1. Wysong, Pippa

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There is buzz in oncology circles these days about the potential role of liquid biopsies in monitoring cancer treatment. Various products are already on the market, but is there too much hype and is it too early for the tests to be widely used in practice?

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Indeed, the abstract book for the 2019 ASCO Annual Meeting listed hundreds of studies of both cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) demonstrating how active the field is. The financial services firm Cowen & Co. were reported as saying that annual sales for the tools could surpass $10 billion as products come online. The Biotech Careers website lists more than 25 companies globally developing or already marketing liquid biopsy tests-and there are likely more start-ups in the pipeline.


"I'm very optimistic that this is going to be a great way to diagnose and manage cancer in patients," said Neal Lindeman, MD, Associate Professor of Pathology at Harvard Medical School. But he cautioned oncologists should have a well-defined purpose for using the test and know the limitations of the technologies. He is also a coauthor of ASCO's 2018 Expert Panel review of ctDNA analysis (J Clin Oncol 2018;36(16):1631-1641). He noted the field is changing so quickly, additional reviews will likely be released about every 2 years.


"Liquid biopsy is very appealing; we want to offer something to cancer patients. But I think we still need to prove that the analysis leads to patient benefit. It's coming, but not as widespread as the adoption is," he said.


Liquid Biopsy Basics

Instead of subjecting patients to surgical procedures to attain tissue biopsies, liquid biopsy technologies use samples of bodily fluids such as blood, urine, or saliva to detect material that is shed or released by tumors. Most of the "buzz" is around using blood samples.


There are three different approaches in the blood liquid biopsy realm, Lindeman told Oncology Times. One is tumor-specific cfDNA-essentially tumor DNA dissolved in solution. "A cancer cell somewhere dies and DNA gets released from the dying cell into the bloodstream as a dissolved molecule."


The second type of liquid biopsy detects circulating tumor cells, whole tumor cells that break off and enter the bloodstream. The third type, in even earlier phases of research, relies on detection of exosomal DNA, which contains both DNA and RNA from the tumor. Often any of the three types are referred to as ctDNA.


Liquid biopsies have various potential advantages over tissue biopsy. As well as avoiding invasive procedures, results would come in more quickly from the pathology lab. They show promise for helping with assessments of the overall amount of cancer in a patient as opposed to only what is sampled by a procedure. And, they would be an easy way to monitor treatment effectiveness.


The first applications for practice may be for the monitoring of cancers and as indicators of treatment success. However, the ASCO review noted that "currently there is a lack of rigorous evidence on clinical validity, let alone clinical utility, because few large, prospective validation studies have been performed on ctDNA-based monitoring."



At this point there are unresolved issues, including the fact there are a variety of approaches used in the technologies, Lindeman said. It's not known yet if one is better than another, plus standards and protocols haven't been developed. In addition, there are unknowns about the cancer cells themselves, what materials might release and when, and what it all means.


In addition, liquid biopsies have high false-negative rates. "If a sample comes back negative, a biopsy should be performed just to make sure there isn't an alteration or cancer present. We still don't completely understand how the DNA ends up in the blood. It could be that it's there at one point and not at another. It may be tempting to think it's gone, but that's not guaranteed." Lindeman noted that, with lung cancer, the false-negative is about 30 percent.


"If there is a positive result, you might prevent a biopsy, but I would not rely on a negative result," he said.


As tests become more sensitive, false-positive rates can rise and may detect signals from normal processes such as cell apoptosis, which have no clinical impact. Another complicating factor is that, in some cases, the same type of mutation can come from tumors in different locations. For example, "KRAS can be in colon cancer, lung cancer, or other areas. Or BRAF, which is in melanoma, can also occur in colon and lung cancer. Treatments might differ for different cancer types. A BRAF lung cancer would be treated differently than a BRAF melanoma," he said. One needs to be certain of tumor locations.



Sanjay Bagaria, MD, a surgical oncologist at the Mayo Clinic, concurs there is a lot of promise with liquid biopsies, but is also cautiously optimistic. Already, "there are patients who are having liquid biopsies done and oncologists are using it. Liquid biopsies are happening whether you like it or not. But you have to understand the limitations. I encourage oncologists thinking of using it to read the studies that are reporting on it and understand what the limits of those studies are, and whether it applies to their patients," he said in an interview with Oncology Times.


He is also coauthor of an editorial on ctDNA for colorectal cancer and believes most are using it in a metastatic setting (Front Oncol 2018;8:297). In the future, the tests may be useful for screening, but he noted the false-positive issues have to be sorted out.


The editorial noted that significant advances have been made in using ctDNA for detecting early-or late-stage cancers, predicting response to therapy, using changes in mutated ctDNA to modify systemic treatments, and for post-surgery surveillance, but added that "many of these studies are limited by their retrospective design and small sample size, and therefore the clinical utility of measuring ctDNA for colorectal cancer has yet to be established."


However, it noted "the advantages of ctDNA are promising, and with novel prospective, collaborative studies, the true benefits of ctDNA in colorectal cancer as well as other malignancies may soon become realized."


Pippa Wysong is a contributing writer.