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T tis,withoutdoubt,anexcitingtimetobeanoncologistoracancerresearcher. Asourunderstandingcontinuestogrowoftheunderlyinggeneticmutationsand combinationsofmutationsthatleadtocancer,sotoodothatnumberofnew,highlytargetedtherapiesdesignedtoattackthedisease.Butwhenitcomestocancer,duetobothitscomplexityanditsstubbornabilitytomutateanddevelopresistancetoinitialtherapies,findingwaystomorepreciselydetectdrivermutationsasearlyaspossibleisoneofthekeystosignificantlyimprovingpatientoutcomes.

Forsolidtumorcancers,gettingthisearlylookatdiseasedevelopmenthasbeenelusive.Typicallyrelyingontissuebiopsies,firstdetectionand

subsequentdecisionsabouttherapeuticregimens,havelimitations.First,thenatureofbiopsies,orcollectionoftissuesamplesviaresectionare,

bynature,highlyinvasiveprocedures.Inmanycases,duetothetypeofcancerorthelocationofthetumor,itmaynotpossibletogetatissue

sample.Second,duetotheheterogeneityofcancer,oncologistsknowthatinformationobtainedfromthesolidtissuemaynotprovideacomplete

pictureofitsnatureand,further,onlyrepresentsasnapshotintime.

“Withtumorbiopsysequencingyouareonlysamplingasmallareaofthatpatient’scancerandtumor,”saidHelmyEltouhky,CEOofGuardant

Health,themakersoftheGuardant360biopsy-freetumorsequencingdiagnostic.“Weknowthatevenwithinasingletumoryouhaveheterogeneity.

Moreover,theuglytruthisforcancerslikepancreaticcancer,cholangiocarcinomaandevenlungcancer,theQNS(quantitynotsufficient)ratecan

beanywherefrom20percentto50percentofcancers.”

Whichiswhythereissomuchexcitementaboutthecomingofageofblood-basedbiopsiesthatareabletocapturerarecirculatingtumorcells

(CTCs)andcirculatingtumorDNA(ctDNA)fordownstreamanalysissuchasnextgenerationsequencingfromasimpleblooddraw.Whiletherestill

remainmorebroad-basedclinicalstudiestodefinitivelyshowclinicalutilityandincludethemasastandardofcare,blood-basedbiopsieshavethe

potentialtoreplacesolidtumorbiopsieswheretheyarenotpossible,aidinearlierdetectionofmetastaticcancer,andperhapsinthefutureeven

provideaplatformformuchearlierdetectionofcanceronsetthanisnowpossible.

Leveraging blood-based biopsies

New techniques allowing for analysis of rare ctDNA

and CTCs in blood make cancer care more preciseByChrisAnderson,SeniorEditor

I

Current applications

The most immediate application for blood-based

biopsies is for monitoring ongoing treatment of

cancer to determine efficacy and to help detect

cancer recurrence and metastases earlier. “I see

this as suppleementing what is being done today

with tissue and also with imaging,” said Jason

Johnson, senior director of product management

in the genetic systems division of Thermo Fisher.

“I don’t see a world where any of those methods

go away, but I see this supporting them with

additional genetic information for oncologists

to adjust treatment.”

Using blood-based biopsies, doctors can monitor

treatment by scheduling regular blood draws that,

depending on the diagnostic technology, would

capture and sequence either CTCs or ctDNA to

compare against information collected at initial

diagnosis. For instance, ctDNA prevalence can be

used to determine whether surgery to remove

the tumor, chemotherapy or targeted drugs are

effectively treating the disease or whether an

oncologist may need to make an adjustment in

the prescribed treatment.

Perhaps more importantly, blood-based biopsies

can aid in the earlier detection of metastatic

cancers. “If you want to be able to use targeted agent

Or as Eltoukhy noted: “What a liquid biopsy, or a

test like ours, enables in oncology is rescuing the

temporal dimension of cancer detection. Now

we can take that blindfold off, so to speak, and

see what happens initially before treatment, what

happens after treatment, and what happens when

treatments fail.”

Adoption of blood-based biopsy

While a number of companies have developed

different platforms for blood-based biopsies, there

is still significant work to be done to have them

adopted as a standard of care and also for their

adoption in molecular pathology labs at hospitals.

But things are progressing. According to Milena

Cankovic, PhD, technical director of molecular

pathology and genomic medicine at the Henry

Ford Health System, her lab has been working on

the validation of next generation sequencing of

targeted cancer panels.

“Then the next step, which I hope will happen

in a few months, is we will start collecting also

patient blood samples to look at circulating DNA,”

Cankovic said. “We want to see if we can detect

the same mutations in plasma as we do in solid

tumors, as this would give us a tool to monitor

patients.”

drugs that will inhibit activated targets, your best

chance of success is going to be having an analysis

done on a tumor that is as close in time to the

isolation of the sample as possible,” said Nic

Dracopoli, vice president for oncology

translational research for Janssen Pharmaceuticals.

“Obviously you can’t keep biopsying people in

remission or even in early recurrence all the

time. So you are very much dependent on some

surrogate circulating marker.”

Under this model of care, Dracopoli said, there

will be a combination of molecular phenotyping

off the large molecular block used to originally

diagnose the cancer, but patients are followed

using blood-based tests to check for new emergent

cancer. This information can be used to guide

therapeutic intervention for recurrence of later

stage disease. Compared to protein biomarker

detection methods, this could give oncologists as

much as an 8-week head start on new treatments.

“To my mind the real time aspect is the issue. It

needs to be non invasive and it needs to be in real

time, to look at the molecular phenotype of the

disease much closer to its current status than its

legacy status taken from an old diagnostic block,”

Dracopoli concluded.

While she added that Henry Ford is at the cutting

edge of care, these blood-based biopsies are only

now making their way into molecular pathology

labs at most health centers. “We need to do the

validation,” Cankovic added. “If we are having

good success with solid tumors and getting

excellent correlation with circulating DNA, then

we might cautiously start to put this together and

consult with clinicians. There might be a point we

reach that we are now confident and we can start

to use these markers.”

But even with this cautious approach to rolling

these methods out in the Henry Ford system,

she admitted that it is information physicians are

eager to incorporate into how they deliver care.

“Oncologists are very knowledgeable about next

generation sequencing approaches and how they

can use the information for better care,” she said.

“So they are quite open and ready to take these

new approaches.”

What the future may bring

As blood-based biopsies continue to penetrate

the market as a monitoring and diagnostic tool

for cancer treatment, there are many who think

there exists potential for these tests to be used to

diagnose cancer at its very earliest stages, even

before detection of solid tumors. André de Fusco,

CEO of cancer diagnostics company Cynvenio

Biosystems, sees great promise for these

diagnostics, especially in light of the development

of new immunotherapy approaches to treating

cancer. “The ultimate promise is the maintenance

of wellness,” he said. “We know things are in the

blood at trace levels for years before they develop

into disease. In cancer today we focus on when a

tumor is four or five millimeters and we can see it

in a scan. At that point it is already billions of cells

and each time your heart pumps it is sending these

throughout the body.”

As de Fusco imagines the future, patients would

have their blood tested for potential cancer as a

routine part of their yearly physical with their

primary care physician. With immunotherapy

approaches to cancer on the horizon, this very

early detection has even more power. “If you are

going to stimulate the immune system, why wait

until you have a tumor the size of a golf ball?” he

asked. “You may as well start treatment when it is

the size of a pinhead and the intervention is lesser.

”Dracopoli agrees. “This is where therapeutic

intervention has to move. It is going to be a lot

easier to intervene in a cell that isn’t hiding from

the immune system and still has active DNA repair

and is able to go into apoptosis, compared to a cell

that is cloaked from the immune system, unable

to repair its DNA, and has no ability to become

apoptotic. If you can avoid those kind of cells and

move into earlier disease therapy it is a reasonable

supposition you will have a better therapeutic

outcome,” he concluded.

Getting there, however, will require long, large

and expensive early intervention clinical trials that

will be challenged to both find patients at risk of

disease and then show in a statistically valid way

that these interventions actually make a positive

impact.

For individual patients, attempting to find what

the “normal” threshold is in otherwise healthy

patients for levels of CTCs or ctDNA is of utmost

importance. “If we test on a population of 100

normal individuals that have no onset of disease,

we are likely to find a couple of people that also

may have a couple of these cells floating through

their body,” noted Cankovic. “And a healthy

person with a healthy immune system will

eventually eliminate those. There is a lot of

anxiety over the chance of a false positive in a

healthy person and I’m not sure if we can ever

reach a threshold where we can say that we have

detected cancer.”

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