Liquid Biopsy Equal to Tissue to Indicate Immunotherapy Response

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A doctor taking a patient's blood sample
[Source: travenian / iStock / Getty Images]

Liquid biopsy is just as good as traditional tumor testing at identifying microsatellite instability (MSI), an important biomarker used to predict response to immunotherapy regardless of tumor type. That’s according to a validation study that included nearly 1,000 patients. Researchers incorporated pan-cancer MSI detection into the 74-gene panel Guardant 360 liquid biopsy assay. They identified MSI status with 98 percent accuracy compared to tissue testing across a variety of cancer types. The results were published today in Clinical Cancer Research, a journal of the American Association for Cancer Research.

The results are particularly important given the Food and Drug Administration’s 2017 tissue-agnostic approval of Merck’s ground-breaking immunotherapy drug, Keytruda (pembrolizumab), for patients with MSI-high tumors. Evaluation of MSI status, which is typically performed via tumor biopsy, is underutilized for several reasons, said co-author Scott Kopetz, M.D., Ph.D., associate professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in a press release.

Lack of patient awareness, inherent invasiveness of traditional biopsy and a lack of routine genetic tumor profiling all contribute to the underutilization of MSI status. Liquid biopsy promises to change that.

“The addition of MSI detection into a routine, noninvasive sequencing panel following the diagnosis of metastatic cancer could direct clinicians to prescribe immunotherapy and provide patients with better outcomes,” Kopetz said. MSI-High tumors account for about 1 percent of tumors, those who could benefit from immunotherapy treatment are not being identified. “By adding MSI testing into a non-invasive screening panel, clinicians can routinely scan for this prognostic factor without ordering a separate test,” added Kopetz.

Immunotherapy is especially critical for patients with advanced cancer. “The addition of MSI detection increases the utility of the assay to direct clinicians beyond targeted therapies to include immunotherapies,” said co-author Martina Lefterova, MD, PhD, in the press release. Leferova is laboratory director and medical director at Guardant Health in Redwood City, California. The results show, she said, that the guardant 360 test “can deliver valid MSI-high results that can be used to guide treatment planning for patients with advanced cancer,”

To validate the addition of MSI detection to the assay, researchersperformed pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available.Out of 949 patients that could be evaluated, cfDNA testing accurately detected 87 percent (71/82) of tissue MSI-High and 99.5 percent of tissue microsatellite stable (863/867) for an overall accuracy of 98 percent (934/949) and a positive predictive value of 95% (71/75).

Researchers also validated the clinical relevance of cfDNA-based MSI detection by reporting the clinical outcomes of immunotherapy in 16 MSI-High gastric cancer patients. They found 63 percent (10/16) of patients achieved complete or partial remission with sustained clinical benefit.

The validation of Guardant360’s MSI detection methods is an important achievement in the development of liquid biopsy technology. Chromosomal positions most often associated with MSI are made up of highly repetitive genomic sequences. Because circulating tumor DNA (ctDNA) fragments are generally much shorter than tissue-derived tumor DNA, accurately mapping these fragments to the genome required innovations in panel design, DNA capture, and bioinformatics analysis.

“Millions of microsatellites exist throughout the genome, but most of them are poorly suited for blood-based clinical genomic analysis,” Kopetz explained. “These results show that a carefully designed panel, combined with efficient DNA-capture biochemistry, and sophisticated bioinformatics tools allow for accurate, sensitive MSI detection.”

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