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Molecular Genetics / June 11, 2019 / by beaconlbs

Liquid Biopsy in Cancer Diagnosis, Detection and Treatment

Recently, there has been much excitement about the potential for liquid biopsy’s possible applications in cancer detection, diagnosis, and treatment. Learn more about the current evidence of clinical utility of cell free DNA in our latest blog.

Generally, liquid biopsy refers to a non-invasive technique of obtaining bodily fluids to analyze biological material in order to elucidate health information for a patient. There has recently been much excitement about the potential for liquid biopsy’s possible applications in cancer detection, diagnosis, and treatment. New research is being published at an astounding rate on this topic. The National Cancer Institute (NCI) defines liquid biopsy as:

A test done on a sample of blood to look for cancer cells from a tumor that is circulating in the blood or for pieces of DNA from tumor cells that are in the blood. A liquid biopsy may be used to help find cancer at an early stage. It may also be used to help plan treatment or to find out how well treatment is working or if cancer has come back. Being able to take multiple samples of blood over time may also help doctors understand what kind of molecular changes are taking place in a tumor.

While this NCI definition restricts the specimen type to blood, liquid biopsy research is also being performed on many different fluids such as: cerebrospinal fluid (CSF), saliva, urine, uterine aspirates, pleural effusions, and stool samples.

There are several types of biomolecules that may be present in a liquid biopsy, including: circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes. ctDNA is a type of cell-free DNA (cfDNA). They are short fragments of DNA shed by the tumor during the process of cell death, also known as apoptosis. Using cfDNA for molecular analysis has been well-described in the literature. For example, it may be used in a prenatal setting to screen for fetal chromosomal abnormalities in a pregnant patient, although the origin of cfDNA is placental. Interestingly, unusual prenatal cfDNA results may indicate an increased risk for maternal cancer. CTCs are tumor cells in theblood. These migrating cells from the tumor source in the bloodstream are the development of metastasis. Reports of the presence of tumor cells in the circulation system can be traced back to 1869. CTCs are in low abundance in the cellular population in a liquid biopsy. However, they can provide a real-time molecular profile of the tumor and may also be useful in determining a treatment plan for the patient. Exosomes are small extracellular vesicles that play an important role in tumorigenesis. They are a rich source of proteins, differing types of RNA and DNA, and lipids that can be used for analysis.

Liquid biopsies have been investigated for a variety of cancer types: endometrial, breast, colorectal, prostate, lung, pediatric central nervous system (CNS) cancers, and oral cancers. This is not an exhaustive list. Historically, a tumor biopsy provides the clinician the information required for diagnosis, and possibly treatment. Performing a tumor biopsy is invasive, costly, and time-consuming. Further limitations are that the biopsy may not capture the heterogeneity in a cancerous tumor, and represents a data point at one given time. Conversely, liquid biopsies are non-invasive, cost-effective, and may be a better representation of the entire tumor (rather than just a single physical site). Liquid biopsies can be done serially over time and may identify changes that provide information on the efficacy of treatment. Information from a liquid biopsy has also been shown to assist in choosing a potential therapy for a patient.

Given the wealth of recent published articles on liquid biopsy technology and the enthusiasm in the scientific community, professional societies are starting to take notice. The American Society of Clinical Oncology (ASCO) and College of American Pathologists recently published a review regarding ctDNA, which is one of many biomolecules that may be included in a liquid biopsy analysis. In summary, they report that although data in the published literature is very promising, further research is warranted before ctDNA analysis should be used in a clinical setting for patient management. Specifically, logistical variables must be standardized, including type of tube in which the blood is collected, handling variables, shipping time and storage, and lab processing. These molecular analyses require unique conditions that must be followed by labs who perform such tests to ensure consistent results between labs. The test must be robust. Clinical validity (the test accurately predicts the presence or absence of a pathological state) and clinical utility (the use of the test improves patient outcomes) have not been adequately documented, outside of a clinical trial. At the same time, ASCO and the College of American Pathologists recognize that ctDNA may play a future role in the management of patients with cancer, and it is “highly likely” new evidence will allow for a reassessment of ctDNA clinical validity and utility.

Additionally, the National Comprehensive Cancer Network (NCCN) recently updated guidelines for the examination of non-small cell lung cancer to include using liquid biopsy. NCCN states liquid biopsy may be used if “the patient is not medically fit for invasive tissue sampling or if there is insufficient tissue for [traditional] molecular analysis techniques and follow-up tissue analysis will be done if an oncogenic driver is not identified.” NCCN also recognizes liquid biopsy may be considered to determine whether a specific mutation (EFGR T790M) is present, which may impact therapy for the patient.

The Centers for Medicare and Medicaid Services (CMS) publishes guidelines payors use to determine coverage for different laboratory procedures. They have unique patient requirements for next generation sequencing (NGS) to be considered reasonable and necessary:

  1. Patient has either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and
  2. either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and
  3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

The commercial laboratory performing the test must meet these standards:

  1. FDA approval or clearance as a companion in vitro diagnostic; and
  2. an FDA approved or cleared indication for use in that patient’s cancer; and
  3. results provided to the treating physician for management of the patient using a report template to specify treatment options.

ctDNA analysis is also specifically mentioned by CMS:

The National Coverage Determination (NCD) does not limit coverage to how to prepare a sample for performing a diagnostic laboratory test using NGS…At this time, liquid-based multi-gene sequencing panel tests are left to contractor [payor] discretion if certain patient criteria are met.

CMS comments give payors the option of determining coverage.8 Indeed, companies who provide clinically-available liquid biopsy tests report coverage by Medicare.

As discussed in this article, a tremendous amount of resources are being devoted to researching liquid biopsy techniques for cancer diagnosis, management, and treatment. Data is promising and advancements are being reported. However, according to some professional societies, liquid biopsy currently lacks consistent evidence to be incorporated into routine oncology care at this time. Payors may pay for liquid biopsy techniques, given CMS guidelines. This field will likely continue to improve and evolve at a rapid pace for patients, clinicians, and payors in the next few years.


  1. Accessed 03/09/2019
  2. Bonner ER, Bornhorst M, Packer RJ, Nazarian J. Liquid biopsy for pediatric central nervous system tumors. NPJ Precis Oncol. 2018 Dec 17;2:29.
  3. Ji X, Chen F, Zhou Y, Li J et al. Copy number variation profile in noninvasive prenatal testing (NIPT) can identify co-existing maternal malignancies: Case reports and a literature review. Taiwan J Obstet Gynecol. 2018 Dec;57(6):871-877.
  4. Lousada-Fernandez F, Rapado-Gonzalez O, Lopez-Cedrun JL, et al. Liquid Biopsy in Oral Cancer. Int J Mol Sci. 2018 Jun 8;19(6). pii: E1704.
  5. Muinelo-Romay L, Casas-Arozamena C, Abal M. Liquid Biopsy in Endometrial Cancer: New Opportunities for Personalized Oncology.Int J Mol Sci. 2018 Aug 7;19(8). pii: E2311
  6. Su KY, Tseng JS, Liao KM, et al. Mutational monitoring of EGFR T790M in cfDNA for clinical outcome prediction in EGFR-mutant lung adenocarcinoma. PLoS One. 2018 Nov 16;13(11):e0207001
  7. Merker JD, Oxnard GR, Compton C, et al. Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol. 2018 Jun 1;36(16):1631-1641.
  8. accessed 03/09/2019
  9. accessed 03/14/2019
  10. accessed 03/14/2019
  11. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3.2019). accessed 03/25/2019
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