Testing ALK rearrangements

Karen Reckamp, ​​MD: Dr Patel, can you talk about the tests for ALK rearrangements in the clinic?

Jyoti Patel, MD: Yeah, thank you, and it’s so clinically relevant. The evolution of how we test our patients has changed rapidly in recent years. Certainly, there was a time when we thought that DNA sequencing or allele-specific sequencing, or PCR [polymerase chain reaction], was essentially sufficient because we had a small number of oncogenic conductors. The terrain has changed. We now have a multitude of oncogenic drivers; we turn to immunohistochemistry [IHC] for PD-L1 for combinations of immunotherapy. Similar to others, I prefer DNA and RNA testing, this is next generation sequencing [NGS]. The advantages of this are that you can make multiple genes at once, that you can have less cellularity. This is one of the things with allele specific testing, you have to have a high tumor cell count to really get a good result and can get a false negative. Additionally, next-generation sequencing with both DNA and RNA can also look for alterations in intronic genes that you would normally only get with FISH. [fluorescence in situ hybridization].

Now, most of us would say that if you have a patient who has just been diagnosed with metastatic or advanced non-small cell lung cancer, in our facility we do reflex and PD-L1 testing, and normally we do it in-house, i get it within 24 hours. Then I do next gen sequencing and usually try to get that result within 2 weeks. There are other places that will get a quick result with PCR for EGFR, mutations if common, then do FISH or IHC tests. Definitely FISH and IHC for ALK are very reasonable. IHC is specific and sensitive depending on cellularity. Plus, you get the result in just one day with PD-L1. FISH testing, in several institutions, and when we started this journey on targeted therapies, people often did FISH for ROS1 and ALK simultaneously. Granted, all of these methodologies are reasonable, but we always seek to perform extensive patient testing for BRAF, RET fusion, NTRK fusion, MEET exon 14. You are looking at a much larger pie.

Tissue management is the biggest problem. When making multiple IHC sections, you use one slide for each, and then you run sequential tests, or maybe you check if EGFR. If it’s negative, then you switch to FISH, and it can cause delays for our patients. Where possible, I would recommend the PD-L1 test with IHC on all patients as well as concurrent NGS for a large number of drivers.

The other thing that has changed a lot is the blood tests. It is in thinking that we will perhaps have a success a decade ago to be fully entrenched in most of our practices. Essentially you are looking for circulating tumor cells, most often you are looking for cell-free DNA for most vendors. Sometimes you get an early lead time, the lead time tends to be shorter. It is usually between 7 and 10 days. Sometimes it’s easier because you do it at the point of service. You take the blood, and it comes out, rather than looking for the tissues and the delays that may be involved in that.

The sensitivity has improved a lot with the different platforms, and that’s something we all need to keep in mind. There are people who may have had experience a few years ago, and they may find it difficult to get mergers or large mutations, especially mergers like NTRK and ALK. Increasingly, we understand that platforms have changed dramatically and that blood biomarkers are often excellent. An important caveat is that although they are specific, they are not always so sensitive. Some patients are excretors and have more circulating DNA. There are others that may have a lower disease burden, so it’s harder to catch. There is approximately 70% agreement between blood and tissue.

There was an interesting study from the World Lung Cancer Conference this year that aimed to do both simultaneously, and it’s still my practice. There is a cost saving by doing it simultaneously, adding blood to the tissues to get people to the right targeted therapy versus expensive chemotherapy or immunotherapy. There is a cost saving and it’s better for the patients, you are more likely to get a hit. What are you doing, Karen, in your establishment? What is your practice in testing?

Karen Reckamp, ​​MD: I’ll just say it’s hard to discuss cost savings, and that’s great data to start disseminating. Usually we do a reflex test. By the time I see a patient, they are usually almost done for our NGS tests, and our NGS includes both DNA and RNA., it is therefore more likely to see larger mergers or alterations. Typically, we only received blood if there was insufficient tissue, and again, in a first-line patient with advanced disease, blood is usually a good source to look for alterations.

I would ask you, for our viewers, when you have an IHC or FISH test that is positive, are you happy with that and would you go ahead, or do you need more testing?

Jyoti Patel, MD: If I have had a few FISH tests, I end up getting curious and watching, and generally doing NGS. What we learn are two or three things. First, co-mutations probably matter. Understanding the company you keep can impact progression-free survival. We have certainly learned that with the KRAS and EGFR stories, for example. It may not be as important for ALK right now, but I certainly think this is an evolving area. The second thing is, if I test positive with FISH or IHC, I believe it. I think the false positive rate is pretty low, so you’re probably good at starting to find a medicine for your patient at this point.

Karen Reckamp, ​​MD: This is good to know, especially if there isn’t enough tissue to do further testing.

Transcription edited for clarity.

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