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Natera Minimal Residual Disease Test Predicts Oligometastatic CRC Patient Outcomes in New Study

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NEW YORK – New data published this week have added to growing evidence that circulating tumor DNA tests may be able to improve treatment decision-making for patients with oligometastatic colorectal cancer who are treated with curative-intent surgery.

The study, which appeared Wednesday in JCO Precision Oncology, is not the first to explore this use case for liquid biopsy, but it is the first to demonstrate this ability for Natera's commercial minimal residual disease assay, Signatera, which involves the creation of patient-specific ctDNA panels informed by tumor tissue exome sequencing data.

The report describes results from the prospective PREDATOR clinical trial, in which investigators from a group of Italian institutions followed 112 oligometastatic CRC patients who underwent surgical resection with curative intent. Some received only surgery, but about 40 percent also had systemic chemotherapy at the discretion of the treating physician.

The researchers determined individuals' MRD status using Signatera tests both after surgery and during ongoing follow-up. They also compared Signatera to CEA protein testing, as well as to an alternative ctDNA approach using droplet digital PCR to specifically target KRAS mutations.

According to the authors, more than half of patients with stage IV colorectal cancer relapse after surgery. While adjuvant treatments are available, they have had only limited efficacy in improving these odds. A reliable prognostic could be of great benefit to help better stratify patients and personalize treatment strategies based on their individual risk.

The current standard of care for most cases is chemotherapy, followed by surgery to remove whatever remains, and potentially post-surgery adjuvant therapy. But there aren't clear guidelines on who should receive adjuvant treatment.

Alexey Aleshin, Natera's vice president of medical affairs in oncology and a coauthor of the paper, said in an email that this reflects the fact that very little data exists in this space.

To fill this unmet need, circulating tumor DNA has attracted attention from other groups as well. A recent study by investigators at Washington University in St. Louis, for example, applied ctDNA detection technology from Roche in a smaller cohort of 24 oligometastatic CRC patients, with promising results.

In PREDATOR, Signatera testing identified 61 patients, a little more than half the cohort, as MRD-positive at either the first testing time point after surgery or a second follow-up test. Of these individuals, nearly 97 percent went on to have progressive disease despite their treatment.

Among a subset of 50 patients who did not receive systemic chemotherapy post-surgery, 35 progressed, of which 32 were ctDNA-positive. According to the investigators, this reflects a test sensitivity of about 91 percent and a specificity of 93 percent.

To compare Signatera to ddPCR, the group analyzed a subset of 27 patients with KRAS mutations. Concordance between the approaches was only 55 percent, with the 12 discordant cases representing instances where Signatera was positive and ddPCR was negative. In addition, among these 12 individuals, 11 developed disease progression, suggesting greater sensitivity and accuracy for the personalized Signatera technology, "even among patients whose tumors showed evidence of containing the RAS mutations of interest," the authors wrote.

CEA, a highly studied proteomic cancer biomarker, also failed to predict patient outcomes with statistical significance.

The group found overall that Signatera MRD-positive status was clearly associated with an inferior overall survival — with nearly all the MRD-negative patients still alive at the time of data cutoff for the study compared to just 52 percent of the MRD-positive patients.

Signatera MRD status remained the most significant prognostic factor associated with disease-free survival even in multivariate analysis.

"Through this study, we are able to show that a personalized ctDNA test is a sensitive prognostic biomarker that can potentially be used to guide treatment decisions for patients with oligometastatic colorectal cancer," Fotios Loupakis, an oncologist at the Istituto Oncologico Veneto, IRCCS, and lead author of the paper, said in a statement.

The study authors wrote that the findings "may provide support for clinical decision-making for perioperative systemic treatment, including a rationale for a more aggressive follow-up" in MRD-positive individuals.

In a statement, Aleshin said that Natera intends to make a case to Medicare for extending the current coverage of Signatera for MRD detection in early-stage CRC to include the oligometastatic population as well.

Expanding on this in his email, he called the study a "first step in a significant expansion of Signatera's intended use in the CRC space."

The study authors wrote that the small size of their cohort bodes caution in terms of immediate implications for clinical practice. Further work in larger groups will be necessary to confirm the performance of the Signatera technology.

Another constraint is that the study only utilized two time points for testing, they added.

In that vein, the investigators said they are now studying ctDNA dynamics in more detail from longer-term serial testing that they performed on a subgroup of patients from the current study. Several individuals who were ctDNA-negative in the study, even at the second testing time point, still had disease progression. Hypotheses from other research have proposed that tests performed immediately post-surgery and even up to four weeks later can be confounded by an increase in overall cell-free DNA triggered by the trauma of surgery. Considering this, it's possible that additional longitudinal monitoring would reveal the emergence of tumor mutations in these patients prior to clinical recurrence, the team suggested.

"Overall, we believe that the use of serial testing can allow for tailoring of treatment regimens, with treatment escalation in patients with progressive disease and the opportunity of early therapeutic interventions with more aggressive follow-up in patients who are ctDNA-positive but have not yet progressed," the authors wrote.

Studies of Natera's technology and competing MRD assays have also found ctDNA clearance to be a proxy of treatment efficacy, so future exploration in this vein would also be valuable, they added.

According to Aleshin, although CRC is the best-known cancer where oligometastatic disease can be treated with curative intent, strategies are starting to be investigated more intentionally in other cancer types. Natera believes its technology could help accelerate such research as well, he said.

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