Cancer diagnostic assays represent a significant and growing segment of the diagnostic field, allowing individuals to be screened for cancer before symptoms arise. Those with a family history of certain cancer types can turn to cancer diagnostics for possible advance warning, such as screening for HER2 and breast cancer risk. But what if it was possible to be screened for multiple types of cancer at once?
That is the aim of a blood test developed by GRAIL Inc., which was recently evaluated in a study for its ability to not only detect cancer, but determine where it originated. The results were published in an article titled “Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA,” which appeared in Annals of Oncology.
The test in question uses next-generation sequencing to analyze the arrangement of methyl groups on the DNA of cancer cells, which play a part in whether genes are active or inactive. Methylation patterns in cancer cells are usually significantly different from those of healthy cells, and when tumor cells die and get shed into the bloodstream (cell-free DNA, or cfDNA), the blood test can detect and analyze it for diagnosis.
“There are few studies interrogating simultaneous detection and localization of multiple cancer types using cfDNA or other analytes. These studies generally analyzed a handful of cancer types in geographically-restricted cohorts or interrogated a single cfDNA-based molecular approach,” the authors explained in the Annals of Oncology paper. “Current commercially available cfDNA-based approaches interrogating single-nucleotide variants (SNVs/indels) that focus on key alterations associated with specific tumor types or treatment options may be hampered by confounding signals from white blood cells (WBCs) or other tissue. Similarly, approaches based on detecting somatic copy number alterations may be limited by smaller relative differences between cases and controls resulting in a need for increased sequencing depth as well as technical variation restricting the signal-to-noise ratio. These approaches as well as others such as protein biomarkers have not yet demonstrated robust TOO [tissue of origin] assignment across a broad range of tumor types to direct a diagnostic evaluation.”
This study analyzed cell-free DNA from 6,689 blood samples, 2,482 of which came from cancer patients and 4,207 of which came from cancer-free individuals. More than 50 cancer types were represented in this population, including breast, lung, colorectal, esophageal, gallbladder, bladder, gastric, ovarian, head and neck, lymphoid leukemia, multiple myeloma and pancreatic cancer.
Remarkably, the overall specificity of this test was 99.3 percent, with only a 0.7-percent rate of false positives. When cancer was detected, the test was able to determine where the cancer originated with 93-percent accuracy, according to GRAIL. As noted in a press release from the Dana-Farber Cancer Institute, when tested in 12 cancers, the assay had a sensitivity of 67.3 percent. Sensitivity increased with later-stage cancers; for stage I, II, III and IV cancer, the test had a sensitivity of 39 percent, 69 percent, 83 percent and 92 percent, respectively. The average sensitivity for stages I to III across all 50 cancer types was 43.9 percent.
“Our results show that this approach to testing cell-free DNA in blood can detect a broad range of cancer types at virtually any stage of the disease, with specificity and sensitivity approaching the level needed for population-level screening,” said Dr. Geoffrey Oxnard of Dana-Farber, who was co-lead author of the study along with Dr. Minetta Liu of the Mayo Clinic. “The test can be an important part of clinical trials for early cancer detection.”
As noted by the authors, there were some limitations to their work, one of them being the fact that “At the time of analysis, complete 1-year follow-up was not available on all non-cancer participants to ensure their ascribed non-cancer status was accurate, thus potentially overestimating the [false-positive rate] and underestimating [positive predictive value].” In addition, “Confusion in TOO identification often occurred among HPV-driven cancers (e.g. cervix, anus, head and neck cancers),” and some cancer types represented had only small sample sizes, “precluding a full representation of heterogeneity within some cancer types,” the authors allowed.
This study is the second of three sub-studies that comprise GRAIL's Circulating Cell-free Genome Atlas study, which included more than 15,000 individuals with or without cancer. The third sub-study will aim to further validate these results. As part of that effort, Dana-Farber has joined the PATHFINDER study, a multi-center clinical trial that will enroll approximately 6,200 individuals across the U.S.
“At GRAIL, we believe that multi-cancer early detection has the potential to significantly reduce cancer mortality,” said Dr. Alex Aravanis, chief scientific officer, head of R&D and a co-founder of GRAIL. “This is a seminal moment in the field of cancer detection. We’ve built what we believe to be one of the largest clinical study programs ever conducted in genomic medicine, and the data published in Annals of Oncology further support GRAIL’s approach and commitment to clinical and scientific rigor.”
GRAIL noted in a press release that the five-year cancer-specific survival rate is 21 percent in patients whose cancer is not diagnosed until it has already metastasized. In patients who are diagnosed in the earlier stages when the cancer is localized, the survival rate is 89 percent. GRAIL recently published data modeling recent statistics from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program that argued that if all cancers currently diagnosed at stage IV were diagnosed earlier, cancer deaths could drop by 24 percent. A blood test like GRAIL's assay that could accurately diagnose and determine the origin of cancer could be a significant contributing factor in the goal of earlier diagnosis and lower mortality rates.