Chris Anderson

Liquid Biopsy Has Proven Its Mettle in the Fight against NSCLC and May Soon Also Be Standard of Care in Other Cancers

It is likely one of the longest periods of foreshadowing in science. In 1869, Australian physician Thomas R. Ashworth first observed circulating tumor cells (CTCs) in one of his patients and suggested the treasure trove of information they might contain. “Cells identical with those of the cancer itself being seen in the blood may tend to throw some light upon the mode of origin of multiple tumours existing in the same person,” he surmised in his research paper “A case of cancer in which cells similar to those in the tumours were seen in the blood after death” published in the Australian Medical Journal.

For more than a hundred years, the promise of using circulating tumor cells as a key to help unlock the secrets of cancer and, more importantly, metastatic cancer, remained a tantalizing possibility. It wasn’t until the 1990s that technology was finally created that could capture CTCs in the blood, and later, CellSearch became the first FDA-approved diagnostic device, which separated and enumerated CTCs to be used as a prognostics tool to predict survival of patients with prostate, colorectal, and breast cancers.

Since then, novel methods for capturing CTCs, and the vastly improved technology for genomic sequencing of not only the DNA of CTCs, but also of circulating tumor DNA (ctDNA), have accelerated both the technological development of liquid biopsies and their adoption as a diagnostic tool in the clinic. This elevation from technology with promise, to one that is playing a vital role in the fast diagnosis of metastatic cancer has occurred with lightning speed.

According to David Brunel, CEO of blood-based diagnostic company Biodesix, as recently as five years ago the tools for a liquid biopsy were not yet robust enough for prime time, and while intriguing, were also very costly. “At the time, we were just entering the heyday of targeted therapies, where the measurement of an actionable mutation would have a targeted drug. Since all that work was done in tissue, there was skepticism about liquid biopsy,” he said.

The questions about the utility of liquid biopsy included whether enough relevant material was shed into the blood, and whether that amount was easy to detect and assay. Furthermore, tissue biopsy has long been the gold standard for testing, and is well understood. At the time the consensus was that “anybody who wants to do a liquid biopsy needs to prove it is at least going to be as good as what we are currently using,” Brunel noted.

Today, amid significantly improved collection and analysis techniques, Helmy Eltoukhy, Ph.D., CEO of Guardant Health, says the adoption of liquid biopsy has followed the same adoption curve as other disruptive technologies, and agrees with Brunel’s assessment.

“When you look at the revolution from wired to wireless technology, wireless only took off when it could provide the same experience and the same capabilities that its wired counterparts could,” Dr. Eltoukhy said. “It is the same thing we see with liquid biopsies—that critical inflection point was getting to a level of performance tantamount to the tissue counterparts.”

Liquid Biopsy in Clinical Care

While academic medical centers have been exploring the practical uses of liquid biopsy, and momentum has been building for a few years, work published last April in JAMA Oncology by Geoffrey Oxnard, M.D., and colleagues at Dana Farber Cancer Institute on the use of droplet digital polymerase chain reaction (ddPCR) for liquid biopsy in non-small cell lung cancer (NSCLC), clearly moved the needle toward application of the technology in the broader medical community.

The research, which compared results of liquid biopsy to standard tissue biopsy for the detection of EGFR and KRAS mutations, found the “predictive value” of plasma ddPCR was 100% for the primary EGFR mutation and the KRAS mutation. In other words, a patient who tested positive for either of these two mutations was certain to have that mutation in their tumor. For patients with the EGFR resistance mutation, the predictive value of the ddPCR test was 79%, meaning the liquid biopsy method found additional cases with the mutation that were missed using standard tissue biopsy.

“There is the possibility that by checking [NSCLC patients] this way to see if they are EGFR mutant or whether they have a KRAS mutation, will give you insight to about half the patients that walk in the door within, potentially, a couple of days,” said George Karlin-Neumann, Ph.D., director of scientific affairs at the Bio-Rad Digital Biology Center. “Speed can be important in getting patients treated weeks, or maybe a month or more earlier, by doing the liquid biopsy.”

Paul Walker, M.D., chief of hematology/oncology at the Brody School of Medicine at East Carolina University had become increasingly interested in the application of liquid biopsy in his practice and noted that presentation of the evidence for its use in NSCLC at last year’s ASCO Conference in June pushed him and his colleague, pulmonologist Mark Bowling, M.D., to adopt a process similar to Dana Farber’s for their patients. (see sidebar)

“We started the program in March [2016],” Dr. Walker noted, “But with ASCO, the validation of liquid biopsy really crystallized my thinking that we were going to use it on everybody at the same time as the bronchoscopy. We often get the liquid biopsy back quicker than we do the tissue qualitative analysis.”

To date, Dr. Bowling said the care team has employed liquid biopsy on 194 patients with NSCLC, and in 37% of those cases, liquid biopsy has suggested ways in which to change the treatment regimen to more precisely address those patients’ disease.

While application of liquid biopsy to inform patient care is leading the way, work to validate and prove its clinical utility as a diagnostic, and monitoring tool is still emerging.

“There is the growing sense that in the years to come we will be doing more cancer types, looking for these mutations to see if this will predict not just molecular changes, but also cancer burden, which might mean you would be less reliant on things like CT scans or other ways of looking at cancer burden,” noted Harold Burstein, M.D., Ph.D., associate professor of medicine at Harvard Medical School and chair of the ASCO communications committee.

“Another story that is emerging—not routinely used in clinical practice, but is around the corner—is estrogen receptor mutations in ER-positive breast cancer,” said Dr. Burstein, who is also a breast cancer specialist at Dana Farber. “It is close to 40%, if not more, of tumors that have ESR1 mutations, which presumably accounts for a substantial fraction of the resistance to antiestrogen therapies.”

For metastatic breast cancer, he added, current practice to discover this information relies on complete biopsy of the metastatic site, which provides a number of hurdles, including the fact that a tissue biopsy only captures the cancer at a moment in time, from a single site, and will likely not find all actionable mutations due to tumor heterogeneity. Furthermore, the tissue biopsies are technically demanding and invasive, such that many patients are reluctant to undergo the procedure.

“Liquid biopsy really opens the possibility of a kind of real-time molecular analysis of the tumor to help inform treatment choices,” Dr.  Burstein concluded.

The Burden of Proof

Despite the success of employing liquid biopsy to inform clinical decision making for NSCLC, researchers, and liquid biopsy technology companies say it is still early days, and that both clinicians, and public and private payers will need compelling evidence of the technology’s mettle.

“I think the medical world everywhere is very conservative, and change is not particularly easy for them,” said Andrew Newland, CEO of CTC separation technology company ANGLE. “What we are doing at ANGLE is putting a lot of emphasis into clinical studies. It is too easy to think the standard of care will change unless we can provide extremely good evidence that has been accredited by institutions of very high caliber.”

Guardant Health is taking a similar tack in its approach to the market. To address this challenge, the company has recently struck partnerships with leading cancer centers such as MD Anderson and the Lurie Cancer Center of Northwestern University, to compile clinical utility data.

“There is a lot of excitement—and rightly so—with liquid biopsy. But, unfortunately, there is a difference between technology and actually changing the standard of care, and getting it reimbursed,” said Dr. Eltoukhy. “There is this talk of liquid biopsy being a $20 billion to even a $100 billion opportunity. But none of that is realizable unless liquid biopsies become a reimbursed—with reimbursed being the operative word—standard of care.

“It is not just at progression, or therapy selection, it is also multiplying that by all the different cancer types where you can do that—breast cancer, lung cancer, colon cancer, etc.—and then further multiplying that by looking at that in the adjuvant setting, first line, residual disease, monitoring, near adjuvant, and recurrent detection.”

In the short term, changes in how payers will reimburse for cancer panels and sequencing may lead diagnostic provides to only focus on those mutations that meet that burden of proof. Where companies providing these service were once reimbursed via code stacking for the related procedure, and may have sequenced for a broad range of tumor mutations, now they are only getting reimbursed for specific actionable mutations.

“Payers have worked toward having the codes changed away from a procedural base, toward an actual particular diagnostic,” said Brunel. “The MACs, more than the private payers, have recognized that there may be a use for broader panels in a triage setting, where you don’t really have many options left and you want to look at that tumor more broadly to see if there might be a mutation that would be targetable in a clinical study. There is going to be payment for panels, but it is not great, so there is more of an argument that needs to be made.”

Despite the need to untangle payment issues, Brunel thinks liquid biopsy is now poised to make a significant leap in adoption across all care settings, not just in academic medical centers.

“Right now, I think most clinicians would tell you liquid biopsy is ready for prime time,” he concluded. “Given turnaround time and access to material—i.e., the ability to draw blood and get a result—it is likely to become as prevalent as tissue.”

Both circulating tumor cells and circulating tumor DNA provide significant insight to each person’s disease and cancer progression. [ttsz / Getty Images]

This article was originally published in the March/April 2017 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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