A Pathologist’s Commentary on The Heterogeneity of EGFR Exon 20 Insertions Found in NSCLC and Considerations for Results Reporting


Dr Shiller emphasizes the heterogeneity between the various EGFR exon 20 mutations seen in patients with NSCLC, and describes strategies for effectively communicating actionable information about a patient’s mutation status to the clinicians receiving the reports.

Joel Neal, MD, PhD: Michelle, we haven't forgotten about you, and I was wondering if you have a molecular pathology or molecular biology opinion on the differences between different EGFR Exon20 insertion proteins that are made from all these gene changes that we talked about. Fortunately, there is not a lot of differences we see in terms of response in these helical, near loop, far loop, but I was wondering if you have any opinions about the structure of these, or function?

S. Michelle Shiller, DO, AP/CP, MGP: I don't have anything to add beyond what you guys have already mentioned. I just will say that the heterogeneity in what we find is real, yes, you have your common Exon 770, 771, and Exon 769, 770, event and they do occur. But again, the Exon 20 insertion is not as common in general. And so, then when you have the unique Exon 20 insertion events, that creates a whole another investigation because there's not as much data on them and a significant data deep dive to say, OK, first of all, well, we believe this to be an Exon 20 insertion. It's not documented anywhere. And secondly, of course, the most important question to you guys as providers is, is this one that the patient's going to respond? And so, I will say, I'm going to be very honest, our turnaround time slows down on these because it becomes, first of all, we're talking with our bioinformatics team, we're talking with our scientific team, all collaborating as to what it is we- how we're going to classify them. Because particularly when they're occurring in the second and third base positions of one code on and the wobble base of the next and we're trying to determine biochemically, do we actually think this is happening? Then we talk to you guys and just we have to sometimes wordsmith and say this is what we predict this to be. We can't predict the biologic impact of this. There isn't data about it. And then I think- actually, my next question, my understanding at least my clinical providers, they follow the patients more closely, but I'm not sure how you guys manage that information. But when it is a complex and unique one, you guys hear from us, and it takes a few more days to sort through that to make sure we put something meaningful out there.

Joel Neal, MD, PhD: Yes. I think some of those cases, that's why we have a thoracic molecular pathology tumor board. But we only meet once a month for about 30 minutes so we can't wait a month for those cases to be signed out. I think both for community medical oncologists out there as well as for the molecular pathologists who are signing out this report, I think it's astounding how many different testing mechanisms there are. How many different companies and institutions who are providing their own testing. And really, there is quite a burden on the molecular pathologist reporting it out to not just say, here's an EGFR Exon 20 insertion, but also, this is very different than the regular EGFR mutations for community medical oncologist who might just say like, EGFR, let me prescribe osimertinib. Making that case that this is a very different kind of mutation. I'm wondering do you put specific drugs and say they're FDA-approved drugs, and like, do you go that far to suggest treatments? Is that in the molecular pathology role or is that up to the treating oncologist to read between the lines?

S. Michelle Shiller, DO, AP/CP, MGP: You actually just transitioned into something I was going to add an additional comment on, and that is, it's incumbent upon us to be very clear about what it is we've detected. And so, if it's an Exon 20 insertion, it's going to be bottom line. The EGFR Exon 20 insertion mutation detected in this case, and then often will parenthetically reference that alteration; has two FDA-approved therapies and we will list them mobocertinib and amivantamab for this event. And then we may mention clinical trials in particular situations. And then we would address any other potential things we saw. Same thing with any other event. It isn't helpful for us to just put the amino acid event and say, well, this is going to respond to an EGFR TKI because it could be an Exon 19 deletion. And so, if it's an Exon 19 deletion, the EGFR Exon 19 deletion detected in this case is predicted to respond to the FDA-approved therapies X, Y, and Z. Now, someone like yourself, someone like Zosia, Lauren and her team, you guys don't need it in that level of detail, but because most patients are treated in the community, I do think, as you've mentioned, for our community oncologists who might just- and maybe they're busier. I'm not really sure you guys would understand that more so than I. If they're moving quickly and they just see EGFR mutation and they go on, and it's not- there's no stop point for them, it does concern us that they would not actually see all that detail. So, we're exceedingly clear, and yes, we do mention therapies. Is it incumbent upon us? Well, I think it helps people. We don't want to step on your toes and we're certainly not going to go start treating the patient, but the feedback we receive from our clinical colleagues is, it is helpful to have that in the report.

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