1. Jenks, Susan

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Five years after the first liquid biopsy test entered the marketplace, several others that track the molecular fingerprints of cancer in the blood have won approval from the FDA. Although the most recent FDA approvals expand the reach of these blood-based tests, identifying more genetic mutations in several new cancers, they fall short of detecting early-stage disease in otherwise healthy individuals-still a distant goal, according to researchers.

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"Liquid biopsy is definitely a game-changing technology,' said Phillip Castle, PhD, MPH, Director of the National Cancer Institute's Division of Cancer Prevention in Bethesda, MD. "But, it's much easier-though far from easy-to work from the starting point, where a person already has cancer."


In fact, all but one of the five tests now available measures DNA snippets and other genetic materials that tumors shed in the blood for clues to cancers in individuals battling advanced disease. Also, each of these tests, except for an early screening product for colon cancer, pairs liquid biopsy to traditional tissue biopsies as companion diagnostics, not as stand-alone tests.


Investigators' interest in moving liquid biopsy closer to a simple blood draw, however, has intensified in recent years with advances in next-generation sequencing, which allows for large-scale DNA analyses. Eventually, the hope is that such a test could identify not just a single cancer, but a wide spectrum of cancers, long before symptoms appear.


"That's the Holy Grail of research," Castle noted, given that improvements in prevention go hand-in-hand with treatment advances. "Imagine if we could find cancers earlier, how much better treatments would work," or even that some cancers might be cured, he said.


Researchers are actively pursuing early detection blood tests. While Galleri is a methylation-based multi-cancer screening test, CancerSEEK scours the blood for incipient disease, using mutated DNA and cancer-related proteins.


"These are the two tests out front in early detection," Castle said. Neither test has gained FDA approval, nor is it yet clear the benefit to patients, he noted. "And, until we're sure of that benefit, we're not recommending them."


Ultimately, Castle and others stressed that, to reach a liquid biopsy's full-screening potential, scientists need a much better understanding of tumor biology.


"Genetic abnormalities are only one piece of the puzzle," said William Cance, MD, a surgical oncologist and Chief Medical and Scientific Officer of the American Cancer Society in Atlanta. "We need to look comprehensively at tumors for the best therapy," from their metabolic changes and protein signatures in the blood to the epigenetic modifications that may occur, as cancers take hold, he said. "It's not just shed DNA in the blood."


Many issues remain unsettled, such as which testing approach works best. One approach measures intact circulating tumor cells, while another -furtherest along, given its apparent improved sensitivity-looks at tumor-related DNA. A third searches for exosomes, an assortment of genetic debris, including DNA and RNA molecules and metabolites in the blood.


Investigators also don't know whether to use these tests in urine, cerebral spinal fluid, or even saliva in the future to monitor changes signaling worsening disease or a new cancer. "There are a variety of biomarkers out there and there's no need to limit yourself," Castle said. "The most important thing is-is it a good test?"


Meanwhile, the more immediate benefits of liquid biopsy continue to evolve. Although tissue biopsy remains the gold standard for guiding patient care, liquid biopsy is considered cheaper and far easier to do, especially if patients are too ill to undergo tissue sampling or have tumors that are inaccessible to treatment.


"The ability to do these tests quickly (and often) is a big advantage in the sickest patients," Cance stated. Not only does liquid biopsy eliminate the need for further tissue biopsies, he said, "it may find mutations where there's a possible new drug available, opening up options that might help or make a difference in a patient's care."


Liquid biopsy also provides a way to monitor tumors as they progress. Because cancer cells change so quickly and reprogram to escape immune defenses, Cance noted that tracking their molecular trail in the blood through repeated blood draws offers a way to keep pace, shifting treatment strategies as needed.


"I think liquid biopsies are here to stay," though still in the early days of development, he said. "They're all part of precision medicine, tailored to the individual."


But, as with all cancer-detection efforts, he said researchers need to know more about which tumors shed the most DNA into the blood, whether some cancers shed none, and most importantly, "whether the DNA we're measuring is from the tumor we're targeting and trying to treat."


That uncertainty lies at the heart of ongoing research. Even normal aging can create DNA mutations mistaken for cancer, according to the FDA, blurring results and raising the risk and potential harm of overtreatment.


Susan Jenks is a contributing writer.