NGS Testing May Be Better Than Single-Gene Testing for Identifying Mutations in NSCLC

Brandon Sheffield, MD

The use of next-generation sequencing (NGS) led to a higher number of patients with non–small cell lung cancer (NSCLC) having genomic alterations identified compared with single-gene sequencing. Moreover, NGS was a less costly testing method.

A study conducted in Canada evaluated the costs of testing using single-gene or NGS panels and estimated the costs of delaying treatment. The gene alterations tested for included EGFR, ALK, ROS1, BRAF, and, as well as KRAS, MET, HER2, RET, NRG1, NRAS, NTRK1/2/3.

Gene alterations with an approved targeted therapy were found in 38.0% of the patients NSCLC tested using an NGS panel vs 26.1% in those tested using a single-gene panel. Testing with an NGS panel was also associated with a shorter time to initiation of targeted therapy at 5.1 weeks vs 9.5 weeks with a single-gene test.

The cost of delaying care was less expensive with NGS vs single-gene testing. According to the study results, the cost of delaying treatment to conduct NGS testing was $3,504 compared with $5,799 with single-gene testing.

In an interview with Targeted Oncology™, Brandon Sheffield, MD, anatomic and molecular pathologist, physician lead of Research, William Osler Health System, discussed relevant biomarkers for testing in patients with NSCLC, and the cost-effectiveness of single-gene test vs NGS.

TARGETED ONCOLOGY: For non–small cell lung cancer, what biomarkers are important to identify?

Sheffield: For non–small cell lung cancer, the treatment is very much defined by biomarkers. To me, it's important to have all those biomarker results before you start treatment. For particular types of non–small cell lung cancer, such as adenocarcinoma or non–small cell lung carcinoma not otherwise specified, I would like our patients to be tested for PD-L1, EGFR, KRAS, BRAF, MET, HER2, ALK, ROS, RET, TRK, and NRG1 results before they get started on their first treatments. There are quite a few in there.

What are your key recommendations for ordering genomic testing in the community setting?

It is critical that oncologists team up with their laboratory professionals, and that they have a good relationship and understanding of where their patients are being diagnosed and where the tissue is being stored. Ideally, the pathologist is the best person to initiate that testing, so that when the patient arrives to meet with their oncologist for the first time, all the results are ready, and that meeting is productive. The oncologist can then provide an accurate treatment recommendation. This helps patients get on treatment faster, and it helps alleviate a lot of the anxiety that they're feeling.

What advice can provide for oncologists in the community setting on how to read pathology results for their patients with non–small cell lung cancer?

There's a lot of information in your pathology reports. There's going to be some histomorphology and some diagnostic markers that help us tell the different subtypes of non–small cell lung carcinoma. This will include things like squamous cell carcinoma versus adenocarcinoma that can affect the type of chemotherapy we choose. Then, there are going to be additional results, such as genetic biomarkers like EGFR, ALK, ROS, and others that we've mentioned. And those will help further refine the treatment with targeted therapy. And of course, there will be a PD-L1 result, which can help inform the use of chemotherapy as well as immunotherapy for their patient. It's very helpful for oncologists when you can get all of this information in a single report.

Wherever possible, encourage your pathologist to do these tests, because if the information is on different reports, and the reports are found in different places, that can make things very difficult. In addition, if there are words or formats or other items in the report that an oncologist doesn't understand, it's important to give that feedback back to the pathologist because everything in the patient's chart should be understandable to the treating physicians.

Can you talk about single-gene test vs next-generation sequencing in terms of cost-effectiveness?

When we talk about biomarker testing, especially genetic biomarkers, they can come in [variations]. Single-gene testing means we're doing markers one at a time. So, we can perform a gene sequence of a single gene like EGFR. Or we can do other single-gene tests that look at proteins like immunohistochemistry for ALK. And there are other single-gene methodologies, things like polymerase chain reaction for gene mutations, as well as FISH for amplifications. Each of these is very effective methods, but each of them only tests for one single gene. In a sense, we're asking the tumor a yes or no question. We're asking, do you have an EGFR mutation? And if the answer is no, then we move on to the next test. Do we say do you have an ALK mutation? If the answer is no, then we move on to the next test. Each single gene test is cheap. But when we do several single-gene tests, this can become very expensive. In addition to the cost of the testing itself, each test consumes a little bit of patient tissue, which can be oftentimes even more of a scarce resource than the dollars that a patient or the healthcare system has.

When we flip over and talk about next-generation sequencing. This is often a more comprehensive test. We perform a single test that captures all those biomarker results simultaneously. That included things like EGFR, ALK, and other biomarkers. So, instead of asking a yes or no question, we're asking a tumor, an open-ended question. We're asking, what driver mutations do you have? And we usually get a very satisfying answer in return.

You are one of the investigators of a study that assessed the cost-effectiveness of single-gene testing vs NGS. Can you discuss the study methods?

This study was performed in the context of a Canadian healthcare system. In Canada, we have a publicly funded system, and the healthcare system is different in every region of Canada. Because if each region has different funding and a different structure for how they do biomarker testing, every patient in each hospital would have a slightly different approach to how their biomarkers are tested.

In this study, we looked to see the economic and financial impact of those different strategies on the healthcare system. So, we inputted tp an economic model, the cost as well as the time it takes to receive those results. What we got back on the other end, is some very helpful information. As we know, single-gene testing is the cheapest option when you do only a very small number of single-gene tests. But we know that in lung cancer, we now have to do up to almost 11 biomarkers.

Next-generation sequencing is the cheapest test in terms of the test itself, the consumables, the plastics, and the chemicals that we use to perform the testing. But what we also found is that next-generation sequencing allows the patient to get started on treatment much sooner than if we use single-gene testing as each test takes a certain amount of time to complete. During that time, patients with lung cancer are still very sick and tend to have a lot of medical needs. And they might be presenting to the emergency room and might even be admitted to the hospital while they're waiting to get started on that treatment. What we found is that the amount of money that our healthcare system is paying to support these patients, while they're waiting to get started on treatment is much more significant than the amount of money our healthcare system is paying for the actual cost of the test itself. The conclusion is that healthcare system should invest in not just the most comprehensive test, but in a test that allows patients to get started on treatment as soon as possible.

In addition to the cost implications of using single gene testing vs NGS, how can this decision impact treatment outcomes?

We know that patients will do best when we find an actionable driver mutation and match that actionable mutation in lung cancer with a targeted therapy, the chances of that are much higher when we use next-generation sequencing. We found in our study that 38% of patients would have a matched targeted therapy using next-generation sequencing, and significantly lower numbers if we were to use any form of single-gene testing.

_REFERENCE:

_{Sheffield B, Eaton K, Emond B, et al. Economic impact of delaying care with single-gene testing versus next-generation sequencing in non-small cell lung cancer. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract MA12.05.}