The Holy Grail of Liquid Biopsies

A new venture aims to screen for cancer with a simple blood test.

Imagine going for your annual medical checkup a few years from now. Your doctor requests a blood sample for the usual routine screening — cholesterol, triglycerides, enzymes, and so on. But now (s)he’s telling you about a new test, one that detects vanishingly small quantities of DNA that circulate in the blood. Capturing and sequencing this free-floating DNA — commonly referred to as a “liquid biopsy” — can reveal the first telltale traces of cancer, long before any other symptoms become manifest.

Liquid biopsies aren’t brand-new. For those who already have cancer, the technology is currently being used to help determine treatment options, assess how well a treatment is working, and predict whether cancer will return or how it will progress.

But the potential of the liquid biopsy is suddenly front-page news, thanks to an announcement last January by Illumina, the powerhouse genomics company. Illumina’s chairman and CEO, Jay Flatley, said he would spin off a $100 million-plus company, fittingly called Grail, to commercially develop liquid biopsy technology to screen for cancer in asymptomatic people. Grail made a splash in part because of the pedigree of its investors, who include Bill Gates and Amazon CEO Jeff Bezos. It’s a further testament to the plummeting cost and increasing accuracy of DNA sequencing, which has already spurred major advances in cancer detection.

If successful, the precious advance warning provided by a liquid biopsy could make a profound difference in the likelihood of a successful cancer treatment, minimizing cost and debilitating side effects and saving many lives in the process. But all that has to be proven in the clinic. And history shows that cancer screening, such as the ubiquitous PSA (prostate specific antigen), is not always the beneficial advance it might appear.

A liquid biopsy has the makings of a simple general screening tool that could be applied across the entire population, not just to those who harbor an increased cancer risk.

The seeds of Grail were sown in 2013, when Illumina made two key acquisitions. The first was Verinata Health, Inc., a company developing a noninvasive prenatal test (NIPT) technology for pregnant women to detect conditions such as Down syndrome. But in some cases, the test was also able to pick up traces of cancer DNA in the mother’s blood. Those results excited Rick Klausner, the company’s second acquisition. He is the former director of the National Cancer Institute who joined Illumina as chief medical officer later that year.

With a market opportunity valued well into the billions — the estimates range from $20 billion to $200 billion — the early detection of cancer cells had been attracting rabid commercial interest even before Grail arrived on the scene. In Hong Kong, NIPT pioneer Dennis Lo is leading clinical studies for a specialized liquid biopsy to detect early stages of nasopharyngeal cancer, which is frequently associated with males who have been infected with the Epstein-Barr virus. In tests of 10,000 men, Lo’s team was able to spot more than a dozen early stage cancers by detecting the viral DNA leaking out of dying cancer cells, providing a window for successful treatment with targeted radiation.

As for more general liquid biopsies, a key advance came in February 2014 from a team at Johns Hopkins Medical School, including famed cancer researchers Bert Vogelstein and Kenneth Kinzler. They reported that they could detect and amplify tiny amounts of circulating tumor DNA (ctDNA) in the blood of hundreds of patients with both early stage and advanced cancers. The Hopkins team found ctDNA in more than 75 percent of patients tested, including cases of breast, ovarian, pancreatic, colon, bladder, liver, and other tumors. Using DNA sequencing, the Hopkins team was also able to identify known cancer mutations in key oncogenes in the ctDNA from patients with metastatic cancers.

For Vogelstein, who had lost his brother to skin cancer the year before, there is an urgent need to improve cancer detection and prevention. A liquid biopsy has the makings of a simple general screening tool that could be applied across the entire population, not just to those who harbor an increased cancer risk. Vogelstein estimates that cancer DNA could be detected when a tumor is about the size of a pinhead — some 10 million cells (at least one billion would be necessary before a tumor showed up on a typical scan).

Illumina has tapped former Google executive Jeff Huber to direct Grail’s quest for the perfect cancer diagnostic. Huber’s appointment came just three months after he lost his wife, Laura, to colorectal cancer. In an interview with Matthew Herper, of Forbes, Huber said that if Grail had existed previously, “there’s a very good chance that the outcome for her could have been different. She could have had surgery before it spread, or she could have gotten treatment before it evolved and mutated [or] before it became more aggressive.”

I should note that not everyone is jumping on the ctDNA bandwagon. Studying ctDNA “doesn’t tell me anything about the biology of the living tumor,” says Mass General Hospital oncologist Dan Haber. Together with his colleague Mehmet Toner, a professor of surgery (who some say coined the term “liquid biopsy”), Haber has been developing a device called the CTC-iChip that identifies tumor cells from the blood.

Meanwhile, a coast away, Huber intends to launch liquid biopsy clinical trials as soon as 2017 and is targeting a commercial launch in 2019. But this will be no easy path. The price must be low enough for the test to be used as a general screening tool. Moreover, can a liquid biopsy truly be 100 percent accurate? Can it distinguish aggressive tumors from slow-growing cancers that need a more watchful approach? And how will doctors pinpoint the location of the tumor from ctDNA? One exciting possibility, recently outlined by Jay Shendure and colleagues at the University of Washington, is to infer the tissue of origin from the telltale spacing and patterning of the proteins around which DNA is packaged.

I just hope the quest to develop a reliable, exquisitely sensitive, and affordable cancer diagnostic won’t prove as elusive as the Grail itself.