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The Importance of NGS Testing

Insights From: Jacob Sands, MD, Dana-Farber Cancer Institute; Benjamin Besse, MD, PhD, Institut d'Oncologie Thoracique; Alexander Drilon, MD, Memorial Sloan Kettering Center; Marcia Brose, MD, PhD, Perelman School of Medicine
Published: Wednesday, Nov 20, 2019



Transcript: 

Alexander Drilon, MD:
The best guess to look for a RET fusion, in my opinion, is next-generation sequencing [NGS]. This is because this is a comprehensive assay that’s able to detect not only RET fusions but other actionable events, such as mutations involving EGFR, ALK, ROS1 fusions or met exon 14 alterations. This is because we’re in an era where we’ve left the 1 gene, 1 test approach, and we’ll have 1 big test that’s able to detect all these different events for which we have matched targeted therapies.

We also know that even if you use a very good DNA-based NGS assay, this can miss a few RET fusions. And so at our institution, Memorial Sloan Kettering Cancer Center in New York, New York, we have complementary RNA-based testing that’s able to find a RET fusion in select cases that was missed by DNA. Beyond this, there are other tests that are able to find RET fusions. In general, these are a little more limited than comprehensive next-generation sequencing. But if you’re in an environment where NGS is not available, you can do something like reverse-transcriptase PCR [polymerase chain reaction] or FISH [fluorescence in situ hybridization].

People may ask about the utility of immunohistochemistry for RET, but that doesn’t track very well and isn’t validated. And so it’s not an available test that can faithfully pick up these alterations, unlike for ALK, for example.

Benjamin Besse, MD, PhD: For patients with localized or locally advanced disease that can be treated, there is no indication for NGS testing because it will not change your strategy for the patient.
For the patient with metastatic disease, or locally advanced disease that cannot be treated radically by surgery or other therapy, NGS testing is quite effective as long as it’s not squamous cell carcinoma.
For all the drivers that we can find in lung cancer, it’s today quite rare to find them in squamous. So I would not test the squamous cell carcinoma unless there is a very particular presentation, such as in never-smoker or light-smoker patients. For all the nonsquamous metastatic or locally advanced disease not treated radically, I recommend an NGS testing up front before starting a new treatment, in particular, in the nonsmokers.

NGS testing up front is key for the metastatic patient because it can change the patient’s management. We know that in a Western population, we will find in 15% to 20% of the cases a driver for which we have a targeted therapy, and in most of the cases this targeted therapy has to be prescribed up front.

In most of the cases, we first screen the more frequent tumor abnormalities such as EGFR and ALK. Then in a second wave, we screen for RET, ROS1, MET, and HER2.

I think this 2-wave NGS screening is OK so far. But if some new RET inhibitor will be available up front, we will have to integrate RET as a reflex testing in any patient with NSCLC.


Transcript Edited for Clarity
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Transcript: 

Alexander Drilon, MD:
The best guess to look for a RET fusion, in my opinion, is next-generation sequencing [NGS]. This is because this is a comprehensive assay that’s able to detect not only RET fusions but other actionable events, such as mutations involving EGFR, ALK, ROS1 fusions or met exon 14 alterations. This is because we’re in an era where we’ve left the 1 gene, 1 test approach, and we’ll have 1 big test that’s able to detect all these different events for which we have matched targeted therapies.

We also know that even if you use a very good DNA-based NGS assay, this can miss a few RET fusions. And so at our institution, Memorial Sloan Kettering Cancer Center in New York, New York, we have complementary RNA-based testing that’s able to find a RET fusion in select cases that was missed by DNA. Beyond this, there are other tests that are able to find RET fusions. In general, these are a little more limited than comprehensive next-generation sequencing. But if you’re in an environment where NGS is not available, you can do something like reverse-transcriptase PCR [polymerase chain reaction] or FISH [fluorescence in situ hybridization].

People may ask about the utility of immunohistochemistry for RET, but that doesn’t track very well and isn’t validated. And so it’s not an available test that can faithfully pick up these alterations, unlike for ALK, for example.

Benjamin Besse, MD, PhD: For patients with localized or locally advanced disease that can be treated, there is no indication for NGS testing because it will not change your strategy for the patient.
For the patient with metastatic disease, or locally advanced disease that cannot be treated radically by surgery or other therapy, NGS testing is quite effective as long as it’s not squamous cell carcinoma.
For all the drivers that we can find in lung cancer, it’s today quite rare to find them in squamous. So I would not test the squamous cell carcinoma unless there is a very particular presentation, such as in never-smoker or light-smoker patients. For all the nonsquamous metastatic or locally advanced disease not treated radically, I recommend an NGS testing up front before starting a new treatment, in particular, in the nonsmokers.

NGS testing up front is key for the metastatic patient because it can change the patient’s management. We know that in a Western population, we will find in 15% to 20% of the cases a driver for which we have a targeted therapy, and in most of the cases this targeted therapy has to be prescribed up front.

In most of the cases, we first screen the more frequent tumor abnormalities such as EGFR and ALK. Then in a second wave, we screen for RET, ROS1, MET, and HER2.

I think this 2-wave NGS screening is OK so far. But if some new RET inhibitor will be available up front, we will have to integrate RET as a reflex testing in any patient with NSCLC.


Transcript Edited for Clarity
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