Overcoming Barriers to Molecular Testing in Non–Small Cell Lung Cancer


A comprehensive discussion on how to overcome barriers that may inhibit access to adequate molecular testing in patients with non–small cell lung cancer.


Joshua K. Sabari, MD: We talk a lot about NGS, we talk a lot about plasma. What are some of the barriers that you see in your clinical practice? I know for tissue NGS, tissue is the issue. We often don't have adequate tissue and often we're wrangling our pathologists to send these studies. And how are you doing this in your practice? And maybe some insightful or some clinical tips for our community oncologists listening in.

Martin Dietrich, MD, PhD: I have a diversified plan for all systems. For me, the obstacles to tissue-based testing are many. Some patients come only with a clinical diagnosis where I do not have tissue. Some patients come pre diagnosed on smaller samples, where I know I will not have enough tissue. Those are small fine needle passes that are basically cytological specimen. I don't think there's any reasonable scenario that I can think of for a liquid biopsy. 100% of my patients can get a liquid biopsy on the day of first visit and they do. And the concerns about authorizations even though often insurances push back on pan ons >50 genes or consider them experimental. That has gotten better. But in general, it's still the problem on the table. And that reference labs that we're working with have been very, very generous in working these issues out. This is a very, very low risk situation for patients. I've never seen a patient getting stuck with a bill and that was unreasonable. They've been very, very generous in the financial assistance. When it comes to the tissue generation, there are plenty of obstacles. I still order it often, unfortunately, with an insufficient tissue result. But then, I look at the pathology reports upfront. Sometimes, the pathologist, they'll mark this tissue blood would be available for additional molecular analysis. But I do review the scans and look for target lesions for rebiopsy. I'm unrelenting when it comes to obtaining tissue results. I do think that it's better. We haven't talked much about sensitivity and specificity. Certainly, for EGFR, for KRAS, for BRAF, those smaller lure complexity alterations, we see very high sensitivity and specificity in the positive predictive value for responses. Virtually, one to one between tissue and liquid. We do see a blind spot that these alterations show when it comes to fusions, when it comes to splicing events like MET exon 14. Tissue there has a lead and an advantage. And while it's logistically more difficult to obtain, technically, the larger DNA and RNA fragments that we can get from tissue are going to be having the upper hand with regards to proper sampling. This requires me to get involved looking at proper site of locations, ensuring that we're not going to biopsy bone, that we're not looking at small samples from the lung. But I typically like to biopsy extra thoracic lesions where that's a super lymph node, hepatic metastases are always very easy to obtain more tissue from the bleeding risk, they're exceedingly low. I wouldn't be able to recall a single significant bleeding complication. Those are great options for patients. And I encourage them to get these rebiopsies. Because the diagnosis is simply not complete. I have a preliminary histological assessment but that's 19-century medicine. That's how I explain it to my patients, and we want to give them state of the art in November 2022 when the only way to do this is having a liquid and a tissue biopsy at the same time. And there are secondary markers that maybe more easily available on a tissue biopsy at the same time. In the end, I like to have both check boxes completed.

Joshua K. Sabari, MD: Just a few months back for me, I have a patient who is young, never smoker, DNA based NGS was non diagnostic. And I like to use that word 'non diagnostic', not negative, right? You go fishing and you don't catch a fish, you don't conclude it that there are no fish in the ocean, you just didn't catch one that day, right? That's the sensitivity of these assays. And the plasma also was non diagnostic. And I reflexed to an RNA based sequencing assay, really looking at fusion flexo. We have some a priority knowledge of looking at specific PCR tiles for different fusion partners. And we identify a RET fusion with an uncommon partner. I'm curious, Martin, are you reflexing to RNA based assay? Are you using any of these fusion type of PCR based assays in your clinical practice if the patient is non diagnostic on DNA based NGS?

Martin Dietrich, MD, PhD: I've made it a common practice for us to order DNA and RNA based platform at the same time. They'd complement each other. And they also generate some additional data in terms of epigenetic expressions that, I think, are becoming more and more valuable looking at pathway activations of mechanisms that are not descriptive in the genome but are epigenetic for micro RNAs. Other epigenetic mechanisms. I do think that in a linearized RNA strand is going to be superior to DNA convoluted an in turn rich strand of DNA analysis. I do this upfront. I try not to reflex them anymore. I know that a lot of the companion diagnostics are based on DNA basis, but this comes to a very profound conflict, because we are approving drugs based on companion diagnostics that are often DNA based, which by my assessment, is probably a second-best option for patients. In fact, and we're going to be seeing the introduction of RNA-based liquid biopsies. But the sensitivity of detection in liquid biopsy will be of interest for fusion detections, and we'll have to see the data how they going to shake out in terms of sensitivity. But certainly, the attempt is going to be to get an RNA based panel for every patient. And the guidelines would support going back and adding on an RNA-based panel. We've had this discussion with payers and looking at basically a second look NGS. Because it's not the same technology, it is a different angle, a different level of sensitivity. And this should be done on every patient. We have such a fusion rich sub type of cancer here that we do need RNA-based technologies on every patient.

Joshua K. Sabari, MD: You brought up two good points minutes ago. Number 1, not biopsying bone if you can avoid it, because we must de-calcify and you really affect the quality, integrity of the DNA. I couldn't agree with that more, Martin, is try to get an area of disease where you can actually have good integrity of DNA, liver lesion, lymph node, for example, lung lesion.

Transcript edited for clarity.

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