The ability to detect and monitor mutational changes in tumors through a simple blood test has spurred considerable development within the field of liquid biopsy. While questions remain about the accuracy of such tests and the most relevant analyte to measure (i.e., circulating tumor DNA, cell free DNA, circulating tumor cells), liquid biopsy could offer significant advantages over conventional tissue biopsies — for example, less invasive testing could enable easier and more frequent monitoring of changes in disease status. Additionally, liquid biopsy may allow a more accurate analysis of the genetic make-up of heterogeneous tumors, as well as enable testing with limited tumor tissue samples. Data is rapidly mounting that supports the use of liquid biopsy to identify druggable mutations and detect resistance to targeted therapies by monitoring evolution of molecular biomarkers over time.
Guardant Health announced data earlier this year showing that the Guardant360® liquid biopsy test outperformed standard tissue biopsy in detecting genomic biomarkers related to non-small cell lung cancer (NSCLC). Researchers studied 282 patients with advanced NSCLC, comparing biomarker test results based on liquid biopsy with those from tissue biopsies. The goal of the study was to identify patients with at least one of seven established biomarkers (EGFR, ALK, ROS1, BRAF, RET, MET and ERBB2) that are either druggable mutations or can aid in treatment decision making. The Guardant360 assay detected alterations in 77 patients, while tissue analysis found them in only 60. For four druggable mutations (EGFR, ALK, ROS1, and BRAF), both the blood-based test and the standard biopsy test provided equivalent results. The comparable specificity & sensitivity between liquid biopsy and “gold standard” tissue analysis is important, as it provides a compelling case for use of liquid biopsy in newly diagnosed patients with advanced NSCLC. Not only is the liquid biopsy less invasive and easier to schedule and perform, but its faster turn-around time – 9 days versus 15 days for tissue biopsy – is a significant advantage too. Quick detection of actionable biomarkers via a simple blood test would allow oncologists to systematically make informed treatment decisions, thus increasing the likelihood for patients to be treated first with targeted therapies that could result in a higher response rate than traditional chemotherapy. The Guardant test also appeared superior to tissue genotyping as it correctly identified mutations in 85 more patients with tumor heterogeneity or tissue insufficiencies.
With respect to reimbursement issues, Guardant recently received a “draft local coverage determination” for the Guardant360 test, which expands Medicare coverage for the test from advanced NSCLC to more than a dozen types of solid tumors with genomic targets.
Other liquid biopsy tests are reporting positive results as well. During AACR, Resolution Bio and its collaborators at Dana-Farber Cancer Institute and Brigham & Women’s Hospital presented a retrospective study showing that Resolution’s test out-performed Guardant360 in detecting actionable gene fusions in NSCLC tumors.
Foundation Medicine also presented data at AACR from a pediatric neuroblastoma trial using its recently launched FoundationOne Liquid test. This blood test was able to identify tumor genetic changes that emerged following treatment with standard or targeted therapies. During the study, five newly diagnosed and 33 relapsed patients were simultaneously tested via both liquid biopsy and standard tissue biopsy methods over time. Repeated testing of circulating tumor DNA identified additional variants in cancer driver genes in 80% of the patients.
More recently, Grail excited the ASCO audience with data from one of their Circulating Cell-Free Genome Atlas (CCGA) studies. While earlier versions of Grail’s liquid biopsy test were based on the genetic code itself, the company’s current test measures DNA methylation, which is a process of gene regulation and a fundamental determinant of cell identity and cell fate. The data reported at ASCO suggests that this newer version of the company’s liquid biopsy test can detect at least 12 kinds of cancers with a very low rate — 1% or less — of false positives. This rate is striking, especially when compared to other common diagnostic tests such as mammography, PSA, or CT scans, which can exhibit false positive rates 10x higher. The detection rates of Grail’s test varied from 59% for lung cancers to up to 86% for head and neck cancers. The test correctly identified the tissue of origin of detected cancers 94% of the times. It also preferentially detected the most lethal cancers over early stage cancers that might not require therapeutic intervention, showing sensitivity rates of 34%, 77%, 84% and 92% across all tumor types, from stage I to stage IV, respectively. In addition, the Grail test could identify tumors when they were still localized and most amenable to treatment. Grail still needs to duplicate its success in larger populations before the liquid biopsy test is ready for broad use. And more competition is on the horizon; Thrive Earlier Detection’s liquid biopsy test, which analyzes proteins secreted by tumors as well as DNA, has shown similar early stage results to Grail.
Despite the promises, additional studies and a better understanding of liquid biopsies are still needed. Risks remain regarding false positive or false negative test results, as well as the potential for overtreatment of slow-growing, possibly harmless tumors detected via these methods. But successful development of this technology has the potential to provide real benefits for cancer patients. Liquid biopsies not only are less invasive, easier to schedule and perform, and provide quicker results than tissue biopsies, but they may also be more accurate at identifying clinically relevant alterations within heterogeneous tumors compared to standard tissue methods. In addition, liquid biopsies may allow better patient monitoring by repeated testing over time, a capability that would help enable the concept of real-time oncology and the ongoing adjustment of therapies as new actionable mutations arise.
What is still needed to prove the clinical utility of liquid biopsy compared to tissue-based testing? In the long term, will we see the emergence of effective urine or saliva-based tests? And will liquid biopsy indeed play an important role in the evolution of cancer care towards real-time oncology?