THE LATEST IN CANCER DIAGNOSTICS
Hearing the words “it might be cancer” paired with your doctor’s perplexed look is enough to send shock waves through your body. Getting to the heart of a diagnosis usually requires a surgical biopsy—removal and examination of the suspected tissue for visible signs of cancer.
Less invasive diagnostic tests—called liquid biopsies—might just bring more choices to doctors and patients. They are becoming today’s reality thanks to our ability to isolate molecules from body fluids. These diagnostic innovations pair technology with the latest in biomarkers, and are rapidly gaining acceptance as a reliable way to screen for cancer and to monitor disease progression and response to treatment. This week we’ll examine the different types of liquid biopsies and how they work.
TERM OF THE WEEK: LIQUID BIOPSY
A liquid biopsy is a test that is able to detect the presence of cancer using blood, urine, saliva, or other bodily fluid as the sample rather than tissue from a specific organ. The technique is possible because cancerous tissues shed cells, DNA, and tiny lipid-encased compartments called exosomes. Liquid biopsies detect the presence of these cancer-associated biomarkers.
DISCOVERY BY CELL-FREE DNA
When cells in the body die, they release cell-free DNA (cfDNA)—this includes dying tumor cells. cfDNA-based tests are a type of liquid biopsy because they seek out a biomarker – in this case, tumor DNA – in body fluids and then identify cancer-specific mutations using PCR or next-generation sequencing analysis.
Trovagene (San Diego, CA) analyzes cfDNA found in urine samples, which patients collect at home. Currently, Trovagene has tests detecting mutations associated with melanoma, colon cancer, and non-small cell lung cancer, as well as the presence of viral DNA for the diagnosis of human papilloma virus. Exact Sciences Laboratories (Madison, WI) uses at-home collection in their colon cancer test, which analyzes cfDNA in stool samples for cancer-associated DNA.
Genomic Health (Redwood City, CA) currently markets tissue-based genomic tests for the detection and classification of breast and prostate cancer, and is developing cfDNA-based tests for breast (blood sample) and bladder (urine sample) cancers.
Qiagen (Hilden, Germany) is developing cfDNA liquid biopsy diagnostics in partnership with pharmaceutical companies such as AstraZeneca (London, U.K.), Tokai Pharmaceuticals (Boston, MA), Novartis (Basel, Switzerland), and Eli Lilly (Indianapolis, IN).
Exosomes are lipid-encased vesicles that contain cellular protein, DNA, and RNA and typically have surface proteins specific to their native cell. These attributes, combined with the fact that they are found in many different body fluids, make exosomes a very attractive possibility for liquid biopsy. The idea is to capture exosomes based on tumor-specific surface markers or to collect exosomes and identify them as cancer-associated by examining the enclosed DNA or RNA.
Aptly named Exosome Diagnostics (Cambridge, MA) has an exosome-based urine and blood tests for prostate cancer on the market, and another in development for lung cancer. Qiagen has a partnership with Exosome Diagnostics to help develop additional exosome-based cancer diagnostics to complement their work with cfDNA.
CONSIDER CIRCULATING TUMOR CELLS
The final category of liquid biopsy is perhaps the most obvious—circulating tumor cells (CTCs), or cells splintered from a tumor and circulating in the bloodstream. The challenge lies in detecting CTCs: some estimates classify them as rare as one circulating tumor cell per billion normal cells!
Janssen Diagnostics (Raritan, NJ) currently markets CellSearch, the single FDA-approved test that allows physicians to identify early CTCs from blood samples. Monoclonal antibodies (mAbs) capable of recognizing proteins on the surface of migrating tumor cells are chemically linked to magnetic nanoparticles and then added to a patient’s blood sample. These tumor-specific mAbs grab hold of the CTCs, and a strong magnetic field is then applied to the sample, isolating the captured cells for identification and analysis. CellSearch is currently used to monitor the efficacy of treatments for breast, prostate, and colorectal cancer. A higher number of CTCs detected may indicate a higher incidence of metastasis, or a less than effective treatment route if used to quantify cancer therapy success.
Another way to identify CTCs may be cell size—CTCs tend to be significantly larger than other cells in the blood, and this size differential may be exploited in a microfluidics-based approach to cell separation. Researchers at National University in Singapore (Singapore) and MIT (Cambridge, MA) have developed a microfluidics chip that routes cells from a blood sample into different channels based upon cell size. Although still in the preclinical research phase, this approach shows promise for capturing a wide range of CTCs.
Epic Sciences (San Diego, CA) adopts a “no cell left behind” game plan thanks to technology developed by the Scripps Research Institute (La Jolla, CA). Automated fluorescence-microscopy identifies the CTCs in blood samples placed on microscope slides. A detailed analysis of three million cells per slide is performed, each blood sample yielding approximately twelve slides. This technology may potentially hone in on the presence of a single CTC. Epic Sciences’ CTC-detecting platform is used by Genomic Health in their Oncotype-Dx AR-V7 Nucleus Detect test, which determines whether or not prostate cancers patients’ tumors have developed mutations that make them resistant to common types of treatment.
Ultimately, the best liquid biopsies may contain a combination of all the above approaches. Biocept (San Diego) is leading the way by developing liquid biopsies that analyze both cfDNA and CTCs. Biocept currently markets liquid biopsy tests for the detection of lung cancer, breast, colorectal, gastric, prostate, and melanoma. Biocept also has its eye on combination liquid biopsies for both colon cancer and melanoma.
Today, liquid biopsies are mainly used for monitoring the progress of or response to treatment of already-diagnosed cancers rather than as initial diagnostic tests. A major goal in the field is to develop tests that can be used routinely to detect cancer in seemingly healthy people, which should translate to better treatment outcomes. Research published by a group at Johns Hopkins University (Baltimore, MD) in January 2018 suggests that a liquid biopsy test that detects both cancer-associated cfDNA and proteins known to be characteristic of certain types of cancer may be better at detecting cancer early on than those that look at just one biomarker. Dubbed Cancer-SEEK, the tool is capable of detecting a number of different cancers, including ovary and liver, and may soon begin testing as a screening tool.
As the technologies to detect cfDNA, CTCs, and cancer-specific exosomes progresses, we can expect to see an increasing number liquid biopsies available, making the detection and treatment of a range of cancers less invasive and more manageable.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.