Like a mill crumbling into a river, solid tumors constantly shed bits of themselves — including their DNA — into the bloodstream. This free-floating genetic material, known as circulating tumor DNA, or ctDNA, contains a trove of information about the tumor.
Advances in technology have made it possible to extract ctDNA from a blood sample, measure it, and analyze it for genetic abnormalities. These tests, known as liquid biopsies, are being used in the clinic and being studied in clinical trials for their potential in guiding cancer care.
How does ctDNA get into the bloodstream?
When cancer cells die, they disintegrate, spilling their contents, which ultimately wind up in the bloodstream. Live tumor cells also can secrete DNA as part of their normal functioning.
What are the potential advantages of a liquid biopsy using ctDNA?
Because ctDNA is carried by the blood, liquid biopsies can be performed with a simple blood draw. Tissue biopsies, by contrast, involve inserting a needle directly into the affected tissue and removing a small sample for examination.
Liquid biopsies are especially useful for monitoring or tracking a patient’s response to treatment over time: it’s far easier and less invasive to periodically collect blood samples than tissue samples.
Liquid biopsies may capture ctDNA released by cancer cells no matter where those cells are within a tumor. Because tissue biopsies usually collect samples from several specific sites in an organ or tissue, they may miss genetically distinct subgroups of cancer cells in other sites.
Tissue biopsies are still needed to establish a cancer diagnosis and unique structural characteristics of certain tumors, which cannot be studied in liquid biopsies.
How are liquid biopsies currently used in the clinic?
For some cancer types, such as breast, colorectal, and lung tumors, it has become standard practice to use liquid biopsies as part of the workup for selected patients, depending on tumor type, stage, and other factors.
In some cases, ctDNA tests are being used to personalize treatment selection. For example, patients with hormone-receptor positive metastatic breast cancer receive ctDNA testing to determine whether their tumor cells are likely to respond to specific targeted drugs.
“We draw blood for testing at the time of their diagnosis and periodically afterwards — if their disease is advancing — to look for potential targets for therapy or signs of drug resistance,” says Dana-Farber Ilana Schlam, MD, MPH, a breast oncologist in Dana-Farber’s Breast Oncology Program.
Other possibilities are being investigated in clinical trials. Many of these studies seek to establish consistent guidelines for interpreting liquid biopsy results and applying them to make decisions that will benefit patients.
“The accuracy of liquid biopsies is high: they produce extremely precise readings of ctDNA levels and genetic mutations,” says Dana-Farber’s Brian Crompton, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “The goal now is to demonstrate that certain ctDNA levels are definitively prognostic — that they can provide reliable information about the tumor’s status, which can be used in making treatment decisions.”
How might ctDNA testing be used?
Researchers and physicians see numerous potential roles for ctDNA testing:
- Detecting cancer early: The presence of ctDNA in an individual’s blood may allow doctors to detect certain types of cancer before symptoms appear or before other tests are capable of finding it. One example is a multi-cancer early detection test being tested in clinical trials at Dana-Farber.
- Selecting treatment: By analyzing ctDNA for specific genetic mutations, liquid biopsies are helping physicians choose therapies that are effective against cancers with those particular abnormalities. These ctDNA tests might also help doctors determine which patients require intensive treatments and which can do just as well with less intense approaches. For patients with early-stage breast cancer, for example, Dana-Farber investigators are testing the use of ctDNA to guide the selection of more intensive treatment to determine if it can stave off recurrence.
- Assessing treatment effectiveness: Studies have consistently shown a connection between ctDNA levels and tumor status: when tumors shrink or disappear, ctDNA levels often decline. Monitoring ctDNA levels during and following treatment may offer a way to gauge how well therapy is working.
- Detecting relapse: Just as a drop in ctDNA counts can indicate that a treatment is effective, a rebound in ctDNA levels may be a sign that a cancer has returned, despite treatment intended to cure it, or that it has resumed its growth, in the case of advanced cancer.
- Tracking changes in tumors’ genetic signature: As tumors grow and evolve, they often acquire new mutations and other genetic abnormalities. Periodic liquid biopsies can reveal these changes as they emerge. Such mutations may represent vulnerabilities within the tumor that can be attacked with targeted therapies. They may also indicate that a tumor is developing resistance and guide a change in treatment.
“Liquid biopsies are an exciting new tool that is already helping guide treatment for patients in some cases,” says Schlam. “We’re also studying the use of ctDNA in clinical trials to be sure these tests help us select interventions that benefit patients.”
What research is being done in ctDNA?
Research at Dana-Farber was critical in demonstrating the ctDNA could be the basis of a practical clinical test. One of the challenges of analyzing ctDNA is determining how much of the ctDNA in a blood sample comes from tumor cells and how much from normal cells.
Dana-Farber and other researchers devised a method called “tumor fraction” that makes this ratio easy to calculate. Follow-on research at Dana-Farber showed that a high tumor fraction is associated with a poor prognosis in patients with metastatic, triple-negative breast cancer.
Dana-Farber researchers are also advancing the use of ctDNA liquid biopsies for diagnosing, tracking, and predicting the behavior of cancer:
- Breast cancer: Schlam is running multiple studies to determine how to use ctDNA in patients with breast cancer for treatment selection and to improve patient outcomes.
- Pediatric Cancers: Work by Crompton and his associates has been critical to adapting ctDNA testing to pediatric patients. That work is now the foundation for a new effort called BrightSeq that aims to design a suite of clinical diagnostics for rare pediatric cancers.
- Colorectal cancers: In a randomized clinical trial by Jeffrey Meyerhardt, MD, MPH, liquid biopsies have shown value as a means of personalizing treatment for patients with early stage colon cancer.
- Blood cancers: A liquid biopsy based tool is being studied to determine if it should be used to help detect relapse and guide treatment of people with diffuse large B-cell lymphoma.
- Early cancer detection: Research from Matthew Freedman, MD, and Sylvan Baca, MD, PhD, led to the creation of a liquid biopsy that reveals early signs of cancer. The team is now investigating its use to identify subtypes of kidney cancer to help guide treatment decisions. The technology is also being studied for its potential to detect changes that cause lung cancer and prostate cancer to resist treatment.
About the Medical Reviewer
Dr. Schlam received her medical degree from Anahuac University in Mexico City in 2014. She subsequently completed her Internal Medicine residency at The Jewish Hospital of Cincinnati and then her Hematology and Medical Oncology fellowship at The MedStar Georgetown Washington Hospital Center in Washington, DC. She obtained her Masters in Public Health from the Harvard School of Public Health in 2024. She was faculty at Tufts Medical Center from 2021 to 2024. In 2024, she joined the staff of the Dana-Farber Cancer Institute as a breast medical oncologist and clinical researcher. Her research focuses on drug development, identifying markers of response to novel therapies and healthcare disparities.