A liquid biopsy based on a multi-cancer early detection assay has been found to detect, with high accuracy, cell-free DNA (cfDNA) fragments shed into the blood by a dozen different cancers, according to results presented during the AACR Annual Meeting 2023. This preliminary test, based on the methylation of cfDNA, was shown to be capable of detecting cells from early-stage disease and those known to shed only small amounts of cfDNA into the blood.
As such, the novel assay provided early hope that one day it may serve as a screening tool to detect cancer among otherwise asymptomatic individuals.
"We have shown that the test can distinguish between normal healthy volunteers and those with cancer," said Ben Ho Park, MD, PhD, the Benjamin F. Byrd, Jr. Chair in Oncology and Director of the Vanderbilt-Ingram Cancer Center, as well as Professor of Medicine in the Division of Hematology/Oncology at Vanderbilt University Medical Center, who presented results at the AACR meeting. "This looks promising because the hardest cancers to detect at earliest stages were still detected with high accuracy."
That said, Park cautioned that the test was "not ready for prime time" and it's "too early to tell" if one day it may serve as a screening tool for cancer-a primary goal for this project. "Obviously, we want to make this a generalized blood screening test, but even then, it will take years to prove that such a test will actually afford better outcomes catching cancers that much earlier," he said.
Detecting cancer in its earliest stages through screening programs has been shown to save lives, but screening technologies are available for only a few cancer types today. In recent years, liquid biopsies-sometimes referred to as the 'holy grail' for cancer diagnostics and screening-has gained widespread acceptance as routine assays for the early diagnosis and monitoring of tumors, a process that's easier, less expensive, and less painful than the collection of tissue samples for conventional biopsy.
With liquid biopsies, clinicians can search for any tell-tale signs of cancer based on proteins, metabolites, and nucleic acids shed by tumor cells into circulating blood. However, cfDNA can be difficult to detect because it's sometimes present in small amounts, especially in people with small tumors or residual disease. Thus, using this technology to screen for multiple cancer types has proved to be challenging.
For this study, researchers turned to aberrant methylated DNA for the early detection of cancer among a variety of tumor types. Here, chemical tags called methyl groups attach to a particular location within DNA where they turn a gene on or off, thereby altering the expression and production of proteins the gene encodes. Different methylation patterns exist between cancerous and non-cancerous cells, and there are differential methylated regions that are tissue-specific, Park noted.
"Using new technology to look for DNA methylation patterns of cell-free DNA (free-floating DNA in the blood shed by all cells-cancer and normal), we were able to detect cancer DNA molecules in the blood with high accuracy," Park summarized.
Study Details
As outlined in this retrospective, case-controlled study, plasma samples from some 4,322 individuals were analyzed, including patients with newly diagnosed treatment-naive cancer, as well as age- and gender-matched non-cancer controls. Samples were obtained across 12 cancer types: bladder, breast, colorectal, endometrial, esophageal, head & neck, hepatobiliary, lung, ovarian, pancreatic, prostate, and renal.
Subsequently, these samples were split into distinct sets to train and test a machine learning classifier consisting of differentially methylated regions developed to distinguish cancer cases from controls. Analysis was conducted using a bisulfate-free, genome-wide DNA methylation enrichment platform (multicenter early detection) using 5-10 ng of cfDNA isolated from plasma. The platform-with a higher signal-to-noise ratio-was designed to increase detection performance, particularly where cfDNA burden was low.
Findings showed the platform was able to distinguish patients from controls with an area under the curve (AUC) measure of 0.94 (0.93, 0.96), with AUCs for individual cancer types ranging from 0.91 to 0.97. The AUC was 0.94 (0.92, 0.95) for Stage I/II cancers and 0.95 (0.94, 0.96) for Stage III/IV cancers. The AUC was 0.92 (0.91, 0.94) in the subset of cancers typically considered low shedding, including bladder, breast, renal, prostate, and endometrial cancers, with similar performance for Stages I/II (0.91; 0.89, 0.93) and Stage III/IV (0.93; 0.91, 0.95) disease in that subset.
Asked if he was surprised by the results, Park stated: "The technology looked very promising, so not surprised, but yes in that, when tested across all these different tumor types with even the earliest stages of disease, the test performed remarkably well. He also noted several liquid biopsies designed to detect multiple types of cancer already are on the market.
"The technology here [with this test], I think, better preserves the quantity and quality of cell-free DNA, translating into what we hope will be a more sensitive test," Park said.
However, he emphasized that the assay was still in an early stage of development and prospective studies will be needed to confirm these retrospective findings.
"A weakness [of this study] is this is all retrospective samples and importantly, as mentioned, not showing any data in how this would be used, for example as a primary screening tool to pick up cancer in otherwise asymptomatic individuals," Park stated, noting that achieving this goal will be among the project's key next steps.
Warren Froelich is a contributing writer.