ctDNA vs. CTCs: The Future of Breast Cancer Monitoring Explained

At the CURE Educated Patient Breast Cancer Summit, held during the 49th Annual Miami Breast Cancer Conference, Dr. W. Fraser Symmans, a professor in the Department of Pathology at The University of Texas MD Anderson Cancer Center, provided a comprehensive overview of how liquid biopsies are reshaping breast cancer care.

While Symmans noted he does not work directly in the field of circulating signals, he offered an objective perspective on the shift from tracking whole cells to analyzing fragments of DNA.

The science of shedding: ctDNA versus CTCs

Symmans explained that tumors are highly vascularized from their earliest stages, leading them to release various signals into the bloodstream. Two primary markers are circulating tumor DNA (ctDNA) — broken down traces of genetic material — and circulating tumor cells (CTCs), which are rare, intact cancer cells.

The industry has largely pivoted toward ctDNA because it is more frequent in the blood and, crucially, can be amplified in a laboratory setting. "That tiny needle in the haystack can be amplified and detected," Symmans noted, whereas CTCs are rare events that cannot be amplified, making them much harder to find. While CTCs were once the focus of research, their clinical use is currently "on the wane" as ctDNA technology continues to evolve.

A liquid biopsy for advanced disease

In the metastatic (advanced) setting, ctDNA is more plentiful and offers a significant advantage over traditional tissue biopsies. Because ctDNA is released from all metastatic sites, it provides an average of the total disease burden. This is often more representative than a needle biopsy of a single spot, which may not reflect how other metastases are behaving.

Furthermore, ctDNA allows doctors to monitor disease evolution. For example, a tumor may develop an ESR1 mutation as an adaptation to circumvent endocrine therapy. Identifying this change through a blood test allows clinicians to switch patients to more effective treatments, such as SERDs, rather than continuing a therapy that is no longer working.

Early detection and MRD monitoring

In early-stage breast cancer, the goal shifts to minimal residual disease (MRD) monitoring after a tumor has been surgically removed. This involves "training" a personalized test on the patient’s own tumor DNA to look for traces of that specific cancer in the blood over time.

While a positive result in this setting has very high specificity — meaning it is a strong warning sign that a recurrence is likely — the field is still working on the "false negative" rate. Some patients may experience a recurrence even if their blood tests remain negative. Symmans also highlighted a "zero data area": the question of whether doctors can safely hold back adjuvant treatment and wait for a positive ctDNA test before starting therapy. Currently, there is no evidence to support this approach, and clinical trials are necessary to find the answer.

A cautionary tale in screening

Symmans also addressed the potential for blood tests to screen healthy individuals for cancer. He cited a massive National Health Service (NHS) trial in the UK involving 125,000 people using DNA methylation patterns. Unfortunately, the trial did not meet its objective of showing a clinical difference. Symmans called this a "cautionary tale," reminding the audience that this is highly sophisticated, bespoke assay development that requires more refinement.

The future of personalized testing

Looking ahead, Symmans envisions a "portfolio of formative results" where blood tests are combined with what is already known about a patient's tumor. The goal is to determine the ideal frequency of testing for each individual — some may need testing every three months, while others might not need to start for years.

Ultimately, liquid biopsy is a "great tool" with tremendous potential, but its best use in every person’s unique circumstance is still being determined through ongoing clinical data.

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