Blood Test That Spots Tumor-Derived DNA in Early-Stage Cancers

http://www.hopkinsmedicine.org/news/media/releases/scientists_develop_blood_test_that_spots_tumor_derived_dna_in_people_with_early_stage_cancers

by ncw96 • 9 years ago

361 63 9 years ago

hopkinsmedicine.org

amitutk• 9 years ago

Didn't Grail raise a billion dollars to do just this?

epistasis2• 9 years ago

This is a fairly crowded space.

Wellacopia2• 9 years ago

I guess what's new is that the scientists found a way to distinguish between cancer dna and other altered/mutated dna so they reduce the occurrence of false positives.

http://fortune.com/2017/06/03/liquid-biopsy-grail-blood-canc... https://www.technologyreview.com/s/607944/grails-1-billion-b...

sjg0072• 9 years ago

Yes but grail is doing deep sequencing I believe.

adenadel2• 9 years ago

That's exactly what they did in the OP: "the sequencing method is based on deep sequencing"

jonathanjaeger• 9 years ago

Tangent: I'm invested in a small cap stock, Sophoris Bio, that's in a P2B study for prostrate cancer with a drug developed out of Johns Hopkins called PRX302 (Topsalysin).

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.

McKayDavis3• 9 years ago

I haven't read the referenced study, but I'm sure this is using the same (or very similar) cell free DNA (cfDNA) sequencing techniques currently used clinically for Non Invasive Prenatal Testing (NIPT) to screen for genetic defects such as trisomy 21 (Down Syndrome).

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.

[1] http://capsprenatal.com/about-nipt/

[2] https://www.genomeweb.com/molecular-diagnostics/aetna-wont-c...

McKayDavis3• 9 years ago

As the linked article doesn't name the paper, here's a link to it:

Title: Direct detection of early-stage cancers using circulating tumor DNA

Link (no paywall): http://stm.sciencemag.org/content/9/403/eaan2415

McKayDavis3• 9 years ago

My super-quick skim of the paper shows that they are indeed using cfDNA. The novelty presented lies in the creation and application of a technique they dub "targeted error correction sequencing" (TEC-Seq).

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.

melling• 9 years ago

According to Craig Venter, early detection is what we need to eliminate cancer:

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

I guess most are treatable if caught early?

Wellacopia2• 9 years ago

Apparently, 2/3 of cancers caught early are curable.

Couldn't find a direct source but I read that here https://www.technologyreview.com/s/607944/grails-1-billion-b...

"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."

screature2• 9 years ago

my understanding is that a big part of determining the stage of a cancer is based on tumor size and spread.

https://www.cancer.gov/about-cancer/diagnosis-staging/stagin...

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.

greglindahl3• 9 years ago

Yes and no. With some cancers like prostate cancers, we're finding and treating cancers which would never kill the patient. And the deadliest cancers are the ones that grow quickly, quickly enough that early detection is extremely difficult.

For other kinds of cancers, like cervical cancer, which grows extremely slowly, early detection is already proven to be a lifesaver.

jghn3• 9 years ago

Something tied to what you said that is often not appreciated by people is that early detection can actually cause harm. In the example you gave of slow growing prostate cancers, in many cases people will now undergo treatment due to the early detection and the treatment winds up being far worse than the cancer itself would ever have been.

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.

jonahx4• 9 years ago

And the deadliest cancers are the ones that grow quickly, quickly enough that early detection is extremely difficult.

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.

hprotagonist• 9 years ago

Slowly but surely. This isn't even close to a real diagnostic, but it's a hopeful proof of concept.

I really do wish detection studies would publish a ROC curve, though, or at least d'.

kurthr• 9 years ago

Yeah false positive vs negative is really critical when you tell people they might have cancer... people will do crazy stuff.

conradev• 9 years ago

There is also Freenome, which raised a $65m Series A to bring something similar to market:

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.

https://medium.com/freenome-stories/freenome-raises-65m-in-s...

sjg0072• 9 years ago

There's a bunch of companies doing this.

AlexCoventry3• 9 years ago

They found none of the cancer-derived mutations among blood samples of 44 healthy individuals.

Is 98% specificity adequate for a cancer test?

epistasis2• 9 years ago

Certainly not for a general screen, but then we just know that the specificity is in the range of (98%, 100%) now, not the exact specificity. And we don't know what other refinements might improve upon what they did here.

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.

AlexCoventry3• 9 years ago

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

How much would it have cost them to increase the number of controls? How did they choose 44?

mnw21cam• 9 years ago

Where did the 98% figure come from?

95% confidence intervals from the binomial distribution are for the specificity to be between 92% and 100%.

gourneau• 9 years ago

I work for another player Guardant Health. We are the Liquid Biopsy market leaders right now. We just raised $360M Series E from SoftBank.

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 jgourneau@guardanthealth.com

zorm• 9 years ago

Guardant Health is a member of the Blood Profiling Atlas for Cancer (https://www.bloodpac.org/members/) too with a commitment to opening up data for faster discovery. So they're good people!

Now you have to wonder why John Hopkins isn't party to it...

_bohm• 9 years ago

Hate to be that guy, but as an alum I have to correct this. It's Johns* Hopkins.

doctoring3• 9 years ago

The company mentioned in the original article (and where a lot of the research was done) is a Hopkins spinout -- Personal Genome Diagnostics. They are indeed a member of BloodPAC.

IBM• 9 years ago

So is Illumina basically the "selling pickaxes during a gold rush" of this space?

killjoywashere• 9 years ago

Yes. Other cool sequencing out there, Pac Bio being the most frequent contender, but illumina has their HiSeq and MiSeq systems in the vast majority of human molecular pathology labs. I may be biased as I trained under their chief geneticist, who's now at UCSD, but I'm fairly confident that's a safe claim. The big issue, as I understand it, is QC. QC for illumina is well understood. QC for Pac Bio can hard.

Gatsky• 9 years ago

Additionally, circulating tumor DNA is fragmented to short lengths, so there is no point in doing long read sequencing such as PacBio or Nanopore.

adenadel2• 9 years ago

I'm not sure if anyone can claim to be the market leader in liquid biopsy right now. If raising money is your metric for success, then Grail has raised $1B and has the backing of the world's leading DNA sequencing company (Illumina).

amelius• 9 years ago

Also, with currently available techniques, how difficult is this field really?

pragone• 9 years ago

This might be the first time in the 7 years I've my degree in it that someone has said they're actually "looking for bioinformaticians"...

maddyboo• 9 years ago

Possibly a silly question, but is it possible for a 'healthy' person who doesn't have any cancer risk factors to get a test like this done?

rrmm• 9 years ago

If you have no other risk factors or symptoms, it's usually not advised to do random testing like that (basically because Bayes' Theorem).

joe5150• 9 years ago

you're probably better off if you don't; incidentalomas are a thing

doctoring3• 9 years ago

It's not a silly question, it's an interesting one to ask.

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.

webreac• 9 years ago

If I am diagnose as early cancer, it could be a good motivation to switch to a more healthy lifestyle: more sleep, less food, ...

leemailll• 9 years ago

Before you head to this, ask them for false positive information

ziggzagg• 9 years ago

When this test has a near 100% success rate, how does it help the patients? Can it really prevent cancer?

rbobby• 9 years ago

Can it really prevent cancer?

No.

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).

AlexDilthey• 9 years ago

All fair enough. The two big immediate challenges in the field are i) that the tumor-derived fraction of total cfDNA can be as low as 1:10000 (stage I) and ii) that it is difficult to make Illumina sequencing more accurate than 1 error in 1000 sequenced bases (in which case the 1:10000 signal is drowned out). This paper uses some clever statistical tricks to reduce Illimina sequencing error; one of these tricks is to leverage population information, i.e. the more samples you sequence the better your understanding of (non-cancer-associated) systematic errors. This follows a long tradition in statistical genetics of using multi-sample panels to improve analysis of individual samples. There are also biochemical approaches like SafeSeq or Duplex Sequencing to reduce sequencing error.

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.

Blood Test That Spots Tumor-Derived DNA in Early-Stage Cancers

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