Importance of Biomarker Testing for RET in Non Small Cell Lung Cancer - Episode 5

The Importance of NGS Testing in NSCLC


Shirish M. Gadgeel, MD, MBBS: At this time, NGS [next-generation sequencing] testing appears to be the most efficient way of identifying genetic alterations that can be targeted for clinical benefit in patients with advanced non—small cell lung cancer. And it is because it allows us to simultaneously assess multiple gene alterations, and in general, requires less tumor tissue compared with some of the older methods that assessed these genetic alterations independently.

Another advantage with NGS testing is that it may be better at identifying translocations compared with some of the older methods, such as IHC [immunohistochemistry] and FISH [fluorescence in situ hybridization].

When it comes specifically to RET translocations, right now we don’t have any IHC test for it. FISH can be utilized to identify RET translocations, but one of the limitations of FISH is that we cannot identify the partner gene. So NGS lines up being probably the best test to identify RET translocations in a tumor in a patient with non—small cell lung cancer.

What is important to note is that for fusions, in general, NGS testing that is DNA based may have some limitations in that a DNA-based NGS assay may not identify all tumors with translocations, including RET translocations. It is difficult to go into all the reasons that are the basis for this limitation of a DNA-based NGS assay. But suffice to say it is important that an RNA-based NGS assay is performed if a translocation has not been identified in a DNA-based NGS assay. And this comprehensive NGS assessment will allow us to detect all tumors with translocations, including RET translocations. I think, if feasible, it would be best to do an NGS assay in patients with advanced non—small cell lung cancer.

NCCN [National Comprehensive Cancer Network] guidelines highly encourage that we use NGS testing to get a comprehensive analysis of all possible genetic alterations in the patient’s tumor. The guidelines suggest that at least EGFR, ALK, BRAF, NTRK, and ROS1 should be assessed. But they do suggest that other alterations, such as HER2, c-MET, RET, are also analyzed since there are targeted therapy options for these patients. In this context, the best way to assess these alterations may be NGS, again, as I mentioned before, because of the ability to simultaneously assess multiple genes and particularly patients with non—small cell lung cancer, where the amount of tumor material available for conducting these tests could be limited.

Therefore, having a test that uses the least amount of tumor tissue is extremely beneficial, and that happens to be an NGS test.

We need to recognize the limitations that may exist in each individual practice. And what I would say is that if it is possible to do an NGS test, then do so in a reasonably quick time. Then it should be what should be done. But I think what the focus should be, based on local availability, whatever resources are locally available, that the practicing oncologist try to get as many molecular alterations assessed as possible.

One of the major limitations in patients with lung cancer is the amount of tumor material available for genetic testing. If one conducts each of these tests independently, different tests are performed to identify the different genetic alterations, then it’s quite possible that one may not have enough tumor tissue left to conduct all the necessary testing. This may lead to the patient requiring a second biopsy.

We now do have the option of doing liquid biopsies or assessing circulating tumor DNA to identify these genetic alterations. But it’s important to note that the sensitivity, in general, of these liquid biopsies is only about 70%, suggesting that if the result is negative with the liquid biopsy, that does not rule out, at least in 30% of the patients, that the patient’s tumor does have a genetic alteration. So a liquid biopsy may, to some extent, overcome the limitations of tissue biopsy, but it is very important that we have tissue results, particularly in the event that liquid biopsy results are not available. And in that context we use a test, such as NGS, to maximize the tests that can be performed or the genes that can be analyzed in the tissue that is available.

Transcript Edited for Clarity