Blood Simple? Grail’s Cancer Screening Quest Faces Tough Questions

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is sampling your blood, not taking a tiny snapshot” with a small blood draw, says Patil. (He thinks morning urine, which has spent all night collecting DNA fragments, will eventually reveal better results.)

At Johns Hopkins School of Medicine in Baltimore, a research team reported in a 2014 paper that the smallest tumors shed enough DNA into the blood to be detected about half the time. Klausner says pushing the number higher than that isn’t the main goal. “The challenge is not whether you can you find every cancer,” he says. “The most challenging thing is detecting the difference between the cancer we care about and the overdiagnosis of cancer,” which is shorthand for mistaking for dangerous cancer either tumors that aren’t destined to be dangerous or things that look like cancer but aren’t.

Healthcare providers are becoming more sensitive to cancer overdiagnosis and the resulting overtreatment. In prostate cancer, for example, clinicians are already building programs to divert patients with likely nonthreatening tumors away from treatment and into a monitoring program. Even though Behfar Ehdaie, a urologic surgeon at New York’s Memorial Sloan Kettering Cancer Center makes his living removing men’s prostates, he eventually wants to see 60 to 70 percent of his patients moved instead into the hospital’s “active surveillance” program.

Which cancers to treat and which ones to just keep an eye on is just one of a bevy of medical questions raised by the prospect of a screening test like Grail’s.

What about the tests that don’t pick up anything? Does that mean someone is cancer free?

“As clinicians we need to avoid false reassurance,” says Joshua Schiffman, a pediatric oncologist at the University of Utah. He specializes in treating families with high cancer risk, including Li-Fraumeni Syndrome, in which a genetic mutation means carriers have a nearly 100 percent chance of getting cancer in their lives.

Or what if a patient’s blood screen picks up a cancer DNA signal, but a follow-up image test shows nothing?

When asked a similar question last month on a conference call, Illumina CEO and Grail chairman Jay Flatley said perhaps the patient simply gets monitored, or retested three or six months later “to measure the rate of change of the overall mutation in the blood.”

“It could be that rate of change determines when you need to begin treating it, or if you ever need to begin treating it, because in some cases these mutations exist and the body is handling it and the cancer will never become lethal,” said Flatley.

It’s unclear if Grail knows more about that rate of change concept than it’s letting on. Beyond one data fragment revealed last month—Flatley said Illumina has an assay that can pick up from a single tube of blood 88 percent of cancerous mutations typically found in lung cancer tissue samples, better than previous attempts—no one is saying much about what’s under the hood. “People who haven’t seen the data will be skeptical, and those who have seen it, joined the Grail scientific advisory board,” says Bob Nelsen of Arch Venture Partners, a Grail investor. (I reached out to all five non-Illumina SAB members; those who responded declined to comment on the Grail data.)

Klausner did describe, however, the data that turned him from skeptic to believer. They came out of a prenatal test from Verinata Health, a company Illumina bought in 2013.

The test was picking up advanced and previously undetected cancer in pregnant women who were checking the health of their babies. It was a small number, says Klausner, but “consistent” with what statistics would predict in that particular group of women. The light bulb went on, he says, when there were no false positives among the 150,000 women tested. Blood tests had the potential to make the right call—at least with advanced cancers.

Despite the new competition, some liquid biopsy companies I spoke with were excited to see how Grail makes out. “I’m a fan of the effort,” says Andre Marziali, CEO of Boreal Genomics in Vancouver, BC, which provides underlying technology for liquid biopsies but doesn’t intend to market tests on its own. He says Grail will collect an enormous amount of clinical data, more than any other entity could do. Whether its test becomes a good business or not, “Grail will accelerate the arrival of ctDNA screening,” says Marziali, using the shorthand for “circulating tumor DNA.”

Victor Velculescu, one of the Johns Hopkins researchers at the forefront of liquid biopsy research—and a co-interim CEO of Hopkins spinout Personal Genome Diagnostics—says the arrival is just a matter of time. “Within five years one can expect some sort of clinical test to be available for healthy populations,” says Velculescu.

New technologies often acquire an aura of inevitability. It’s important that checks and balances are put in place to ensure liquid biopsies that screen healthy people actually work. Because, as we learned from the prostate test, better health through screening is not inevitable, as Memorial Sloan Kettering urologist Behfar Ehdaie notes: “Probably one million men in the PSA era have gotten surgery that did no good, at best, or perhaps did them harm.”

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