What is a liquid biopsy and what does it do?
March 21, 2022
Previously, we have reported that the FDA has granted a breakthrough device designation to Datar’s TriNetra Prostate Blood test for prostate cancer screening by detecting rare circulating tumor cells (CTCs) in the bloodstream. Although the FDA has not yet approved any test to “screen” cancer using circulating tumor cells, a “liquid biopsy” which analyzes circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) from patients’ blood is already utilized in the clinics to select the best therapy or to monitor cancer patients.
Scientists now believe that, even in the early stage, tumors of breast, prostate, liver, pancreas, lung and colon could shed cancer cells which enter the bloodstream. The cancer cells which freely circulates in the bloodstream are called circulating tumor cells (CTCs). Most of them do not survive due to the hostile environment in the blood stream. But if just one cell manages to survive and then exit into a distant organ, this cell could grow into a metastatic tumor.
Circulating tumor cells (CTCs) are extremely rare to be found in the blood. There is approximately one circulating tumor cell (CTC) out of one billion red blood cells and other blood cells in 1 mL of the blood from a cancer patient. Due to its rarity, isolation of circulating tumor cells (CTCs) could be quite challenging and costly, but comprehensive genetic information of cancer can be obtained from CTCs because their full genetic materials (DNA and RNA) and proteins are intact inside of the cells. In addition, isolated CTCs might reveal an additional mutation(s) which renders them resistant to the current treatment. Thus, the information from CTCs could allow oncologists to adjust the treatment to overcome the resistance. In addition, CTCs can be grown in a petri dish (more accurately, a tissue culture dish) in a laboratory, so that scientists may be able to analyze mutations to predict possible resistance to a treatment or to discover novel therapeutic targets.
A liquid biopsy can be also performed by using circulating tumor DNA (ctDNA). Circulating tumor DNA (ctDNA) is broken pieces of DNA released into the bloodstream from dead cancer cells of the tumor tissue or dead CTCs. The quantity of circulating tumor DNA (ctDNA) depends on the type of cancer and its location, but generally, it is easier and thus cheaper to isolate circulating tumor DNA (ctDNA) than circulating tumor cells (CTCs).
A tissue biopsy is still a gold standard to diagnose cancer; however, a liquid biopsy using circulating tumor DNA (ctDNA) can be used as an alternative in the clinic. Some patients may not be able to have a tissue biopsy due to the inaccessibility of the tumor (e.g., brain or lung tumor) or other risk factors which prevent an invasive surgical tissue biopsy. In this case, a liquid biopsy can be done by collecting and analyzing ctDNA via a simple blood test to discover a mutation(s) responsible for cancer development, and the results can guide physicians to select an individualized treatment for each patient.
A liquid biopsy using ctDNA (a ctDNA test, henceforth) is also used as a complementary to a tissue biopsy. Because a ctDNA test can be easily repeated, faster and cheaper than a tissue biopsy, patients can start life-saving treatments in a timely manner while waiting for the results of a tissue biopsy. However, the information obtained from ctDNA represents only a fraction of those from the entire tumor because ctDNA is a short fragment of the entire DNA. Thus, a ctDNA test may miss an important mutation responsible for the tumor development. As a result, patients may not receive the best- suited treatment.
Another benefit of a ctDNA test is to assess minimal residual disease (MRD) after surgery or during and after a treatment. Minimal residual disease (MRD) refers to a small number of cancer cells remaining after a surgery or a treatment which cannot be detected by imaging techniques such as CT scan, MRI or PET. Studies have shown that the presence of ctDNA is well correlated with minimal residual disease (MRD), even when imaging techniques cannot detect it and that detection of minimal residual disease (MRD) may indicate poor prognosis of cancer (1). Thus, a ctDNA test allows physicians to monitor patients for minimal residual disease (MRD), so that they could adjust treatments for cancer patients.
Many studies have shown that a ctDNA test is also useful to predict how well cancer patients respond to a treatment and to assess risks of recurrence in the patients with cancer of breast, colon and GI. The first study has shown that measuring ctDNA quantity in the blood from patients with metastatic breast cancer is specific and highly sensitive to predict how well patients are responding to a treatment and how long patients would survive before their cancer gets worse (2). Most recently, a group of scientists and physicians at the University of California, San Francisco analyzed ctDNA in the blood of the patients with early breast cancer who underwent chemotherapy prior to a surgery (3). They found that the patients who had ctDNA clearance in their blood after chemotherapy had no sign of cancer in their breast tissue. When patients’ breast cancer got worse even with chemotherapy, a blood test showed that there were ctDNAs in their blood, meaning that detection of ctDNA in the blood can tell whether cancer patients have cancer or not after chemotherapy without performing a tissue biopsy. Moreover, the presence of ctDNA was well correlated with recurrence of metastatic cancer. Surprisingly, when the patients had no ctDNA in their blood, even though their breast tissues still had signs of cancer, they still lived longer, meaning that the clearance of ctDNA in blood might be an early and reliable sign of how well patients respond to chemotherapy.
In conclusion, a liquid biopsy using ctDNA is a very useful tool to guide physicians to select personalized treatments for patients as well as to monitor patient’s cancer more effectively. It also allows physicians to predict how well patients respond to a treatment as well as a risk of recurrence of cancer in the future, so that cancer patients could receive the best possible care.
Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives, Peng et al., Frontiers in Oncology, 2021
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer, Dawson et al., NEJM, 2013
Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival, Magbanua et al, Annals of Oncology , 2020