, how you see the field moving, and what you’re doing for your patients.
Joshua Bauml, MD: Thanks. Every patient who comes in, at least with nonsquamous, non–small cell lung cancer at Penn Medicine, has a DNA-based mutation assay and an RNA-based fusion assay. It’s done in house. The advantage of the RNA-based fusion assay is that it is much better at detecting fusions. We know that DNA-based assays can miss them. We also know that things like MET exon 14 skipping alterations are difficult to identify because they happen in the intron. Most of the time, when I detect a MET alteration at my site, it’s not detected on our mutation analysis. It’s detected on the fusion as a 13-to-15 fusion. That’s MET exon 14 skipping.
In terms of my incorporation of liquid biopsies, I do use them rather frequently. There was a series done by my colleague Charu Aggarwal showing increased sensitivity and identification of alterations when it’s done concurrently with tissue in the first line. I will say, I’m more likely to do it when I’m questioning the quantity of the biopsy. If a patient comes as a second opinion and I don’t know the adequacy of the sample, I will send a liquid biopsy in that first visit. In addition, if a patient is very sick, I will send a liquid biopsy at that visit because it comes back faster. I do a lot of concurrent liquid and tissue testing.
The critical element is that now, with 7 FDA-approved targets for lung cancer, doing single-gene testing is definitely not tissue efficient. There was a wonderful ASCO [American Society of Clinical Oncology Annual Meeting] presentation by Nate Pennell showing that it’s also not cost efficient. From my perspective, there is no role at this time for single-gene testing. We should be doing panel testing broadly.
Benjamin Levy, MD: Those are all good points. Lyuda, what is your approach on testing at UCSD [University of California San Diego]?
Lyudmila Bazhenova, MD: At the time of the first consultation, we do both liquid and tissue biopsies. If the liquid biopsy comes back positive with oncogenic drivers, treat based on that. Don’t wait for tissue. The tissue is NGS [next-generation sequencing], of course. I haven’t done single-gene testing for quite some time. I do use RNA assays, but only if I don’t find an oncogenic driver on the DNA assay. Practicing in California, our incidence of EGFR mutation, ALK mutation, and everything else is pretty high, so I just can’t easily justify RNA assays on everyone just yet. But if my DNA assay didn’t find anything, especially if I have a nonsmoker, then I refer to the RNA-based NGS.
Benjamin Levy, MD: Becca, what is your experience at Massachusetts General?
Rebecca Heist, MD: Similar to what Josh was saying, we do NGS on both DNA and RNA to detect point mutations and fusions. We do think that the RNA-based testing is important to catch all the rearrangements for the reasons that Josh outlined. We test all advanced non–small cell lung cancer patients. With these multiple alterations, you can see them across all histologies and all smoking histories, so it’s important to test everyone. We use liquid as well. It’s complementary. For example, if you look at a series of autopsies and at different metastatic sites, there are differences among the sites. You can imagine that there are limitations to what a tumor biopsy would get you. Liquid biopsy obviously has the mutations as well. If it’s not a very DNA-shedding tumor or if disease is confined within the lungs or not widely metastatic, you might not pick up as much. These are complementary mechanisms. I do think the days of testing only a very small number of genes and then doing sequential testing are way behind us. We cannot be doing that with the number of alterations that we have good targeted therapies for.
Benjamin Levy, MD: Yes, those are all great points. The only thing I will add is, first, a consideration of liquid for all patients, given that tissue oftentimes is not sufficient. A negative liquid biopsy tells you nothing, but a positive essentially rules it in. Second, all of us are probably doing our in-house assays. If you’re not, and you’re sending it out to a commercial platform, make sure they’re doing RNA sequencing as well. There are too many fusions that are better picked up by these platforms that are now relevant and actionable, and they’re missed. We know it. There’s a big difference in the discussion that goes down. There are big differences in the outcomes for these patients when you’ve identified a target and can deliver targeted therapy vs if you can’t. I would just make a call for everyone to think about where they are sending it to if they aren’t doing it in house, and whether they are optimally interrogating the tissue to pick up on all relevant alterations.
Thank you all for this rich and informative discussion. Before we conclude, I’d like to get final thoughts from each of you. Lyuda, you get first crack.
Lyudmila Bazhenova, MD: That was wonderful. The moderating was great. My colleagues were fantastic. It’s very nice to feed off one another. The 1 thing I wanted to bring up that we didn’t discuss in the testing is managing your PD-L1 positivity before you know your NGS. Many of us have in-house PD-L1 testing, so it’s very likely that your PD-L1 results will come before your molecular testing results. I strongly advise not to start immunotherapy for PD-L1 greater than 50% if you do not know your molecular alterations. If it’s an EGFR patient, (a) immunotherapy is not going to work, and (b) you can potentially increase the risk of pneumonitis if you then sequence with EGFR TKIs [tyrosine kinase inhibitors].
Benjamin Levy, MD: OK. Next, Josh?
Joshua Bauml, MD: It’s been an honor to participate. I’d like to give you all a blue ribbon with a gold star on it for today’s presentation. The key point, now that we’re talking about these different targets, is that it is absolutely essential that every patient get tested. We have to make sure the testing is done—that it’s done correctly, and that it’s done comprehensively—so we can make sure we improve the outcomes for every patient.
Benjamin Levy, MD: Thank you, Josh. Blue ribbon and gold stars in the mail today, overnighted. Becca, what are your final thoughts?
Rebecca Heist, MD: Thanks, everyone. This has been fun. As has been said before, testing is so critical. There are so many alterations that matter, both with FDA-approved drugs and drugs that are not FDA approved but are in clinical trials and are very active. We need to be testing everyone. All of us on this panel have the incredible luxury of these molecular pathology departments within our institutions that supply us with state-of-the-art testing. For many people who don’t have that, who are sending tissue or liquids out, we need to develop better ways to be able to interpret the quality of the test that’s being used. Too often we see patients referred with such-and-such alteration. When you actually look, they weren’t testing for it correctly. That’s a big area that needs focus because we know that there are good drugs to use, but the testing needs to be done correctly.
Benjamin Levy, MD: Again, those are really good points. I want to thank the panelists. This was a fun exchange, and probably the easiest exchange I’ve done through Zoom in a while. You guys made my job pretty easy today with all the intelligent commentary and perspective from each of your institutions. Thank you again. To our viewing audience, we hope you found this OncLive® Peer Exchange® discussion to be useful and informative.
Transcript Edited for Clarity