Blood-based Liquid Biopsy Test Accurately Detects More Than Fifty Types of Cancer

The Circulating Cell-free Genome Atlas study (CCGA) was a prospective, case-controlled, observational study and demonstrated that a blood-based multi-cancer early detection (MCED) test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy.

Liquid biopsy analysis of circulating cfDNA from peripheral blood has emerged as a valuable diagnostic tool in oncology, since sample collection is quick and minimally invasive. In cancer patients, cfDNA consists in part of cancer-derived circulating tumor DNA (ctDNA), and it has been shown that tumor-related genetic and epigenetic alterations can be detected by analyzing cfDNA in cancer patients. As a consequence, cfDNA analysis holds great promise for precision oncology and personalized therapies, and is currently being evaluated in a broad range of clinical studies.

The CCGA study was designed to develop and validate an MCED test to detect cancer signals across multiple cancer types and predict CSO via a single blood draw. Modeled data from this test have shown that its use in the general population could shift cancer detection from stage IV to earlier stages (stages I-III), potentially reducing cancer mortality. CCGA was divided into three studies; in the first, a comprehensive comparison of genomic sequencing approaches identified that whole-genome bisulfite sequencing (WGBS; detecting genome-wide DNA methylation status) outperformed other methods. In the second study, the selected WGBS assay was refined into a targeted methylation assay, and machine learning classifiers for cancer detection and CSO prediction were developed.

The objective of this third and final CCGA study was to validate an MCED test version further refined for use as a screening tool. To this end the GRAIL, Inc. (Menlo Park, CA, USA) Galleri MCED test was used to evaluate 4077 participants (2823 with cancer and 1254 normal controls),

Results revealed that the MCED test detected cancer signals from more than 50 different types of cancer and found that across all four cancer stages (I, II, III, IV), the test correctly identified when cancer was present (the sensitivity or true positive rate) in 51.5% of cases. The test's specificity (the true negative rate) was 99.5%, meaning that the test wrongly detected cancer (the false positive rate) in only 0.5% of cases. For all cancers, detection improved with each cancer stage with a sensitivity rate of 16.8% at the early stage I, 40.4% at stage II, 77% at stage III and 90.1% at stage IV - the most advanced stage when symptoms are often showing. In addition, the multi-cancer early detection test correctly identified the tissue in which the cancer was located in the body in 88.7% of cases.

First author, Dr Eric Klein, chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic (OH, USA), said, "Finding cancer early, when treatment is more likely to be successful, is one of the most significant opportunities we have to reduce the burden of cancer. These data suggest that, if used alongside existing screening tests, the multi-cancer detection test could have a profound impact on how cancer is detected and, ultimately, on public health. We believe that cancers that shed more cfDNA into the bloodstream are detected more easily. These cancers are also more likely to be lethal, and prior research shows that this multi-cancer early detection test more strongly detects these cancer types. Cancers such as prostate shed less DNA than other tumors, which is why existing screening tests are still important for these cancers."

The third CCGA study was published in the June 24, 2021, online edition of the journal Annals of Oncology.

Related Links:
GRAIL, Inc.
Cleveland Clinic