5 ms·

As a pathologist, good luck. The problem with early detection is getting enough signal. These liquid biopsies have historically worked for large occult tumors t

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.

Gatsky 4y 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/ https://pubmed.ncbi.nlm.nih.gov/837366/
- threeseed 4y 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 4y ago
    Seems like an odd example when HIV/AIDS can be prevented through PrEP now.
    - arcticbull 4y ago
      HIV/AIDS is a bad example but theres a bunch of cancers or tumors that you get very late in life, which grow slowly. A good example is an acoustic neuroma [1]. In many cases, you're going to die long before it takes you out. [1] https://en.wikipedia.org/wiki/Vestibular_schwannoma https://en.wikipedia.org/wiki/Vestibular_schwannoma
- adamredwoods 4y ago
  The endgame will never be prevention. The chance of getting any cancer is high (1 in 8 for prostate). We would have to bring some of these probabilities down, maybe by 100x? Can we even get to 10x? I hope we can get there for some cancers, for example, using the new HPV vaccine. https://www.cancer.org/healthy/cancer-causes/general-info/lifetime-probability-of-developing-or-dying-from-cancer.html https://www.cancer.org/healthy/cancer-causes/general-info/li...
- bsder 4y 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.
doctoring 4y 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)02046-9/fulltext https://www.annalsofoncology.org/article/S0923-7534(21)02046...
- Hellbanevil 4y 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 4y ago
    Sorry for your loss, what were the symptoms that led him to feel that something was wrong?
JohnJamesRambo 4y ago
I’m flabbergasted that you think the entire field of early detection of cancer from blood tests hasn’t thought of this.
- arcticbull 4y 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-psa-test/ https://www.nhs.uk/conditions/prostate-cancer/should-i-have-... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082531/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082531/ [3] https://sphweb.bumc.bu.edu/otlt/mph-modules/bs/bs704_probability/bs704_probability6.html https://sphweb.bumc.bu.edu/otlt/mph-modules/bs/bs704_probabi...
  - adamredwoods 4y ago
    Always get a second opinion for anything major.
    - arcticbull 4y ago
      While good advice, in general, in the US, liability pushes doctors to act when they have any signal.
woke_neoliberal 4y 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_Liu_Poster_Final.pdf https://grail.com/wp-content/uploads/2020/12/ASCO_2019_CCGA2...
- killjoywashere 4y 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.
catchclose8919 4y 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...

Gatsky 4y 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/ https://pubmed.ncbi.nlm.nih.gov/837366/

threeseed 4y 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 4y ago
  Seems like an odd example when HIV/AIDS can be prevented through PrEP now.
  - arcticbull 4y ago
    HIV/AIDS is a bad example but theres a bunch of cancers or tumors that you get very late in life, which grow slowly. A good example is an acoustic neuroma [1]. In many cases, you're going to die long before it takes you out. [1] https://en.wikipedia.org/wiki/Vestibular_schwannoma https://en.wikipedia.org/wiki/Vestibular_schwannoma
adamredwoods 4y ago
The endgame will never be prevention. The chance of getting any cancer is high (1 in 8 for prostate). We would have to bring some of these probabilities down, maybe by 100x? Can we even get to 10x? I hope we can get there for some cancers, for example, using the new HPV vaccine. https://www.cancer.org/healthy/cancer-causes/general-info/lifetime-probability-of-developing-or-dying-from-cancer.html https://www.cancer.org/healthy/cancer-causes/general-info/li...
bsder 4y 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.

doctoring 4y 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)02046-9/fulltext https://www.annalsofoncology.org/article/S0923-7534(21)02046...

Hellbanevil 4y 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 4y ago
  Sorry for your loss, what were the symptoms that led him to feel that something was wrong?

JohnJamesRambo 4y ago

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

arcticbull 4y 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-psa-test/ https://www.nhs.uk/conditions/prostate-cancer/should-i-have-... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082531/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082531/ [3] https://sphweb.bumc.bu.edu/otlt/mph-modules/bs/bs704_probability/bs704_probability6.html https://sphweb.bumc.bu.edu/otlt/mph-modules/bs/bs704_probabi...
- adamredwoods 4y ago
  Always get a second opinion for anything major.
  - arcticbull 4y ago
    While good advice, in general, in the US, liability pushes doctors to act when they have any signal.

woke_neoliberal 4y 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_Liu_Poster_Final.pdf https://grail.com/wp-content/uploads/2020/12/ASCO_2019_CCGA2...

killjoywashere 4y 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.

catchclose8919 4y 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...