SAN DIEGO (GenomeWeb) – Singlera Genomics on Thursday presented data from a circulating tumor DNA assay it is developing for early cancer detection at the annual American Society of Human Genetics meeting being held here.
The firm, which was founded in 2014 and has offices in La Jolla, California and Shanghai, China, is focused on analyzing methylation, which has previously been shown to be tissue specific and thus holds promise for early cancer detection since it could be used to trace tumor DNA to its site of origin.
Singlera makes use of a method that identifies methylation haplotypes, which was developed by Kun Zhang – a cofounder of the company and a bioengineering professor at the University of California, San Diego – and described last year in Nature Genetics.
In a presentation, Athurva Gore, associate director of bioinformatics at Singlera, described data from a collaboration with the Taizhou Health Science Institute of Fudan University in China. Researchers at Fudan University had been conducting a longitudinal health study between 2008 and 2018 and had blood samples from more than 100,000 adults between the ages of 30 and 80. Over the 10 years of the study, they tracked the patients' health and found that 575 patients had been diagnosed with cancer within four years of the study.
Singlera partnered with Fudan to analyze 159 pre-diagnostic samples from individuals who developed cancer, as well as 358 post-diagnostic samples and 676 samples from healthy participants with no cancer diagnosis at any time during the study.
The firm used its PanSeer assay, which analyzes 12,000 methylation sites across 600 genomic regions using the methylation haplotype method. Rather than look at average methylation across a region, the assay looks at specific patterns of methylation that occur in cancer samples, Gore explained.
To develop the bioinformatics, Singlera used about one-third of the samples for training. Then it applied the assay for the remaining samples to detect five types of cancer: colorectal, esophageal, stomach, liver, and lung.
From the post-diagnostic samples, the researchers accurately called all 16 colorectal cancer samples, 38 of the 41 esophageal cancers, all 20 liver cancer samples, 42 of 57 stomach cancer samples, and 45 of 46 lung cancer samples for an overall sensitivity of 89.4 percent.
In addition, among the samples from individuals who eventually developed cancer but had not yet been diagnosed, Singlera was able to predict cancer up to four years before a clinical diagnosis. It detected cancer three to four years before clinical diagnosis in 26 of 42 cases. In 35 of 47 cases, the assay detected cancer two to three years before the diagnosis, and in 30 of 39 cases it detected disease one to two years in advance. In 22 of 31 cases, PanSeer picked up the cancer signature up to one-year before conventional diagnosis.
However, the assay did have a relatively high false positive rate at 7 percent, accurately calling 461 out of 498 healthy samples as noncancer.
Gore said that while this false positive rate would be too high for a general population screening test, the company is working on techniques to improve it.
Gore said that one publication describing the PanSeer study and another describing a separate assay focused specifically on colorectal cancer are pending publication in a peer-reviewed journal.
In addition, he said the firm plans to do a prospective study to determine whether PanSeer improves patient outcomes and is cost effective.
The company is also developing a colorectal cancer assay that uses the same methylation haplotype technology. According to Dale Yuzuki, associate director of business development at Singlera, the firm plans to seek US Food and Drug Administration clearance for the assay and expects to speak with the agency soon about the requirements for a prospective clinical trial.
In a retrospective analysis of more than 1,200 individuals, including those with pre-cancerous adenomas, stage I, and stage II through IV cancers, the assay had a 91 percent sensitivity for detecting adenomas, and a 94 percent to 97 percent sensitivity for stages I-IV. Specificity was 99 percent.
While the firm is focused on bringing the colorectal test through FDA clearance, Yuzuki said that it had not decided on a specific commercialization strategy for its pan-cancer assay — whether it would also pursue FDA clearance or focus first on launching it as a laboratory-developed test.
Yuzuki said he anticipates that the colorectal test would serve a similar market as Exact Sciences' stool-based genetic screening test, Cologuard, which has FDA approval and is used as a noninvasive screen with positive results reflexing to a colonoscopy. From a commercial standpoint, that is an attractive market since reimbursement is already established, he noted.
Other companies also have their eye on the early cancer detection market. CellMax Life, for instance, began a clinical trial earlier this year of its circulating tumor cell colorectal cancer screening test in the US with the goal of submitting it for FDA clearance.
CellMax already offers its test in Asia and has said that prior to FDA approval, it would offer it as a laboratory-developed test in the US under a self-pay model for around $200.
Freenome is also looking to enter the early colorectal cancer test market and presented data earlier this month on its cell-free DNA-based assay, which demonstrated an overall sensitivity of 82 percent and a specificity of 85 percent in a cohort of mostly early-stage colorectal cancer patients.
And Grail is conducting a 15,000 person trial including both those at initial cancer diagnosis and before treatment, as well as those without cancer, in order to build a reference set of cell-free DNA profiles on which an early detection test can be based. In addition, Grail plans to launch an early detection test for nasopharyngeal cancer in Hong Kong this year.
Many other companies also offer so-called liquid biopsy assays, which sequence ctDNA as a way of genomically profiling tumors that can't be biopsied, or to monitor progression or treatment response. Singlera's focus, however, is firmly in the early detection space.
Yuzuki said that one difference between Singlera and other companies in that market is the firm's methylation haplotype technology, which enables it to detect a methylation-based cancer signature with less DNA than other methods. The process of bisulfite conversion, which is used to detect methylation, causes much of the DNA to be lost or damaged, Yuzuki said, and plasma samples have small amounts of cell-free DNA to begin with.
He declined to disclose the specifics of the method since there is a pending patent application, but the UCSD researchers previously described it as similar in concept to linkage disequilibrium, which describes co-segregation of adjacent variants on chromosomes.