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Natera Builds Data Backing Serial ctDNA Changes to Aid CRC Patient Management, Treatment Decisions

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NEW YORK – Natera highlighted the publication of new data this week demonstrating that its personalized, tumor-informed residual disease test Signatera can be used to stratify colorectal cancer patients based on growth or stability of their circulating tumor DNA levels over time.

Published last week in Clinical Cancer Research, the study concluded that serial ctDNA analysis in colorectal cancer patients after surgery, specifically assessment of ctDNA "velocity," or doubling time, has a strong prognostic value that "provides unique opportunities for guiding decision-making."

In a statement, Andres Cervantes, professor of medical oncology at the University of Valencia and senior author of the study, said the results are evidence that personalized and tumor-informed ctDNA analysis offers "more value than just a positive or negative result."

When Natera reports Signatera test results, the company includes both a positive/negative readout on MRD status, as well as a calculation of the mean number of tumor molecules observed per mL of plasma.

The company has previously validated the approach for early detection and prediction of impending cancer recurrence, showing that Signatera assays can detect recurrence months earlier than radiologic imaging and that ctDNA positivity at single or multiple time points after surgery is highly predictive of future recurrence.

Researchers have also been exploring serial ctDNA changes for some time, but mainly as a tool for disease or treatment response monitoring — not necessarily as a prognostic measure in their own right.

Natera VP Alexey Aleshin said this week that the new data suggest a novel utility for quantifying ctDNA changes — showing that not only do these changes correspond to tumor activity, but they can predict CRC patients' prognosis, much like changes in the protein biomarker PSA are used to assess prognosis in patients with prostate cancer.

Aleshin said that while it's intuitive that the amount of ctDNA in a patient's blood could serve as a proxy for tumor burden, the fact that ctDNA doubling could predict prognosis hadn't yet been documented.

"In prostate cancer, PSA velocity or PSA doubling time has been known to be exceedingly prognostic. It can predict how fast [a tumor] is going to recur and how good a patient's prognosis is going to be long term. We speculated that possibly ctDNA could have similar [utility], and I think this is the first time that's actually been demonstrated," he said.

In the study, investigators from collaborating institutions in Denmark and Spain collected serial blood draws from 168 stage III CRC patients undergoing curative intent treatment, sampling individuals before and after surgery and then at regular intervals throughout adjuvant chemotherapy surveillance for up to three years. Natera then tested these samples using its tumor-informed, personalized Signatera assays.

Comparing patients' molecular MRD status to their reported outcomes, the group saw that individuals who remained MRD-positive after completion of adjuvant chemotherapy were highly likely to recur, and that ctDNA positivity could predict radiological recurrence with a lead time of almost 10 months on average.

The stratification of recurring and non-recurring patients in the trial was starkly reflective of MRD status. One-hundred percent of those who cleared their ctDNA and remained clear of MRD during and after adjuvant treatment were recurrence free at the three-year cutoff point, while zero percent of those who only saw transient ctDNA clearance avoided recurrence.

According to Aleshin, Natera continues to be heartened by how consistent these binary results have been for Signatera across multiple studies. "We kind of find the same thing over and over, which I think is very reassuring to the community," he said. "We're building this evidence towards the fact that … if you don't clear your ctDNA in the adjuvant setting, you're not going to be cured, and I think that that's very powerful, both for clinical decision-making and for [adjuvant] drug development in that, for the first time, we may not need to do studies that take years to run."

To explore the potential of ctDNA velocity as a prognostic, the researchers then sought to divide the cohort into MRD-positive, recurrent patients with slow-growing tumors — with a 27 percent average increase in ctDNA per month — versus those with fast-growing tumors, which grew an average of 137 percent per month.

According to the authors, the subset with slow-growing cancers had similar three-year overall survival rates to patients who did not relapse at all, while those with fast-growing tumors experienced much poorer outcomes, with a three-year OS rate of only about 38 percent.

In terms of implications for clinical decision-making, Aleshin argued that there are already ways that this could be useful to physicians.

"Let's say a patient is one year out from surgery and you detect ctDNA. The question then becomes how likely is the cancer to come back, how quickly, and how aggressive is it? With a binary result that may be hard to know. But now with ctDNA velocity … if you see the ctDNA is doubling very quickly … you know it's [likely] a very aggressive cancer," he said.

"That can be helpful in guiding next steps for that individual," he added, "knowing whether this is coming back in months or years."

For ctDNA velocity to inform more specific interventions, such as intensification or de-escalation of drug therapy, Natera and others advancing genomic MRD technologies will have to persuade the pharma community to pursue clinical trials.

"I think that's the eventual hope, that we can actually further personalize therapy for patients," Aleshin said.

In the meantime, Natera expects larger, currently ongoing studies will further validate these initial ctDNA velocity findings, most notably the CIRCULATE-Japan study, and its recently announced US counterpart.

"We hope that this data will kind of galvanize the community to possibly want to incorporate velocity in treatment decision studies," he added.

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