Liquid biopsies: Understanding ctDNA and circulating tumor cells

What if we could know more about a tumor just from a patient’s blood sample? While this concept is well-established with blood cancers like leukemia, lymphoma and multiple myeloma, it’s now being applied to solid tumors, including breast cancer, colorectal cancer, bladder cancer, prostate cancer, pancreatic cancer, melanoma and lung cancer.

Known as a liquid biopsy, we can learn what’s going on inside a patient’s body by examining circulating tumor DNA (ctDNA) or circulating tumor cells captured with a blood draw.

Anthony Lucci, M.D., shares more on these tests, including how they work, their current limitations and the hope for their future.

What is ctDNA testing?

Tumors are made up of cells, and at the center of those cells is DNA. As cancer cells go through their life cycle, fragments of DNA can enter the bloodstream. This is known as circulating tumor DNA – or ctDNA, for short.

ctDNA testing examines a patient’s blood to detect DNA fragments from cancer cells. There is a misconception that cells only shed DNA when dying, but Lucci says that’s not the full story. Cancer cells have constant turnover. They die and make new cells. So, as a tumor grows, the amount of ctDNA may be higher.

The technology is still fairly new, but the information found in the blood may help guide cancer care. “In some cases, we can diagnose, monitor or potentially even identify new targets for therapy based on the little fragments of DNA that are floating around,” Lucci says.

What is the difference between ctDNA and cfDNA?

Tumor cells aren’t the only cells in the body releasing fragments of DNA. When cells that aren’t from a tumor shed DNA, it’s considered cell-free DNA – or cfDNA.  

But how can physicians tell the difference when examining a blood sample? “One way we distinguish the two is that cfDNA are typically longer strands of DNA while ctDNA are typically shorter length fragments,” Lucci says.

What are circulating tumor cells?

Circulating tumor cells are another way to learn about a cancer through a liquid biopsy. But instead of examining DNA fragments in the blood, a whole tumor cell is captured. “The whole cell can also give us a lot of information,” Lucci says.

These cells not only reveal the presence of a tumor; they also indicate that a cancer is progressing or spreading. “Most people would agree that circulating tumor cells are the seeds of metastases,” Lucci says. But it has been difficult to prove because circulating tumor cells are rare, and they are heterogenous. They’ve also been found in early-stage disease.

Lucci foresees that ctDNA and circulating tumor cells will be used in combination to offer the best picture of what’s happening with a cancer inside a patient.

How are liquid biopsies being used in cancer care?

There are a few ways that they’re being used. First, they may be a good prognostic tool, meaning they can help predict the risk of recurrence. “There’s a lot of published data showing that circulating tumor cells can help determine whether a patient may be at a higher risk for relapse,” Lucci says. This was seen with a large breast cancer study in which patients whose number of circulating tumor cells was rising or not decreasing while they received chemotherapy did worse.

Secondly, liquid biopsies may help guide therapy selection. Through a blood sample, it may be possible to identify gene mutations that can be targeted with specific drugs or look for markers that make a patient eligible for some therapies. “In the future, we could help patients avoid unnecessary drugs, or if they're really at high risk, they can get something that provides a big benefit and change the course of their treatment,” Lucci says. For example, preliminary data shows that if the PD-L1 protein is found on a circulating tumor cell, immunotherapy may be a better option for some patients with melanoma. There’s also data showing that certain mutations identified by ctDNA testing can already be used to guide treatment choices for diseases like lung cancer. “This shows the feasibility of guiding treatment in other disease sites based on liquid biopsy,” Lucci says.

Lastly, Lucci hopes that as liquid biopsies improve, they could help monitor a patient’s response to therapy. By taking samples before treatment and during its course, it may be possible to track a therapy’s effectiveness or identify new mutations that develop.

“We can possibly pull together a dynamic picture of how the tumor cells are either going up or down with the treatment without additional invasive biopsies or imaging,” Lucci says. “We can get answers of what's going on in places like the bone and the liver without having to put needles everywhere, which is unpleasant for patients.”

How are clinical trials improving liquid biopsies?

Although the prospect of liquid biopsies is exciting, the technology is still new, and their best use is still undefined. “We just don't know what to do with all this information yet,” Lucci says.

Take, for example, the breast cancer clinical trial that linked circulating tumor cells to shorter survival. When blood samples showed no decline in the number of the circulating tumor cells after a round of chemotherapy, switching to different chemotherapy drugs didn’t help. “The problem is that no one's really sure what's the best treatment to get rid of the circulating tumor cells,” Lucci says. “So unfortunately, it hasn’t improved treatment yet, and it just makes patients nervous getting such results.”

But Lucci and others aren’t giving up, and they’re partnering to find the best way to move this technology forward into the clinic. He encourages patients to talk with their doctors to see if liquid biopsies will be helpful in their care and to consider joining a clinical trial, if it’s right for them.

“My hope is – and I really do think – in the next couple of years, we'll have a much clearer picture of how and when to use liquid biopsies to get the best possible results for our patients,” Lucci says.  

Request an appointment at MD Anderson online or by calling 1-877-632-6789.