Overcoming Challenges of Molecular Testing for NSCLC

Jared Weiss, MD:The biggest challenge to molecular testing in the community is nontesting. A lot of patients are not getting guideline-recommended molecular testing, and I’m not talking about pie-in-sky new rare mutations. There is a huge rate of nontesting, even for EGFR in the first-line, and that data is not new. When patients are testing, in my opinion, testing is not always broad enough. So, talking about the nontesting problem, I think education is one answer to that. Another answer, though, are the noninvasive tests. Sometimes it’s not safe to get at the spot that needs to be biopsied; sometimes the patient declines it; sometimes the practitioner is afraid of hurting the patient by ordering that biopsy; and sometimes local expertise doesn’t allow it. Noninvasive testing can answer all of these. We’re talking about plasma-based testing for cell-free DNA or perhaps urine testing. The advantage of these is they don’t require a biopsy and they can bring molecular testing to a wider group of patients. The disadvantage is that not every tumor sheds DNA. And so an actionable change can be present, which is missed by these detection methods.

I think the breadth of testing question is a function and part of cost. The next-generation platforms and, really, broad platforms in general, can be rather expensive and turnaround times can be longer than we’d like. I believe that’s evolving over time. As the technology evolves, the cost is coming down, so I think that it will become more applicable to a larger segment of the population to just test for everything.

The payoff has been remarkably the same across the targeted therapy indications. Whether you’re looking at EGFR as standard of care, ALK, ROS1, and even some of the newer changes that we’re seeing in emerging trial data—some as little as 1 month old—for example, MET deletion 14, it’s amazing how similar the results always are. If you have a patient with an actionable molecular change and you treat it, you almost always see a response rate of roughly two-thirds, which is more than double what you expect with chemotherapy. Your treatment is almost always less toxic than chemotherapy, and you, of course, de-medicalize the life of the patient by allowing an oral therapy instead of being in the infusion room every week or every 3 weeks.

In my opinion, the best way to improve this communication is to do it at a multidisciplinary tumor board. I think there is something very powerful to having every expert related to a multidisciplinary question in the same place, looking at the same images, and looking at the same pathology and having a conversation about it. Now, that’s not always practical in every context, but we do have these things called computers that you can video conference on. And virtual tumor boards are being used much more often in the community. I think this is a wonderful thing. When that doesn’t work, it’s really a simple, old-fashioned telephone call or e-mail—direct attempts at communication. In busy practice, that can often be challenging. This is where a nurse navigator can be very useful for ensuring that that communication is done properly.

I would also say that redundancy is helpful. So, if I’m ordering, for example, a biopsy for the purposes of T790M testing, I don’t want my pathologist to use up all of that tissue proving that it’s cancer and proving that it’s lung cancer. And so, what I do is, in addition to having called the molecular pathologist before ordering that, I ask whoever is doing the biopsy to write on the requisition—I usually supply this to them in written form, typically e-mail—“We know this patient has lung cancer. We know they have EGFR mutation. The question is T790M. Please restrict your testing to that.” And what they’ll do is they’ll just do one H&E (hematoxylin and eosin) stain; simple slide, so that they know where there’s cancer. They’ll micro-dissect that and just test that for molecular testing.

Weiss case 2:

A 62 year-old neversmoker with stage IV adenocarcinoma

• Mutation testing showed an EGFR exon 19 mutation
• The patient was treated with erlotinib for 1 year; he developed diarrhea and rash which was successfully managed
• After 3 months, his disease showed progression on CT; he remained without symptoms.
• He subsequently developed cough and shortness of breath, correlated to progression of a centrally located lung lesion on his follow up CT scan
• Repeat biopsy and molecular testing of the central lesion showed EGFR T790M-positivity
• He was switched to osimertinib therapy and achieved a partial response
• The patient reported dramatic improvement in his well-being