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Natera's Liquid Biopsy Exome Could Enable Recurrence Monitoring Without Tissue Samples

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NEW YORK (GenomeWeb) – By announcing last week that it would begin offering whole-exome sequencing of liquid biopsy samples for research customers, Natera is laying the groundwork for enabling its patient-specific cancer monitoring approach, Signatera, to work without initial tumor tissue sequencing.

Although the move to provide blood-based exome sequencing also serves a more direct purpose — giving the company an arm in the therapy selection market currently led by targeted sequencing tests like Guardant Health's Guardant360 — Natera CEO Steve Chapman said this week that exploiting synergies between plasma exomes and the company's existing Signatera program will be a main focus.

In a separate announcement this week, the firm noted the publication of new results from a study of Signatera in which investigators from Cancer Research UK, Imperial College London, and the University of Leicester reported that the bespoke panel approach allowed them to detect breast cancer residual disease and relapse up to two years earlier than imaging in a group of patients with early-stage tumors.

Most liquid biopsy tests so far have focused on therapy selection in later-stage patients, with some firms, like Guardant Health, then pivoting to address recurrence or therapy monitoring. But Natera's first commercial foray into blood-based cancer testing was for treatment monitoring. The company develops bespoke, patient-specific PCR assays, based on available genome-wide tumor tissue data, which can then be used to deeply profile patient blood samples for evidence of waxing or waning disease.

Chapman said Natera estimates that this monitoring application is worth up to $15 billion per year in the US. But therapy selection represents another $6 billion or so market that the firm currently does not address.

"Commercialization of the plasma exome enables us to tap into that therapy selection [market] … so expanding our market opportunity is one reason to do this," Chapman said. "But we also [see] links between [this] and Signatera … that are very compelling," he added.

For one, current pharmaceutical research customers, and future clinical customers, may have cohorts or patients who do not have any tumor tissue available, or whose biopsy samples fall short of requirements. Right now, there is no way to apply Signatera for these cases, but with plasma exome sequencing, there could be.

One example, Chapman said, would be pharmaceutical companies that want to use Signatera to do retrospective studies of patient blood samples and don’t have enough corresponding tissue for genome-wide sequencing.

This could also impact the clinical implementation of the assay, considering that in certain cancer types, like lung cancer, biopsy samples frequently fail to meet thresholds necessary for comprehensive molecular analysis, added Alexey Aleshin, Natera's oncology medical director.

For Signatera's most immediate clinical application — monitoring the blood of patients who have had their cancer surgically removed — the issue of tumor tissue availability is less pressing, Aleshin said, adding that surgical removal yields much more cancer tissue than biopsies.

But even in the context of surgery, there still may be instances where tissue doesn't cut it and a blood-based option could allow Signatera to be used where it otherwise could not.

Although Natera plans to launch a clinical version of Signatera this year, company officials said last month that the firm would continue to focus mainly on pharma deals until it can secure reimbursement from Medicare and commercial payors. That doesn't mean that it won't be amassing clinical utility data to try to promote that reimbursement, though.

In the study published this week, in Clinical Cancer Research, UK investigators followed 49 patients with various breast cancer subtypes who had recently completed treatment with surgery and adjuvant chemotherapy. Researchers collected samples from each patient every six months for up to four years for Signatera analysis.

Signatera Assays designed for the patients successfully detected 16 out of 18 relapses that occurred in the cohort, with a median lead time of about 8.9 months over standard-of-care screening methods. Among 31 patients that did not relapse, the tests reported zero false positives across 156 plasma samples tested.

In its promotion of the results, Natera highlighted that a third of the patients in the study had no actionable hotspot mutations, meaning their Signatera assays had to feature more esoteric markers.

According to Chapman, this highlights the advantage the personalized Signatera approach has over static panels. Various academic groups have also utilized bespoke panel-based approaches for post-surgery cancer monitoring. But while Chapman said that it is possible that others may commercialize tests that use the same concept as Signatera, Natera believes that its proprietary techniques go "beyond the concept," and will help it distinguish itself.

One aspect that may play into the firm's future integration of exome sequencing with Signatera is the fact that its library preparation methods enable it to first run a Signatera assay and then go back into the same sample for exome analysis.

"Imagine someone is monitoring a patient … doing quarterly Signatera blood draws, and at some timepoint they notice something – in year two or three they see recurrence … We [can] go back to the libraries we have drawn and do a much broader assessment on the exome and [investigate where] there is emergence of resistance mutations or drivers," he explained.

"It gives the ability to reflex back to the same sample with no need to do another expensive test," he added.

The firm's blood-based exome analysis, which covers approximately 20,000 genes, is expected to launch in the second half of this year for research use only. Exactly how that may then translate into clinical services is still unclear, Chapman said.

Whole-exome sequencing of plasma-borne tumor DNA has been demonstrated by other groups, but prior studies have shown that it can be challenging in cancer cases that shed little DNA into circulation. Investigators from the Broad Institute and various partner centers reported previously, for example, that they could recapitulate about 90 percent of the genetic features seen in patients' matched tissue samples using blood-based exome sequencing. But this was only in the half of clinical samples that had enough ctDNA present for accurate plasma exome analysis in the first place.

So far, Natera has not published any data on the accuracy of the method, its limits of detection, or reproducibility across different cancer types or stages, so a variety of questions remain as to its limitations and how it might compare to existing panel-based liquid biopsy tests used for therapy selection.

Chapman said that Natera does expect to publish data soon, with a paper in press that compares whole-exome sequencing of plasma and matched tissue, showing "strong concordance."

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