NEW YORK – UK-based diagnostics firm GeneFirst is ramping up a clinical validation and feasibility study for a blood-based colorectal cancer detection assay using the firm's ATOM-seq technology, which could support its first clinical implementation.
Led by University of Leeds professor Philip Quirke, the 36-month project received a supporting grant last August for £1.4 million ($1.9 million) from the UK's National Institute of Health Research.
Working with Quirke, the company is hoping to demonstrate that the use of its test would reduce the number of colonoscopies performed in people who receive concerning results from the fecal occult blood and fecal immunochemical tests that are a standard first-line screen in the NHS's current UK-wide colorectal cancer screening program.
"The idea is to test this out in combination with health economic analyses, to look at the cost effectiveness of this implementation from both a patient perspective and also for the hospital," GeneFirst COO Winnie Wu said in an interview this week.
The company believes that its platform can improve upon other blood-based mutation detection technologies that rely on ligation or PCR-based capture, picking up more of the circulating tumor DNA that occurs at extremely low fractions in early-stage patients.
ATOM-seq (Adaptor Template Oligonucleotide Mediated-sequencing) is a next-generation sequencing library preparation method designed to improve the efficiency and sensitivity of mutation detection for liquid biopsies or other challenging samples where target DNA molecules may be present at very low frequencies.
Although it has been marketing the method for research use since 2019, GeneFirst hadn't described it in detail before a recent publication in Scientific Reports, which includes results of a range of analytical validation experiments.
Study authors describe ATOM-Seq as based on the oligo annealing and polymerase-driven extensions and amplifications that form the basis of all PCR reactions. The method allows for the capture of free 3' ends of any available nucleic acid, making it resistant to highly damaged and fragmented DNA. The technique then applies linear amplification to generate multiple copies of captured molecules, enhancing sensitivity and aiding in the reduction of error rates in the final library by improving the reliability and power of unique molecular identifiers.
In the study, company researchers used both reference materials and clinical samples, demonstrating detection of known SNVs down to allele frequencies of 0.1 percent using as little as 20-25 ng of cell-free DNA.
The group also demonstrated high concordance between paired cfDNA and FFPE clinical samples and showed that ATOM-seq could be applied to total nucleic acid samples (combined cfRNA and cfDNA), capturing and enriching for both RNA and DNA molecules in a single reaction for detection of both mutations and gene fusions.
According to Wu, GeneFirst has already developed a research-use targeted hotspot panel for colon cancer-specific somatic mutations in liquid biopsy or FFPE samples, as well as similar kits for lung and breast cancer, and for pan-cancer applications.
For the new clinical study with the University of Leeds, the company may tweak its existing CRC assay, adding additional biomarkers.
"The program only started a few months ago, and due to Covid we've had some slight delays," Wu said. "Right now, we are looking at the compatibility of the test with a variety of different sample materials including cell-free DNA and also fecal samples … [but] we hope to start the clinical validation later on this year."
The most direct clinical competitor for an ATOM-seq-based blood test, if GeneFirst is successful in this validation and feasibility project, would be Exact Science's Cologuard, a stool-based epigenetic assay that has been on the market for several years.
GeneFirst is not the only firm vying to overtake Cologuard, which, despite improved detection over FIT, still requires the collection and shipping of stool samples, which contenders argue reduces uptake and screening compliance compared to potential blood-based options.
For the UK market at least, Wu said that GeneFirst is imagining its test used as a frontline screen, with the goal to identify patients that may not need to have a colonoscopy.
But the challenge for blood-based methods in colorectal cancer screening is that tumor DNA is shed into the blood in minute amounts, if at all, in early, asymptomatic cancer patients — a roadblock that GeneFirst is hoping ATOM-seq can overcome. At least some previous blood-based CRC detection attempts have failed to reach a high enough bar of sensitivity and specificity for significant clinical adoption, most notably Epigenomics' Epi ProColon assay, which recently received a non-coverage determination from the US Centers for Medicare and Medicaid Services.
Other companies now targeting the same niche include Exact Sciences, Guardant Health, and Freenome. Unlike GeneFirst, these firms have eschewed solely mutation-based methods in favor of genome-wide methylation signals to boost the detection of early colorectal tumors.
If these assays successfully enter the market, which CMS's recent national coverage determination has implied they could in the US based on their existing sensitivity and specificity data, the bar for ATOM-seq to meet or exceed will become much clearer.
Looking forward, Wu said that GeneFirst also anticipates beginning similar validation studies to the Leeds project for other cancer applications. "We are, at the moment, in conversations with other key opinion leaders and researchers about how we could potentially use [the platform] in different ways, whether it's for patient stratification [or] therapy guidance or disease monitoring," she said.
"Establishing clinical effectiveness is a very crucial part of this," she added. "So further down the road once we have solid, good clinical data [for CRC detection], I think that will really help open doors to other avenues."