[Susanna Quinn] Welcome to The Cancer SIGNAL, a podcast presented by GRAIL, where we tell the stories of multi-cancer early detection testing. I’m your host, Susanna Quinn.

Today, we welcome Dr. Nima Nabavizadeh, an associate professor of radiation medicine at the Oregon Health and Science University, as well as the chief medical officer within the Cancer Early Detection Advanced Research Center—CEDAR for short—at OHSU.

Dr. Nabavizadeh has a specialization in the treatment of gastrointestinal cancers, lymphomas, and hematologic malignancies. And he, as his title suggests, is at the forefront of early-detection research initiatives, serving as the principal investigator for a multitude of cancer early detection clinical trials.

One of those clinical trials is the GRAIL PATHFINDER 2 study. Dr. Nabavizadeh, we are honored to speak with you today and learn more about this exciting and innovative study. Welcome to The Cancer SIGNAL.

[Dr. Nima Nabavizadeh] Thank you so much for having me.

[Susanna Quinn] We are recording this episode just ahead of the European Society for Medical Oncology, the ESMO 2025 Congress in Berlin.

[Susanna Quinn] GRAIL presented data from the PATHFINDER 2 study. Before we dive into the results, could you give us some background on PATHFINDER 1 and what was learned from that study?

[Dr. Nima Nabavizadeh] PATHFINDER 1 was a first-of-its-kind interventional clinical trial looking at the safety and feasibility of the Galleri multi-cancer early detection test. That study provided, number one, safety information to allow us to feel comfortable to move forward with further clinical trials in larger prospective populations.

The original PATHFINDER study also showed that the Galleri MCED test was able to identify novel cancers, cancers which do not have any kind of cancer screening methodologies for. And the PATHFINDER study really provided us with an initial glimpse at the test metrics for this Galleri MCED study that then the PATHFINDER 2 study—which we’ll be talking about today—helped kind of further refine in a much larger representative-use population.

[Susanna Quinn] Could you give us an overview about PATHFINDER 2? How was the study set up, who participated, and what was it looking to find?

[Dr. Nima Nabavizadeh] Yeah, the PATHFINDER 2 study is again a multi-institutional interventional study examining a broad population of over 35,000 participants within North America over the age of 50, who do not have a clinical suspicion of cancer. It’s a cancer screening study, and its goal is to determine the safety and performance of the Galleri multi-cancer early detection test in this representative population, so that we can detect many cancers before symptoms appear and when they’re easier to treat.

[Susanna Quinn] What was the most significant outcome from PATHFINDER 2?

[Dr. Nima Nabavizadeh] So the PATHFINDER 2 preliminary results—which we presented at the ESMO annual meeting—was for the first 23,000 participants on the study that had a 1-year follow-up and we identified a signal-positive rate. Out of those 23,000 patients, about 1% had a signal-positive test showing a clue or indication for cancer that required further workup.

Furthermore, this test was found to be highly specific, meaning that we avoided false positives at a great degree. The specificity was 99.6%, and what that means is really this test did a great job at minimizing false positives and unnecessary workups for folks that did not have cancer.

Furthermore, the test found a positive predictive value of 62%. And what this means is that this test—the results of this test, especially a positive result—is something that both providers and patients should take seriously, because the test is meaningful. A positive test has a 62% chance of indicating a true cancer. And in comparative terms, positive predictive values of our normal cancer screening methodology—such as mammography for breast cancer and colonoscopy for colon cancer—those positive predictive values are 10% or less, meaning that both providers and patients are used to dealing with these types of false positives. But what was really impressive about the PATHFINDER 2 results is really this high positive predictive value that is meaningful.

[Susanna Quinn] And was there an extra sensitivity to the more deadly cancers in the test?

[Dr. Nima Nabavizadeh] So in this 1-year follow-up, sensitivity at 12 months was found to be 74% in a pre-specified subgroup of 12 cancers responsible for nearly two-thirds of all cancer-related deaths. And when you loop in all of the cancers that we know of, the sensitivity at 12 months was 40%—showing that there really is a complementary value in providing multi-cancer early detection tests on top of our kind of standard screening methodology, such as colonoscopies, mammograms, low-dose CT for patients with high risk, who are high risk for lung cancer.

[Susanna Quinn] And of course, it detects cancers that we don’t generally screen for.

[Dr. Nima Nabavizadeh] Absolutely.

[Susanna Quinn] Dr. Nabavizadeh, could you talk about some of the more, the most significant outcomes from PATHFINDER 2?

[Dr. Nima Nabavizadeh] Absolutely. In the PATHFINDER 2 study, we found that the Galleri multi-cancer early detection test detected approximately 7 times as many cancers when added to US Preventive Service Task Force A and B guideline–recommended screening tests, and those were for breast cancer, cervical, colorectal, and lung cancer. And just over half of Galleri-detected cancers found were at an early stage.

Furthermore, the study found that Galleri triples the number of cancers detected when added to US Preventive Services Task Force C recommendations, so that now includes prostate cancer. So when you include a screening test for prostate, breast, cervical, colorectal, and lung, adding the Galleri test triples the number of cancers detected.

And the test is especially sensitive to many of the deadliest cancers that are typically caught too late, such as pancreatic cancer, liver cancer, and ovarian cancer, and about half of Galleri-detected cancers are found at an early stage.

[Susanna Quinn] It’s just incredible. Can you explain to listeners why this is significant, and to whom this is significant?

[Dr. Nima Nabavizadeh] Yeah, absolutely. The Galleri multi-cancer early detection test really helps fill an unmet need to screen for deadly cancers for which we don’t have current screening methodologies for. So, who is it significant for? I would say it’s significant for the general population, which is really what the PATHFINDER 2 study was aimed at looking at, and examining. So this, again, these are participants over the age of 50, who really have no clinical suspicion of cancer. These are normal, healthy patients looking for cancer screening opportunities.

[Susanna Quinn] Could you talk about what a CSO [Cancer Signal Origin] is and what we learned about it in the PATHFINDER 2 study?

[Dr. Nima Nabavizadeh] Sure. So yeah, whenever a clinician such as myself—you know, I was the principal investigator on the PATHFINDER 2 study—gets a signal-positive finding for a participant, there’s a result of, there’s a signal that there’s a cancer within this patient that we need to identify.
And on top of that, the Galleri multi-cancer early detection test is able to identify where that signal is coming from through the epigenetic changes on the DNA. And why that’s important is that it provides the physician some type of guideline on where to look and where to hone in the diagnostic workup, rather than looking throughout the whole body for a cancer signal. The Cancer Signal Origin result on the Galleri test provides clinicians with a framework on how to really maximize the diagnostic workup, to minimize the amount of time needed to find this cancer, and to hopefully reduce waste in that cancer workup as well.

[Susanna Quinn] Let’s dig into the numbers around sensitivity and PPV, positive predictive value. Can you explain what these terms mean and what the study found for both?

[Dr. Nima Nabavizadeh] Sure. So, PPV is the positive predictive value, and again this is a metric that helps build trust in the test—telling the physician and the patient that the results are meaningful and should be taken seriously.

So in the PATHFINDER 2 study, the PPV for the MCED test was almost 62%. And what that means is that a patient with a signal-positive finding has a 62% chance of ultimately being diagnosed with a cancer. And again, this positive predictive value far outshines the positive predictive values that we’re used to right now with colonoscopies and mammograms, which are in the 10% or less range.
So this is a really important, meaningful metric for clinicians and for patients.

The sensitivity of a test refers to how many cancers you’re able to find within the general population. The sensitivity at 12 months was 74% in a pre-specified subgroup of 12 cancers responsible for two-thirds of all cancer deaths, and the sensitivity, again at 12 months, was 40% for all cancers.

What’s notable about the PATHFINDER 2 study is that we’re not finishing follow-up at 12 months. We’re going to continue follow-up for all these participants for up to 3 years, to really hone in on what the true sensitivity of this test is.

[Susanna Quinn] To help put this in context for listeners, how does this compare to existing standard-of-care cancer screenings?

[Dr. Nima Nabavizadeh] So, the US Preventive Service Task Force has level A- or B–guideline recommended screening tests for cervical, colorectal, lung cancer, and breast cancer. And these tests have a high sensitivity. They pick up on a lot of true cancers, but their specificity is not as high as their sensitivity, meaning that false positives are inherently a part of cancer screening for most patients.

You know, I provide an example: A woman in her 50s who is eligible for all four screening modalities has, on a yearly basis, around a 40% chance of having one of those tests be a false positive. And that is something that has a lot of impact and cost, both psychosocially and in regards to potentially unnecessary workup and diagnostic harm.

The specificity of the Galleri test is very high. It’s 99.6%, meaning that the number of false positives are very low. Less than 1 in 200 people who receive this test get a false positive finding. And why that’s important is that it provides some trust in the test. It may minimize harm for patients, and—something else that was notable out of the PATHFINDER 2 study—is that less than 1% of all 25,000 analyzed patients, less than 1%, so about 150, had a protocol-directed invasive procedure. So, 99.5% of people who received the Galleri multi-cancer early detection test did not undergo any kind of diagnostic harm with any kind of invasive procedure. I think this is a meaningful result for this test to provide some comfort to both providers and patients, that the results are meaningful and should be followed up on.

And one thing I want to add, too, is the sensitivity. You know, by design, whenever you’re creating a new cancer screening test, there’s always a balance between sensitivity and specificity. And by design, the specificity of the Galleri multi-cancer early detection test is high. And what that means, in turn, is that the sensitivity is limited to some degree, which brings the point that this test really is not meant to replace the standard-of-care screenings that we know, such as mammograms and colonoscopies, but to be used complementary to that.

Mammograms and colonoscopies have a very high sensitivity, which is why their specificity struggles.
And the Galleri multi-cancer early detection test is basically another screening modality to be used in a complementary fashion, to help screen for those cancers that we don’t have other screening methods for.

[Susanna Quinn] Thank you, thank you for clarifying that. That’s important. Safety was a primary objective in PATHFINDER 2. What did you learn about the safety of the test?

[Dr. Nima Nabavizadeh] Yeah, I mean, like I mentioned previously, because of the high specificity—and because of the high positive predictive value largely because of the high specificity—the number of patients that had to deal with a false positive finding were very low, and only 0.6% of all patients had a protocol-directed invasive procedure.

And the invasive procedures were even greater for the folks that were eventually found to have a cancer. So, if there’s a clue for a cancer, there’s then maybe an imaging finding that shows a potential cancer in some organ. Certainly, you’ve got to imagine that participants are going to be undergoing invasive procedures to biopsy those lesions. But again, what was very reassuring about the PATHFINDER 2 study was the overall safety, and that less than 1% of people had a protocol-directed invasive procedure.

[Susanna Quinn] Amazing, truly. Are there any other learnings from this study that you’d like to share with us?

[Dr. Nima Nabavizadeh] Another finding from the PATHFINDER 2 study was the time to diagnostic resolution. And what that means is, the time interval between a signal-positive finding that I, as the principal investigator, receives and relates to the patient, to the time that we conclude all imaging, biopsy, specialist workup, to prove whether or not a cancer does exist within that participant.

And what was exciting about the PATHFINDER 2 study is that the median time of diagnostic resolution was 46 days. And why that’s significant is that, you know, the whole goal here is early detection. And if you identify a cancer, you want to try to get to diagnostic resolution, and you want to get to a point of cancer treatment as soon as possible, because, you know, days and weeks our cancer is growing, and cancer is shifting from an early stage to a later stage.

Having a diagnostic resolution of a month and a half, I think is very favorable, and really speaks a lot to the study teams, and the coordination the study teams brought, and the level of dedication that the clinical research coordinators and the PIs across the PATHFINDER 2 study invested into this study.

[Susanna Quinn] Particularly when you’re talking about such fast-growing cancers, like pancreatic and ovarian, diagnostic resolution is so important to be fast.

[Dr. Nima Nabavizadeh] I think this really kind of opens up a really exciting chapter in cancer screening. So many people are diagnosed with cancers way too late, and only if we had one test that attempts to screen for cancers, would we be able to really make a difference when it comes to both mortality from cancer and tolerability of cancer treatments.

And you know, as a radiation oncologist, early detection is paramount. There are many cancers that I treat both in early stages and in later stages, and without a doubt, cancer treatment at early stages are more tolerable and are more successful.

And, you know, the PATHFINDER 2 study showed that the Galleri multi-cancer early detection test has a possibility of bridging that unmet need of cancer screening for all these cancers that we’re really kind of flying blind with.

[Susanna Quinn] Certainly, the idea that we can catch so many more cancers at an early stage is really probably our best weapon of fighting cancer at this point.

[Dr. Nima Nabavizadeh] Yeah, what’s exciting too is, there’s, you know, having enrolled the most amount of patients on the PATHFINDER 2 study, over 6,000, we have a lot of experience at OHSU in regards to working with patients with signal-positive findings.

And I’m hopeful that one day we’ll be able to share the stories of these patients who we’ve found early-stage cancers treated in a curative fashion, who are now leading normal lives and are really kind of outspoken about cancer screening in general, and it’s just really exciting. And we’re just kind of, we’re just touching the surface right now in all of this.

[Susanna Quinn] Thank you so much. We here at the GRAIL podcast [The Cancer SIGNAL] are trying to share the stories of so many patients who have caught their cancer early-stage through the Galleri test. We really appreciate you joining us today and sharing these findings.

[Dr. Nima Nabavizadeh] Thank you for having me.

[Susanna Quinn] Listeners, be sure to visit GRAIL’s YouTube channel to watch this episode there. We will link to it in the show notes for this episode. This is The Cancer SIGNAL presented by GRAIL. Please subscribe so you don’t miss an episode, and thank you for listening.

VoiceOver
Based on a clinical study of people ages 50 to 79 around 1% are expected to receive a cancer signal detected result, which includes predicted cancer signal origins. After diagnostic evaluation, around 40% of people are expected to have a confirmed cancer diagnosis. The Galleri test is prescription only. The Galleri test is recommended for use in adults with an elevated risk for cancer, such as those age 50 or older. It is not recommended for individuals who are pregnant, 21 years or younger, or undergoing active cancer treatment. Galleri should be used in addition to routine cancer screening. Galleri does not detect a signal for all cancers. False positive and false negative results do occur. For more information, including important safety information, please visit galleri.com.

Important Safety Information
The Galleri test is recommended for use in adults with an elevated risk for cancer, such as those age 50 or older. The test does not detect all cancers and should be used in addition to routine cancer screening tests recommended by a healthcare provider. The Galleri test is intended to detect cancer signals and predict where in the body the cancer signal is located. Use of the test is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.

Results should be interpreted by a healthcare provider in the context of medical history, clinical signs, and symptoms. A test result of No Cancer Signal Detected does not rule out cancer. A test result of Cancer Signal Detected requires confirmatory diagnostic evaluation by medically established procedures (e.g., imaging) to confirm cancer.

If cancer is not confirmed with further testing, it could mean that cancer is not present or testing was insufficient to detect cancer, including due to the cancer being located in a different part of the body. False positive (a cancer signal detected when cancer is not present) and false negative (a cancer signal not detected when cancer is present) test results do occur. Rx only.

Laboratory/Test Information
The GRAIL clinical laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and accredited by the College of American Pathologists. The Galleri test was developed — and its performance characteristics were determined — by GRAIL. The Galleri test has not been cleared or approved by the Food and Drug Administration. The GRAIL clinical laboratory is regulated under CLIA to perform high-complexity testing. The Galleri test is intended for clinical purposes.