killjoywashere 5 days ago

As a pathologist, good luck. The problem with early detection is getting enough signal. These liquid biopsies have historically worked for large occult tumors that are spilling a bunch of DNA. They won't work for in situ tumors, almost by definition. Maybe some really agro DCIS, but generally if the tumor hasn't broken across the basement membrane, you're going to have a hard time getting signal in the blood stream. Contradictory evidence is most welcome.

  • doctoring 5 days ago

    This isn’t quite right — I think you’re thinking about circulating tumor cells (CTCs).

    These tests on the other hand detect circulating tumor DNA (ctDNA), among other things. It is well known that tumors shed DNA and other material more than normal cells, even at early cancer stage. (Of course, later stage and more aggressive tumors are more indeed likely to shed more.) The detection limit for some of these tests is in the range of single digit copies of DNA fragment per mL of plasma.

    Furthermore, the goal isn’t necessarily to detect every cancer as small as it could possibly be. Even if you don’t do a great job at finding all cancers at stage I, you may still save lives by detecting cancers at an earlier stage than they otherwise would have been found. Finding something at stage II instead of III or stage III instead of IV may well mean the difference of a shot for curative resection / radiation. (Whether these tests would be remotely cost-effective at attempting this at population scale... I leave as an exercise to the reader & healthcare system.)

    Grail had a paper with some scant info on their test performance in multiple cancer types across all cancer stages. https://www.annalsofoncology.org/article/S0923-7534(21)02046...

    • killjoywashere 4 days ago

      > I think you’re thinking about circulating tumor cells

      No, I'm very clear on ctDNA, cell-free DNA, whatever you want to call it.

      My point stands: early detection goes back to in situ lesions.

      The first problem is finding in situ lesions, which is hard.

      The second problem is the amount of fear-induced care this generates. These tests are screening tests, so the vendors will lower their operating points to get their false-negative rates down, which will drive up fear, which will drive up follow-on testing, which will drive up follow-on treatment. How much is what matters.

      US healthcare costs are already astronomical to the point of becoming a national security problem. And you want to spend more?

      • doctoring 4 days ago

        Your original comment stated:

        > They won't work for in situ tumors, almost by definition.

        Which isn't true. The studies from multiple companies' tests demonstrate that they _can_ detect in situ tumors. Not always super duper well, and not always for every single cancer type, but still.

        Whether this is a good idea / cost-effective is another question, and certainly a big deal as you point out.

    • Hellbanevil 5 days ago

      My father had a liver tumor for 15 years. We all knew something was wrong, but he said his doctor said it was scar tissue from a hernia operation.

      At first diagnosis, the doctors told him to go home.

      He later got a call from a doctor who said he would operate. He then called back and said he couldn't. I imagine the hospital looked at the tests, and found it traveled to far, and disallowed the Wonderboy doctor to waste money.

      The Wonderboy doctor called back and said sorry. I would have been nice if the doc didn't drag him into office visits, and give him sanctimonious speechs on alcoholism though. This was a good hospital in the Bay Area.

      My point is if this study pans out, he probally would still be around?

      (If you have money. Get a full body scan. And no they don't pick up on small tumors, but are better than nothing.)

      • sizzle 4 days ago

        Sorry for your loss, what were the symptoms that led him to feel that something was wrong?

  • Gatsky 5 days ago

    Yup this is what needs to be tested, in other words can cancers be detected early enough so that people are more likely to be cured with treatment. Secondary benefits of detecting early are needing less extensive surgery, less intensive chemotherapy and radiation, less expensive next generation therapies in the long run.

    We should also remember that the assays are improving all the time.

    Having said all this, early detection is not prevention, and the endgame still remains prevention I think.

    This whole field also serves as further confirmation that everything intestesting was discovered in the life sciences in the 1970s [1].

    [1] https://pubmed.ncbi.nlm.nih.gov/837366/

    • bsder 4 days ago

      > Secondary benefits of detecting early are needing less extensive surgery, less intensive chemotherapy and radiation, less expensive next generation therapies in the long run.

      This is true, but you have to not have too many false positives.

      A friend of mine went to get her mammogram, and it saw "something". She was a mess until the biopsy came back negative. "Mess" meaning high blood pressure, palpitations, etc.--that false positive could very well have killed her with a cardiac event. A screening test like this that has even worse false positives will kill some people like her.

      Another one has always had negative mammograms and extensive 3D imaging. Suddenly, her breast blew up to twice its size. Everyone assumed it was a localized infection because she just had a negative mammogram set less than 30 days earlier. The only reason they bothered to order a biopsy was to try to break whatever lymph clog was causing her "edema". Oops--Stage 3 invasive lobular breast cancer throughout the entire breast.

      You can't see lobular breast cancers on mammograms because they never form a lump, they just inflitrate all throughout the normal cells. They're about 30% of all breast cancers and a screening test that can flag these (even with a false positive) would be a godsend. Being able to flag people for a followup MRI would be a significant improvement if it doesn't have too many false positives. A screening test like this would be quite beneficial.

      As always in medicine, things are complicated.

    • threeseed 5 days ago

      But the other question is whether the endgame is prevention or treatment at all.

      Are some types of cancer better treated like HIV/AIDS where it's simply managed.

      • jmcgough 5 days ago

        Seems like an odd example when HIV/AIDS can be prevented through PrEP now.

  • catchclose8919 5 days ago

    You gave no way of "guesstimating" how bad/good the signal is and how easy it is to improve detecting it once you start working on it. Maybe cell do quire often leak more DNA than you'd expect, maybe there's some drug or phisical-activity people can do before testing to temporarily increase overall cell damage and DNA leakage etc.

    Don't assume your gut feeling correlates with reality in such a quantitative problem. There might be low hanging fruit here - and it might save your freakin life man! Biochemical testing is not intuitive and the details are best lead to quantitative biochemists and such. Heck, even what Theranos embarked on doing could've lead to breakthrough improvements for some tests if they had been honest and focused the money on the research avenues that could've produced results...

  • woke_neoliberal 5 days ago

    You are correct - meaningful amounts of DNA are only shed when the tumor breaks the basement membrane.

    You can see a breakout at the bottom of this poster [1] from Grail (developing a methylation based liquid biopsy) showing sensitivity per-cancer and per-stage.

    Sensitivity increases as stage increases, as expected, and cancers like Leukemia are well detected. IIRC, the stage classifications vary across different tissue types as to when the cancer breaks through the basement membrane - would be compelling if sensitivity of the assay rises in accordance.

    [1] https://grail.com/wp-content/uploads/2020/12/ASCO_2019_CCGA2...

    • killjoywashere 4 days ago

      Yeah, now break out the prevalence of each of their 21 cancer types in the population. The overall cancer prevalence is only 0.4%, so, b-school math (not to be used in actual calculations) is 0.02%. With a 99% specificity and a 80% sensitivity, you're going to get a lot of false positives and a lot of false negatives. Oy vey.

  • JohnJamesRambo 5 days ago

    I’m flabbergasted that you think the entire field of early detection of cancer from blood tests hasn’t thought of this.

    • arcticbull 5 days ago

      Folks love the idea of doing something instead of doing nothing, even when doing nothing leads to better outcomes. Classic example is the prostate cancer PSA antigen test. It is not recommended in the UK and I believe is no longer recommended in the US. [1]

      The problem with this kind of screening is even tests that are highly accurate in a population with a high incidence rate are super duper inaccurate when used against the general population. False positives often have significant consequences, including invasive tests and surgeries with their own risks. tl;dr Bayes' rule is a bitch. [2, 3] I doubt they've solved this problem - but I sure hope they have because why wouldn't I?!

      > "A patient goes to see a doctor. The doctor performs a test with 99 percent reliability--that is, 99 percent of people who are sick test positive and 99 percent of the healthy people test negative. The doctor knows that only 1 percent of the people in the country are sick. Now the question is: if the patient tests positive, what are the chances the patient is sick? - The intuitive answer is 99 percent, but the correct answer is 50 percent...." [3]

      [1] https://www.nhs.uk/conditions/prostate-cancer/should-i-have-...

      [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082531/

      [3] https://sphweb.bumc.bu.edu/otlt/mph-modules/bs/bs704_probabi...

      • FollowingTheDao 5 days ago

        Doing nothing, yes, that’s my motto.

        This test would be a fear driven profit center for these companies. I don’t like them at all. Easy way to sell the test isn’t it? “You don’t want cancer do you?”

        My father was diagnosed with pancreatic cancer. The doctors gave him six months to live. They said “if she goes on chemo will get a year”. Both myself and my sister-in-law who is in oncology nurse advised him not to go on chemo. But he did. He died a month after starting chemo because it caused his bile duct to clog and it shut down his liver.

        Yeah, so doing nothing, that’s my motto.

      • adamredwoods 5 days ago

        Always get a second opinion for anything major.

        • arcticbull 5 days ago

          While good advice, in general, in the US, liability pushes doctors to act when they have any signal.

          • adamredwoods 4 days ago

            It can go both ways, there is liability in wrong diagnoses. But-- based on my experience, all the doctors have been quite thorough in any diagnoses. In terms of cancer, one area people sometimes miss is asking the pathologist for a second reading on the cells.

            • arcticbull 4 days ago

              Apologies, to be clear - I completely agree with you, and yes a second opinion especially in something as important as cancer is excellent advice.

    • refurb 5 days ago

      Translating science to an actual product that becomes commonly used and embedded in the treatment guidelines is incredibly hard.

      Science can be a breakthrough and really interesting and yet still no practical for use in medicine.

      A really good example was Pfizer's inhaleable insulin. I mean, I don't need some MBA to tell me it's better than sticking yourself with a needle! Turns out it was a wildly impractical solution looking for a problem that doesn't exist.

      Same thing with cancer diagnostics. Unless you can draw a line all the way from diagnostic use to results to improved outcomes, it's just data.

      • radus 4 days ago

        This is why we do trials.

        • refurb 4 days ago

          Incorrect.

          Pfizer’s inhaled insulin was approved by the FDA.

          But nobody wanted to use it because it didn’t solve a real problem.

          • radus 3 days ago

            Allow me to contextualize and re-state:

            > Unless you can draw a line all the way from diagnostic use to results to improved outcomes, it's just data.

            This is why we do trials, to figure out if we can draw a straight line from results (pre-clinical) to outcomes (clinical). This is the question that the cancer diagnostic trial will hopefully answer - can we improve outcomes using these diagnostics?

            I don't completely see the relevance of your story about inhaled insulin. As far as I can tell it was not better than standard of care in a meaningful way, whereas with this trial there really isn't a standard of care to speak of, and this is going to be the largest such trial to date. Plenty of drugs fail to make an impact in the market, for a variety of reasons, which can't always be predicted ahead of time.

            Elsewhere you write that this is not going to provide actionable information. I largely agree with this statement - as of today. I also think that this trial will provide valuable information about the landscape of cancer diagnostics in general, information which may be increasingly relevant in the future and may turn out to be actionable. This is the most relevant quote from the source article that speaks to why they are doing this:

            > Q: Given the doubts, why proceed? > A: The exciting thing is, we don’t have screening tests for the lethal cancers like pancreas and ovarian. We’re desperate. But we have to put our emotions aside and do our due diligence to evaluate these technologies and be able to speak with confidence about what this can and can’t do.

            For 75 million dollars, the cost of a year of maintenance for a handful of fighter jets, I think it's worth it, and I'd much rather have the NCI running this than a private company. If this trial completely falls on its face and public money keeps being expended in this direction, then I would certainly revisit my opinion about the worthiness of trials of this nature.

    • koheripbal 4 days ago

      As someone likely in tech, you should know that bad ideas often still get funding and positive PR.

      • JohnJamesRambo 4 days ago

        No I was in cancer research and this field isn't new at all. People have been working on it and finding ways to avoid false negatives and positives and increased specificity for a long time. Tumor cells shed all kinds of aberrant proteins and glycosylation patterns that you can detect in the blood.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760063/

adamredwoods 5 days ago

Here's the actual (ahem) PowerPoint in PDF:

https://prevention.cancer.gov/sites/default/files/uploads/ma...

Interestingly, I've never heard of cfDNA fragmentomics:

https://www.aacc.org/science-and-research/clinical-chemistry...

>> Well, initially, the main motivation for studying a cell-free DNA analysis is to look for species of DNA that might have been released from various organs that might be useful for doing diagnostics on them. So, for example, we have analyzed DNA that came from the placenta for prenatal diagnosis. We’ve analyzed DNA release from tumors for cancer assessment, but we need to somehow distinguish these molecules of interest with the molecules that are just floating around in the background that might not be from a diseased organ or the organ of interest. So previously, when the field first started, we tried to use genetic differences. For example, for tumor, we might be looking for mutations that were present in the tumor genome and use those features to distinguish the tumor DNA from the non-tumor DNA. But then, as time went on, we realized that those DNA of interest, they typically are shorter. For example, the DNA from placenta or tumor cells, they are shorter than the background DNA that we are not as much interested in. Then, when we looked into why these DNA molecules are shorter, then we found out that the fragmentation process is actually non-random. From this point onwards, people started as, why is it not random and how does the cell control which part of genome becomes fragmented and how can we make use of these fragmented features? And very soon, I mean, it became a field and the studies—the number of studies just exploded.

lacker 5 days ago

At some point DNA sequencing will be cheap and sensitive enough that consumers will be able to do it whenever they feel sick, and measure even tiny fragments. Instead of swabbing your nose for a Covid test, you could be swabbing your nose for an "everything" test. You have your DNA on file and then anything out of the ordinary is brought to your attention. Maybe some warning signs of cancer like this, maybe just identifying the precise mild cold you caught a couple days ago.

  • abbirdboy 5 days ago

    This already partially exists: https://kariusdx.com/

    We use this in the clinical setting when our standard PCR tests, cultures and serologies come back negative. This test is better for when we have exhausted more specific tests. Having such a broad sequencing of dna in the blood is not clinically useful because you may not be sick but be positive for quite a lot of things. Blood isn’t sterile. What would we do about it? Unclear, probably nothing, unless we have associated clinical findings/symptoms that correlate. Also a very expensive test.

  • ekianjo 5 days ago

    not every pathogen sheds dna strands throughout your whole body. its a lot more tricky than what you seem to suggest.

    • cjbgkagh 5 days ago

      Wouldn’t it work for anything that a PCR test could be used for. Seems like a there could a useful subset.

      • R0b0t1 4 days ago

        It would, but it generally takes many samples to piece together good evidence for a match. New technology related to reading DNA strands directly could probably make this feasible.

        • cjbgkagh 4 days ago

          I think the tech is relatively eminent and is part of the future I am looking forward to.

  • hoten 5 days ago

    Is sequencing a binary thing, or would there be reason to continuously do a swab for purposes of DNA analysis (or, as often as the technology advances).

    In other words, is this a one-and -done thing?

    • cjbgkagh 5 days ago

      You’re not looking for your DNA, you’re looking for the DNA/RNA of viruses that shouldn’t be there. Checking sequences against a list of known pathogens.

CodeBeater 5 days ago

I'm pleasantly surprised at the effort being put into avoiding false positives.

I can easily imagine a doctor put in a tough spot whilst deciding to treat a possible early stage cancer. If he gets it wrong a malpractice lawsuit is surely to ensue.

I really hope we live to see a future where physicians have less noisy data to work with, especially regarding early detection.

  • SoftTalker 5 days ago

    I'm not entirely convinced that "early detection" results in anything but more worry, more time in doctors' offices and clinics, more time taking very unpleasant medicine, more time undergoing surgery, and absolutely devastating financial consequences.

    • gubneor 5 days ago

      Late detection is better? Ignorance is bliss? There is no golden path?

      What if early detection failures at scale lead to better medicine? What if more patients lead to more science?

      Resigning to, "fuck it, we aren't there yet" seems overly defeatist.

      • inglor_cz 5 days ago

        Not the OP, but to use an analogy, we are obviously misusing antibiotics "just in case".

        Between "no cancer" and "definitely cancer", there will be a gray field of "maybe cancers" and doctors will feel the psychological push to "do something" about them. Overmedication can kill as well, and it can definitely injure. There is a reason why doctors are reminded of the ancient "First, do not harm" maxim during their training - it is still valid.

        I am not yet convinced that this is going to be a problem, but I don't want to ignore this scenario either.

  • adamredwoods 5 days ago

    Not just early detection, but detection in remission and being able to accurately tell which treatments are working!

thadk 5 days ago

CxO-level health insurance programs have been covering routine cancer-detecting liquid biopsies for at least 5 years, no?

melling 5 days ago

Craig Venter says early detection is the way to eliminate cancer:

https://youtu.be/iUqgTYbkHP8?t=15m37s

  • threeseed 5 days ago

    But that's kind of not the issue here.

    It's that false positives in the cancer detection process can sometimes be more likely to kill you than if you didn't check for cancer in the first place.

    And of course all the flow on effects where the cost of detecting cancer and doing all of these exploratory surgeries means you spend less money on food, well being, basic medical care, dental care etc. Which then may kill you faster than just living with the cancer.

  • adamredwoods 5 days ago

    And then what? Blast with chemo? Radiation? We don't have proper tools to stop cancer yet.

    • doctoring 4 days ago

      Wait, but we do have the tools...

      We can (and do) cure so many cancers. Usually with surgery, +/- chemo/radiation. Sometimes just radiation.

      It's hard to overstate how curable most cancers are at early stage -- for some it's well over 90% and approaching 100%.

      The whole point of these screening tests is to try to find more cancers at more curable stages.

    • yazaddaruvala 5 days ago

      The smaller it is, the safer the operation, the less chemo needed, etc.

    • bergenty 5 days ago

      So you’d rather not know?

      • refurb 5 days ago

        If it's not actionable information, then it's not worth the time or the cost.

        "Our test indicates you have a 90% chance of <tumor type> cancer cells somewhere in your body. There is no solid tumor, so there is nothing to remove. We can do more work-up to try and find it, but unfortunately the government won't reimburse the cost because it's not cost-effective. Or we could just start giving you chemotherapy for a year, then check later and see if there is any cancer. But there is a chance this is a false postive and you don't have any cancer at all. How do you want to proceed?"

      • FollowingTheDao 5 days ago

        At this point, since we don’t know if these early biomarkers lead to any significant harmful outcomes, yes, I would rather not know.

        If after they do a few decades of test with This and show me that The DNA they found was linked to premature death, then maybe.

  • FollowingTheDao 5 days ago

    Of course you did! He’s a businessman! Always looking for a way to make a profit! I mean he tried to patent our genes!

kemmishtree 4 days ago

Reading all the comments here, there's a legit but crazy sounding scientific voice crying out in the wilderness "hey we need solid-state utility-scale molecular sensing and this is weirdly the way to get there." www.molecularreality.com If you want to help, get in touch.

formerkrogemp 5 days ago

I have a different question. Who will be able to afford this, and under what insurance plans?

  • doctoring 5 days ago

    Per the article, Grail’s test is already on the market at $949. Insurance does not cover this —- yet. (That is a big goal of many of these companies).

    This is not cheap but not also not insane. Grail’s test screens for 50 different cancers (at a range of test performances, sure, but as the article mentions, many cancers currently have no screening mechanism). As comparison, the non-insured price of things like MRI and CT scans can run into the tens of thousands of dollars.

  • killjoywashere 5 days ago

    No idea, but the signal:noise ratio is likely to make CERN look like a bargain.

yieldcrv 5 days ago

> NCI advisers endorsed a $75 million, 4-year pilot study

Did any donations and city-wide marathons have any effect on the funding for this particular study? Just seeing what the best use of energy is.

carvking 5 days ago

Sometimes the treatment is worse than the decease.

But more profitable.

  • jmcgough 5 days ago

    Yes, the entire field of cancer treatment is a scam and every oncologist spends 12 years of school/residency just so they can make as much as a good software engineer with no degree.

    • FollowingTheDao 5 days ago

      The doctors and oncologists are not the problem, it’s the companies that make these tests for the pharmaceutical companies that make the drugs Who make billions of dollars and then when something goes wrong you can pay the fine and no one goes to jail.

      Have we nut learned anything from the Sackler brothers?