When it comes to cancer, late stage diagnosis is correlated with less effective treatment and a poor prognosis. And while cancer research has mainly focused finding cures, there is an unmet need for diagnostic tools that allow for early detection of disease- at a time where there is a far higher chance of survival.
Conventional cancer screenings require surgery, and are often invasive and uncomfortable, resulting in patients being screened less often. For this reason, alternatives that allow for better patient compliance, as well as more informative and personalized cancer monitoring, are being investigated.
Next Generation Sequencing (NGS)
Now, the field of identifying biomarkers for the purpose of early cancer detection, often referred to as ?Liquid biopsies? may offer a non-invasive and easily assessable alternative to the traditional tissue biopsy. They rely on blood samples to analyze trace amounts of free floating tumor DNA that is present in the blood stream. And while liquid biopsies have been around for some time, the rise of genomics with the use of Next Generation Sequencing (NGS) has allowed for the genetic profile of cancer to be identified and used to detect disease early, as well as characterize specific tumor subtypes that allow for more efficient use of personalized and targeted therapies. 
With NGS and liquid biopsy technology, screening for cancer may become something that is easily and quickly done at a routine checkup. Researchers are currently working toward this vision, as well as studying novel ways to indicate early cancer through other body fluids such as urine, plasma, or even breadth.
At the 2016 American Society of Clinical Oncology (ASCO) meeting in Chicago, Ill (June 3-7, 2016) liquid biopsies were a topic of many presentations and abstracts, which show promising expectations for the future of disease detection, monitoring, and treatment. We sat down with several professionals in the field, who discussed the expectations for liquid biopsies, as well as provided interesting perspectives on some of the controversies that are currently surrounding the industry.
Circulating Tumor DNA (ctDNA) Screening with Guardant360
While still in the early stages, liquid biopsy evidence is being gathered for several cancer types. A study presented at an ASCO Oral Abstract Session on Monday, June 3rd showed evidence from one of the largest cancer genomic studies ever conducted, which included over 15,000 patients with over 50 different cancer types. In this study, somatic genetic profiles were determined by Guardant360 (Guardant Health Inc.), a highly accurate ctDNA NGS test that targets 70 genes. The data showed that a next generation sequencing analysis of circulating tumor DNA (ctDNA) from patients with advanced stage clinical cancer showed an overall accuracy of 87% when compared to previous results from tissue sequencing projects, and this was raised to 98% when blood tests were done less than 6 months apart.
Furthermore, this study demonstrated clinical utility among patients with lung cancer. Tissue was insufficient for testing or partially tested in 63% of the 362 patient group, but for these cases, ctDNA testing identified key genetic mutations at frequencies that were consistent with what is present in published literature. This provides these patients with an actionable target that they would not have otherwise been able to reach. Before this study, evidence had only been gathered from cohorts of small size, so a test of this caliber is adding a substantial amount of evidence for liquid biopsies. 
In mirror of the growth in the body of evidence for liquid biopsy, the technology is advancing rapidly as well. ?Lots of companies are working in the space, lots of academics are working in the space, and I think it?s going to revolutionize the way we analyze cancer and evaluate patients? stated Amit Kumar, PhD., the Vice Chairman of ITUS Corporation and Executive Chairman of Anixa Diagnostics Corporation.
Early Detection with Cchek?
Anixa Diagnostics is currently developing a platform for an inexpensive, non-invasive cancer screening blood tests for the early detection of tumor based cancers called Cchek?. Researchers at Anixa believe that Cchek? will be able to look for many cancer types, and the test has already shown to successfully indicate stage I and stage II breast cancer, which is a situation in which patients can still often be treated effectively. ?As we go forward we will continue evaluating other cancers,? stated Kumar, ?we will do larger numbers of tests, we will continue doing blinded studies, and then eventually submit this technology for FDA approval.? 
In addition to finding cancer at the optimal stages for treatment, testing for different mutations in the blood can allow for physicians to identify which patients may benefit the most from certain drugs or drug combinations.
For this reason, if incorporated in to regular practice, liquid biopsies have the potential to support the efforts being made in targeted therapies such as Antibody Drug Conjugates, or ADCs. ?The promise of liquid biopsy can be several things, starting from early detection to therapy monitoring and recurrence analysis.? stated Jimmy Lin, MD, PhD, MHS, the Chief Scientific Officer for Oncology at Natera. Natera, a genetic testing and diagnostics company that has focused heavily on non-invasive prenatal testing (NIPT) in the past, are joining the efforts for early diagnostics by developing their own liquid biopsy technology. 
Lin clarified that one of the goals Natera is giving physicians the tools needed to take action and make decisions in a way that is deliberate. ?We want to identify action points within medical dilemmas where we can help them,? he specified.. ?We really want to look at genomics at which disease and stage- then you have a panel size, not just everything under the sun.? mentioned Lin.
According to Lin, this type of specificity becomes especially important when considering all the factors that affect the usefulness of liquid biopsy. While there is a lot of debate over liquid biopsy effectiveness, there needs to be specific considerations for different applications, disease type, unmet clinical needs, and evidence should then be judged for each in its own. ?A lot of people talk about liquid biopsy as this sort of homogeneous big field, states Lin, ?and a lot of the bigger studies, unfortunately, are very homogeneous and not very precise.?
For these reasons, researchers at Natera are not under pressure to be the first to market with their liquid biopsy, but are instead focused on establishing specific evidence before launching, which mirrors the strategy that the company implemented for their non invasive prenatal testing (NIPT) technology. ?At the time, there were four major companies, and we were the last to launch, but we are now the US volume leader for our test, since it is more sensitive and effective.? mentioned Lin, ?Once we have the technology, we need to look at specific cancers and what the decision points may be, which is why we are taking our time and not rushing to launch.?
False Positives and False Negatives
While the benefits of liquid biopsy are apparent to many in the field, there are still many concerns in the development of these novel diagnostic tools. The issue of false positives and false negatives remains a controversial topic, as issues like these could have a great impact on patient lives. The consequences of both, false positives and false negatives, need to be carefully considered in assessing the usefulness of liquid biopsy. However, like every aspect of cancer, generalizations are not easy to make, as disease type, tumor marker, and patient, all must be considered.
Lin emphasized this as he explained how the subject of false positives and false negatives needs to be addressed on a tumor and patient specific basis, rather than directed toward the field as whole. Lin explained that something such as lung cancer will have a higher rate of false positives due to the high rate of DNA damage that can occur before the cancer has even happened, whereas with something like childhood cancers, the same background of mutation rate is not expected, and therefore false positives are far less likely. ?Everyone will tell you that every cancer type, subtype, and patient is different? stated Lin, ?but the talk about liquid biopsies is often generalized.? 
For researchers at Natera, considering which cancer and cancer subtype is present is essential, that way corrections can be made to determine false positives and false negative rate based on the background of each disease type. ?We need to be precise about precision medicine,? stated Lin, ?We emphasize that every cancer is so different, so we need to keep the same precision when it comes to liquid biopsies.?
Monitoring Treatment Progression
The scope of liquid biopsy use is not limited to early detection for faster treatement; there is also great clinical utility in being able to monitor cancer throughout the process of treatment. Just recently, the Journal of Thoracic Oncology published a new study that showed Trovera?, the non-invasive urine and blood-based biopsy developed by Trovagene, is able to successfully identify an EGFR mutation in non-small lung cancer (NSCLC) patients. The blinded study, which collected urine and plasma specimens from 63 patients with stage IIIB-IV NSCLC, showed that the EGFR T790M mutation can be detected from circulating tumor DNA with a high sensitivity, one that was in concordance with tumor tissue. In addition, urine and plasma testing in combination was able to identify 12 T790M-positive cases that were undetectable by tumor tissue samples. Since about 60% of NSCLC patients receiving Tyronise Kinase Inhibitor therapy develop resistance because of the EGFR T790M mutation, the there is great clinical significance in being able to identify these cases with high specificity. 
Furthermore, Trovagene recently announced their Precision Cancer Monitoring (PCM) technology was also featured in a patient case report published in Cancer Discovery. This study showed that the liquid biopsy was able to identify the presence of the BRAF V600E mutation in patients with colorectal neuroendocrine carcinoma- a rare type of colorectal cancer. The use of a BRAF-MEK inhibitor has only recently been used in this tumor type and has resulted in successful treatment when the BRAF V600E mutation is present, and Trovagene?s diagnostic tool could provide a way to easily monitor these patients?s response throughout the process. 
Last editorial review: August 9, 2016.
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