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Grail’s Goal Is Early Cancer Detection

Illumina Inc., a major force in San Diego’s genomics industry, launched a spinout last month loaded with both cash and cachet. But experts say it’s destined for challenges on its quest for oncology’s “holy grail.”

The company, aptly named Grail, made headlines this month when it recruited a top Google executive, Jeffrey Huber, to take the startup’s helm.

The company just launched in January, when Grail came out the gate with $100 million in startup capital from big-name investors such as Microsoft founder Bill Gates and Amazon founder Jeff Bezos.

But the majority of that cash came from ARCH Venture Partners and Illumina itself, the world’s biggest maker of DNA sequencing machines. The San Diego company, currently valued at $23 billion, has expertise (and technology) that will lend itself well to Grail’s goals.

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Grail is developing a simple blood test that would detect cancer early. Really early. Potentially before a tumor — or any symptoms — are noticeable. The concept has piqued both medical and public interest, as such early detection of cancer could dramatically increase survival rates.

“We hope today is a turning point in the war on cancer,” said Illumina CEO Jay Flatley. “By enabling the early detection of cancer…we aim to massively decrease cancer mortality by detecting the disease at a curable stage.”

Rick Klausner, Illumina’s chief medical officer and a board member of Grail, has described the test as a potential preventative health service (think mammograms and other cancer screenings) that one day, it is hoped, will be offered as part of a health plan. The idea is seductive.

“Tests and tools that allow doctors to identify the presence of cancer at its earliest stages, before the disease has even begun to have serious effect, are absolutely critical,” said Dr. Scott Lippman, an expert in cancer research and treatments at the University of California, San Diego and director of its Moores Cancer Center. “The more precisely yet expansively they can informphysicians, the better the prognosis and outcome for patients.”

The company announced that the test could be available as early as 2019, costing individuals $1,000 or less. Illumina estimates the market value of those tests could be $20 billion to $40 billion if the test can detect stage 2 cancer. If the test can detect stage 1 cancer, the market value could reach $100 billion to $200 billion, the company stated.

Illumina clarified in a statement that it does not expect revenue from Grail in 2016, and expects the operations will dilute Illumina’s earnings per share by $0.15.

Is Blood Best?

Grail’s new test would be a new and improved liquid biopsy (tests that detect tumor cells and fragments of tumor DNA that have been shed into the blood). Grail is adding a “secret sauce” of analytical improvements to boost the test’s efficacy.

Liquid biopsy tests are increasingly used by doctors to guide cancer treatment once a patient has already been diagnosed. The tests often make it easier for doctors to choose personalized treatments for cancer, a disease that varies greatly from person to person. They can also help doctors monitor a patient’s response to a particular drug regimen.

But some are skeptical that the blood is the best place to look for tumor cells and fragments of tumor DNA.

“These DNA are genomically damaged, and so they are less healthy across the board,” said Toni Schuh, the CEO of liquid biopsy firm Trovagene Inc., in an interview last year. “They’re like little zombie cells: they grow fast, but die fast.”

Schuh said the damaged cells may be short in numbers, or difficult to capture as they drift throughout the blood. The urine, however, is another story. Schuh, whose company makes urine-based liquid biopsy tests, says tumor DNA lasts longer in the urine than in the blood. Collecting urine samples is easier than having blood drawn, and unlike blood samples, which must be refrigerated, urine can be shipped at room temperature.

Chirag Patil, a neurosurgeon at Cedars-Sinai Medical Center in Los Angeles who also researches precision cancer treatments, said he, too, was skeptical that blood tests are the way to go. He thinks morning urine, which has spent all night collecting DNA fragments, will eventually reveal better results.

At the recent JP Morgan Healthcare Conference, Flatley addressed these concerns.

“In the earliest stages of disease, so few molecules from the cancer are present that targeting any small set of mutations for detection fails, simply due to statistical sampling,” Flatley said. “That challenge drives the need to look across a very broad set of potential mutations and to sequence at extraordinary depth to improve the signal-to-noise ratio. Only Illumina can sequence at the price points necessary to enable the large-scale trials required to demonstrate clinical utility and to ultimately market a test that is sensitive and economical across the global populations.”

Overdiagnosis

If the skeptics are wrong, and Grail is able to produce a blood test that is 100 percent reliable at detecting cancer early, Grail still might have challenges ahead. For example, some are concerned that this kind of test, should it reach the market, could lead to the overdiagnosis of cancer.

After all, it’s possible that the test could uncover tumors that were never destined to spread or otherwise harm the patient. Or worse, it’s possible that the test could misdiagnose the patient altogether. Many cells, not just cancerous ones, have mutations that are also found in tumors that could mistakenly send up red flags. Screening could even lead to death or injury through unnecessary biopsies, surgeries, and drug regimens for people wrongly diagnosed or whose cancer might never have progressed.

Cancer treatment can be scarier for patients than the disease itself, said Keith Robison, a computational biologist with years of experience in genomics and drug discovery, most recently at Cambridge-based Warp Drive Bio. Robison considered the unintentional consequences of Grail’s potential cancer test in a recent blog post.

“Modern targeted therapies and immunotherapies are huge improvements on radiation therapy or cytotoxic chemotherapy, but are hardly benign,” Robison wrote. “Immunotherapies are amazing, often resulting in cures, but torquing up the immune system can also induce autoimmune disorders. So do you treat healthy individuals with these powerful agents just because they seem to be shedding EGFR mutant DNA? Do you send the patient for PET imaging? If they are shedding KRAS mutant DNA, for which no treatment exists at the moment, what do you do? If the liquid biopsy screams “cancer” but it can’t be found by other approaches, does an otherwise healthy patient go on chemotherapy? Or do you just watch and wait?”

Proving It

Robison’s questions are shared by experts in the field, which is why regulatory agencies are carefully monitoring companies developing cancer detection tests.

One San Diego company, Pathway Genomics, last year began offering a liquid biopsy test aimed at detecting early-stage cancer. The U.S. Food and Drug Administration almost immediately challenged the company, saying the test needed regulatory approval. The agency, in a letter to the company in September, also said that it had not found “any published evidence that this test or any similar test has been clinically validated as a screening tool for the early detection of cancer.”

Grail must also prove to doctors, patients, health regulators and insurers that its high-tech test actually results in better outcomes for patients. And it has a plan for that, according to Illumina’s CMO Klausner.

Confirmation First

In the first phase of the test’s launch, the company will only test people who have been screened with other methods first — such as a mammogram for breast cancer or a CT scan for lung cancer — and found something suspicious. Instead of heading right to a knife-and-scalpel biopsy, they could do a confirmatory test with Grail’s product.

Clinical studies to prove the confirmatory test’s worth should only take a matter of months, Klausner told business tech website Xconomy, because healthy people are getting screened for cancer all the time. If immediately after a positive screen the patient takes a Grail blood test and also submits a tissue biopsy, then 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.

The second phase of proving Grail’s blood test will require partnering with a large national government that has single-payer health care, Klausner said. Grail’s experimental test would become part of the national health program. That process would lead to massive amounts of data — the whole genomes of hundreds of thousands of people — that Grail hopes would prove the test’s utility.

Despite possible hurdles along the way, Grail has incited a lot of excitement around its cancer detection test. With the backing of Illumina, the company’s majority owner and the provider of useful discounted technology, Grail might have the cash and horsepower it needs to overcome its challenges.

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