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.
Lincoln Nadauld, MD, PhD
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 NTRK 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.”
In an interview with OncLive®, 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.
OncLive: How would you classify the use of NGS?
Nadauld: 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—we also calculate tumor mutational burden, PD-L1 status, and microsatellite instability—high (MSI-H) status, in addition to fusions such as NTRK.
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 NTRK1/2/3, 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 BRCA1/2, p53, 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 . 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—I’m a medical oncologist so that’s my first love—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.