Kim 00:08
Welcome to The Cancer SIGNAL, a podcast presented by GRAIL, where we discuss the impact of early cancer detection, the science behind multi-cancer early detection and insight into how this approach has the potential to shift the cancer paradigm. I’m your host Kim Thiboldeaux. Today we are joined by Dr. Chuck McDonnell. Dr. McDonnell is a radiologist with Sutter Medical Group in Sacramento, California. He received his medical degree from Johns Hopkins University School of Medicine and has been in practice for more than 20 years. He is also the principal investigator for the PATHFINDER study, which was just recently published in The Lancet. Welcome to the show Dr. McDonnell.

Dr. McDonnell 00:48
Thank you so much. It’s great to be with you.

Kim 00:50
So Dr. McDonnell, before we dig into the PATHFINDER study results, let’s level set a little bit. Can you describe for our listeners, the current cancer screening landscape, and what may have led to the need for this study?

Dr. McDonnell 01:04
Yeah, sure. Well, in this country based on guidelines, recommendations, we screen for up to five cancers. And we do that because over the years, we’ve learned that intercepting these most common cancers early has a significant impact on patient outcomes. For example, less extensive treatment, lower costs, and most importantly, the best chance for cure. Despite that, however, majority of cancer deaths are from cancers that we don’t screen for routinely. And this is the foundation for the need for, that this trial begins to address.

Kim 01:41
Dr. McDonnell, could you just drill down for our listeners a little bit more about the specifics of that, what are the tests that we have available now for what cancers? What’s recommended?

Dr. McDonnell 01:51
Sure, that’s a great question. So I think I’ll start with breast cancer since it’s Breast Cancer Awareness Month, but the standard screening for breast cancer is mammography, typically starting at 40 and screening every year. For high risk patients that have family history, for example, or a known mutation in the family, enhanced screening with MRI, which is a very sensitive test for breast cancer would be indicated. Of course, colorectal cancer is recommended, the age to start screening for that has been reduced recently because of the increasing incidence of younger people. So starting at age 45, the gold standard would be colonoscopy. For cervix cancer, we screen with pap smears. For prostate cancer, there’s a blood test called PSA – prostate specific antigen – that can be used for screening. And then for patients that are high risk for lung cancer, so for example, smokers with significant smoking history, there’s screening chest CT, unenhanced low dose lung screening CT, very sensitive for lung cancer.

Kim 03:05
That’s really helpful. Thank you for breaking that down. I think it’s always good for all of us to remind ourselves about those screenings. Great, so let’s dive in a little bit, Dr. McDonnell on the study. Give us some background. When did this study begin? How many participants, who were they, what was the criteria for participation?

Dr. McDonnell 03:23
Sure. We began recruiting participants in December 2019. And did so through December 2020. We recruited participants across I believe it was seven esteemed health systems across the country. And ultimately, over 6600 participants accrued into the trial. And they had to be 50 years of age or older, and not have had any cancer or treatment for cancer in the past three years to participate.

Kim 03:55
And 50 years or older, because our risk goes up at that point?

Dr. McDonnell 03:58
Yeah, exactly. The risk of having a cancer drops off pretty dramatically at a younger age than 50. And it just doesn’t make sense to spend the money on the trial, you know, for participants that are not going to have cancer.

Kim 04:15
And Dr. McDonnell, what was the PATHFINDER study looking to evaluate if you can explain that to us?

Dr. McDonnell 04:21
Yeah so basically, just to look at how this kind of multi-cancer early detection blood test might fit into the clinical setting. But more specifically, what does it take for somebody that tests positive to ultimately figure out whether they do in fact have cancer or not – we call that diagnostic resolution. Secondarily, we looked at the overall performance of the multi-cancer early detection test. And then also, how long did it take to achieve this diagnostic resolution?

Kim 04:53
And so drumroll, Dr. McDonnell. What did the results show? What did we learn from this study?

Dr. McDonnell 04:57
Well, we learned a lot. We know that if we do the routine screening, single organ screening that’s recommended for people, we’ll identify a certain number of cancers. But if you add this blood test to that you will more than double the number of cancers identified, which is significant. We also learned that most of the cancers that are identified with the blood test are cancers that we don’t currently screen for. We learned some other things like for example, not only does the test provide whether there’s a cancer signal or not, but what might be the source of that cancer signal? And this is significant because this can lead to a more streamlined, more targeted workup to figure out does the patient have cancer or not? Rather than having to do a whole body imaging test like a PET scan or something on everybody that tests positive.

Kim 05:49
Got it. Excellent. Dr. McDonnell I know that false positives are a common concern of those considering MCED – multi-cancer early detection. Can you first of all explain for our listeners, what are false positives and what was the false positive rate in the study? What did we learn from that?

Dr. McDonnell 06:08
Yeah, great question. So a false positive for a screening test is where the screening test is looking for something and the test says, hey, we think you have what we’re looking for. But then on further evaluation it turns out that they don’t, in fact, have what the screening test said that they had. And that’s, so that’s a false positive. So in this case, the test says the patient has a cancer signal. But ultimately, we don’t confirm a cancer in them, but maybe something else like a premalignant condition, for example, that’s not quite cancer. And that’s considered a false positive. False positives are a major concern or criticism for cancer screening in general because it creates anxiety and cost. But one of the main things we learned with this PATHFINDER study is that this multi-cancer early detection test has a very low false positive rate – less than 1%.

Kim 07:03
Wow, wow, really interesting. What a, what an important finding. So tell me in your in your opinion, do you consider the learnings from this study significant? And if the answer is yes, in what ways?

Dr. McDonnell 07:17
Yeah, I think this study is a significant milestone in cancer early detection, cancer screening. It’s really a glimpse into the future of cancer screening, cancer early detection. I think that allows us to see how adding a blood test that can evaluate for over 50 types of cancer can significantly add to cancer diagnosis over what we’re currently recommending for people. You know, the single organ screening tests that we currently perform are, require a lot of infrastructure, and to have a single blood test that can screen for so many cancers without that infrastructure is significant. I think, clearly, the results of this trial make it crystal clear that we need to continue to evaluate and study this test, this technology so that it can be more broadly implemented and covered by insurance, for example.

Kim 08:12
Interesting. So Dr. McDonnell, let’s talk about sort of practical implications of this study. For example, how should clinicians take these findings into consideration?

Dr. McDonnell 08:22
Well, in addition to being able to see what’s on the horizon, the near horizon for cancer screening in general, they could take into account that for patients that might be interested in doing more than generally recommended screening right now, that more than what’s generally recommended for screening for cancer right now, that this would be an option because it is available with a doctor’s prescription. And I think just in general, to realize the potential of being able to more than double the amount of cancers diagnosed with a test like this, I think it’s pretty significant.

Kim 09:01
And if I’m a person considering multi-cancer early detection, what should I as an individual as a consumer take away from this study?

Dr. McDonnell 09:10
Yeah, well, I think I have to emphasize that if you’re considering this test, it’s additive, not replacement. So in no way should you think that taking this test will allow you to forego your screening mammogram or your colonoscopy. That’s not the case. So I think that’s the most important thing. But also probably important to realize that at this point, it’s not a covered benefit by your insurance. And certainly having this test and testing negative in no way means that you shouldn’t talk to your doctor, if you’re having some sort of symptoms, you know, that there might need additional evaluation.

Kim 09:48
And Dr. McDonnell, just to clarify for our listeners, when you say it’s not a covered benefit, you’re saying that likely my insurance is probably not going to pay for it right now. So I have to get it some other way, pay for it myself or get it through some other means or…

Dr. McDonnell 10:03
Exactly. You know, it’s just too, when new technologies come along, typically they’re not paid for by insurance. But until more studies are done and it becomes more mainstream, there’s more evidence to substantiate the cost associated with it. And this is just too new to be covered by insurance at this point. At least that’s my understanding.

Kim 10:28
Understood. Let me dig in if I may Dr. McDonnell, on the Lancet study a little bit. I think there were some things that it would be helpful for our listeners to understand. So number one, just clarify for us. Again, what the test is detecting. Talk about this idea of a positive cancer signal. What does that mean, what’s communicated to the patient and then what has to happen from there when a positive signal is detected?

Dr. McDonnell 10:54
Yeah, so what the test does, when our cells die, whether they’re cancer cells or normal cells, little fragments of DNA are shed into the bloodstream. And what this test does is it filters out those fragments from everything else in the blood, and then labels and sequences each one of those fragments. This generates an enormous amount of data that we need machine learning to interpret. And, as I mentioned earlier, it looks for a cancer signal but also the potential source of the cancer signal. So once a patient or participant tests positive for a cancer signal, what I tell them is, it doesn’t mean that they have cancer, but it does mean that we want to do more testing, to rule out that they do or don’t have cancer. And so depending on what the cancer signal origin is being suggested by the test, we do a targeted workup until we’re either confirmed that there’s cancer or we’re confident that there isn’t. And for the, for the trial, that was published in The Lancet that we refer to that as diagnostic resolution. In other words, we confirm cancer or we’re confident that they don’t have cancer, or we found something else that’s not quite cancer, perhaps, that would account for that signal.

Kim 12:12
So in the study, it says that you achieved a fairly high rate of diagnostic resolution within about three months, again, in practical terms, so what exactly does that mean?

Dr. McDonnell 12:24
Yeah, so by the time I talk to a patient and give them the results, and start ordering additional tests, and then those tests get scheduled, and then eventually, you know, they’re able to get the various tests, you know, when it’s convenient for them. You know, it can take weeks before we’ve worked out everything to where we’re confident that they have cancer, or that they don’t. And sometimes it’s a biopsy, for example, that needs to be scheduled after an imaging study, and then by the time that biopsy gets done, and then takes a while for pathology results to come back. So you know, there is a certain amount of time invested before we’re confident that they do or don’t have cancer. But a majority of the time, that was less than three months, which I think was pretty good.

Kim 13:14
Less than three months. Okay. So less than three months. Good. It sounds good. I’m the patient. [laughs] I’m weeks, I’m months, I’m waiting for this test. What I’m imagining, in my mind is a high level of anxiety, right? Or I know sometimes called scanxiety. Right? Because they have to go through scans, other tests, other workups to get an answer. So in clinical terms, maybe sounds like a good period of time, maybe from a patient or consumer perspective, sounds pretty anxiety provoking. I’m just curious, did you guys study anxiety in these patients? Did you talk about it? Was there any findings on that?

Dr. McDonnell 13:53
Yeah, that was part of the study. That part I think, is going to be part of a separate publication. So it wasn’t addressed in the recent Lancet article. But what we found is that, that there is only mild anxiety associated with testing positive, particularly in those where we, well, particularly in those patients that test positive, but that it does return back down to baseline. And the amount of anxiety that we identify is right about what we see with any other screening tests, like mammography or colonoscopy where, you know, something is found that needs additional testing. And, of course, there is some anxiety associated with that. But no more with the multi-cancer, early detection blood tests than with other screens.

Kim 14:44
Interesting, helpful, helpful to know. Thank you. And now that the final results from the PATHFINDER study have been published, what’s next? Are we what are we looking at more research? Are we looking at more studies? What are we looking at as next steps here?

Dr. McDonnell 14:57
Yeah, thanks for asking that. So as it turns out, in order to learn more about this multi-cancer early detection test, and so that ultimately we can implement it in routine clinical practice with insurance coverage, we’re conducting, participating in PATHFINDER 2. It’s currently recruiting participants across the country, I think, like 29 sites across the country. This is going to be like four times the size of PATHFINDER. It’s going to follow patients for three years after they take the test rather than one. And it’s, you know, people participate in research trials because out of altruism, they want to help other people, they want to be a part of the future of medicine. But this, this is a trial where it’s really a lot of personal benefit. They get a free test, they get results back. And if they test positive, the workup to confirm whether they have cancer or not, is also covered by the, by the study. So the wonderful opportunity to participate in research. And so yeah, for several more months, at least, we’re looking for participants for PATHFINDER 2.

Kim 16:02
Great, extremely helpful. It’ll be exciting to see the next phase of research as it unfolds. Dr. McDonnell, I want to thank you so much for joining us today for sharing your insights on the PATHFINDER study. Very interesting and helpful. So thank you for being here. This is The Cancer SIGNAL, presented by GRAIL. I’m Kim Thiboldeaux. Please rate and review our podcast and be sure to subscribe to learn more about the impact of early cancer detection on future episodes.

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 aged 50 or older. The Galleri test does not detect all cancers and should be used in addition to routine cancer screening tests recommended by a healthcare provider. Galleri is intended to detect cancer signals and predict where in the body the cancer signal is located. Use of Galleri 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.

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GRAIL’s clinical laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and accredited by the College of American Pathologists (CAP). 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. GRAIL’s clinical laboratory is regulated under CLIA to perform high complexity testing. The Galleri test is intended for clinical purposes.