This cluster of circulating tumor cells (CTCs, shown in red) originated from the blood of a breast cancer patient. Credit: Min Yu (Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC), National Cancer Institute/USC Norris Comprehensive Cancer Center

Liquid biopsies involve sampling and analyzing bodily fluids, such as blood, urine or saliva, to look for signs of cancer or other diseases. A range of disease biomarkers can be detected, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes and proteins. The information gleaned from liquid biopsies could help clinicians diagnose, monitor and treatcancer more efficiently, providing insights not possible with traditional surgical biopsies.

As part of its efforts in the liquid biopsy space, ANGLE has developed the Parsortix system. The technology captures CTCs from a blood sample and enables a variety of downstream analyses to be completed. In a recent study from the University Medical Centre Hamburg-Eppendorf, Parsortix was used to successfully harvest CTCs to investigate the causes of brain metastasis in non-small cell lung cancer (NSCLC) patients. We spoke to Andrew Newland, CEO, ANGLE, to learn more about the study, the challenges of harvesting CTCs and how the Parsortix system overcomes some of these challenges.Andrew also discussed the value of characterizing CTCs in clinical trials for new drugs. Anna MacDonald (AM): What advantages do liquid biopsies offer over traditional surgical biopsies? Andrew Newland (AN): Liquid biopsies are based on a blood test. This has multiple advantages but in particular: firstly they are non-invasive requiring only a simple blood draw and do not require an invasive surgical procedure, with the associated costs and potential complications. Secondly they can be repeated often to check on current status of the disease, and response to treatment, whereas the tissue biopsy can only be done once for a given cancer site. This enables personalized medicine with treatment tailored to the patients current condition. AM: Can you explain what circulating tumor cells are, how they can be used to detect and monitor cancers, and why they are so challenging to isolate? AN: CTCs are cancer cells that have left the primary site (or the secondary sites) and are circulating in the blood stream as seeds to spread the cancer in the metastasis process. If they can be captured and harvested for analysis, they can be investigated to determine the current status of the cancer. This provides the information needed for personalized treatment tailored to the patients current condition the right drug at the right time. The CTCs are challenging to isolate because they are very few in number, generally around one CTC for one billion blood cells. AM: Can you give an overview of how the Parsortix system works to capture and harvest CTCs? How does this approach compare to other methods? AN: The Parsortix system captures CTCs using a patented microfluidic structure which separates the CTCs based on their larger size and lack of deformability. Key advantages of the Parsortix system compared to alternative CTC approaches are that it is epitope-independent (does not rely on antibodies to capture CTCs) and captures all types of CTCs including those that are mesenchymal. It also allows easy harvest of the CTCs (recovery from the system) for analysis unlike filtration systems, which have the added problems of clogging up and lack of purity in addition to problems of harvesting the cells for analysis. AM: What benefits does it offer over biological affinity-based methods of CTC isolation? AN: The affinity-based systems are based on binding antibody-coated magnetic beads to the CTCs. These systems fail to capture the clinically significant EMTing and mesenchymal CTCs as they do not express the cell surface markers targeted by the antibodies. In addition, the antibody capture process kills the cells negating the ability to culture the CTCs and potentially changing the RNA and protein expression of the cells. AM: Parsortix was used in a recent study that investigated the causes of brain metastasis in NSCLC patients. Can you tell us more about the study and the significance of the findings? AN: Brain metastasis is where the primary cancer has spread to the brain. Treatment is difficult because it is not known how the cancer is developing in the brain and a surgical tissue biopsy to investigate this is too dangerous. It had been thought not to be possible to harvest CTCs from brain metastasis due to the blood-brain barrier. However University of Hamburg-Eppendorf demonstrated that this was possible using the Parsortix system. AM: ANGLE has recently applied for FDA clearance for Parsortix, for use in metastatic breast cancer. If approved, what difference could this make to patients and clinicians? AN: This would be the first ever FDA cleared platform for harvesting CTCs from patient blood for subsequent analysis. It would open up a whole range of possible diagnostic uses to tailor treatment for metastatic breast cancer patients, that can be validated with additional clinical studies. Despite being recommended in the US National Cancer Guidelines, 50% of MBC patients are too sick, the tumor too inaccessible or insufficient tissue is available for a successful tissue biopsy of the metastatic site. For these patients there is no current information on the cancer to guide treatment. A liquid biopsy would open up alternatives for these patients based on a simple blood test. All MBC patients would benefit from the potential to have repeat biopsies using the Parsortix system to tailor their treatment more effectively. The liquid biopsies can be used to determine whether a drug is being effective, to select which drugs would be effective and to monitor patients in remission to determine, in advance, whether there are signs indicating a risk of relapse. Such early detection may allow treatment to reduce relapse. AM: What value can the characterization of CTCs bring to clinical trials? AN: Analysis of CTCs in clinical trials for new drugs, may allow the identification of likely patient responders so that drugs can be targeted. CTCs enable DNA, RNA and protein analysis providing a more complete picture of the cancer than DNA analysis alone. CTCs may also reduce the time and costs of drug trials by providing early information on drug effectiveness as well as enabling faster enrolment. Liquid biopsies allow serial monitoring of patients over different time periods, which is not possible with tissue biopsies as these cannot be repeated. This longitudinal monitoring may provide more accurate and more timely information of the performance of the drug facilitating clinical trials. AM: In what areas do you envisage liquid biopsies are likely to make the most impact? Will there still be a place for surgical biopsies? AN: The Parsortix liquid biopsy is intended to be additive to surgical tissue biopsies. Tissue biopsies are the current gold standard and will likely continue where the tissue is accessible and the procedure not overly invasive. There is no expectation that liquid biopsy will replace tissue biopsy. Liquid biopsies will be used for repeat biopsies, which is not possible with a tissue biopsy (you cannot cut out the same tissue twice), to provide up-to-date information and where the tissue is inaccessible and/or the biopsy is overly invasive (such as brain metastasis). Andrew Newland was speaking to Anna MacDonald, Science Writer, Technology Networks.

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Exploring the Challenges and Opportunities of Harvesting CTCs - Technology Networks