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FAQs: Importance of Biomarker Testing in NSCLC

Matthew Gubens, MD, MS

Associate Professor
Medical Director, Thoracic Medical Oncology
University of California, San Francisco
San Francisco, California

Matthew Gubens, MD, MS: consultant/advisor/speaker: AstraZeneca, Bristol-Myers Squibb, Cardinal Health, Genentech/Roche, Genzyme/Sanofi, Guardant, iTeos, Surface; researcher (paid to institution): Amgen, Celgene, Johnson & Johnson, Merck, Novartis, OncoMed, Trizell.

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Craig Mackinnon, MD, PhD

Direct Division of Genomic Diagnostics and BioInformatics
University of Alabama at Birmingham
Birmingham, Alabama

Craig Mackinnon, MD, PhD, has no relevant financial relationships to disclose.

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Released: August 31, 2022

Key Takeaways

  • The use of complementary DNA- and RNA-based broad next-generation sequencing biomarker testing approaches is critical for the identification of as many actionable oncogenic driver alterations as possible.
  • RNA-based next-generation sequencing is generally superior to DNA-based next-generation sequencing for gene fusion detection in NSCLC.
  • Ordering comprehensive next-generation sequencing–based testing and PD-L1 testing upon diagnosis can speed up the initiation of optimal biomarker-guided treatment.

In this commentary adapted from a discussion between Matthew Gubens, MD, MS, and Craig Mackinnon MD, PhD, the experts address important clinical questions about how to integrate biomarker testing into treatment strategies for patients with non-small-cell lung cancer (NSCLC).

Does testing for MET alterations generate more accurate results with DNA-based vs RNA-based next-generation sequencing (NGS) for patients with NSCLC?

Craig Mackinnon, MD, PhD:
Either DNA-based NGS or RNA-based NGS can be used to detect MET alterations, including exon 14 skipping mutations. DNA-based NGS can detect splice site mutations, single nucleotide gene variants, and insertion/deletion mutations (indels), all of which can result in MET exon 14 skipping mutations. On the other hand, RNA-based NGS reveals the functional outcomes of these splicing mutations. Either approach is useful, and it is not uncommon for laboratories to use both as complementary approaches, but RNA-based NGS is superior. Therefore, if for any reason—such as the associated costs—only 1 of the 2 NGS approaches can be used, I would recommend RNA-based NGS primarily because it is more sensitive and provides functional outcomes of splicing mutations. In the near future, I hope more testing platforms will include both RNA- and DNA-based components that can be used simultaneously to detect gene alterations such as MET alterations.

Can RNA be reliably obtained from liquid biopsies for RNA-based NGS in the determination of genetic abnormalities?

Craig Mackinnon, MD, PhD:
Historically, one of the major problems of working with isolated RNA is that, due to its structure, it is relatively unstable and undergoes rapid degradation. Although RNA can be detected and isolated from the plasma, the isolated RNA levels are usually very low. Therefore, it is not a great analyte for testing. Several approaches to stabilize RNA are under development. I hope RNA isolated from the plasma soon can become a better analyte for the detection of genetic abnormalities.

Would you recommend automated reflex testing to ensure appropriate diagnostic workups for all patients with newly diagnosed NSCLC?

Matthew Gubens, MD, MS:
I think reflex testing is ideal, but it depends heavily on the system in which these orders are being made. The type of tests ordered for patients with newly diagnosed NSCLC, and by whom, varies by institution and system. In some institutions, it is standard to order comprehensive genomic profiling as soon as the patient is diagnosed and tissue biopsy samples are available. Even at my academic center, this process has evolved over time and remains a work in progress. For example, we have reflex testing when the tissue sample is processed by our thoracic pathologists, but not necessarily by others. We have taken the approach of involving our interventional pulmonologists so they can automatically start the ball rolling on obtaining liquid biopsy samples or ordering in‑house NGS tests, even if the initial sample is from a metastatic lesion. For institutions or systems that do not have in-house testing, decisions must be made about which vendor to send the requests to, and by whom, and in which patients and samples. It is all about figuring out who the preferred vendor is and making sure an operational and efficient process is in place to ensure that tissue samples are immediately sent out for NGS testing to guide initial treatment decisions. There is no doubt that the logistics for automated NGS-based testing on all samples are still challenging in many institutions. It definitely requires a multidisciplinary effort.

Craig Mackinnon, MD, PhD:
We have very similar experiences at my institution. Hence, at the University of Alabama at Birmingham, we have initiated an automated reflex ordering process so that the pathologists, working closely with the treating physicians, can initiate comprehensive NGS-based testing as soon as the patient is diagnosed with NSCLC. More recently, we have built electronic ordering systems in an attempt to reduce the barriers to automated reflex testing. We have found that using this approach has made it less difficult for the medical oncologists to order NGS testing from the in-house laboratory or send the specimen to preferred outside vendors. 

How can reflex testing be implemented if the disease stage is unknown?

Matthew Gubens, MD, MS:
In some cases, the associated cost or insurance coverage is a barrier for automatically ordering reflex testing. In other cases, the tests may be covered by the medical insurance company only for patients with advanced-stage disease, and it may not necessarily be covered for patients with stage Ib NSCLC, for example. Dr Mackinnon, at your institution, is it up to the pathologist to look up the medical record for the patient before initiating reflex testing?

Craig Mackinnon, MD, PhD:
No. Ordering comprehensive NGS-based testing is largely driven by the medical oncologist at my institution. I think the bar is continuously being lowered, and disease stage is less of a contributory factor for initiating reflex testing for all patients with NSCLC. The more information the medical oncologist has, the better the treatment the patient receives. Staging has become less of a barrier at my institution for advocating for reflex testing for all patients who are newly diagnosed with NSCLC.

Your Thoughts?
What are the challenges you experience in your practice when it comes to requesting NGS-based testing for your patients with NSCLC with unknown disease stage? Answer the polling question and join the conversation in the discussion box below.

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