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Liquid biopsy—much to do about something

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Karen Titus

March 2016—Lynette Sholl, MD, isn’t fully sold on that hottest of feverishly hot topics, liquid biopsy. “It’s kind of a sexy colloquialism, I suppose,” says Dr. Sholl, associate director, Center for Advanced Molecular Diagnostics, and associate pathologist, Brigham and Women’s Hospital, Boston. “Is there an official definition?”

Although she had been tasked with writing a State-of-the-Art paper on liquid biopsy in lung cancer—the plan was to submit it for publication following the USCAP meeting in March—she’s focused on clinical practice, not language. “We essentially refer to it as ‘plasma cell-free DNA testing,’” says Dr. Sholl, who is also assistant professor, pathology, Harvard Medical School. “Our lab code is ‘plasma EGFR.’”

Dr. Lynette Sholl and colleagues, including thoracic oncologist Geoffrey Oxnard, MD, of Dana-Farber Cancer Institute, are looking at ways to apply plasma cell-free DNA testing in lung cancer. They will begin this spring to use it in-house for EGFR relapse patients.

Dr. Lynette Sholl and colleagues, including thoracic oncologist Geoffrey Oxnard, MD, of Dana-Farber Cancer Institute, are looking at ways to apply plasma cell-free DNA testing in lung cancer. They will begin this spring to use it in-house for EGFR relapse patients.

In the opposite corner of the country, in San Diego, Mark Erlander, PhD, and his colleagues at Trovagene are focusing on developing assays for circulating tumor DNA, in both urine and blood. You could call these liquid biopsies, but Dr. Erlander isn’t a fan of the term, either.

“It’s totally overused,” says Dr. Erlander, Trovagene’s chief scientific officer.

Clearly, Dr. Erlander and Dr. Sholl won’t be collecting any medical marketing awards. Nevertheless, the science behind the label is vibrant. “Everyone’s excited about this,” says Karen Kaul, MD, PhD, chair of pathology and laboratory medicine, NorthShore University HealthSystem, Evanston, Ill. “It’s a hot topic—whatever that means.”

Liquid biopsies inspire plenty of electrifying words. Interest is “skyrocketing,” says one pathologist. The field is “exploding,” says another observer. The potential is “mind-boggling,” adds a third.

Unless you’re Shakespeare, thrilling language will take you only so far. The term liquid biopsy is tossed about as much as Pericles. But as Dr. Sholl points out, a precise definition is up for grabs.

Cell-free DNA is one broad category—but in and of itself, it covers more than tumor biology (think prenatal diagnosis). A subset of cfDNA, circulating tumor DNA, narrows things down, though in the oncology literature cfDNA and ctDNA are used interchangeably, says Dr. Erlander. “But ctDNA is the only way I can think about it,” he says. The other term is simply too broad, to his mind. “If you run around talking about cell-free DNA, there are lots of different kinds. So what one are you talking about?”

“There are a number of takes on what we mean when we say ‘liquid biopsy,’” agrees Dr. Kaul.

Dr. Erlander

Dr. Erlander

A brief jog through history provides some clarity. When DNA- and RNA-based molecular pathology took off in the mid-1990s, Dr. Kaul says, it gave pathologists the ability to look for circulating tumor cells in blood. It didn’t take long for physicians to envision how this might yield deep insights, along the lines of discovering the migration pattern of a rare, secretive bird: Imagine following a tumor as its cells entered the bloodstream, circulated, landed, and grew into a metastatic lesion.

“In theory, this was very, very plausible,” says Dr. Kaul. “In practice, it was more difficult.” Early methods allowed pathologists to identify cells present in tiny numbers. “It was pretty much a rare event analysis,” Dr. Kaul recalls. “But it didn’t tell us much about the capacity of that cell to form a metastatic lesion. I suspect there are a variety of cells that get into the bloodstream.” Whether they can metastasize is another matter. “We don’t really know what the markers are that convey that capability.”

Two decades later, molecular pathology shows no sign of stagnating. Next-generation sequencing, in particular, has revolutionized pathologists’ understanding of which mutations are important in cancers, and new tools are being applied to blood and urine samples. Hence, “liquid biopsy.” Dr. Kaul adumbrates three different target types:

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