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Anticipating Clinical Launch, Natera Shares New Data on ctDNA Cancer Monitoring Tech

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NEW YORK (GenomeWeb) – Natera shared new data this week on its recently-launched Signatera technology, the first foray for the company into the oncology field.

Company investigators showed three posters at the annual meeting of the American Association for Cancer Research — one that reported validation data for the company's blood-based cancer monitoring approach, and two others that applied the technology in colorectal and bladder cancer, in collaboration with researchers from Denmark's Aarhus University.

Although the term 'liquid biopsy' has become a shorthand for any technology that analyzes circulating cell-free DNA, the approach that Natera has developed is not intended to fill the same role as a traditional biopsy.

Instead, the company is running with a concept that has emerged over the last few years, in which sequencing data from a patient's tumor tissue is used to create a bespoke panel of mutations that can then be monitored non-invasively over time.

There are two main niches where this monitoring may improve patient care. The first is tracking disease state. In the same way that imaging might be used to visualize whether a cancer patient's tumors are growing, shrinking, or staying the same, researchers have recently begun to show that mutated DNA molecules in the blood — their presence, absence, rise, or fall — can reflect cancer status in real time.

Another area where blood-based DNA analysis has been getting much attention is in the assessment of minimal residual disease — in this case, lingering cancer mutations in the bloodstream — in patients with early cancers who had surgery or some other presumably curative treatment.

Natera launched Signatera for research use only soon after the publication of results from the TRACERx trial, which showed that the approach could predict relapse in post-operative lung cancer patients an average of 70 days sooner than imaging.  The firm is now aiming to release a version for clinical use by the end of this year.

But while research efforts are accelerating in this area, some leaders in the field have expressed caution that amid increasing marketing by commercial firms, clinicians may be losing sight of the fact that there is no proven clinical utility yet — and little clinical validity data— for ctDNA assays in monitoring patients, and

A recent report by researchers from the American Society for Clinical Oncology and the College of American Pathologists stressed this point, for example.

According to Solomon Moshkevich, Natera's senior vice president of product and strategy, part of Natera's game plan has been to make sure that the areas at which it is targeting its technology are ones where it is easier to make a case for clinical utility and for cost effectiveness, for example in areas of medical practice where imaging is already used to monitor patients, providing a clear yardstick for blood-based testing to measure up to.

Another area where there is strong promise for technologies like Natera's is in studying (and potentially guiding) adjuvant treatment. Although adjuvant drug regimens have become a standard part of care for several tumor types, there are few tools that clinicians can use to help decide which patients really need added therapy, and who could potentially forgo it.

For example, in early-stage colorectal cancer, 80 percent of patients are cured by surgery alone while 20 percent relapse and often develop fatal metastatic disease, but oncologists struggle to predict which of these segments their patient falls into.

For drug companies, having a way to pick out the subset of patients who are at risk of recurrence offers a way to enrich trial populations for new adjuvant treatments.  In the clinic, it could help doctors avoid unnecessary therapies in patients who don't need them.

Fittingly, the colorectal cancer adjuvant setting is one of the first areas where researchers have made a case for circulating DNA monitoring. Researchers from Johns Hopkins, for example, began sharing data a few years ago that showed that the presence of circulating DNA mutations could help distinguish stage II colorectal cancer patients who are highly likely to relapse after a surgical tumor resection.

Natera's Signatera mirrors the approach taken by the Hopkins researchers in several ways, in that it involves sequencing data from a patient's tumor tissue to design a personalized panel of alterations that are then tracked in the blood.

At AACR, one of the company's poster presentations replicated some of the same findings that the Hopkins team showed. Jimmy Lin, the company's chief scientific officer, said that in 130 patients followed after surgery, Natera could see a clear prognostic differentiation between those who were ctDNA positive and those who were ctDNA negative.

Following subjects over time, they could also see ctDNA levels going down in response to treatment and could also identify patients treated with adjuvant chemotherapy who had lingering tumor DNA in their blood, all of whom went on to relapse.

The company also reported on research in bladder cancer, from a study with Aarhus of 50 patients followed from diagnosis through neoadjuvant treatment and cystectomy, and then moving forward as they either did or didn't relapse.

"The biggest surprise [here] was that ctDNA status at diagnosis is prognostic for relapse regardless of the intervention," Lin explained. "It looks like this can be a new way of thinking about staging for bladder cancer."

As in colorectal cancer, circulating DNA was also present as a marker of residual disease after surgery, and could be tracked during drug treatment as a real-time biomarker of response and an early indicator of relapse. Overall, there were nine relapses in the cohort, and Natera's assays were able to detect these in ctDNA a median of 128 days earlier than clinical presentation.

Moshkevich said this week that the firm has been getting a lot of attention from drugmakers since it launched Signatera for research use last year.

In drug development, having a way to track patients' cancer status easily and accurately at multiple timepoints should be attractive because of the potential to aid clinical trials — either allowing recruitment of high-risk patients, signaling a drug is working earlier, helping to identify failures faster.

The basic principle behind Signatera — identifying bespoke targets from tumor tissue sequencing to follow in blood — isn't proprietary to Natera. Groups like the Hopkins team that published on a similar approach, and others, are taking a similar tack.

But Moshkevich argued that Natera's methodology has advantages. This includes special methods the firm uses to identify the best targets to use — both based on their clonality and on the likelihood that the company can design probes that will be successful in capturing them.

Lin added that Natera is also using proprietary methods for extracting DNA efficiently and preparing libraries.

"Other people lose molecules before they even start working if they are using off-the-shelf stuff," he said.

According to Moshkevich, there may be less inertia in the adoption and expansion of tests like Signatera than there has been for other liquid biopsy tests for cancer diagnosis and molecular profiling because of how much easier it is to show that ctDNA can do the same job as current monitoring, but more sensitively and more easily.

"Right now, we are in a place where we are doing a lot of retrospective studies with pharma, but we are already in discussions for prospective studies [using Signatera] for patient selection or for measuring treatment response," he said.

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