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Technology No Longer a Hurdle, but Clinical NGS Faces Reimbursement and Biological Knowledge Issues

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Next-generation sequencing is ready for the clinic, according to experts speaking on a panel at Hanson Wade's NGS Data Analysis conference in San Francisco last week.

Indeed, the technology is already being used in the clinic for certain applications. Sequencing-based noninvasive prenatal tests for aneuploidies have taken off; exome sequencing is being used in limited cases to diagnose rare diseases; and gene panels are being used in oncology.

While there are still challenges to overcome before next-gen sequencing sees widespread adoption, the main hurdle is no longer the technology itself. Rather, the main challenges are related to reimbursement, clinician acceptance, and a better understanding of the biology.

Maher Albitar, chief medical officer at NeoGenomics, an oncology reference laboratory based in Fort Myers, Fla., said that the technology is good enough for targeted sequencing applications, but the problem with whole-genome sequencing is that there are still too many unknowns about the clinical significance of certain variants.

For instance, Albitar said that he is working on developing next-gen sequencing assays to monitor minimal residual disease by sequencing plasma or urine from cancer patients to detect circulating tumor DNA. In these instances, he said, next-gen sequencing is a good tool because "you know what the abnormalities were to start with," and the technology can work with low input samples and has a high sensitivity.

The main challenge with using next-gen sequencing in this context, he said, is understanding the significance of low-frequency variants. "If I see a mutation, even in the PIK3CA gene, but I see it in 1 percent of the DNA, what is the clinical significance? Is this enough to say this patient has cancer?"

Other technologies that have typically been used to measure minimal residual disease, like Sanger sequencing, cannot reliably detect mutations below 10 percent to 20 percent frequency. Experts agree that mutations present below 10 percent frequency are clinically significant, but no one knows yet what an appropriate threshold is to call a mutation significant enough to intervene.

"We need clinical data to support what we are seeing," said Albitar.

Richard Bourgon, a bioinformatician at Genentech, agreed that using next-gen sequencing in this way, to monitor cancer patients throughout the course of treatment, would be an important application.

"The ability to noninvasively over time monitor individuals and associate actual outcomes several years later with signals we picked up on previously" will be a good use of the technology, he said. "It's not do whole-genome sequencing and put you on drug A. There are some examples of that, but that's a longer way off."

Payor and clinician acceptance

Aside from understanding the clinical significance of the data that can be detected with next-gen sequencing, it will be important to gain acceptance among payors.

Bourgon said that one problem is that payors and clinicians are making decisions about the technology itself rather than the specific test. "I think it's important to decouple the technology by which you measure something from that something itself," he said. For certain applications, "NGS can yield the consistency and accuracy rates that are needed to be used clinically."

Additionally, said Bourgon, who is using the technology to evaluate biomarkers in tumors, there are many cases where "a single biomarker will not get at what you need." By contrast, next-gen sequencing has the "ability to integrate a variety of [biomarkers] into one test."

Payors "should look at the test and how it's performed," when determining whether or not to reimburse, not "whether I do it by next-gen or not," added Albitar.

However, Albitar distinguished between two types of testing — tests that are direct to consumer, versus those that are ordered by physicians. For tests that consumers order directly, like from 23andMe, for instance, the consumer "gets the data on their own and at their own risk," he said. Physician-ordered tests on the other hand should be covered by insurance similarly to other tests.

Since clinicians are the ones who will order next-gen sequencing tests, they will also have to be knowledgeable about and accepting of the technology. Albitar said that physicians are likely to be more accepting of targeted sequencing tests versus exome or whole genomes.

"As a physician, I don't want to know about it if I can't readily interpret it," he said. Comprehensive sequencing tests can also create additional liability for physicians, if a patient is carrying a variant that confers disease risk, but that variant is either misinterpreted or not yet well enough understood to accurately convey disease risk. "The more data, especially if we don't know what to do with the data, is more liability. I want [a test] to be as precise as possible and with as little data as possible that can help make a decision," he said.

However, said Bourgon, that extra data is important for building up our knowledge base of variants, what they mean, and how they impact disease. "How do we enable the collection of data in these settings to apply to research so we can expand on our set of things that are actionable?" he asked.

One possibility, he said, is to perform whole-genome sequencing in the context of a clinical trial in such a way that the data can then be fed back into the research cycle. However, it would be important to do so in such a way that does not prolong the clinical trial. Additionally, the way in which individuals are consented to such trials would have to be changed. "There's a huge resource there, but legally and practically there are challenges," he said.

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