If you find this type of thing interesting and want to be part of it, we are hiring lots of folks. My team is looking for bioinformaticians, Python hackers, and machine learning people. Please reach out to me if you want to know more firstname.lastname@example.org
Variant classification alone is an incredibly challenging problem. Oncologists are not geneticists, and most hospitals do not have in-house geneticists. Additionally, there is potential liability involved with mischaracterizing genetic alterations.
Now you have to wonder why John Hopkins isn't party to it...
Not-so-obvious point #1 is that the presence of cancer-associated mutations in blood != cancer. You find cancer-associated mutations in the skin of older probands, and assumedly many of the sampling sites would never turn into melanomas. A more subtle point is that cfDNA is likely generated by dying cells, i.e. a weak cancer signature in blood might also be indicative of the immune system doing its job.
Point #2 is that it's not necessarily about individual mutations, which are, due to the signal-to-noise ratio alluded to above, difficult to pick up. One can also look at the total representation of certain genes in cfDNA (many cancers have gene amplifications or deletions, which are easier to pick up because they affect thousands of bases at the same time), and the positioning of individual sequenced molecules relative to the reference genome. It seems that these positions are correlated with gene activities (transcription) in the cells that the cfDNA comes from, and cancer cells have distinct patterns if gene activity.
> Last year, we raised $5.5 million to prove out the potential of this technology. Now, it’s time to make sure that it’s safe and ready for the broader population.
NIPT is a non-invasive blood screening test that is quickly becoming the clinical standard of care. Many insurance companies now cover the entire cost of NIPT screening for
for at-risk pregnancies (e.g. women of "Advanced Maternal Age" (35yo+)). The debate is moving to whether it should be utilized/covered for average-risk pregnancies as well.
Title: Direct detection of early-stage cancers using circulating tumor DNA
Link (no paywall): http://stm.sciencemag.org/content/9/403/eaan2415
Figure 2 shows the sequencing error rate reduced from around 1e-4 using conventional NGS to 1e-6 using TEC-Seq.
This increased sensitivity allows for discovery of early cancer at levels that are undetectable using existing cfDNA testing techniques.
Targeted capture using Agilent's SureSelect is pretty common in the cancer field. Their custom implementation allows for oversampling (30,000x) which, along the enzymatic error correction, allows them a high confidence in the target they chose to evaluate.
Overall, I think this is neat.
I really do wish detection studies would publish a ROC curve, though, or at least d'.
The short answer is: probably not, but maybe!, as some of these tests and assays are sometimes run on "healthy" people as part of testing and validation. So you might be able to convince some of these labs or companies to "test" you. But my spouse, who is one of the authors of the OP paper, ran into this issue when one of the lab members tested "positive" for a cancer-associated mutation during early-phase development of some of the assays. (They were running the stuff on their own blood.) The team was kind of stumped: the tests at that point were intended for characterizing cancer, with only inklings of ideas that it could be used for screening for cancer in seemingly-healthy people. It highlights the challenge: then what?
The outstanding question in this space is indeed: then what? We're getting to the point where we can detect tumor DNA with extremely high sensitivity. But if you are found to have DNA in your blood that could be from cancer, then what?
Whole-body CT scan? PET scan? MRI? And you find a node, a nodule, a mass... then what? Biopsy it? And then what? Cut it out? Chemotherapy? Watch it?
Each step is fraught with cost and worry and risk and potential morbidity, eg CT scans irradiate you... which can cause cancer.
We have no idea what to do with the information at this point. In fact, in some cases (as mentioned in other threads) even when we KNOW you have a specific cancer, it turns out to be better to watch and wait rather than do anything, because it can be expensive and harmful and risky to go hunting, when the cancer turns out to be slow and predictable. But it took us decades to figure that out, and to figure out which this was the case for.
So I would advise not getting such a test anytime soon, even if you could. There's nothing to do with information at the moment. As for the lab member, they ended up not doing anything about that result.
But it is still a good question, because the only way we begin to find out what to do with this kind of information is to begin collecting it.
I guess most are treatable if caught early?
For other kinds of cancers, like cervical cancer, which grows extremely slowly, early detection is already proven to be a lifesaver.
As the technology improves it's getting better at making predictions on the severity of the cancer and that can be used to guide treatment, or lack thereof. It's still far from perfect however.
I have never quite bought this argument. ISTM it's not the early detection that causes harm -- it's the inappropriate treatment of early detected cancer that causes harm.
"South Korea is the poster child for the problem of overdiagnosis" of thyroid cancer, Welch says. About 15 years ago, doctors there started a mass campaign to screen for thyroid cancer. That vastly increased the rate of thyroid cancer, to the point that it exceeded cases of breast cancer and other common malignancies.
Yet Welch notes that the mortality rate from this cancer didn't change at all. "So all these extra cases were cases of thyroid cancer that weren't destined to bother people," he said. Instead, that rash of overdiagnosis sent people into needless surgery.
Harmless thyroid tumors are surprisingly common. Decades ago, pathologists in Finland noticed that more than a third of the people they saw in autopsy had thyroid tumors, but the cancers had no negative consequences.
Cancer treatment is not benign and (believe it or not) not all cancers will always causes harm.
For instance, in 2012 a study in the New England Journal of Medicine (NEJM) by Archie Bleyer and H. Gilbert Welch found that, while there had been a doubling in the number of cases of early stage breast cancer in the 30 years since mass mammographic screening programs had been instituted, this increase wasn’t associated with a comparable decrease in diagnoses of late stage cancers, as one would expect if early detection was taking early stage cancers out of the “cancer pool” by preventing their progression. That’s not to say that Bleyer and Welch didn’t find that late stage cancer diagnoses decreased, only that they didn’t decrease nearly as much as the diagnosis of early stage cancers increased, and they estimated the rate of overdiagnosis to be 31%. These results are in marked contrast to the promotion of mammography sometimes used by advocacy groups. Last year, the 25 year followup for the Canadian National Breast Screening Study (CNBSS) was published. The CNBSS is a large, randomized clinical trial started in the 1980s to examine the effect of mammographic screening on mortality. The conclusion thus far? That screening with mammography is not associated with a decrease in mortality from breast cancer. Naturally, there was pushback by radiology groups, but their arguments were, in general, not convincing. In any case, mammographic screening resulted in decreases in breast cancer mortality in randomized studies, but those studies were done decades ago, and treatments have improved markedly since, leaving open the question of whether it was the mammographic screening or better adjuvant treatments that caused the decrease in mortality from breast cancer that we have observed over the last 20 years.
Now suppose an early screen detects this cancer. Since we still have difficulty discerning whether or not your cancer is really "bad" or not you'll likely undergo immediate treatment. This treatment leaves you feeling horribly ill for the duration with all sorts of side effects. After treatment you're left with urinary leakage and erectile dysfunction.
I don't know about you but if you were to tell me that I could live the rest of my days with a minor cancer growing in my body minding its own business I'd choose leaving it there vs the side effects of the treatment.
If a blood test can detect it, couldn't it be economically feasible to have people do it monthly, with a mailed kit and return envelope? Doesn't seem like much more work than taking vitamins, certainly less than going to the gym.
I'm sure there would be types of cancer that would benefit, but it would involve a lot of study of outcomes.
Would it need to? If your test ever came back postive, you'd go into the doctor, presumably retest to confirm, and then start appropriate treatment, regardless of how fast-growing the discovered cancer was.
To be clear: I'm not arguing, just genuinely curious as this isn't a subject I know much about.
Since none of the treatments we have are 100% effective, they can be worse than useless, actually increasing the overall death rate, and ensuring that the end of life is long, drawn-out, and horribly painful.
The point you're making seems orthogonal to me. Unless you're claiming that treatment is never worthwhile for such cancers, no matter how early they're detected, but Greg's original statement seemed to imply otherwise.
That's likely not right. I would believe something more boxed in...like 20% of patients who die within 30 days of starting chemotherapy died from it versus the cancer.
I think most treatment is focused on killing/removing tumor cells and reducing tumor, so the earlier stage a cancer is detected, the less tumor have to remove, and the better the chances of removing all the tumor so there's nothing left to grow, spread, or metastasize beyond the initial tumor site.
Couldn't find a direct source but I read that here
"Grail Inc., a Silicon Valley startup that last year began laying out a bet that the “cure” for most cancers isn’t a new drug, but tests that catch tumors at an early stage when they can still be successfully treated."
Is 98% specificity adequate for a cancer test?
But their data is too valuable to hold back until they had the final result of a test that could be taken to the FDA and approved for general use. This is valuable science, that impacts the directions that others are taking with their research.
I'm not saying you're doing this, but it's a common trend on HN and for other non-scientist technical people to forget that scientific journals show the process of science, not completed science. A journal is not a textbook that one can pick up and read a complete, final story, where all the false starts and uninteresting tangents are skipped. Journals are a way for scientists to communicate about their current progress, and that's an essential part of the scientific process. There has to be room to say: "here's where we are." Especially when they are able to get to the point of where they are right now.
Also, this was published in a very high profile journal, on a highly competitive topic, so take it all with a huge grain of salt. The senior author of this paper does good work, and many people are talking about similar preliminary results, but it takes time to prove these things.
How much would it have cost them to increase the number of controls? How did they choose 44?
There's also the interesting question of: if the test came back positive in a seemingly-healthy control, how would you know if that was a true positive or a false positive? It's still early in the game as to how to work up a cancer detected only in blood. The gold standard is tissue biopsy, but how far are you willing to go to hunt that down? It's a tough one.
Source: My spouse is one of the authors of the study in question.
You can estimate the likelihood from cancer prevalance.
95% confidence intervals from the binomial distribution are for the specificity to be between 92% and 100%.
What this is, is a test to detect cancer. The cool thing is that it should detect various cancers early (even before symptoms are showing).
The earlier cancer is detected the sooner a patient can start treatment. And the earlier treatment starts the better the odds of surviving.
And as a blood test this could end up being a standard part of an annual checkup. Especially for patients at greater risk (eg. men over N years, smokers, etc).
That and the article about blood tests shows there's a lot they're working on for noninvasive or minimally invasive procedures to help prevent cancer early on.