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The early promise of “liquid” cancer tests

A powerful technology that continues to evolve, researchers say, has rekindled interest in liquid biopsies as a way to disrupt tumor progression.

The technology, genetic sequencing, is allowing researchers a closer look at the genetic trail tumors leave in the blood as cancer develops. That capability, as these new “liquid” blood tests work their way into clinics, may further a deeper understanding of how tumors alter their molecular masks to defy treatment. And it may help identify changes that foreshadow early, more treatable, disease.

The tests scour the blood for DNA fragments and other genetic materials that tumors shed as they grow. Some tests measure intact circulating tumor cells; others, circulating DNA alone; and still others look for exosomes, a grab bag of genetic debris that includes DNA, RNA, and metabolites.

Which approach, eventually, may best guide cancer treatment decisions in the future has yet to be determined—one of many unknowns that researchers face as commercial interest in liquid biopsies increases. The India-based consulting firm RNCOS estimates that the market will cross the $1 billion mark by 2020. At least 30 companies are competing for a market foothold.

According to Richard Schilsky, MD, SVP and chief medical officer of the American Society of Clinical Oncology (ASCO), such tests’ great promise is to monitor tumors over the long term as they change genetically to escape detection and develop resistance. “No one is suggesting they should be used yet for early screening or as a diagnostic test. We’re not ready for that type of use,” he said.

Where liquid biopsies will probably carry initial patient benefit, Schilsky and others said, is as a backup or as a possible alternative to surgical tissue biopsies, the standard method doctors use to get information about tumors’ genetic makeup and how best to treat them. But biopsies can be painful, carry considerable cost, and may not be possible, depending on a tumor’s location or a patient’s health. So having a noninvasive and potentially cheaper way to track—and perhaps even diagnose—early cancers with a simple blood test someday has long held appeal. “We need to know if one mutation found by liquid biopsy is representative of the tumor burden. And if you have one mutation, can you base your treatment on that one mutation?”

Prenatal Ties

Liquid biopsies began to gain traction in the cancer community about two years ago, although the technology is not new. Cell-free DNA technology—that is, measuring circulating DNA in the blood—grew out of prenatal testing for fetal abnormalities. Those tests, separating fetal from maternal DNA in the blood, unexpectedly detected several maternal cancers. That discovery led to liquid biopsies’ entry into the far larger cancer market today.

Blood analysis by PublicDomainPictures. CC0 public domain via Pixabay.

Among the many companies funding liquid biopsy development are industry giants such as Johnson and Johnson, Illumina, Qiagen, Foundation Medicine, and Roche. Roche won approval in June from the US Food and Drug Administration for the first liquid biopsy test for patients with advanced non–small-cell lung cancer. The test picks up mutations in a mutated gene on the surface of cells, found in 10%–20% of lung cancer patients. Many of these patients often respond to the targeted drug, erlotinib (Tarceva), which tamps down the rapid cell division characteristic of all cancers.

Guardant Health, based in Redwood City, CA, recently completed a study of its liquid biopsy assay, which measures 70 cancer-related mutations in the blood. Results of the study, the largest to date, were released at the annual ASCO meeting in Chicago this past June.

“What we intended to do is identify those mutations that can be treated,” said Philip Mack, PhD, director of molecular pharmacology at the University of California, Davis, Comprehensive Cancer Center. “Otherwise, there would be no impact on the clinical situation.”

Mack, a consultant for Guardant, presented the study’s findings. Overall, the genomic patterns identified by blood tests in 15,000 patients with some 50 tumor types closely matched those documented in tumor-profiling studies in the literature.

Also, in a cohort of nearly 400 patients, direct comparisons were made between circulating DNA in the bloodstream and tissue samples previously removed from the same cancer patients. If a mutation was detected in the blood it also was picked up in the tumor 94%–100% of the time. The assays also identified several treatment resistance–related mutations, which the investigators said the original tissue biopsy missed.

Fifteen percent of patients, however, had no detectable tumor DNA.

“You’re always going to miss something, but 15% is pretty good,” Mack said. What most people are concerned about is false positives, especially in early disease, when tumors shed far less DNA than their fast-growing, aggressive counterparts, he said.

Research Hurdles

At this point, using biopsies as a diagnostic tool has several limitations. Researchers don’t yet know, for instance, which tumors shed the most DNA into the blood. Also uncertain is whether some tumors shed no detectable DNA at all.

“This is a most intriguing question,” said Sudhir Srivastava, PhD, MPH, chief of the cancer biomarker research group in the National Cancer Institute’s division of cancer prevention. The typical volume collected for routine bloodwork is 4mL for adults. “To detect a single DNA mutation in the blood, you need 5–10 mL of blood,” he said, illustrating the technical challenges ahead, despite rapid advances in gene sequencing over the past decade.

Srivastava called for more comparison studies between tissue samples and liquid biopsies.

“We need to know if one mutation found by liquid biopsy is representative of the tumor burden,” he said. And, with tumors’ diversity, he added, “If you have one mutation, can you base your treatment on that one mutation?”

For now, Srivastava said he agrees that the most immediate use for these blood-based tests will be monitoring treatment, predicting recurrence, and tracking resistance.

But caveats remain. Sensitivity needs to improve. And “if we want to use these tests to find early mutations associated with drug resistance, it’s only useful if we can offer patients an alternative therapy to stop exposure to harmful side effects,” ASCO’s Schilsky said.

Looking Ahead

According to Mack, investigators will meanwhile follow up on the early Guardant data to look for additional mutations that contribute to cancer’s rise. Multicenter clinical trials in patients with advanced cancers are planned, he said—to not only validate these new molecular findings but also intervene as resistance develops.

Of the three blood-based approaches to capturing cancer information, Mack said he feels measuring circulating tumor DNA remains the optimal way—and the one with the fastest turnaround time.

But even that approach, he conceded, may not be up to finding cancers anytime soon in a routine blood test in seemingly healthy people.

“Early-stage tumors are hard to detect,” Mack said. “And precancerous tumors might not show up at all with this technology.”

Whether a combination approach might work better remains to be seen. At least one company in England is exploring that possibility, believing side-by-side technologies may show more about tumor DNA content, said Leonard Lichtenfeld, MD, deputy chief medical officer of the American Cancer Society in Atlanta. If successful, however, such tests must be refined enough to overcome concerns about detecting “something that may not turn into cancer, but lie dormant for many years,” he said. “Our need is to identify which information we can detect has true clinical implications for the individual.”

Schilsky puts it another way: “If you have a test with infinite capacity to interpret mutations, what does that mean? The clinical community has to sort out its real value.”

A version of this blog post first appeared in Journal of the National Cancer Institute.

Featured image credit: blood tubes by keepingtime_ca. CC BY-SA 2.0 via Flickr

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