Advancing ctDNA for Minimal Residual Disease Detection in Breast Cancer

Circulating tumor DNA (ctDNA) is described by The University of Texas MD Anderson Cancer Center website as DNA fragments which are released into the bloodstream from tumor cells and these fragments of tumor cells can often lead to minimal residual disease (MRD), which is when cancer cells remain in the body after treatment.

In a presentation given by Dr. Debu Tripathy at the recent 42nd Annual Miami Breast Cancer Conference and the Educated Patient Breast Cancer Summit, he explained how ctDNA is used to in cancer detection and how it can also indicate the presence of MRD, a signal suggesting there is cancer in the body, according to the National Institute of Health.

“Tumors that are in the body are fed by blood vessels, and the veins also drain these areas, just like they drain other organs and tissues, and DNA that comes from the cells are present in the blood. They do get broken down eventually, but we can actually measure this, and we've been able to do this for a long time, but our techniques have become very sensitive, so that we can now pick up very small amounts of residual tumor that may ultimately lead to a metastasis.,” he explains.

Tripathy previously served as a professor and chairman of the Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, in Houston, and as the editor-in-chief at CURE, prior to his retirement in March of 2025.

Understanding ctDNA and its Applications in Oncology

For years, researchers have suspected that small clusters of tumor cells can exist in patients with early-stage cancer, contributing to late recurrences. In breast cancer, for example, recurrence can occur decades later, implying the presence of dormant tumor cells. Now, with recent advances in technology, investigators have been able to detect minuscule amounts of tumor-derived DNA in the bloodstream, even at single-molecule levels. This development has provided evidence that ctDNA generally signals an impending relapse.

Tripathy goes on to explain that by using highly sensitive techniques, researchers are beginning to distinguish tumor DNA from normal DNA. In recent studies, patients have been tracked over time to evaluate those with detectable ctDNA and those without; consistently, patients who have detectable ctDNA experience worse disease-free survival compared to those without.

“The big question is: how can we now really prove that we can not only measure tumor DNA? However, there's no point in doing it unless we can do something about it, of course. [Therefore], the goal here is to refine the technology to make it as sensitive and accurate as possible, and then to test different strategies to see if we can lower the risk of recurrence, as we have done over the last 50 years or so,” he emphasized.

Because many patients with advanced breast cancer have already undergone primary surgery and adjuvant therapy, Tripathy describes this approach as a “potential second chance at a cure” if the patient is at risk of recurrence. To achieve this, studies have been designed to detect ctDNA; if no detectable tumors appear on scans and only MRD is identified through ctDNA, patients can be enrolled in trials aimed at altering the course of their disease. Tripathy says the goal of this approach is to prevent recurrence entirely, offering the possibility of long-term remission.

Advancements in Liquid Biopsies for MRD Detection

Liquid biopsies, an important part of MRD detection, focuses on ctDNA and is a minimally invasive blood tests that analyzes DNA fragments shed by cancer cells to gain insights into a patient's cancer status, according to The University of Texas MD Anderson Cancer Center website. Importantly, Tripathy goes on to note that these liquid biopsies are an important subject that is under investigation at present. Many of these biopsies, he says, are being performed in patients with advanced breast cancers to better understand their biology, as well as better understand their mutations. In turn this helps direct physicians to the the type of therapy that is best suited for each patient.

Other areas of ongoing research are now even looking for healthy patients who've never had cancer for early detection, he explains. For these research areas, investigators are aiming to better understand what alterations are present in the DNA that may predict not only a patient’s risk of developing cancer, but what type of cancer or what organ it may originate from.

Tripathy also went on to note some of the limitations and challenges in detecting residual disease with conventional imaging. While the Signatera assay is widely used and was recently approved for Medicare reimbursement, its sensitivity may be insufficient for certain applications. More sensitive assays are needed for reliable detection of MRD, and ongoing interventional trials are evaluating different approaches. Institutions conducting these trials are working toward more precise methods to improve clinical decision-making and patient outcomes, Tripathy emphasizes.

“It's a wonderful tool to look at DNA in the blood from tumor cells, or even from people who may have such a small amount that they're at risk for developing a cancer or recurring from a cancer that they had earlier, and how we're starting to use this and test this."

Future trials will likely focus on integrating novel, more potent therapies and refining ctDNA detection to improve patient stratification and outcomes, he concludes.

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