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Blood Test for Genetic Changes in Tumors Shows Promise as Alternative to Tumor Biopsy

, by NCI Staff

So-called liquid biopsies assess mutations and other changes in DNA shed from tumors into the blood.

Credit: Jonathan Bailey / NHGRI

In the largest study of its kind to date, a test that assesses DNA mutations and other changes in genetic material shed from tumors into the blood—a so-called liquid biopsy—produced results highly similar to those of traditional tumor biopsies.

The patterns of genomic changes identified by the test in a large collection of patient blood samples largely matched patterns of genetic changes seen in large tumor biopsy profiling studies, researchers reported last week at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

And in a cohort of nearly 400 patients with several types of common cancers, in most cases the test identified the same mutations in the patients’ blood samples as were seen in their tumor biopsy samples. The liquid biopsy also identified mutations that are linked to treatment resistance but that had not been detected in the original tissue biopsy.

The study’s lead academic investigator, Philip Mack, Ph.D., of the University of California Davis Comprehensive Cancer Center, acknowledged that there is still work to do to better understand how best to use liquid biopsies and what role they might eventually play in patient care.

But at this point, based on the study’s findings, he said the evidence suggests that liquid biopsies could be an alternative when traditional tumor biopsies “are not practical, accessible, or feasible.”

An Easier Way to Get the Same Information?

Tumor biopsies are an essential part of cancer care. They can confirm a cancer diagnosis, identify the cell type of the tumor, and, increasingly, they are used to determine whether a patient’s tumor contains particular genetic alterations that may make them candidates for targeted therapies.

However, tumor biopsies require invasive procedures, including surgery, and some patients may not be candidates because of poor health or because of a tumor’s location in the body. In addition, after the initial testing and analyses of biopsy samples, not enough additional tissue may be left for comprehensive molecular profiling, or it may not be of sufficient quality for profiling, Dr. Mack explained during a press briefing.

To overcome these barriers to gathering genetic information about a patient’s cancer, researchers have developed technologies for capturing and analyzing DNA and other types of genetic material released by tumor cells into blood.

Similar Frequency and Alteration Patterns

The study presented at the ASCO meeting used a test developed by California-based Guardant Health, called Guardant360. The test uses next-generation sequencing to analyze DNA shed by cancer cells, known as circulating tumor DNA (ctDNA).

Funded by Guardant Health, the study used blood samples from more than 15,000 patients with more than 50 types of tumors. The researchers compared whether the Guardant360 test, which profiles ctDNA for mutations and chromosomal rearrangements in 70 cancer-related genes, detected alterations in these genes at the same distribution and frequency observed in previously published genomic profiling studies that used tumor biopsy samples, including The Cancer Genome Atlas.

And, by and large, the liquid biopsy test was highly consistent with gene alteration patterns reported in traditional tumor tissue testing. For example, Guardant360 identified the same critical mutations in important cancer-related genes like EGFR, BRAF, KRAS, and PIK3CA at frequencies very similar to what had previously been identified in tumor biopsy samples, statistically correlating to 94% to 99%.

In a second component of the study, the researchers evaluated nearly 400 patients—most of whom had lung or colorectal cancer—who had both blood ctDNA and tumor tissue DNA results available and compared the patterns of genomic changes. The overall accuracy of the liquid biopsy in comparison with results from the tumor biopsy analyses was 87%. The accuracy increased to 98% when the blood and tumor samples were collected within 6 months of each other, they reported.

The liquid biopsy performed well even though levels of ctDNA in most samples were extremely low, often less than 0.4% of the total circulating DNA in the blood, Dr. Mack said. (Circulating DNA can come from multiple sources other than the tumor, including the skin, bone marrow, and gastrointestinal tract.)

In the matched blood ctDNA/tumor biopsy samples, the liquid biopsy also identified genetic alterations not present in tumor biopsy samples that are known to make tumors resistant to therapy. These included mutations in the EGFR, ALK, and KRAS genes that are known to cause resistance to currently available targeted agents.

Overall, the test identified these resistance mutations in 27% of patients, Dr. Mack said during an interview. In most cases, he continued, the mutations were likely not present at the time of the initial tumor biopsy, instead emerging as a patient’s disease progressed on therapy.

Based on the genetic changes found via these liquid biopsies, in nearly two-thirds of patients the researchers identified tumor biomarkers that could provide the patients’ treating physicians with information to potentially help guide treatment options. This included identifying patients who were candidates for FDA-approved drugs or enrollment in clinical trials testing investigational therapies against these mutations.

What’s Next for Liquid Biopsies?

Liquid biopsies are an area of intense study and commercial activity, explained Luis Diaz, Jr., M.D., of Johns Hopkins University, during a session on clinical genomics at the ASCO meeting.

“The field has really exploded,” said Dr. Diaz, whose research focuses on genomic diagnostic approaches. 

FDA Approves First Liquid Biopsy Test

On June 1, the Food and Drug Administration (FDA) approved the first liquid biopsy test for use in cancer. The cobus EGFR Mutation Test v2 detects key mutations in the EGFR gene that makes patients with advanced non-small cell lung cancer candidates for treatment with the targeted therapy erlotinib (Tarceva®). The FDA approved the test previously for this indication using tumor specimens. The new use is for the detection of these mutations in circulating tumor DNA from blood samples.

“Liquid biopsies for comprehensive molecular profiling are available to patients and physicians now and can be a great source of additional tumor genetic information when tissue biopsies are not available,” said Dr. Mack. “But caution should be used in their interpretation until clinical trials are completed that confirm their therapeutic utility.”

For patients with advanced cancer, Dr. Diaz suggested such tests may be most valuable to help monitor changes in a patient’s disease over time and direct treatments when tumors recur or progress. Some studies also suggest that liquid biopsies may eventually be able to help direct care for patients with earlier-stage disease or help monitor disease progression in people with precancerous lesions, he said.

But more research is needed before liquid biopsies are used routinely in cancer care, said Richard Schilsky, M.D., of the University of Chicago, during the press briefing. The current study, Dr. Schilsky noted, was not a randomized trial, and there’s no evidence yet that the liquid biopsies under development or that are commercially available improve patient outcomes.

“Just because a test can be done, doesn’t mean it should be done,” he said. “The burden is on all of us to demonstrate true clinical utility of the tests that are out there.” 

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