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

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pan-cancer tests for broad swaths of the population could be available in 2019 for $1,000, perhaps less. Here’s their plan.

Phase one has a narrower focus, to test only people who have been screened with other methods—for example, a mammogram for possible breast cancer, a CT scan for lung cancer, or PSA for prostate cancer—that have found something suspicious. Instead of heading right to an invasive biopsy, they could do a confirmatory test (also known as a reflex test) with Grail’s product. Reflex tests could become available in the next year or two, says Klausner.

Near-term clinical studies to prove their worth should take months, not years, he says, because healthy people are getting screened for cancer all the time with mammography, PSA tests, and the like. If immediately after a positive screen they take a Grail blood test and also submit to a tissue biopsy, Grail can compare results. If the tissue and liquid biopsies match up over hundreds, even thousands of patients, it might be evidence enough to justify diverting people away from tissue biopsies after a negative liquid biopsy.

Grail is already talking to “a variety of partners” to set up those studies, says Klausner.

Phase two—far more ambitious—is proving Grail’s blood test should be used to screen for a cancer in a wide healthy population, not just as a follow-up for those who’ve already had a positive mammogram, CT scan, or PSA test. To do so, Grail wants to partner with a large national government—perhaps more than one—that has single payer healthcare, Klausner says.

The Grail test would become part of the national health program, just as an experiment, at first. That process would then lead to huge reams of data—the whole genomes of hundreds upon hundreds of thousands of people—that Grail hopes would prove the test’s utility.

The massive trial would hinge upon a concept called “stage shift.” The medical field measures a cancer’s size and reach in stages. Stage one is the smallest and most contained, and stage four typically means it has spread throughout the body and is nearly always fatal. Grail wants to detect people’s cancer at the lowest stage possible—shift the detection from higher to lower stages—because, Klausner says, a lot of data suggest doing so means better outcomes.

The broad outline from Klausner goes like this: Test as many people as possible to get baseline numbers on how many people have stage one cancer, how many have stage two, and so on. Those who test negative get follow-up tests at regular intervals. Over time, if the screen works as hoped, the cancers found during each follow-up round will exhibit a stage shift: an increase in stage one and two cancers and a decrease in stage three and four cancers, which implies that by catching (and treating) the lower-stage tumors the program is preventing some high-stage tumors from developing.

There are big logistical and statistical caveats with this approach.

When testing for a stage shift, finding more cancers earlier is only relevant if the number of late stage cancers does, in fact, go down, says Barry Kramer, director of the Division of Cancer Prevention at the National Cancer Institute. If there is little or no decrease in late stage disease, he says, there is probably no reason to use the screen. In other words, the shift must be absolute, not relative, to be promising. The difference in practice is subtle and tricky to tease out, says Kramer.

Klausner understands the danger—“we’re not naive about these problems”—and says Grail will indeed test for an absolute, not relative stage shift.

[This paragraph previously said Grail “will not” do a randomized trial. It has been changed to reflect more uncertainty. We apologize for the error.] But Grail isn’t likely to do what many, including Kramer, say is the best way to know if a screening method is doing more good than harm: randomized controlled trials measuring a test’s effect on patients’ mortality. “Speaking very generally, the accepted measure of screening’s effectiveness is preventing or delaying deaths,” says Donald Berry, a biostatistics professor at University of Texas M.D. Anderson Cancer Center and a member of Grail’s advisory board.

Berry declined to comment on Grail’s plans specifically. But Klausner said he doubts Grail will design randomization into its trial, adding that randomization isn’t necessarily the best way forward in a massive population study. Details of the trial design will emerge over the next year, he says, after input from Grail advisors like Berry and from “the broader medical community. It will be an exhaustive and interactive process.”

And while measuring the effect of the screening test on mortality is still a long-term goal for the Grail study, Klausner has his eye on a nearer horizon: stage shift data that are so dramatic that the medical community is convinced to adopt the test by 2019.

It’s a shockingly ambitious timeframe, possible to even contemplate because Grail has the backing of Illumina, its majority owner and provider of discounted technology, and the financial backing of some of the world’s richest people. They’ll need the horsepower and cash to crunch the entire genomes of hundreds of thousands of people with “ultra deep”—read “extremely redundant and extremely expensive”—sequencing.

Not everyone is convinced the technology—including what Klausner says is a “secret sauce” of analytical improvements—can find the right bits of DNA sloughed off by tiny tumors into a patient’s bloodstream. “You’re saying a few million cancer cells [in a microscopic tumor] will have shed exactly the four or five mutations you need to look at,” says Chirag Patil, a neurosurgeon at Cedars-Sinai in Los Angeles who also researches precision cancer treatments.

To consistently find those multiple mutations, “you’d have to have a breakthrough technology that in real time … Next Page »

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