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Researchers, Clinicians Grapple With Liquid Biopsy Use in Recurrence Monitoring and Prediction

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NEW YORK (GenomeWeb) – To date, most clinical liquid biopsy tests have been used to identify clinically actionable mutations in patients who already have cancer, most often advanced stages of the disease.

But more recently, both clinical research efforts and the commercial sphere have focused a great deal of attention on how these tests can be used to predict recurrences or to monitor earlier-stage patients for signs of spreading tumors.

According to researchers in the field, the rapid advance of these new applications is creating a complicated picture for both their own community and more importantly for clinicians considering how these tests may benefit their patients.

Efforts are underway, for example, using a range of different technologies to sift the blood for everything from DNA fragments, to live tumor cells, to extracellular vesicles.

Tests are being developed that may be able to better predict which patients who have a tumor surgically removed can be considered cured and which will go on to recur. Others are intended to closely monitor patients after initial treatment to catch recurrences as early as possible, or to look for signs that circulating tumor material is likely to seed metastases or not.

And while clinical researchers seem to largely view these efforts as still experimental (though immensely promising), multiple companies have already begun to market tests using circulating tumor DNA, CTCs, or other analytes to scan the blood of patients for early signs of a recurrence.

Earlier this month, liquid biopsy firm Cynvenio Biosystems launched a blood-based monitoring service to track disease status or to surveil for early signs of recurrence in breast cancer patients. The new program, called ClearID Total Insight, is a 12-month service that includes Cynvenio's sequencing-based liquid biopsy testing, along with a proteomic test that gauges the activity of natural killer (NK) cells, each performed up to four times.

Other early movers in this area include Taiwan-based CellMax Life, which offers liquid biopsy tests for both early detection of new colorectal cancers in asymptomatic but at-risk individuals, and monitoring for resistance or recurrence in treated patients.

In the US, Pathway Genomics also offers blood-based mutation testing both for early detection and recurrence monitoring. The firm says on its website that physicians can use its CancerIntercept Monitor test to monitor tumor evolution, assess residual disease, and check for recurrence.

Johns Hopkins investigator Ben Park, who is leading research into the use of circulating tumor DNA to predict breast cancer recurrence, said that physicians who pay attention to the data that has been collected and published by companies or by academic researchers should still consider the use of blood tests to monitor or predict recurrence experimental.

"Any oncologist who actually looks at the data should realize that we are not quite there yet," said Park. "One really has to prove not only the accuracy of a test, but the merit of a test. That's the only way you are going to convince physicians like me," he added.

Park is leading a multi-center clinical trial investigating whether tumor DNA lingers or disappears in the blood of triple negative breast cancer patients treated with neoadjuvant chemotherapy and whether this can predict which patients will go on to recur and which will not.

The group has begun to recruit patients — about 10 so far at Hopkins and a few more at collaborating sites — and plans to follow a total of 229 over several years using a digital PCR method to look for tumor DNA in patients' blood before, during and after neoadjuvant chemotherapy treatment at various intervals.

According to Park, picking a narrower niche, like the neoadjuvant setting provides a foundation for building the kind of clinical utility evidence that he argued physicians should demand from these emerging technologies.

"Part of the reason we designed this in the neoadjuvant setting is because there you can imagine the utility is already built in … If we prove that this is [akin to] a sentinel node biopsy but in blood, we can [potentially] offer women in the near future the option of not doing surgery."

Moreover, he said, the outcome of the study could also have direct relevance to the design and implementation of future clinical trials in the neoadjuvant or adjuvant space. If lingering ctDNA serves as an accurate predictor of future recurrence, it can be used to select patients for these trials, avoiding unnecessary treatment in those who are likely to be cured by a single treatment or surgery alone.

Park's trial comes on the heels of similar work by another Hopkins group in collaboration with the Institute of Medical Research in Melbourne, Australia, which showed last year that circulating tumor DNA can be used to identify colorectal cancer patients who are more likely to recur after surgical tumor resection.

But outside of specific clinical contexts like adjuvant or neoadjuvant treatment, the utility of liquid biopsy for predicting recurrence or monitoring for recurrence may be harder to define, Park said.

Another area of growing interest in liquid biopsy is using blood tests as an adjunct or improvement for existing screening tools to pick up recurrences earlier or detect them more sensitively and specifically.

Researchers from the University of Pennsylvania recently described results from a study measuring the number of circulating tumor cells in 48 patients with locally advanced lung cancer treated with chemoradiation.

Like many groups interested in CTCs, the UPenn team — led by radiation oncology research fellow Chimbu Chinniah — has its own unique method for detecting cancer-specific cells in circulation. The group developed an adenoviral probe that detects the elevated telomerase activity that is a hallmark of cancer cell replication.

Though they didn't use their test to guide treatment for patients, they did track eventual outcomes, looking at how the presence of CTCs before or after treatment corresponded to disease progression or metastasis.

At a median follow up of 10.9 months, nearly half the patients in the study experienced recurrence or progression, as detected by conventional surveillance scans and biopsies. Fifteen of 20 patients who recurred had elevated CTC counts following treatment. For many patients, CTC levels were negative immediately following treatment but subsequently rose in the months following treatment.

Investigators are also looking at the use of exosomes — a type of extracellular vesicle — either to predict which patients will later go on to see their cancer metastasize or to identify this process earlier than current methods allow.

Last week, Weill Cornell announced a project to develop blood tests to predict the spread of cancer in children and adults funded by the Sohn Conference Foundation.

Weill Cornell pediatrics professor David Lyden, who is leading that effort, said in an interview this week that his group approached liquid biopsy from a different angle than most – starting with studies of the pre-metastatic environment and then happening upon exosomes as a vehicle for priming future metastases.

They then backtracked to look for these exosomes in blood as a precursor to metastasis. Specifically, the team is working on identifying a menu of exosomal biomarkers that not only predict metastases, but predict their occurrence in specific tissues.

According to Park, it may be harder to consider and measure clinical utility in some of these areas than it is in others.

Just because a test can predict recurrence or pick up a metastasis earlier than other tools doesn't mean that that makes a difference for patients compared to current screening methods. That said, there is clearly a rationale emerging in these studies for how such testing could benefit patients.

In their efforts in locally advanced lung cancer, Chinniah and colleagues at UPenn saw that changes in CTC number can occur rapidl, and in contexts where it appears that the added information might change how doctors treat their patients.

For example, he and his team saw one patient who was negative for CTCs at a four-month post-treatment follow up. A few months later, however, the same patient had imaging that showed what could have been post-radiation tissue changes, or it could have been early signs of recurrence.

"This is something you see frequently – and it's hard to know [what to do,]" Chinniah said. "If you had an additional input like CTCS it could help guide you one way or another."

In the study, the researchers saw elevated CTCs at the time of the inconclusive imaging. Six months later, the patient had clear disease progression, metastasis to the brain, and then passed away a few months later.

For this individual, there were more than 200 days between when the team saw the rise in CTC counts and when it was deemed clinically to be a recurrence, Chinniah said. On average, across the study, CTCs picked up recurrences about six months earlier than imaging.

This doesn't necessarily prove clinical utility, but it suggests it, he argued.

"In theory, it makes sense — that when patients have less of a disease burden and you can treat that earlier on before it progresses to advanced stages of metastasis they should have better outcomes, but we have to study that in more detail," he explained.

According to Lyden, the burden of proof may not necessarily have to be high, considering the limitations of current approaches to monitor and predict metastasis or recurrence.

In pediatric cancer, for example, he said, "patients have a very high chance of metastasis overall, but we don't know which organ a tumor is likely to metastasize to."

Any test that offers an added value over the limited tools clinicians have right now can't help but hold an allure.

Cynvenio CEO André de Fusco said that many clinicians in the oncology space believe that it's important to monitor patients closely, and that interest in better tools for this aspect of patient care was a driver for the company in creating its new yearly monitoring product.

The company hasn't yet publicly shared data demonstrating its tests validity or utility, but expects to begin presenting its work at professional meetings this year.

Lyden suggested that, close monitoring via liquid biopsy could prove attractive to healthcare providers even in lieu of data that speaks definitively to the impact on patient outcomes, but in Park's opinion, clinicians should pay close attention to utility. This is going to be hard as these types of tests continue to move forward, though, he said, because the questions to be asked about utility differ from case to case.

In the adjuvant and neoadjuvant treatment setting, it might be enough for a test to improve the ability to conduct effective and efficient clinical trials. Or, it may need to prove that it can save healthcare dollars by reducing unnecessary treatment in patients likely to be cured by surgery or by a single therapy.

In recurrence monitoring, questions about whether earlier detection actually improves patient outcomes pose a different challenge.

According to Park, the rapid advancement of liquid biopsy for recurrence monitoring or prediction also heralds what the field will face with future tests for a related use: predicting or monitoring cancer development in healthy people.

Some of the clinical utility questions the field is now having to grapple with in the recurrence space closely mimic those that will be important if and when these tests for a more general population come to fruition.

Park and his colleague at Hopkins, for example, are also studying ctDNA methods as an adjunct to mammography in the breast cancer space as a way of better discriminating between actual cancers from indolent tumors that don't require treatment.

The argument for utility in that case, for example, could be much easier than for general screening tests being developed by companies like Grail, Freenome, and others, where long-term efforts will be needed to demonstrate that blood-based early detection does actually improve health outcomes the way clinicians hope it will.

"I'm sure there will be populations where you can pick up cancer earlier and make an intervention, but there will still be the question, 'Does that make a difference compared to regular screening?'" Park said.

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