Next-generation sequencing has increasingly become more valuable to physicians treating cancer at academic medical centers, but these tests also need to be incorporated more into community oncology practices. A recent study, presented at the 2019 ASCO Annual Meeting, demonstrated that the use of these tests has increased in the community setting as the technology, and the use and approval of matched therapies, continues to develop.
Andrew McKenzie, PhD
Next-generation sequencing (NGS) has increasingly become more valuable to physicians treating cancer at academic medical centers, but these tests also need to be incorporated more into community oncology practices. A recent study, presented at the 2019 ASCO Annual Meeting, demonstrated that the use of these tests has increased in the community setting as the technology, and the use and approval of matched therapies, continues to develop.1
A team of researchers, led by Andrew McKenzie, PhD, collected and analyzed information from oncologists in the Sarah Cannon Research Institute network who have ordered NGS-based molecular profiling for patients between 2012 and 2018. McKenzie et al completed a comprehensive analysis of these data to find trends in the use of NGS-based testing in the community.
In 2012, the rate of which physicians ordered NGS-based testing in the Sarah Cannon network was 5.75 per month, but this increased to 440 tests per month in 2018. Additionally, 11 total oncologists were ordering tests in 2012 compared with 269 in 2018. Physician utilization in 2012 was at an average of 6 tests per physician versus 22 tests per physician in 2018.
Oncologists primarily used archived tissue in 2012, with a median time between collection and test results of 131 days. Although archived tissue still provides the physician with information regarding the presence or absence of mutations, research has shown that the mutational landscape of the tumor can evolve and develop overtime. However, by 2018, there was a 74% decrease in the median time between biopsy and receiving the test results, indicating a trend toward using fresh tissue for these tests. In 2018, the median time between collection and test results was 34 days.
Plasma-based NGS testing was introduced in 2014; these tests allowed physicians to order tests using a blood draw rather than conducting a biopsy for tissue. The use of plasma-based NGS testing made up 4.9% of NGS-based tests in 2014 versus 40.1% in 2018.
“Plasma-based NGS, as you can imagine, is easier to do in the clinic because all that is required is a blood draw instead of a biopsy,” said McKenzie. “When that came on board in 2014, we saw a real explosion in ordering of those plasma-based tests….”
In an interview withTargeted Oncology, McKenzie, manager for the Personalized Medicine Program at Sarah Cannon, discussed the growing trends of NGS-based testing utilization in the community setting and the results from this analysis conducted at Sarah Cannon. He also highlighted the value of NGS to both the physician and patients with cancer and how utilization could be increased over time.
TARGETED ONCOLOGY: Why was it so important to conduct this study?
McKenzie:This study was important because a lot of what we know about results from NGS and its utility is based on what’s been published out of academic medical centers. That’s hugely valuable information, but 1 of the things I think it misses is that connection to the majority of patients in the United States who have cancer. It was important for us to summarize that information to say what’s actually going on from a test-ordering and utilization point of view all the way through the actual results that come back, and how similar or different these results are from what we know is published in the academic medical center setting. That was the motivation for this study and why we thought it would be extremely important for us to get our hands on that. As 1 of the largest providers of clinical trials in the nation and in connection with hundreds of thousands of patients with cancer, we thought we had a pretty unique opportunity to do that survey and collect the data that we presented.
TARGETED ONCOLOGY: How was this study designed?
McKenzie:This is a pretty unique study in that at Sarah Cannon, we don’t have a say, necessarily, in how the doctors practice medicine. They order these tests and do these tests as part of their routine clinical practice, so it wasn’t a big initiative that was kicked off at Sarah Cannon to entice people to order these types of tests; this is a survey of how these tests are being used in the community setting. That’s the background.
It is just a survey to see what’s going on within the community, [to see] how that mirrored what we know is going on in the academic medical center space. Also, how does it align with the new advancements that are coming out in the field of genomic medicine? For example, with approvals like larotrectinib (Vitrakvi), did we see any correlation between the amount of testing and those types of broad approvals in that molecular oncology landscape? That was the design. It was not an interventional way to convince people to do this. It was to take 2 steps back and survey what people are doing and how medical oncologists in the community setting are utilizing these tests and this information.
TARGETED ONCOLOGY: What were the key takeaways that came out of this analysis?
McKenzie:This survey, taken between 2012 and 2018, [included] popular, commercially available NGS-vendor data. What we noticed between 2012 and 2018 was a market increase in the total number of molecular profiles that had been ordered within our network. I think that number is just under 6 per month on average in 2012 and rose to about 440 a month in 2018. That’s just in the community setting. I think folks probably would have thought it would have to take a bit longer than that, so we were excited to see that.
In conjunction with that, we saw the individual physicians1 who might have dabbled and ordered a test here or there—those physicians began ordering multiple tests per year, which indicated to us that there was some sort of value being gained by ordering these tests that keeps the physician going back looking for something. We’ve got a lot of hypotheses on why that is and why they keep finding that value, but it’s nothing we are ready to share yet. A lot of interesting thoughts came out of that.
We went a little further to break it down by the types of testing. NGS testing can be broken down into 2 main categories whether you isolate a block of tissue and get the DNA out of that tissue to run the test or if you isolate the DNA out of a patient’s plasma by routine blood draw. We call those either tissue-based NGS or plasma-based NGS. The plasma-based NGS, as you can imagine, is easier to do in the clinic because all that is required is a blood draw instead of a biopsy. When that came on board in 2014, we saw a real explosion in ordering of those plasma-based tests, now compromising about 40% of all NGS testing that happens within the community setting, which is important to note. I think it’s an important trend that we saw here, and 1 we wanted to point out for folks to see.
The tissue-based testing is interesting because it seemed to always result in a few more mutations than the plasma-based testing did. That can be due to a number of different factors that our team has had to educate our medical oncologists around. Just because this test detected more genetic mutations doesn’t mean it is a better test, and we qualify all of the mutations as actionable, potentially actionable, or unactionable, so our next foray here is to make sure that when these results back, that the physicians are understanding the percentage of the mutations that come back are actionable, potentially actionable, or unactionable from a therapeutic standpoint. That’s a really important distinction to know; just because they detect more mutations, it doesn’t mean that it is a better or worse test.
The last couple bits, I think, display how these tests are utilized in the clinic. When the tests first came out in 2012, it seemed like, and data suggest, that most of the doctors were using archived tissue that they had had saved from a prior biopsy that they would send off to get the NGS testing. To the order of around 131 days in 2012that’s how long it was between the biopsy and when the doctor would order the test. We know from the literature that the mutational landscape for any 1 individual tumor changes overtime and through treatment. Getting a clear and recent picture of that mutational landscape is crucial to provide information about potential next therapies. Relying on old, archived tissues is not something that we would recommend, but that seemed to be the trend when these tests first came out. Doctors weren’t necessarily willing to go in and get a fresh biopsy for this, but that dramatically changed over the course of our study.
In 2018, I think the median time was 34 days between biopsy and receiving a test result, which is an incredible reduction in time. And it’s a signal that doctors are willing to go get fresh biopsies to get a clear, recent picture of the tumor mutation landscape before making that treatment decision, which we think is vital to making these tests as useful as possible.
The shift to using non-archival tissue in recent years is something our group is excited about. That was the big take home. Not only are doctors using it more, but we think they are using it in the right way more. That’s what the survey told us.
We haven’t yet seen this type of information come out in the community setting, so we wanted to make folks aware that this isn’t something that is specialized to an academic medical centerthese tests, NGS-based tests for cancer care, are becoming routine in the community setting. Doctors are getting increasingly savvy about when to use it, which patients might receive the most benefit from it, and then, of course, connecting those results to either clinical trials or on-label therapies that might be available for their patients.
TARGETED ONCOLOGY: Why is it so significant to see this increase of NGS-based testing in the community setting?
McKenzie:This gets us to the motivation for why our program even exists, which is to democratize access to these cutting-edge therapies and technologies that exist. The perception is that you only get this kind of care and access to technology and therapies if you are lucky enough to go to an academic medical center. For us, it’s important to get the message out that that’s not completely true.
Our program at Sarah Cannon is dedicated to democratizing that access to cutting-edge therapies and technologies to patients that are seen in the community setting. That’s our whole motivation for running these types of studies, for getting the awareness out, and for having programs that we do here, like the personalized medical program. [We want] to arm our doctors and research staff with all the information they can regarding these tests so that they feel comfortable ordering the tests for their patients and are comfortable with deciding what to do when the results come back.
TARGETED ONCOLOGY: Are there any specific patients where you believe NGS testing is more important than in other populations?
McKenzie:We recently put out an opinion piece in January.2Howard A. “Skip” Burris, III, MD, is an author, and I am the lead author on that. Our opinion is that patients with cancer who have metastatic disease should get molecular profiling or broad-based NGS done. The reason we think that is because there are things that can be illuminated on these tests that aren’t illuminated in other places that we think can benefit patients who have metastatic disease. With recent approvals of things like larotrectinibdisease-agnostic but molecularly driven FDA-approvals—doing these types of tests can reveal results that you otherwise might not illuminate with other technology. [We see the] same thing with tumor mutational burden (TMB), which is emerging as a very important biomarker for response to immunotherapies, and getting that look is very difficult unless you do this broad-based NGS. That’s our opinion. Folks with metastatic cancer should get this type of testing.
In part with that, we think that patients with metastatic cancer should have access to clinical trials, and a lot of the clinical trialsaround a third of the clinical trials that we run at Sarah Cannon—require the knowledge of the absence or presence of a molecular alteration. In some of those studies, the molecular alteration isn’t 1 you would typically test in standard-of-care testing, so that’s why we think that obtaining this information as early as possible for patients with metastatic cancer has the potential to open many more treatment options for that patient. That’s why we believe that.
TARGETED ONCOLOGY: What are the next steps that are necessary to incorporate more NGS into more community practices?
McKenzie:We think it is crucial that this type of technology be available to any patient with cancer. In our experience, the biggest barrier that we have come across for folks opting [to include] this as part of their practice is an education gap. What do I do with the results? That is the same question we continue to get back from the doctors that we work with. In our opinion, molecular education is vital for getting this information into the hands of other community oncology practices.
We know that is true in folks who also say there is a cost barrier, a tissue-scarcity barrier, but the root of it is if a doctor understands the value that can come out of these tests, those other reasons become secondary to the value they can get out of the test. It’s been our position that if we can arm the doctors with as much information as we can regarding these tests, then the information that comes back, proving the value, and connecting those results to targeted therapies, immunotherapies, and clinical trials, will become a natural thing doctors will want to do and get for their patients.
TARGETED ONCOLOGY: How do you see the role of NGS testing evolving in the next decade?
McKenzie:I think what we are going to see is a trend toward the majority of patients with late-stage or metastatic cancer getting broad-based molecular profiling. I think the type of NGS testing we will start seeing will be more comprehensive, less hot-spot, less of these targeted panels, and probably [move] into a space that’s more whole exome, or in 10 years, I wouldn’t be surprised to see whole-genome sequencing become much more common. Beyond that, I’m hoping we will see the integration of tumor-normal NGS, sequencing both the germline and the somatic mutation landscape all at once so you get that picture right up front to make the best treatment decisions for your patient upfront and have that information as early as possible in the treatment plan for a patient. That’s probably how I see it, becoming broader, deeper, and becoming easier to access than it is now.
I assume too that we will see more papers come out justifying the use of NGS from a value-based medicine perspective. I think that is going to turn the tables a lot on how these tests are covered and how comfortable doctors will be in ordering it in response to that.
TARGETED ONCOLOGY: What other challenges do you think should be addressed in the next few years?
McKenzie:We are arming the physician with this information and being very proactive in molecular education for physicians so that when a patient comes in, they don’t have to ask or answer questions they don’t know. The flip side of that is true too, arming the patient and being able to empower patients to talk to their physicians about these tests.
We’ve talked a lot today about the potential benefits of NGS, but I think there is also reason to be measured in those expectations. Not every report comes back with actionable alterations, but if you don’t seek, you’ll never find it. That’s our mantra. For patients, I think giving them that same level of education is very important, such as what to expect and what not to expect, as well as what conversations they should have with their physician and how to bring that up. Those are things that I think are equally as important as defining these trends and how the tests are being adopted. It’s how comfortable the patient is with bringing this type of information up to the doctors and how we provide the same level of support to them as we do to our doctors. That’s what I would like to see flourish here in the next few years.