Molecular residual disease tests analyze blood samples for evidence of cancer cells lingering in the body after treatment with surgery or chemotherapy.
Traditional approaches to monitoring the disease, such as biopsies or imaging, sometimes indicate remission even when cancer cells remain. Natera’s Signatera MRD test looks for traces of circulating tumor DNA in the bloodstream that conventional assessments may miss.
Launched for clinical use in 2019, Signatera is increasingly being used to assess cancer remission and predict relapse, helping drive strong revenue growth for Natera.
Although it is broadly covered by Medicare, most oncologists have not adopted the test as a regular tool, said Solomon Moshkevich, Natera’s president of clinical diagnostics. The company expects volumes to continue to grow as it builds evidence supporting the test.
“The vision here, the expectation, is that within our lifetimes, this will become as ubiquitous as a CT scan is today,” Moshkevich said.
In an interview with MedTech Dive, the executive discussed Signatera’s role in guiding treatment decisions, a recent Food and Drug Administration approval, and progress toward early cancer detection screening.
This interview has been edited for length and clarity.
MEDTECH DIVE: What are the advantages of molecular residual disease testing over standard methods of monitoring patients for cancer remission and recurrence?
SOLOMON MOSHKEVICH: The test is designed to detect and quantify levels of tumor-derived DNA that's floating in the blood. Think of it like a more sensitive version of a CT scan.
You're doing it multiple times throughout treatment to see, is the tumor getting bigger or smaller in response to therapy? Once you’ve completed therapy, and if you had a surgery, for example, then you're doing it to see if the cancer is coming back in different parts of the body.
Imagine a single molecule of tumor DNA in a tube of blood, relative to on a scan. In order to detect the cancer, you're talking about something that's a clump of cells that's already a centimeter or bigger, and trying to visualize, over time, if that clump is getting bigger or smaller, differentiating that from scar tissue from a surgery. If somebody had surgery, they got their cancer removed, it's pretty hard to track in that area. Maybe they had radiation. It can be hard to interpret on a scan what's actually happening there, versus in the blood.
Signatera can very accurately quantify how many copies of tumor DNA we see in that tube of blood. It's an incredibly powerful tool for both treatment monitoring and for recurrence monitoring.
How are oncologists using the test today?
The test works across cancer types in solid tumors and many hematologic, or blood-based, malignancies. It's personalized for every patient's cancer. The way that works is we get a piece of the tumor, either from the biopsy or the surgery, and that's sent to our lab. We also get a piece of normal DNA, which is just a regular blood sample, for example. There's a part of that blood sample that's always going to be normal, what's called germline DNA. We do DNA sequencing of both of those, and we look at what mutations do we find? DNA mutations in the tumor that are not in the normal DNA are what are leading to the uncontrolled cell growth that is the cancer. Then we identify a subset of those mutations that we see, and those become the signature, or the fingerprint for that cancer.
No two cancers will have the same signature mutations. Then we design and develop a custom test that only looks for the presence of those tumor-specific signature mutations in the blood of the cancer patient. That's why it's called Signatera, because it's looking for that unique signature. And that's why it works across cancer types as well, because every cancer is different, and every test is different for that patient's cancer.
What cancer types can the test detect?
The big uses are where, unfortunately, the high-incidence cancers are. Colorectal cancer was the first indication to get covered by Medicare. Breast cancer, we were very early with strong validation data. The Signatera test is covered by Medicare for serial use in colorectal cancer, breast cancer, muscle-invasive bladder cancer — which is where, in addition, we got FDA approval, because we had an incredible study — ovarian cancer, lung cancer, and any patient who's undergoing immunotherapy for monitoring the effectiveness and therapy response. That list of covered indications is growing fast as we generate and publish new evidence.
In the past quarter, over 50% of oncologists ordered the test. Many of those physicians have started ordering it regularly on a large subset or all of their patients, but some physicians have not yet. Many physicians, most, have not yet adopted it as a regular tool across all of their patients, the way that they do a CT scan, for example.
The FDA recently approved Signatera CDx as a companion diagnostic for Genentech’s immunotherapy in muscle-invasive bladder cancer. What is the significance of that approval?
Signatera, and all of Natera's tests, are lab developed tests regulated by the Centers for Medicare and Medicaid Services, not by the FDA. The reason that the FDA got involved here, and that we approached them proactively, is because we ran a trial that was sponsored by Genentech that treated patients who were positive by our test. Patients were treated with Genentech’s immunotherapy drug, which is atezolizumab. The FDA, in order to approve that drug, also has to review and approve the companion diagnostic that goes with the drug.
The trial was run in early-stage muscle-invasive bladder cancer patients after they got surgery. Patients were tested with Signatera every six weeks up until their first year, and if the patient turned positive at any one of those time points, they were randomized to receive the immunotherapy from Genentech or a placebo. If the patient was negative on Signatera, then they were simply observed, no treatment. In the patients who remained negative for that whole first year, they had incredibly good outcomes: 100% of the patients were alive at one year, and 97% of patients were alive at two years with no additional systemic therapy after surgery. So, in a nutshell, if you test negative with Signatera, you don't need extra treatment.
Oncologists are trained in medical school that if you're going to give adjuvant therapy, meaning after surgery, you have to start it quickly after surgery. If you delay, the traditional wisdom goes, then you lose your opportunity to benefit that patient. This trial just turned that upside down. You can wait and monitor the patient, and if they turn positive later, and only then initiate treatment once you see that they need it, they still benefit significantly. There was no penalty to the patient to wait until their MRD test turned positive and to treat that. That's a huge thing, because it changes the paradigm. It's something that now is going to be evaluated across every major cancer type, and totally change how cancer is managed.
What is Natera working on in early cancer detection?
We've shown very promising data in colorectal cancer, and that's going to be the first indication that we move forward to the FDA. The trial will be completed this year. The data will become available next year, and the submission to the FDA would be next year.
Multi-cancer early detection would be next on the list after colorectal. We have high hopes. We're investing a lot. I think that eventually it will become part of standard workup for patients above a certain age, and initially it will be most useful in patients who are at elevated risk. I think it will take a lot longer for the test to be covered and widely adopted in all patients, even average risk.
But for now, we're focused on our oncology portfolio and driving the evidence and the adoption for the Signatera test, and creating as much patient access and insurance coverage as possible.
