Hope and Hype Push Liquid Biopsies in Oncology

Damian McNamara

March 05, 2016

LA JOLLA, California — Liquid biopsies — blood tests that can detect circulating tumor DNA — could help detect cancer more accurately, guide individualized therapy, and better monitor patients' progress during treatment if they live up to their promise, said experts speaking here at the Future of Genomic Medicine (FOGM) IX.

However, it is early in the game, and researchers are still wrangling with specificity and identifying the most clinically relevant genetic variants to target.

The question is, "How can this be useful for patients?" said Victor Velculescu, MD, PhD, from Johns Hopkins University in Baltimore, Maryland. "One way is monitoring during therapy: real-time monitoring could be huge in terms of changing therapy and saving money on drug development."

"This is kind of a 'brave new world' we're entering," said Helmy Eltoukhy, PhD, cofounder and chief executive officer of Guardant Health, a Redwood City, California, company that produced 20,000 liquid biopsy tests in 2015. Guiding late-stage cancer treatment and a role in surveillance for recurrent malignancy will likely be the first applications, followed by early-stage detection in the future, he predicted.

Treatment response will be the most valuable aspect for patients and physicians, said Dr Eltoukhy. "Our viewpoint is there are a lot of tools, and the gold standard is not tissue biopsy, the gold standard is not liquid biopsy — the gold standard is clinical response."

Location Matters

Evaluating cell-free DNA in a blood sample offers a potential solution to an existing challenge. "It's going to be remarkable," said Dr Velculescu. "You can see things in the plasma that are not present in the tissue, perhaps because of heterogeneity of tumors," he explained. In other words, the same tumor in the same patient can yield differing results from a tissue biopsy, depending on where a clinician takes it, whereas circulating tumor DNA could reveal a more comprehensive makeup.

Location also counts with liquid biopsies. On the plus side, they could provide answers for the up to 40% of patients who cannot get a tissue biopsy because of the location of their tumor, said Dr Velculescu. However, some types of brain tumors might be harder to detect, presumably because of the blood–brain barrier, he explained.

Although improving sensitivity of liquid biopsies is still a work in progress, these assays are highly specific, Dr Velculescu added. "There are many tests out there that are not very specific. One of the beauties of circulating DNA is that it comes from a clone, so it's very specific to a neoplastic disease."

Dr Eltoukhy said accuracy remains a challenge, but added that among the first 10,000 samples evaluated with his company's tests, detection rates were in the 70% to 80% range, with the exception of gliomas. "That's higher than we expected."

Improving Precision of Immunotherapy

The search for somatic mutations unique to tumors is essential, and researchers are comparing tumor and nontumor analyses to find answers. "One can use these mutations for immunotherapy," said Dr Velculescu. "But can we do a better job of predicting which patients are more likely to respond?"

Once researchers identify all the somatic mutations, the next step is finding the subset likely to produce a higher treatment response. Patients with a high number of unique somatic mutations would be expected to elicit a high response to therapy, he explained, as reported by other researchers in the June 25, 2015, issue of the New England Journal of Medicine.

"There are extremely exciting opportunities in immunotherapy today that none of us can ignore," Dr Velculescu said. "Every one of these tumors has a mutation that could be targeted by the immune system."

Superlative Surveillance?

Compared with traditional posttreatment recurrence surveillance, liquid biopsies could provide answers faster. Instead of waiting 9 months for a tumor to appear on imaging, liquid biopsies could detect recurrence in as little as 3 months. "This gives you 6 more months to intervene," Dr Velculescu said.

"It's an extremely exciting space. Probably the most interesting will be surveillance for individual treatment monitoring over time," said Ali Torkamani, PhD, from Scripps Translational Science Institute in La Jolla, California, when asked by Medscape Medical News to comment.

"We may be able to detect recurrence earlier. [Tumor] DNA shows up in the blood early, and 6 months later, the mass shows up." Clinicians do not have a lot of information that early detection of recurrence changes long-term outcomes, he added, but in colorectal cancer, "intensive surveillance improves survival to some degree."

 
The cost has to come down dramatically from where it is today, from $5000 to a few hundred dollars. Dr Helmy Eltoukhy
 

During a panel discussion, Eric Topol, MD, from the Scripps Translational Science Institute and editor-in-chief of Medscape, pointed out that cost is one of the biggest obstacles still to overcome.

"We really believe in walking before you can run," said Dr Eltoukhy. "We're thinking about reimbursement to make this more clinically useful...so no late-stage cancer patient would be denied when they need it most. The cost has to come down dramatically from where it is today, from $5000 to a few hundred dollars, so we need economies of scale."

He added that he does not believe cost will be the stumbling block, but rather, "understanding how clinicians and patients will use the information will be the longer-term [concern]."

The Long-term Vision

With more than 1000 patients now in clinical utility studies, Guardant Health is amassing useful data, Dr Eltoukhy said. "We're finding new mutations that have not been reported and are working with a pharmaceutical company [to develop therapies]."

The longer-term vision is to detect patients with cancer at an earlier stage, effectively transforming patients who would be diagnosed at stage IV to stage II patients, for example. "Targeted therapies and surgery would be much more effective in earlier disease," said Dr Velculescu.

"Most early-stage patients do not get adjuvant therapy," he added. "Wouldn't it be nice to look in the plasma after surgery for an indicator of how these patients will do?"

Dr Velculescu is founder of Personal Genome Diagnostics and is on the advisory board for Janssen Diagnostics. Dr Eltoukhy is chief executive officer and cofounder of Guardant Health. Dr Torkamani had no relevant financial disclosures. Dr Topol is editor-in-chief of Medscape and host of Medscape One-on-One, in which he converses with the most interesting people influencing medicine.

Future of Genomic Medicine (FOGM) IX. Presented March 4, 2016.

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