By now, it’s likely that you’ve heard the terms ctDNA, cfDNA, Next Generation Sequencing (NGS) and liquid biopsies thrown around, and with many acronyms and various test types out there for colorectal cancer, it can become confusing to understand how they can impact treatment and care.

Let’s Start with the Basics.

ctDNA vs. cfDNA & How We Sequence Them

DNA is information that is stored inside a cell’s nucleus, containing the genetic or hereditary material that makes us who we are. DNA consists of four bases, A, G, T, C, and these base combinations are the foundation of our genetic code.

When a cell dies, it releases cell free DNA (cfDNA) into the bloodstream. cfDNA is a term that broadly describes the different types of DNA freely circulating in the bloodstream at any given time. This includes circulating tumor DNA (ctDNA), which is released when tumor cells die. Thus, if the lab detects ctDNA, we know that a patient has tumors present.

We’ve known that tumors release ctDNA for a while, but research now allows us to better understand what to do with this information. When the small fragments of DNA are released into the bloodstream, scientists can capture the fragments and sequence them to look for mutations through something known as Next Generation Sequencing (NGS). 

NGS is a broad term for how researchers look at DNA to determine the different types of mutations present. NGS testing can be done in both tumor biopsies and liquid biopsies. It is much quicker and more efficient than older methods of DNA sequencing. It also only requires one test to look for a panel of mutations, rather than multiple tests. 

It’s important to note that not all DNA that is captured is tumor DNA. In fact, the majority of the cell free DNA in your bloodstream is just your normal DNA! But in patients with cancer, a small amount of ctDNA can be detected, and this is what helps researchers look for mutations and profile the tumor, all with a simple blood draw!

What is a Liquid Biopsy and How Does it Capture ctDNA?

A liquid biopsy is a non-invasive blood test that detects ctDNA. Unlike a tumor biopsy, which often requires surgery, liquid biopsies only require a sample of blood, and are quicker, easier, and less painful to obtain.

Once a patient has a liquid biopsy and the NGS test conducted, results will be compiled into a report that highlights molecular mutations. Reports can indicate whether one’s tumor is Microsatellite stable (MSS) or instable (MSI-H), if there are mutations present in common CRC biomarkers like BRAF, KRAS, or NTRK, and the levels of ctDNA. Generally, the higher the levels of ctDNA, the more cancer present, and vice versa.

What Else Can ctDNA Tell Us?

Not only can liquid biopsies and ctDNA tell us if cancer is present, it can also tell us:

• The best individualized treatment selection
• Why a patient may not be responding to treatment, potentially due to new mutations or resistance mechanisms
• If the disease has returned
• How likely it is for a patient to have a recurrence

One study presented at the American Society for Clinical Oncology (ASCO) in 2017 showed that cancer recurrence after surgery for stage III CRC patients is much more unlikely if their ctDNA test comes back negative; if it comes back positive, a patient is more likely to experience a recurrence.

FDA Approval and Paying for Liquid Biopsies and NGS Testing

In April 2018, the Centers for Medicare and Medicaid Services (CMS) announced a National Coverage Decision (NCD) that NGS testing will be covered in all states throughout the US. This means that NGS tests are now available to all Medicare beneficiaries with solid tumors as long as the NGS test has FDA approval. 

In August 2020, the FDA approved two liquid biopsies from Guardant Health and Foundation Medicine. Read more about these tests and what they mean for patients. 

The news about Foundation One and Guardant’s tests is exciting because there are now two liquid biopsies approved by the FDA, and will therefore be reimbursed under the CMS’s NCD. Many are hopeful that private insurance will also follow suit and reimburse for these tests.

We encourage all patients to have their biomarkers tested. If you have not had biomarker testing, are unsure if you’ve had biomarker testing, or want to pursue a liquid biopsy test, we encourage you to speak with your doctor about the best course of action, as well as your insurance company to determine what is covered. 

It’s clear that ctDNA can provide much needed insight for both patients and providers. Although there is still much to learn from these tests, the promise they hold is immeasurable.