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.
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.)
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].
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.
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...
>> 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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
[+] [-] killjoywashere|3 years ago|reply
[+] [-] doctoring|3 years ago|reply
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...
[+] [-] Gatsky|3 years ago|reply
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/
[+] [-] woke_neoliberal|3 years ago|reply
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...
[+] [-] catchclose8919|3 years ago|reply
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...
[+] [-] JohnJamesRambo|3 years ago|reply
[+] [-] adamredwoods|3 years ago|reply
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|3 years ago|reply
[+] [-] abbirdboy|3 years ago|reply
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|3 years ago|reply
[+] [-] hoten|3 years ago|reply
In other words, is this a one-and -done thing?
[+] [-] CodeBeater|3 years ago|reply
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|3 years ago|reply
[+] [-] adamredwoods|3 years ago|reply
[+] [-] thadk|3 years ago|reply
[+] [-] melling|3 years ago|reply
https://youtu.be/iUqgTYbkHP8?t=15m37s
[+] [-] threeseed|3 years ago|reply
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|3 years ago|reply
[+] [-] FollowingTheDao|3 years ago|reply
[+] [-] kemmishtree|3 years ago|reply
[+] [-] formerkrogemp|3 years ago|reply
[+] [-] doctoring|3 years ago|reply
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|3 years ago|reply
[+] [-] unknown|3 years ago|reply
[deleted]
[+] [-] yieldcrv|3 years ago|reply
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|3 years ago|reply
But more profitable.
[+] [-] jmcgough|3 years ago|reply