DUBLIN – Thrive Earlier Detection Corp. and its academic and clinical collaborators have provided a first glimpse at the utility of a liquid biopsy test as a screening tool for picking up cancers in an asymptomatic population. In an interim one-year readout of data from the prospective five-year DETECT-A study in 10,000 women, an early version of Thrive’s Cancerseek test picked up 26 cancers ahead of standard-of-care screening, while the latter modality picked up another 24 cancers that Cancerseek missed. Neither category of test picked up a further 46 cancers, which were detected by symptomatic diagnosis.

The data were reported earlier today during the American Association for Cancer Research annual meeting, which was held virtually because of the COVID-19 pandemic, and also in the April 28 issue of Science, in a paper, titled “Feasibility of blood testing combined with PET-CT imaging to screen for cancer and guide intervention.” Corresponding authors on the paper were Kenneth Kinzler, Bert Vogelstein and Nickolas Papadopoulos, at the Sidney Kimmel Cancer Center at Johns Hopkins University, in Baltimore, who are co-inventors of the Cancerseek test.

This is the first sizeable prospective study of a liquid biopsy assay in a cancer-free cohort. Up to now, most clinical studies of such tests have been retrospective undertakings. Finding cancers that are asymptomatic and that are not routinely picked up at present represents the great promise of liquid biopsy testing, as early detection leads to better outcomes in the majority of cancers. Doing so with useful levels of sensitivity and specificity is a much higher bar to clear than demonstrating high levels of accuracy in testing clinical samples from patients with a confirmed cancer diagnosis. “This is, in my mind, one of the critical first steps in studying this technology,” Adam Buchanan, assistant professor at the Danville, Penn.-based Geisinger Genomic Medicine Institute and Geisinger’s clinical lead on the study.

The trial recruited 10,006 women, between the ages of 65 and 75, through the Geisinger Health System in mid-Pennsylvania, and 9,911 eventually participated. Each subject provided a baseline blood sample, which was tested with an early prototype version of Thrive’s Cancerseek liquid biopsy test, which analyzes cancer-associated mutations in almost 2,000 genetic loci across 16 genes, as well as a panel of nine validated protein-based cancer biomarkers.

Those who had an initial positive test were then invited to provide a second sample in order to conduct a confirmatory test, in order to determine whether the identical biomarker was again abnormal, and to exclude benign mutations that can arise during the production of blood cells (a phenomenon known as clonal hematopoiesis of indeterminate potential). If no other likely cause could be established, those with a positive test then underwent a positron emission tomography-computed tomography (PET-CT) scan, in order to confirm the diagnosis and localize the cancer, which was further confirmed by biopsy. The participants also continued to undergo routine screening with currently used modalities, including mammography and colonoscopy.

The 26 cancers first detected by Cancerseek included nine cases of lung cancer, six of ovarian cancer and two of colorectal cancer. Seventeen of them (65%) were early stage – defined as localized or regional – including five cases with stage I tumors. Fifteen were detected by ctDNA analysis and 12 by elevated protein biomarkers (one subject had abnormal levels of both a ctDNA mutation and a protein biomarker). Routine screening picked up an additional 20 breast cancers, three lung cancers and one colorectal cancer. Twenty-two were localized or regional, including 16 stage I breast cancers. Of the 46 cancers not picked up by either modality, 10 were stage I uterine cancers, which are often detected at an early stage because of post-menstrual bleeding. In all, 38 of these 46 cancers were localized or regional – 26 were stage I malignancies. “I’d characterize it as ‘okay but needs improvement’,” Buchanan said. The blood test had a sensitivity of 27.1% across all cancers and 31.1% for seven that currently have no screening options at present. Combining Cancerseek with current standard-of-care testing resulted in a sensitivity of 52.1%, which represents a doubling of the cancers detected during screening.

The study also reported that 1% of participants underwent a PET-CT scan on the basis of a false positive blood test and that 0.22% underwent a futile diagnostic procedure. “It’s acceptable – of course we always want to further refine it,” Buchanan said. “I think there’s room for improvement there.”

The test employed in the study was an early version, developed in 2016, of Cancerseek. Since the investigators completed the study design and obtained institutional review board approval, they have developed machine learning methods to improve its sensitivity and specificity by analyzing the ctDNA mutation more comprehensively and have reported on a simple polymerase chain reaction (PCR) test for aneuploidy (an abnormal number of chromosomes), which further improves sensitivity. Thrive has so far remained loyal to the basic principle of analyzing ctDNA for cancer-associated mutations, while extending the test to other analytes.

A confirmatory test in a much larger and more diverse population – with a matched control group – is required to fully evaluate the clinical utility of Cancerseek. “We cannot say that the test saves lives or improves clinical outcomes at this time,” Buchanan said. But meanwhile, the present phase I study has another four years to run, during which participants will undergo two further blood tests. “We presume that some participants will move categories,” Buchanan said. That movement will, inevitably, alter the test’s reported sensitivity. The subjects are scheduled to undergo a second blood test this fall. It’s not clear at this point whether the COVID-19 pandemic will disrupt this plan. “It’s certainly a concern right now,” Buchanan said.

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