Natera’s Signatera test has shown potential in a newly-published survey for guiding treatment decisions after surgery by identifying colorectal cancer recurrence at an average of 8.7 months earlier than radiologic imaging by detecting traces of tumor DNA in the blood after surgery.
The prospective, multicenter study enrolled 130 patients with stage I–III colorectal cancer from Aarhus University, Randers, and Herning hospitals in Denmark. Researchers from those hospitals and Natera found that the Signatera test detected molecular recurrence from 0.8 to 16.5 months earlier than standard-of-care radiologic imaging
Serial testing picked up 14 out of 16 relapses (patient-level sensitivity 88%), and among patients who did not relapse, all but one of 456 post-surgical blood samples correctly tested negative (test-level specificity 99.8%), the researchers reported.
Their study, “Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer,” was published yesterday in JAMA Oncology.
The study used Natera’s Signatera research-use-only test to evaluate molecular residual disease (MRD) in 829 blood samples collected serially throughout the patient monitoring period. Signatera’s clinical launch is planned for later this quarter.
“We look forward to making this test available for clinical practice and pharmaceutical drug trials,” said Alexey Aleshin, M.D., MBA, Natera’s oncology medical director. “This study highlights Signatera’s potential to change post-operative management of colorectal cancer.”
In the study, researchers found that MRD status was the most significant predictor of relapse after adjusting for all other known risk factors, including disease stage and lymph node status. Signatera MRD-positive patients who did not receive treatment relapsed in 93% of cases—while among patients who remained MRD-negative, the relapse rate was just 3%, according to the study.
Natera said the results underscored the potential of MRD status to risk stratify patients more accurately after surgery to determine which patients need additional therapeutic interventions and which could be safely monitored.
Driving “A Paradigm Shift”
“The results show the potential of blood-based MRD detection to drive a paradigm-shift in how patients are managed during the course of their disease,” Claus Lindbjerg Andersen, M.Sc., Ph.D., of Aarhus University, the study’s lead investigator, said in a statement. “Our study showed unequivocally that Natera’s personalized multiplex PCR-based next-generation sequencing is a highly sensitive approach for detecting molecular residual disease in the blood.”
The study also reported the first published demonstration of Natera’s plasma-based whole exome sequencing capability, in which there was strong concordance between whole exome results from the plasma and tumor biopsy at time of metastasis.
Natera said it will also offer a research-use-only service for plasma-based whole exome sequencing to create a personalized assay when tissue is not available, or reflexively for Signatera ctDNA positive cases, to characterize resistance mutations, actionable mutations, neoantigens, and tumor evolution.
The service will be designed to interrogate approximately 20,000 genes from ctDNA to detect somatic mutations, representing a significant increase in coverage over most commercially available fixed liquid biopsy panels, according to Natera. If ordered as a combined service, researchers can first use Signatera to monitor patients for the presence or absence of ctDNA, and for positive patients they can reflex to a plasma exome to characterize tumor evolution using the same exact DNA library sample.
Natera expects the service to become available in the second half of this year.
According to Natera, Signatera is the first custom-built circulating tumor DNA (ctDNA) test for molecular treatment monitoring and MRD assessment. Signatera’s methodology differs from currently available liquid biopsy tests, by providing each individual with a customized blood test tailored to match the clonal mutations found in that individual’s tumor tissue.
That difference is intended to maximize accuracy for detecting the presence or absence of MRD in a blood sample, even at levels down to a single mutant molecule in a tube of blood, Natera said.
Signatera also allows researchers to track additional mutations of interest, up to several hundred mutations, for clinical studies.
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths, with 1.3 million newly diagnosed cases each year worldwide. Despite the rise of screening and advances in treatment regimens, the five-year mortality rate remains at about 40%.
However, Natera cited multiple studies showing the Signatera RUO method’s ability to detect molecular residual disease, measure treatment response, and identify recurrence months or years earlier than the standard of care for a variety of cancer types—including breast cancer, early stage non-small cell lung cancer, bladder cancer, and colorectal cancer.
Across multiple cancer types, Natera added, studies have shown a positive Signatera RUO result without further treatment has predicted clinical relapse over 98% of the time.