
Blood Test That Spots Tumor-Derived DNA in Early-Stage Cancers - ncw96
http://www.hopkinsmedicine.org/news/media/releases/scientists_develop_blood_test_that_spots_tumor_derived_dna_in_people_with_early_stage_cancers
======
gourneau
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
Guardant Health is a member of the Blood Profiling Atlas for Cancer
([https://www.bloodpac.org/members/](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
Hate to be that guy, but as an alum I have to correct this. It's Johns*
Hopkins.

~~~
dEnigma
Interesting. I always heard it as "John Hopkins", and I guess every time I
read it I also auto-corrected it to "John" in my head. It's actually his
great-grandmother's maiden name[1]

[1][http://www.hopkinsmedicine.org/about/history/history1.html](http://www.hopkinsmedicine.org/about/history/history1.html)

------
AlexDilthey
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.

------
conradev
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...](https://medium.com/freenome-stories/freenome-
raises-65m-in-series-a-from-andreessen-horowitz-gv-and-others-1c64c4302f71)

~~~
sjg007
There's a bunch of companies doing this.

------
McKayDavis
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/](http://capsprenatal.com/about-nipt/)

[2] [https://www.genomeweb.com/molecular-diagnostics/aetna-
wont-c...](https://www.genomeweb.com/molecular-diagnostics/aetna-wont-cover-
noninvasive-prenatal-testing-average-risk-pregnancies)

~~~
McKayDavis
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](http://stm.sciencemag.org/content/9/403/eaan2415)

~~~
McKayDavis
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.

~~~
Amygaz
It's "funny" how they take all their high quality enzymatic reagents from the
company NEB and do this error-repair step (which something NEB has claimed and
shown that people should be doing with their NGS sample), and whole they use a
high fidelity polymerase (Phusion), they don't use the highest fidelity (e.g.
NEB Q5 or Kapa HIFI). Also, NEB makes a specific kit to repair NGS samples
(i.e. Called pre-CR). Combined this would have translated into a 10-fold lower
error rate (so regular NGS 10^-4, this paper 10^-6, then 10^-7 with even
better enzymes).

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.

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

------
maddyboo
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?

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

~~~
hycaria
But if you don't, it's not worth it ? Everyone could benefit from a healthier
lifestyle. I have a hard time believing that would be a wake up call for a
significant percentage of people (see smokers, obesity, ...).

~~~
intrasight
I recently discussed this very question with a colleague, and we both agreed
that it probably would be a "wake up call". Currently, we really lack quality
heath data, and so the loudest pundit or charlatan is who people listen to.
And what they mostly present are anecdotes. Having high-fidelity health data
about me as an individual and as part of various cohort study groups would
allow my doctor to say "This is you now. These are the various future you's if
you pursue these different lifestyles".

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

[https://youtu.be/iUqgTYbkHP8?t=15m37s](https://youtu.be/iUqgTYbkHP8?t=15m37s)

I guess most are treatable if caught early?

~~~
greglindahl
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.

~~~
jghn
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.

~~~
amluto
> 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.

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.

~~~
jghn
Yes, that's exactly what it is. Thus the argument is that indirectly early
detection causes harm. As I mentioned later on in my post a lot of current
research is going into determining if and when treatment must be done instead
of the more common behavior of just diving in wholeheartedly.

~~~
kilotaras
"Early detecting causes harm" sounds absurd. That's akin to saying that
"eating food" (and not dying from hunger) leads to harm from cancer treatment.

~~~
xxXXxx-
We also have a case study of over diagnosis from Korea:

[http://www.npr.org/sections/health-
shots/2017/05/09/52756929...](http://www.npr.org/sections/health-
shots/2017/05/09/527569291/dont-screen-for-thyroid-cancer-task-force-says)

"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.

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

~~~
sjg007
Yes but grail is doing deep sequencing I believe.

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

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

Is 98% specificity adequate for a cancer test?

~~~
epistasis
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.

~~~
AlexCoventry
> 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?

~~~
doctoring
It costs a lot, unfortunately. Sequencing is still fairly expensive, and the
methods in OP are fairly complex on top of that.

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.

~~~
AlexCoventry
> 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?

You can estimate the likelihood from cancer prevalance.

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

~~~
rbobby
> 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).

------
jonathanjaeger
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.

