All patients with cancer, regardless of tumor type, should undergo next-generation sequencing (NGS) to have a comprehensive and precision medicine-focused treatment plan, explained Lincoln Nadauld, MD, PhD. However, the uptick of this testing needs to become much more widespread.

“I believe that we are significantly undertesting patients in this country,” said Nadauld. “I believe the vast majority of patients, in the United States at least, are not having microsatellite instability—high, mismatch repair, and 

 fusion status routinely tested in their tumors, and they are deprived at times of having these therapies because we don’t know their biomarker status—because we don’t test for it.”

, Nadauld, executive director of Precision Medicine and Precision Genomics at Intermountain Healthcare, shed light on the current use of NGS and the ongoing efforts to make this testing more widespread across the United States.

: NGS in oncology [allows] the treating physician to identify multiple actionable variants in a patient all at once, and it allows a physician to map that patient’s treatment course so you can identify what targeted therapies or immunotherapies they might be eligible for and identify what clinical trials they might go on. It allows you to develop a comprehensive treatment plan for that patient over the course of their anticipated care.

What is the current use of NGS beyond the academic setting?

It is still emerging. Community oncologists are still uncertain of two things: uncertain of the timing of when to order the testing, and also uncertain of how to interpret their results. Those 2 uncertainties have led to slow adoption.

Therefore, when should oncologists order this testing and how can they best interpret results?

It’s useful to order the testing anytime, as soon as you know a patient has advanced or metastatic disease. The reason for this is, in those patients with metastatic disease, you can identify patients for whom would make them eligible for novel targeted therapies and immunotherapies. Second, you can identify clinical trial options for those patients. Because of those reasons, it’s important to order NGS testing as soon as you know a patient has advanced or metastatic cancer.

You head the Precision Genomics program at Intermountain Healthcare. What is its mission?

[The program] launched 6 years ago, and our goal has been to offer precision medicine treatments for patients with advanced cancer, and to perform NGS and genomic testing in all patients with advanced or metastatic disease of any tumor type. We have built our own in-house testing to do this and we performed not only a NGS test that is capable of seeing all of the mutation types—including fusions, indels, copy number variants, and point mutations&mdash;we also calculate tumor mutational burden, PD-L1 status, and microsatellite instability—high (MSI-H) status, in addition to fusions such as 

In addition to all of that, we do a molecular tumor board review of every single case in our system that is ordered. That comprehensive approach of doing a full genomic analysis and a molecular tumor board review has resulted in us providing targeted therapies to a large cohort of patients. We've reviewed the outcomes of those patients compared with a controlled cohort of patients who did not receive NGS.

Patients who received precision medicine approaches had an increase in overall survival (OS), and from an economics standpoint, we found that it costs less per patient, per week, to use a precision medicine approach than if we did not. Our goal has been to offer precision medicine to physicians and patients across all 23 of our hospitals and our 180 physician clinics to anyone with metastatic or advanced cancer of any type.

You mentioned a chunk of actionable biomarkers. Could you expand on those that are able to be targeted with FDA-approved therapies once they are identified via NGS?

There are therapies now approved by the FDA that are tumor agnostic, meaning they are approved solely on the presence of biomarkers. Biomarker status is the indicator for use of these therapies; those include a variety of immunotherapies and checkpoint inhibitors. Many of the checkpoint inhibitors are approved based on the presence of MSI-H status; they’re also approved for use in patients with mismatch repair deficiency detected via a mismatch repair test, such as immunohistochemistry.

There are also targeted therapies for patients who harbor fusions in 

, which is in a tumor agnostic way. We have numerous therapies that are now FDA approved, based entirely on biomarker status.

How can NGS also help identify predictive or prognostic factors, or even resistance mechanisms?

There are some biomarkers that are prognostic for survival in certain disease types, and there are some biomarkers that of course we know are predictive, and that they would respond to certain therapies. Of course, NGS can identify resistance mutations that are arising; this is very well described in lung cancer. We know there are resistance mutations following EGFR inhibitor therapy and those emerging resistance mutations can be identified by NGS. There is significant utility in these applications.

The other thing we find when we do genomic analysis on patients when we do NGS tests, we often will find mutations that suggest they may harbor a germline mutation and that allows us to order a separate germline test. That has happened many times, where we will find a patient who harbors a 

, or mismatch repair gene mutation, and then raise the question of them having an inherited form of cancer. We have done the germline testing to confirm that and then do cascade testing in their relatives.

Then, it changes the whole scenario for that patient and their families. We are finding, and evidence is supporting the fact, that inherited germline mutations are responsible for a significant percentage of cancers; that is true in about 15% or so of all cancers. Doing NGS brings the added benefit of being able to identify in many cancers with underlying germline mutations that we would have otherwise missed. This is because the patients don’t typically meet the criteria for germline testing, according to national guidelines.

How could NGS help with identifying patients who could be eligible for certain basket trials?

A major benefit to patients with NGS is determining their eligibility for a variety of clinical trials. Increasingly we see that clinical trials include biomarker status as an enrollment criteria, so you have to have a particular biomarker present in the tumor in order for a patient to be eligible. We know that, historically, we have not been good as a community across the country at enrolling patients on clinical trials. When we don’t routinely test for the presence of biomarkers, we automatically eliminate the patient for being eligible for targeted therapy and immunotherapy clinical trials. It is only by programmatically and uniformly testing for these biomarkers that we know their eligibility for certain FDA-approved therapies and for many of these clinical trials. We need to be more dedicated to interrogating the status for our patients’ tumors.

Have you ever experienced a case of a patient who had their cancer misdiagnosed prior to them undergoing NGS?

What I have had happen several times is a patient come in who had previously been treated elsewhere who had not had in-depth genomic test. When we performed NGS, we have found targeted therapy options for that patient so they could get better on-label targeted therapies. We have also found new clinical trial options for those patients on the presence of certain biomarkers, and they have been able to enroll on those studies and do very well on an investigational agent. This is an opportunity for patients to receive outstanding care that can improve their OS, that they [would] have had missed essentially because their tumor had not had a genomic test.

Have you had experience working with regional payers and involving them in various ways to get local or regional payments in the absence of national payments?

We are in the process of working with MolDX for that exact purpose. In the meantime, we have been working with individual payers. We have had success with payments from a variety of commercial payers; we can get some payments from Centers for Medicare and Medicaid Services for limited coverage just for certain genes, but we are working to get regional and national coverage determinations formally. That process, in the last few months, has improved and clarified, and we are hopeful that we and others can be successful in moving through a more transparent process.

What other research efforts would you like to highlight?

We are launching an effort in June where we will be doing germline sequencing using an NGS test in all patients with cancer—of all tumor types and all stages. We believe the data are indicating that a significant percentage of patients harbor pathogenic germline mutations that they have inherited and they will pass on. We believe we have sufficient technology capabilities and an understanding to identify and make an impact for those patients and their families. We have taken the unusual step, and proactive thoughtful step, of launching germline testing in all patients starting June 1 [2019]. We are thrilled about that; we think it’s complementary to previous goals of doing NGS in all patients with advanced or metastatic disease, and we think there are going to continue to be opportunities for this.

Our Precision Medicine program has really expanded in the last few years—the charge from our health system is to offer precision medicine across all disciplines. While we were born and raised in oncology&mdash;I’m a medical oncologist so that’s my first love&mdash;we have really expanded our precision medicine offerings into cardiovascular medicine, women and newborns, pediatrics, primary care, mental health, nephrology, and a variety of other disciplines.

Our system of 23 hospitals and 180 clinics is organized in 14 different clinical programs. We have precision medicine programs in 10 of those 14 programs, and we anticipate having an initiative in all 14, and we are using NGS as a backbone for providing precision medicine opportunities for patients in all disciplines. We are in a very objective fashion measuring the outcomes associated with these efforts. We are seeing good results, and we anticipate publishing those soon. Our precision medicine program has the depth and breadth that goes far outside of oncology; it is very exciting.

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Lincoln Nadauld, MD, PhD, sheds light on the current use of next-generation sequencing and the ongoing efforts to make this testing more widespread across the United States.

NGS Should Be Administered for All Patients With Advanced or Metastatic Cancer

Next-generation sequencing (NGS) is the future of oncology, said Steven N. Kalkanis, MD, but its widespread use is dependent on researchers translating the data into improved patient outcomes.

“As a society and healthcare industry, we need to invest heavily in NGS because we have tools linking a patient's own genetic code with the genetics of what is driving their disease,” said Kalkanis, professor and chairman of the Department of Neurosurgery and medical director of the Henry Ford Cancer Institute. “We can design a treatment that is specific to them.”

The field has come a long way in terms of identifying actionable biomarkers across tumor types. These molecular markers, detected through NGS, can then be paired with FDA-approved therapies, allowing for more personalized treatment. This testing can also provide insight into why patients develop resistance to standard treatments.

, Kalkanis, who is also the Mark L. Rosenblum Endowed Chair in Neurosurgery and co-director of the Henry Ford Neuroscience Institute, explained how NGS testing fits into cancer treatment today and efforts that need to be made to enable its widespread use in the future.

: Overall, we are living through an inflection point in medicine. Everything nowadays is viewed through a personalized targeted approach; NGS is what makes that possible. We are seeing its use in oncology, where it has had the biggest impact. One of the more exciting things is also happening in diabetes, heart disease, and a whole host of other diseases. We are now learning that some of these biomarkers and genetic aberrations can give physicians important clues as to how to tailor treatment specifically to a patient. It used to be treatment based just on the disease, but now it's based on the disease and the individual patient's genetics. This has created a cascading series of events that allow for NGS to happen.

We all need to ramp up in terms of our ability to do the testing and to do it in a cost-efficient way. We should be doing it in a high-yield setting where we know it's going to potentially change treatment. For instance, in oncology there are several different chemotherapies and radiation therapies that may work better, or not, based on someone's NGS profile. 

How widespread is the use of NGS in oncology, and what can be done to make this more universally utilized?

Anyone can do the testing, but it is a complex algorithm to understand how one patient's hit on a particular biomarker impacts their treatment. Is it enough to put them on a certain therapy or clinical trial? That is the bottleneck for making NGS widely accessible. The expense and the intellectual capital needed to interpret the data are what’s impacting the use of NGS right now. However, we're now seeing that most academic centers around the country are investing in this [testing] as a path forward for the future. If you look across the country, there are probably 50 to 60 notable sites that have stepped forward and said they are going to make NGS the cornerstone of treatment.

Some of the things we are doing at Henry Ford Health System through telemedicine is attempting to link our experience here with community hospitals that may not have this capability. We're reaching out to a network of community physicians in smaller hospitals to say, “If you have a patient with this particular type of cancer, and you've done testing, let's talk about ways in which we can collaborate in clinical trials.” Oftentimes, that creates a win-win situation.

Our overall goal is to keep patients close to home but also to have the benefit of advanced testing, where appropriate. NGS is not something that can be recapitulated in every clinic across the country, again, because of the expense and the experience it takes to interpret the data. 

What are some of the actionable biomarkers that can be detected by NGS?

There are so many; that's the exciting time we live in. Five years ago, there may have been 2 or 3, while today, there are numerous, depending on which disease you're talking about. Everyone knows about 

, there are biomarkers that predict benefit from immunotherapy, and in brain cancer, there's 

 story is really compelling because now we can stratify the patients who are long-term survivors in the dreaded disease of glioblastoma.

The exciting thing is that now research is focused on changing a patient's genetic profile to a more favorable one if we know from the outset what their genetics are. Depending on which disease type you choose, there are several biomarkers that are coming to the forefront. There are probably too many to mention here. 

What about prognostic indicators and identifying mechanisms of resistance?

There are several interesting stories that have come out in terms of resistance because now, with NGS and precision medicine, we can tell what else what might be going on that makes a patient resistant to a medication versus someone who responds. For example, a certain type of ovarian cancer in some patients led to a remission with a therapy, while in some patients it did not. With NGS testing, we were able to figure out that part of this tumor encoded something that acted almost like a viral vector or infection. It wasn't actually an infection; it was part of a virus that was causing a repeat in the genetic code that kept causing the cancer to repeat itself despite treatment. As soon as that viral particle was discovered, we developed a target that blocked that repeat of the virus. Suddenly, the therapy started working more effectively.

Other exciting opportunities may lie in drugs [that are already] inside medicine cabinets across the United States for other [indications]. These might be effective in oncology based on new prognostic indicators. [For example], there have been stories coming out about how diabetes medications block the cell division process in some cancer types, leading to remission. It's not designing a new drug, it's taking a drug meant for another purpose and giving it in the right settings to patients with cancer who have this biomarker [detected via] NGS testing. You're going to see a whole area of advancement in real-time. 

You mentioned cost is a challenge, but is there potential for NGS to ultimately be cost-effective?

That's 100% the case, and that's the exact argument we've been giving to insurance carriers and those who are trying to design the payer system in this country. When you think about it, without NGS testing, you would put every patient through the standard of care. Some patients will do well on the standard approach, but a large number of patients will not.

Therefore, in those patients, you are paying for standard of care and then you are paying for second- and third-generation testing almost by trial and error. With NGS, if you know ahead of time that the standard of care is not going to work, going directly to a targeted treatment may, in fact, be more expensive. Looking at the whole episode of therapy, you are cutting out the cost of going into standard-of-care testing. You also won't waste precious time.

At the end of the day, you are spending less and getting a better outcome. We are trying to package this in a more holistic way in terms of how the patient does overall in the lifespan of what we will throw at them to treat their disease. We are seeing cost savings from that perspective. However, that's the daily struggle we face with insurers who are looking at cost per unit. 

What is your experience dealing with local and regional payers with regard to NGS?

Their perspective is that this all falls under the domain of research, and as soon as you have a tried and true thing, they are willing to consider it. The problem is that all of this is playing out in real-time all over the world. These are new treatments coming forward, and these patients don't have time to wait 5 or 10 years for all of these studies to be fulfilled. If this was your wife, mother, or daughter, and you had evidence to show an approach works, what is enough to cause it to be paid as opposed to being left in a research bucket and not reimbursed?

What we've done—and this is a daily pushback that we get&mdash;is we constantly meet with payers and tell them we have a process here through our 15 disease-specific tumor boards where we vet every one of these NGS tests. If we can show by consensus that this testing will absolutely change the treatment and offer a targeted therapy for a given patient, then the insurance company will say, "If it's gone through these checks and balances, we will pay for it." That's a big win for us, because it's allowed for a fast tracking of getting patients the treatment they need.

It's hand-to-hand combat on a daily basis when it comes to showing the value of NGS. I can see it from their perspective because they don't want every physician who potentially can order a test to just click a box and say, "Let's do this." It does need to be rooted in some evidence that it can improve outcomes. 

What is your take-home message about the future role NGS testing will have in oncology?

There's no question we are living the future. NGS testing is the future of getting a better outcome for the most devastating types of cancer. It is also applicable in diseases beyond cancer. Again, it's not just dollars, it's also the expertise as to how NGS should be used. It's also going to take cooperation between healthcare systems that may be competitors on some level. With the sharing of data, you get better outcomes. 

Steven N. Kalkanis, MD, explains how next-generation sequencing testing fits into cancer treatment today and efforts that need to be made to enable its widespread use in the future.

Updates in Next-Generation Sequencing | Special Issues

NGS Should Be Administered for All Patients With Advanced or Metastatic Cancer

NGS Enables Individualized Treatment Approach in Oncology