#525: Multi-Cancer Early Detection Testing

Summary

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The Curbsiders Internal Medicine Podcast

Episode #525: Multi-Cancer Early Detection Testing
Date: May 18, 2026
Guest: Dr. Margaret Tempero, Deputy Director, UCSF Helen Diller Family Comprehensive Cancer Center

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Main Theme & Purpose

This episode explores the rapidly evolving field of multi-cancer early detection (MCED) tests—blood-based technologies aiming to detect multiple cancer types before symptoms arise. Hosts Drs. Matthew Watto, Paul Nelson Williams, and Molly Hoiblein interview Dr. Margaret Tempero about the state of the science, current evidence, promises, misconceptions, pitfalls, test characteristics, and the real-life consequences and challenges for patients and practitioners.

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Key Discussion Points & Insights

1. Background & Rationale for MCED Testing

• Limited current screening: Only 4-5 cancer types have USPSTF-endorsed screening (breast, colon, cervical, lung for high-risk, with a guarded recommendation for prostate). This leaves most cancers undetected until late stages. (05:05)
  • Quote, Dr. Tempero:
    “If you look at the SEER statistics...they keep really good records on about 19 different organ sites... But we only have recommendations from the US Preventive Services Task Force for four. There's a guarded recommendation for a fifth, and that's for prostate cancer.” (05:05)

2. How MCED Tests Work

• Rooted in ‘liquid biopsy’ concepts: Detect cell-free DNA, methylation patterns, proteins, metabolites, and other “tumor signals” in blood.

• Two major tests currently available:

  • GRAIL (Galleri) – cell-free DNA methylation, can localize signal to tissue of origin.
  • Exact Sciences (Shield/MCED) – looks at DNA and proteins, but does not localize the tissue.

• Multi-omics & machine learning: Increasing test complexity, opportunity, and challenge. (09:18)

  • Quote, Dr. Tempero:
    “I think we're only starting to scratch the surface of what we might be able to test…we're kind of at the beginning of a journey.” (09:18)

3. Test Characteristics — The Realities

• Sensitivity concerns:

  • Greater ability to detect late-stage (especially stage IV) rather than early cancers—opposite of what patients often expect.
  • Some cancers are “good shedders” (e.g., many head and neck cancers), while others (e.g., pancreatic) are “poor shedders” and difficult to detect, even at advanced stages. (13:51)

• False positives and false negatives:

  • Galleri’s large “Pathfinder 2” study: ~30% of positive signals were false positives.

  • Some true positives may also represent indolent or clinically insignificant cancers.

  • Quote, Dr. Tempero:
    “Their most recent large study in the United States, the Pathfinder 2 study, showed a false positivity rate of 30% of their positive signals… 60% of them are finding something real, but...not all cancers need to be treated.” (10:51, 22:16)

• Importance of standard-of-care screening:

  • MCED tests should remain additive, not replacements, for established screening.

    • Quote, Dr. Tempero:
      “All of our messaging always [should] include the importance of standard of care screening...If multi-cancer detection tests reach their potential, they're in addition to standard of care screening. They're not a replacement.” (10:51)

4. Current Practicalities: Ordering and Access

• Most MCED tests are self-pay ($900–$1500). Some “Shield” colorectal screening is insurance-covered.
• Can be ordered via physician or even through company-facilitated telemedicine consultations—raising concern about lack of counseling for test interpretation and follow-up.
  • Notable quote:
    “You can get the test...the patient can go on the website...they can be connected to a telemedicine doctor...they don’t even actually need their primary care doctor to be involved.” (19:47)

5. Downstream Effects & Potential Harms

• Risks of MCED and whole body MRI (WB-MRI):

  • False positives leading to anxiety, unnecessary imaging, invasive procedures, radiation exposure, and financial cost.

  • Direct-to-consumer marketing increases demand among concerned but average-risk patients.

  • Many findings are benign, incidental, or of no immediate consequence—causing more harm than benefit for most patients.

  • Quote, Dr. Tempero:
    "There's a lot of anxiety in that period of time. I had a patient tell me that he wished he hadn't done it...I was miserable." (42:14)

6. Specific Patient Scenarios

• Negative MCED test:
  • Does not rule out cancer; regularity of testing (annual?) is undefined.
  • Standard screenings must still be followed.
• Positive MCED test (no localization):

  • General workup includes PET-CT; low specificity leads to extensive, potentially fruitless, diagnostic odysseys.

  • Tissue localization provides more actionable pathways; guidelines are in development to standardize workup.

  • Notable quote, Dr. Williams:
    "If I just had a patient who came up with a test that said cancer somewhere...it's just a nightmare scenario." (39:21)

7. Populations Most Likely to Benefit—Not Average Risk

• Hereditary high-risk patients (e.g., Li-Fraumeni, Lynch): Could gain value from MCED, but research and insurance coverage for these groups lag.
• Older adults (e.g., Medicare population): Data collection ongoing (REACH study, 50,000+ subjects, results in 3–4 years).

8. Data Gaps and Call for Research

• Many available MCED and WB-MRI companies lack transparency or large-scale trials; need for academic, population-based studies is critical.
• Stage shift (finding more stage I/II, fewer late-stage cancers) accepted as a proxy endpoint for effectiveness—mortality data remains a long-term goal.
  • Quote:
    “Most of us who are interested in this field think stage shift is sufficient.” (35:45)

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Notable Quotes & Memorable Moments

• Dr. Tempero:
  “We’re just beginning this—it’s a work in progress.” (16:40)

• On test interpretation and patient counseling:
  “If [the test is] positive, we try to come to a decision quickly...if we don’t and have done all necessary testing, we bring them back for another test in six months to see if [the] signal disappears.” (24:32)

• On whole body MRI quality:
  “Generally the first thing we do is we repeat the MR and make sure that we’ve got the best quality imaging.” (29:13)

• On the current landscape:
  “It’s an individual decision to get any of these types of non-traditional screening tests...remember that the tests aren’t perfect, that you may have a false positive...and cause a lot of anxiety.” (46:30)

• Dr. Williams’ humor and apprehension:
  “If I just had a patient who came up with a test that said cancer somewhere...it’s just a nightmare scenario.” (39:21)

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Timestamps for Important Segments

• 05:05 — Epidemiology of current cancer screening
• 06:33 — Science and mechanism of MCED/lab technologies
• 10:51 — Test characteristics (sensitivity, specificity, real-world data, false positives)
• 19:23 — Ordering, insurance, and access to MCED tests
• 24:32 — Downstream consequences: workup, anxiety, follow-up
• 26:31 — Whole-body MRI: evidence, practice, and pitfalls
• 32:10 — Interpreting negative test results; counseling
• 35:45 — Study endpoints: stage shift vs. mortality
• 37:56 — How to work up a positive, non-localizing MCED test
• 42:14 — Psychological harms and patient anxiety
• 43:23 — The future: who benefits, needed research, and where field may go
• 46:30 — Take-home points

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Summary Table: Key Points for Clinicians

| MCED Testing | Current Realities | |-------------------------|------------------------------------------------------------------------------------------------| | Who may benefit? | Primarily investigational, highest-yield for high hereditary risk; average risk not supported. | | Promise | Detect multiple cancers early, possibly including those without current screening. | | Limitations | Sensitivity varies by cancer type/stage; not for replacement of standard-of-care screening. | | Harms | False positives, anxiety, unnecessary testing, procedures, radiation, financial cost. | | Test characteristics| ~1–2% positivity rate, up to 30% false positives (Galleri). | | Actionable findings | Localization makes targeted workup possible. | | Regulatory status | Most are self-pay, limited insurance coverage; not FDA-approved as generalized screening. | | Biggest knowledge gap| Impact on mortality, best populations to test, optimal frequency remain unproven. |

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Take-Home Points (Dr. Tempero, 46:30)

• MCED tests are promising but not ready for routine use in average-risk patients.
• They should not replace standard screening; may become part of annual maintenance if/when proven valuable.
• Risks of anxiety, false positives, unnecessary workups, and costs are not negligible.
• Shared decision-making and thorough patient counseling are critical.
• The field is evolving—high-quality data still forthcoming.
• Most important: “It’s an individual decision...remember the tests aren't perfect.”

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Resources & Further Reading

• USPSTF Cancer Screening Recommendations: https://www.uspreventiveservicestaskforce.org
• Galleri MCED Test: https://www.galleri.com
• Exact Sciences MCED/Shield: https://www.exactsciences.com

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This episode provides an expert, measured perspective on MCED testing: promising and exciting, but unproven, potentially anxiety-provoking, and currently a supplement—not a replacement—to existing, evidence-based cancer screening practices. Proceed with curiosity but also caution, both as a clinician and as a patient.

Transcript

[A]

Hey, before we get to the show, I wanted to remind you to check out our [e-mail] curbsiders. If you haven't signed up yet, sign up now to get ad free episodes, twice monthly, bonus episodes, and a whole bunch of other cool [e-mail] curbsiders. You know, Paul, I started telling everybody

[B]

the benefits of eating dried grapes.

[C]

I don't know, man. Are we. I don't know. I'm trying to force a Raisin pun in there.

[B]

I feel like you could guess this.

[C]

Yeah, we get there eventually.

[A]

Yeah, Paul, it's about raising awareness and that's what.

[D]

So that's.

[C]

Yeah, I knew raisin had to be in there. The awareness. That's a nice touch, Paul.

[B]

You'll notice that's lightly on topic for this evening.

[C]

Sure. No strong work. Better than a cancer pun, probably. The Curbsiders podcast is for entertainment, education and information purposes only. And the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of the host and should not be interpreted to reflect official policy or position of any entity aside from possibly cash, like more hospital and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much. We aren't responsible if you screw up. You should always do your own homework and let us know when we're working.

[B]

Welcome back to the curbsiders.

[A]

I'm Dr. Matthew Frank Watto, here with

[B]

my great friend, pun lover and America's primary care physician, Dr. Paul Nelson Williams. Hi, Paul.

[C]

Hey, Matt, how are you?

[B]

I'm doing well.

[A]

I always like when you like my pun.

[B]

It just feels like a better start

[C]

to the show, which is why some of your episodes are bad.

[B]

All right, Paul, we have a great show tonight. Great co host as well. First, would you remind people what do we do on Curbsiders?

[C]

Sure. As a reminder, Matt, we are the internal medicine podcast. We use expert interviews to bring in clinical pearls and practice changing knowledge as you alluded to. We are joined by Curbsiders stalwart, teach, creator and showrunner, producer, writer extraordinaire, the great Dr. Molly Hoiblein. Molly, how are you?

[E]

I'm good. Thank you for that beautiful introduction, Paul, and happy to be here. We had a great discussion today about multi gene early cancer detection testing. Kind of the early stage that it's in, the promise that it might be able to offer, but also the real limitations that are currently present at this point. Our guest today is Dr. Margaret Tempero she is the Deputy Director of the UCSF Helen Diller Family Comprehensive Cancer center at Mount Zion. She has led national research projects for gastrointestinal cancer, including pancreatic cancer. She has held editorial positions on prestigious journals such as Cancer Research, Journal of Clinical Oncology, Clinical Cancer Research, and the American journal of Medicine. Dr. Temporow is a professor of hematology and oncology and is the Doris and Don Fisher Distinguished professor in Clinical Research.

[B]

And a reminder that this in most episodes will be available for CME credit for all health professionals through VCU Health at curbsiders vcuhealth.org A note to the listeners that our guest Dr. Temporo did disclose that she has received research funding by Grail which makes the gallery test which we do talk about on this episode. That being said, the discussion on this episode was fair and balanced without showing favoritism to any specific test. And please enjoy the show. Margaret We've been talking for a little while and we really want to get into the topic, but the first thing the audience always wants to know is what is a hobby or interest that you have and you're currently enjoying. That's like outside of your practice of medicine?

[D]

Well, currently I'm addicted to the games section of the New York Times, particularly spelling beef. And if I don't make it to genius level in the morning by 7:30 it's a bad day.

[A]

Paul, do you know about this?

[B]

This is not something that I'm doing.

[C]

I'm aware of it. I am competitive with the world and hate myself if I don't do well and I was not thriving immediately so gave up on it before I felt even worse about myself. But I have played it and familiar with it.

[A]

Paul recently admitted that he was playing

[B]

a video game that was too hard so he turned it on easy mode so he could enjoy it and he felt guilty but he proud of himself for taking that leap.

[C]

So I'm doing the work.

[B]

Doesn't sound like you can do that with these New York Times games though.

[A]

All right, well let's get into it

[B]

because we have limited time. Molly, would you get us to our case from Cash Slack?

[E]

Absolutely Excited to talk about this today. So we have a patient coming into our primary care clinic, john. He's a 55 year old male and he's here for his annual physical. He's generally healthy and up to date on all his cancer screenings and he wants to talk to you about these new cancer screening blood tests that he's seen on social media. He's worried about his Cancer risk, as several of his friends have been recently diagnosed. So to start us off, could you give us a bit of the epidemiology around our current cancer screening programs? How effective are they at finding cancers, and what percent of cancers actually have a USPSTF recommendation for screening?

[D]

Well, it depends kind of on how you count the cancers, right? Because there are probably over 200 different types of cancers that can occur. But commonly they're grouped like all the leukemias are grouped into one bucket when it comes to national statistics. And if you look at the SEER statistics, they keep really good records on about 19 different organ sites. So that's kind of the ballpark. And then we only have recommendations from the US Preventive Services Task Force for four. There's a guarded recommendation for a fifth, and that's for prostate cancer. But we do have recommendations for lung cancer in patients who were previously heavy smokers, for colon cancer starting at the age of 45, for breast cancer and for cervical cancer. And if you look at all of these, the ones that really seem to link to a decrease in mortality, it's the ones that the U.S. preventive Services Task Force have recommended.

[E]

Given that really is a small percentage of the cancers that we were able to identify through screening. And certainly many patients are hesitant to undergo invasive screening tests like colonoscopy. It's understandable that these blood based multicancer tests are an area of excitement now in medicine and also social media. How do these tests work and what is the science behind them?

[D]

Well, I can tell you how they work, and the science behind them actually sort of grew out of our need to identify genetic targets for therapy. So it started with the liquid biopsy. We've known for a long, long time that tumor cells can circulate in the bloodstream. Fragments, parts of tumor cells, such as fragments of DNA, can circulate in the bloodstream. But it's only been recently that we've had the technology to really capture these tiny little bits of material and amplify them in a way that you can actually characterize them. And so, you know, it just has taken some time for the technology to get to the point where we could use the material from the blood.

[B]

Can I just give a little background to the audience? Because I was not very familiar with this world, and I've been doing a lot of reading just to prepare for this interview. So I just want to lay a little foundation and then maybe have you comment on things. So with these tests, right now it looks like there's two tests. The one made By Grail, like you said, it's a cell free DNA. It's looking at methylation patterns and it can localize. And then the one by Exact Sciences is another one that's commercially available. It looks at I think cell free DNA, but also looks at I think some proteins or something. But that one doesn't localize. You said the one by the gallery test, by Grail does localize, this other one doesn't. So that kind of speaks to what might happen downstream if you get a positive test. But the other thing I noticed about this is that there's lots and lots of tests in the pipeline and you mentioned some may or may not be going through the same like steps to be, to validate their testing as, as the gallery test has been through. And that I came across this term of multi omics, meaning like we might look at the g, the, the genes related, the proteins, the epigenome, all these kind of things. So this gets to be really complicated, like big data machine learning stuff. And then finally I just wanted to, to say I was surprised because like the hope would be that you're going to detect all these very early cancers. But a lot of the articles, and I think one that your group wrote talked about this gradient where you're actually detecting, you have a higher sensitivity or you're detecting more stage 4 cancers maybe because they're putting more into the blood than the earlier stage cancers and you'd almost hope it'd be the other way around where you're detecting mostly early cancers, not, not the later stage. So I know that's a lot, but I just wanted to lay it out for the audience because this is a, I think most people will have very little baseline knowledge of this, of this world and what's going on.

[D]

Yeah, it's a fair point. And you bring up the other potential is that there are signals that your body gives off when a cancer is being developed. Right. You have immunosensors, so you may have changes in cytokine profiles in the blood. You may have odd metabolites that you wouldn't normally have circulating in your blood if you didn't have a certain type of cancer. So I think we're only starting to scratch the surface of what we might be able to test. And some of the tests that are being developed do include other analytes, such as maybe proteins that might be expressed in the process of an invasive cancer as proteases eat away and the cell is moving deeper into the tissue. So I think we're kind of at the Beginning of a journey. I don't see that we're there yet clearly, but I see encouraging signs and that's what keeps me hopeful.

[B]

The promise of these tests, these multi cancer early detection tests, when people hear about them, they think, oh, that's great, it's just gonna, they're gonna look at my blood. They're going to find very early cancers or even pre cancers and then that's going to prevent these late stage cancers. I think that's what people think. And they think, oh, they're going to have this great sensitivity for finding this. Can you talk a little bit about the test characteristics of what we have so far?

[D]

Sure. I think it's really important that all of our messaging always include the importance of standard of care screening, that we never will back off from that. If the multi cancer detection tests reach their potential, they're in addition to standard of care screening. They're not a replacement. And there are people who are very, very health conscious and maybe they've had cancer among their friends, such as this case has had or perhaps in their family or maybe they've experienced cancer or maybe they have a hereditary predisposition to, to getting cancer. So they are naturally wanting to seek something else. We try to, for those patients who want the test, we try to educate them about the chance of a false positive. That's what we're really most worried about because that leads to unnecessary imaging and sometimes unnecessary procedures. Right now the most data that we have is for the test that is developed by a company called Grail and the test is called Gallery and it's gone through some pretty major studies. I have to commend the company actually for trying to actually get and gather data which isn't being done by some of the other companies. That said, their most recent large study in the United States, the Pathfinder 2 study, showed a false positivity rate of 30% of their positive signals. 30% were false positive. This hasn't been published yet, but I've seen the data from presentation at a European meeting A few months ago. They did a randomized trial with the National Health Service in the United Kingdom that did not meet their primary endpoint. Their primary endpoint was to increase the numbers of stage three and stage four cancers. They didn't reach that primary endpoint. They did reach and encouraging reduction in stage four and an increase in stage one and two.

[B]

Okay, so yeah, and I looked into this. This is probably something we'll cover for the audience on a future digester hotcakes when it gets published. Which Might be because it's not officially published yet, but you can look on ClinicalTrials.gov and you can kind of see what's happened. They did change their primary endpoint, which I know are our statistics guy is always talking about that as, like, why did they do that? Making sure that that was done in a way that makes sense. But they kind of narrowed the primary endpoint from decreasing all stage three and four cancers to a hierarchical way that they went through it. But the gist of what you're saying is that these multicancer early detection tests are going to be complementary to the standard of care screenings that we're already doing, at least in the near term.

[D]

Well, that's what we hope. But I think when you consider the array of cancers that these tests are able to detect, potentially some cancers appear to be high shedders of DNA. For instance, the Grail test is based on methylated DNA, which gives you a methylation pattern and a tissue of origin. So you kind of know where to look with that particular assay. And it may be that as time goes on and we get more data, we may find that particular cancers are better suited to this type of an assay. I spent my career working on pancreatic cancer, which is almost always detected too late, and it's a very poor shutter. Even patients who have metastatic disease, very rarely can we pick up. Not very rarely, but in maybe 20% of the cases we can. And we can't pick up analyzable material from the blood, even in very advanced cases. So I don't think we should be thinking of these as sort of a just one size fits all, because there may be subgroups of cancers that are better suited for this type of an assay. And so I think we need to keep an open mind.

[E]

Do you have some examples of what those ones that do seem to be better detected are?

[D]

We don't have all the aggregate data. We don't have all the data yet from the National Health Service, But I think it's a responsibility of the company to be able to start putting that together. There is a sense of those who use the test frequently that head and neck cancers are very commonly picked up at an early stage. And that's one that we often miss because let's say something in the nasopharynx where there's sort of asymptomatic for a while and we would miss those early ones. So I think that we need to just keep an open mind and think about the various factors that would influence the shedding of this nuclear material into the blood. The Grail is also doing a study right now that we're involved in called reach, and this is in the Medicare population. So the study in the National Health involved patients over the 50 and over. So now this is going to be an older age group. And as you know, most solid tumors at least are diseases of aging. So as we get into older age groups, we may be able to enrich and have better performance of a test. So I think, again, we're just. We're just beginning this. It's.

[B]

Yeah.

[D]

The work in progress.

[A]

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[C]

I would like to ask about the practicality of what it looks like in the present day of ordering these tests. Just reading articles. Some are not FDA approved, but they're clia waves that they can actually be a prescription for. But maybe they're covered. But most are not covered. So what if someone was considering one of these tests? I guess what does it look like at the ground level in terms of what a patient can expect, in terms of what is covered, how they pay for it, that kind of stuff. I'm not sure if you're able to speak to that or not, but I feel like that's also something that might be helpful to know.

[D]

Sure. The only blood based test for cancer detection that I know of that is reimbursed by insurance is SHIELD and that's from Exact Sciences. The others are all self pay. You can get the test, a physician can order the test. The patient can go onto the website of the company and they can be connected to a telemedicine doctor who can interview them. And what they are trying to do is make sure that the patient isn't symptomatic, that you know there isn't some other better way of approaching what their patient's goal is. But then the telemedicine doc can order the test for them. So they don't even actually need their primary care doctor to be involved.

[C]

I have so many complicated feelings about that. Sorry, sorry.

[D]

Go ahead. I do too. I do too.

[E]

And then they can just go to a commercial lab and get a blood draw and get the results back online.

[D]

You can't go to a commercial lab without an order.

[E]

Right. They need an order. Right.

[D]

And there's a special kit. These require special blood collection kits for extraction of DNA. So they have to have a special kit.

[B]

And I think it's Mark Hyman's company that Function Health. You can order so many types of tests. I've talked about my concerns with like you can order Parkinson's plasma biomarkers on that without there must be a doctor on their end. That's like signing off on the order saying that the patient's been counseled or something because people can also order the gallery test through that as well. And I'm good. And the worry is are they gonna forego the standard of care screening and do they understand the characteristics of tests? Cause I think a lot of doctors don't even know the characteristics of these tests that are out there right now. So in broad strokes, the two. So the exact science is shield test, that's a colorectal cancer thing, right? That's the one that's, you know, been approved. But the exact scientist also has like a multi cancer detection test and grail and gallery is the other one. So out of those two, can you talk about the sensitivity specificity just so the audience knows, like if patients are getting those tests, like what is, like what can we expect?

[D]

Well, first of all, you can't really talk specifically about sensitivity and specificity because you're talking about 50 different cancer possibilities in the test. Right? And we don't have the gold standard of whether they actually have cancer or not in case there's a false negative. So we don't have that follow up data. What I can say is that the positivity rate is about 1 to 2%. So 1 to 2 in 100 folks will have a positive signal. Out of that positive signal, the only one where we have real data on is the gallery test. And that's where the positive signals are 30% of the time false. But on the other side of the coin that 60% of them are finding something real. But of course, what your ultimate goal is to find something that's real and important, right? So if you're finding an indolent thyroid cancer or a prostate cancer that doesn't need treatment or an indolent lymphoma that could probably sit there for a few years before treatment is needed, that's not much help to the patient. But that's part of the game. It's part of the game. You can't avoid it. You can try and help them understand that not all cancers need to be treated, that not all cancers are bad, that not all cancers will kill you. And that's a lot of the education that we go through. We do not at UCSF offer the test. In our cancer diagnostics clinic. We are there to take care of the patients who have for whatever incentive that they have, they get a multicancer detection test or they get a whole body. Mr. And something is discovered. And then they come to us and we work it up. And our goal of course is to try and come to a decision quickly about what's the cause of the signal. And if we don't and we've done all the necessary testing, we bring them back for another test six months later to see if that signal disappears.

[B]

So Eric Topol wrote this book, Superagers. One of the things he talks about there, he talks about cancer. He has this kind of stack of interventions or things that you might look at to determine who then might need more aggressive cancer screening. Because the way we do cancer screening now is this very just kind of broad based population screening. How are you talking to people about the promise of these tests? If a friend or family member came to you and said, should I get this? Are there people with certain family histories where you think it actually might be ready for them to get it? Or would you just tell everybody at this time, like, we need more information, we need to wait for these tests to get to the next generations where they are going to have better operating characteristics and we're going to have less false positives. We're going to find stuff earlier. What do you think?

[D]

Well, the patients who have hereditary predisposition are already in some cases getting whole body Mr. Scans on an annual basis. Take a patient with Li Fraumani for example, that has an underlying predisposition for multiple cancers, many of which we don't have any screening strategy for. And so for those patients, you might think that if they could afford it, those would be good options. They can probably get the whole body Mr. Reimbursed, but they're not going to get a multicancer detection, blood based assay reimbursed. So I think we need to do studies in these populations, and that's a big mission of mine actually, is to apply multicancer detection testing in a context of a clinical trial to patients at hereditary risk.

[B]

Molly, is now a time to talk about whole body mri or do you have other ways to take this?

[E]

Yeah, I think we sort of brought it up. So, Paul, I know you or a lot of whole body MRIs for all of your asymptomatic low risk patients.

[C]

Lyme serology, my fatigue panels. Yeah, it's. It's all part of the package.

[E]

But, you know, I mean, I do see these patients come in with these reports sometimes and it's, you know, sort of overwhelming. That says there's this adrenal adenoma and then our team does a real scan and that there doesn't seem to be anything. And how do you counsel patients who are average risk about whole body MRIs or how should clinicians look at those?

[D]

Well, we don't recommend them first of all, but we have to accept the fact that there is direct to consumer marketing for whole body. Mr. As well as multicancer detection testing. So patients who are worried about their health will take advantage of it. And some patients, in fact I had one recently in the cancer diagnostics clinic who thought he should have an mri, apparently was having symptoms. So this was not an asymptomatic patient, but he couldn't get his doctor to order the test so he took it upon himself to get a whole body. Mr. So sometimes it's the agency for the patient, right, that they really feel that they need to have something done. Their doctor doesn't agree. And so this is their way of getting the information that they think they need.

[B]

Looking up the evidence for the whole body mri outside of Li Fraumeni syndrome, where certain hereditary cancer syndromes, it seems like it's in guidelines for those you were mentioning they could be covered, but for just the average person asymptomatic wanting to go in and get a whole body mri, we really don't have any evidence to say with certainty that they increase detection of earlier important cancers or that they improve mortality. And that's definitely what people are going into them thinking is going to happen for them. And I know it's hard to get somebody to understand the statistics of that. And you don't know for sure. Maybe they are going to be the one in a million person that actually goes in and finds something that would have killed them if they hadn't got that test. And I'm sure there's those stories out there on the Internet. So it's kind of a fraught situation. But can you talk about the quality difference between there's a couple companies that direct to consumer market these and then there's the research, like if you got one at ucsf, a whole body mri, the difference in quality there versus if you get one of these kind of budget ones which are still pretty expensive but that are not done at a major center.

[D]

Well, I will say that some of these companies like ESRA are trying to use AI to improve their imaging so that they can do shorter imaging but get better, higher quality images. I mean, shorter time for the image. But you're quite right that when we're presented with a patient who has gone to get a whole body. Mr. At one of these centers, generally the first thing we do is we repeat the. Mr. And make sure that we've got the best quality imaging.

[B]

So what I'VE heard. I was at a conference recently. I was speaking with some oncologists about this issue, asking their thoughts what they think. And they were saying that these other places are using lower quality scans. They're thicker slices. The read quality is not going to be the same as you're going to get at an academic center. And that's kind of what I was getting at there. So I think people, again, they think that they're going to benefit from it. And my level of certainty that they're going to benefit from it is low. Especially if it's one of these kind of, you know, budget quick scans. That's where they're trying to just like mass produce these or, you know, I just, I think that the, the marketing and the hype is really high right now. So.

[D]

Well, and they're not providing us any data. Right. They're not giving us any data about out of the last 1,000 scans, what did they find? How did it influence the healthcare of that person? So it's a black box as far as I'm concerned. I would love if we had a real role for whole body Mr. In patients outside of hereditary predisposition, then I would want it to be done at some place like UCSF where we have very high quality instrumentation.

[A]

Yeah.

[B]

And I mean it's a great idea. I mean everybody wants to detect cancer early in a way that's safe. But I think the issue is right now you're potentially exposing people to just the cost and the worry and the downstream testing. So I think we should talk about that. But Molly, do you want to bring us to the next part of the case and maybe that'll get us into some of the, you know, the consequences, repercussions that of how we're going to handle what we find.

[E]

Sure. Yeah. So we, we've kind of covered this, but I think it's really important to hammer home. But just say for our case, John did go forward and get the testing. He did the multi cancer early detection blood test and his results came back with no cancer signal. So how would we counsel a patient like this? What does that mean for him? Should he repeat it in a year? Could he skip all his other screenings? Where should we take that?

[D]

Well, it doesn't mean that he doesn't have cancer because it's possible that the test missed something. If he's really concerned, I would suggest that he repeat it again in a year. I mean you have your, you know, your prevalence and incidence. Right. Until you start screening on a regular basis, you don't really know. You don't get into the real territory of what is really a new case. Right. Versus a case that's been sitting around in your body for a year or two before it happened to come to attention.

[C]

Yeah, I guess that's the. It seems to me these tests including the whole body mri like it's almost more fraught to have a negative test because I don't know like did the patient then like yeah, I can live forever now. Like I don't know exactly what that means. And you know cancer is being so different and you know normal colonoscopy buys you 10 years whereas a normal low dose CT scan for lung cancer you. It's not really useful unless you're doing these things annually. So I just. If a patient would have this done and come back with a negative test, I'd be happy for them I suppose. But I'm still not sure where to go from there in terms of counseling, in terms of follow up and how worried we should be and what to do in terms of sort of the standard issue cancer screenings or not.

[D]

You know, again it's going to boil down to what the patient wants. Right. Because that's how it all started. He came in and he wanted to get this test because he was worried about whether he had an underlying malignancy. And the only way to be sure that he doesn't is to repeat the test at a later time over maybe three years. But when you think about it, if these tests prove to be valuable then they become a part of your annual healthcare maintenance. But they have to prove they're valued to get there.

[B]

Do you think is the trajectory that. Do you think we will have data for. It sounds like for the multi cancer early detection tests. I think we'll. It sounds like we're going to more likely to get data there. The whole body mri they're almost. They're disincentivized to study it. At least the companies that are already just doing this and making. Making money off of it. But do you think they're like an academic center would do a study of this? It seemed like it'd be a very expensive study and like it's a big resource to tie up with a whole body MRI for, for a clinical trial.

[D]

The NCI has put together under the direction of Phil Castle something called the Vanguard study and basically it's a network of institutions. We are not part of that. I wish we were by the way. We're not part of that. But they do an assessment of each tool, each assay that is given to them and then they have, you know, they're equipped to do these large scale population based randomized trials. And I think that's where we will get the data. Because some companies seem to be reluctant to invest in the clinical trial. We haven't seen any real clinical trial data except a very relatively small study for a cancer guard. I'd love to see them do a clinical trial. I'd love to have them invest in a clinical trial. But that doesn't appear to be their strategy.

[E]

And do you think the NHS Galleria study, their approach of looking for a stage shift, is that a reasonable approach to this? Because actually looking at mortality would take so long that probably the technology would be obsolete by the time we get that data. Is that a good way of looking at it or do you think there's a better way to structure these?

[D]

Most of us who are interested in this field think stage shift is sufficient.

[B]

Can you define that?

[D]

Yeah, so just identifying fewer cases of advanced stage three in the case of the NHS study that they did three and four. But I would argue that for a lot of solid tumors, stage three is still curable. It's not in pancreatic cancer, but it is in colon cancer, for example. So, you know, maybe they should have made their cut point at stage four reduction in stage four cancers, which are obviously lethal in most everybody except for some miraculous things that are happening in the immunotherapy world and in melanoma and some other diseases. But I think reducing the stage four cases would be very helpful. I also understand the argument about mortality and looking at impact on mortality. But in pancreas cancer, you could achieve that goal. But in breast cancer, well, let's not use breast cancer as an example because we already have a screening strategy for that. But let's say in some other malignancy like prostate cancer, where patients live for a very long time with their disease, you know, it would take forever. You would like to be able, if you think you have a tool, you'd like to be able to introduce it earlier. Not everyone agrees with me about that. There are staunch supporters of impact on mortality and I understand their position and respect it.

[B]

If we change our case a little bit, instead of him having a test that comes back with no signal, if it did come back with signal, just practically speaking, if somebody comes to my office, they've had a gallery test or they've had the exact scientist's test done, and let's say we don't have a specific, like localizing, I guess the Gallery test might give a localization. This other exact sciences test doesn't. It just says cancer signal detected. So what, what should we do with that?

[D]

So on the cancer signal detected without a tissue of origin, the recommended approach is a whole body PET ct. But we all know, I know, and we all know that there are some tumors that aren't very FTG avid or might be so small that they don't register with a tissue of origin direction. At least you know where to look. For instance, if it's bladder, well, you can start with urine cytology. You know, you can do some simple things and so you can look for blood in the urine, for example. I mean you can just start simply and get, get to just focusing on that particular organ. We're working right now, a group of us across the country who are very interested in the use of these, these assays are putting together guidelines for a workup when you have a tissue of origin signal. And so we've gone through every publication I hope will come out in the spring. But we've gone through every tissue of origin site and created a diagnostic pathway for each site, which I hope is helpful.

[B]

That sounds very helpful.

[C]

Well, I can certainly appreciate the value, but if I just had a patient who came up with a test that said cancer somewhere like all right, balls in your court, buddy. It's just a nightmare scenario. And especially I can't imagine the anxiety of a false positive where you do the million dollar workup and it's negative, but you still have this blood test that's a cancer at some point and what do you do with that? And how aggressive are you with things? It just seems, again, I can appreciate the value, but also I can also see how scary and frustrating it might potentially be as well.

[D]

Well, that's why I think that's why the tissue of origin signal is so helpful. But because of direct to consumer marketing, a patient may not understand that there's a difference between not having a tissue of origin and having a tissue of origin. So we're also creating FAQs on our website so that we can provide some level of direction if they're choosing to go down this route. So we're not recommending routine use of these assays, but if you choose to do them, here are some things to think about and some caveats because I think they need to understand the pros and cons. So a lot of what I'm thinking about right now is education to the consumer.

[A]

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[E]

Are there any major points that we didn't cover around that education?

[D]

Well, one thing we haven't talked about is anxiety. Some patients are, you know, really eager to know everything, right? And if they have a positive signal and we work it up thoroughly and we don't find anything, and we say, come back again in six months, we'll repeat the test. If it's still positive, we'll go through this journey again. If it's negative, then it was a false positive. That happens. There's a lot of anxiety in that period of time. I had a patient tell me that he wished he hadn't done it because he had a positive signal. We couldn't find anything. It went away. But he said, during that whole period of time, I was miserable. So I think we need to keep the message out there about what potential harm there can be. Not just the emotional harm, but also potential harm from unnecessary exposure to radiation, unnecessary procedures, which there isn't a procedure on the face of the earth that doesn't have some complication rate.

[B]

So, Margaret, what do you predict in the next five years in this field? What do you think? As if we're primary care. What will change for us? What will change for you as the specialist receiving these consults?

[D]

Well, I Think that as the data accumulates and hopefully the responsible companies developing these assays will collect that data and make it available. We may find that as I mentioned earlier, multi cancer detection test is probably best for maybe three or four cancers, not the 50 cancers that they're advertising right now. And once we narrow down that, then perhaps you can look at the high risk populations that are at risk for those particular malignancies. And thinking of head and neck cancer with smokers and especially with smoking combined with alcohol. So I think that we'll be able to refine these indications a little bit better. And in the current study in the Medicare population, I'm really hoping that because of the older age of those patients that maybe we could also pick a Cutoff. Right. Age 65 and older, it is reasonable to get a annual multi cancer detection test. It's not going to find everything, but maybe it'll find some things that could be taken care of easily and not be a burden to you.

[B]

This is the REACH study you said that you're conducting. When do you expect results for that?

[D]

It'll be years because we're accruing 50,000 subjects. There's a synthetic control, so real world control, which the FDA agreed with and we'll complete accrual probably at the end of 2027. Then there's got to be three more years of follow up. Right. Because the last people will be enrolled at the end of next year. So it'll be a while before we have that data. But I think it's going to be very, very important data because that age alone, as I mentioned earlier, is a risk factor for many of the malignancies that are so lethal. Pancreas cancer is really a poster child for that because every decade the incidence increases dramatically.

[B]

Wow. Well, this, this is a field that I'm just fascinated with. Definitely have cancer in my family. These are, this is something I thought about myself. But I, you know, after reviewing the data, I'm not exactly jumping in to get, to get this testing for myself. I would love for some take home points that you want the listeners to remember about the discussion we've had tonight.

[D]

I think the caveat, again, it's an individual decision to get any of these types of non traditional screening tests. So if one elects to do that, to remember that the tests aren't perfect, that you may have a false positive, that that false positive could lead to unnecessary procedures and exposure to radiation and cause a lot of anxiety. So I think it's really the cons that we need to emphasize in our messaging to patients.

[B]

All right, thank you. We will head to our out.

[C]

This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole.

[E]

There's an S there Paul.

[B]

Thank you Molly.

[C]

You made it even worse than it had been previously. So congratulations. Still hungry for more? Join our Patreon get all of our episodes Ad Free twice monthly bonus [e-mail] curbsiders just a peek behind the curtain. By the way I do read this from script still after 10 years and just watching Molly slowly insert in real time the letter S into the script was a little bit devastating.

[B]

Amazing.

[C]

You can find our shownotes@the curbsiders.com and sign for a minute list to get our weekly shownotes in your inbox. This includes a Curbsiders Digest which recaps the latest practice changing articles, guidelines and news in internal medicine.

[B]

And we're committed to high value practice changing knowledge. And to do that we need your feedback. So please email [e-mail] a reminder that this and most episodes are available for CME credit for all health professionals through VCU Healthurbsiders VCUhealth.org A special thanks to our writer and producer for this episode, Dr. Molly Hoy blind and to our whole Curbsiders team. Our technical production is done by podpace. Elizabeth Proto does our social media. Jen Waddle runs our Patreon. Chris the Chu Manchu moderates our discord. Stuart Brigham composed our theme music and with all that until next time, I've been been Dr. Matthew Frank Waddo and

[E]

I've been Dr. Molly Hoiblein and as

[C]

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