The Nuance of ctDNA and How It Guides Further Treatment

  • ctDNA’s real power is in its contrast: a positive result is a strong warning signal that the risk of recurrence is higher in patients, while a negative result offers only partial reassurance, Dr. Neal Vasan, director of Breast Cancer Translational Research at NYU Langone, says.
  • A ctDNA‑negative result does not rule out recurrence, and its reliability varies across breast cancer subtypes — a key reason researchers are still refining how ctDNA should be interpreted and used in care.
  • “If you can clear your ctDNA by cycle two, day one, that is prognostically better,” Dr. Vasan says. But if ctDNA reappears later, especially in the minimal residual disease setting after neoadjuvant therapy, surgery, and adjuvant treatment, it remains uncertain, with no consensus yet on how clinicians should respond.

For Dr. Neil Vasan, director of Breast Cancer Translational Research at NYU Langone, circulating tumor DNA (ctDNA) represents one of the most important frontiers in breast cancer care.

“I think that ctDNA is the future,” he says, but further explains that the power of ctDNA lies in its nuance: a positive result is a strong warning signal, while a negative result offers reassurance but not certainty.

Neil Vasan, MD, PhD, a breast oncologist

A Positive ctDNA Result Carries Real Prognostic Weight

According to Dr. Vasan, the evidence is consistent and compelling.

“There is a high positive predictive value that women who have positive ctDNA have a much higher chance of recurrence,” he says.

When ctDNA is detectable after treatment, it often reflects microscopic disease that has not yet appeared on imaging.

This clarity, however, does not extend to negative results.

A Negative Result Isn’t a Guarantee

“The negative predictive value is not so great,” Dr. Vasan notes.

A ctDNA‑negative reading does not mean recurrence is off the table. Its reliability varies across breast cancer subtypes, and that variability mirrors a broader trend across oncology: ctDNA is a powerful tool, but not uniformly predictive.

“Are you definitely not going to recur if you’re ctDNA negative? Those numbers are really quite variable,” he explains. That uncertainty is why researchers continue to refine how ctDNA should be interpreted and how it should guide care.

A Diagnostic Tool Already Embedded in Metastatic Care

While ctDNA’s prognostic role is still evolving, its diagnostic value in metastatic disease is more defined.

“We use it very commonly now… to establish genomic biomarkers,” Dr. Vasan says. Many patients can undergo ctDNA testing instead of a tissue biopsy in later-line settings, where obtaining tumor tissue can be difficult or risky.

The advantage is clear: ctDNA reflects global metastatic disease, not just a single biopsy site. That broader snapshot often reveals resistance mutations that shape treatment decisions.

Using ctDNA to Guide Therapy

The therapeutic use of ctDNA — switching treatments based on emerging mutations — is where the field becomes more complex.

“This is where things are much more modern art,” Dr. Vasan says, acknowledging the ongoing debate.

Still, there are bright spots. In metastatic breast cancer, certain mutations predict resistance to specific therapies:

  • ESR1 mutations: resistance to aromatase inhibitors
  • PIK3CA mutations: relevance for PI3K inhibitors
  • RB mutations: resistance to CDK4/6 inhibitors

One of the clearest examples of ctDNA-guided therapy is the SERENA‑6 trial, which used serial ctDNA testing to identify patients who developed ESR1 mutations. Those women were randomized to continue their current therapy or switch to an oral SERD.

Dr. Vasan noted that the clinical trial is considered a “positive trial,” signaling that ctDNA‑guided switching may improve outcomes.

Clearing ctDNA Matters — But Recurrence of ctDNA Raises New Questions

Across multiple clinical trials, clearing ctDNA early is a strong prognostic marker.

“If you can clear your ctDNA by cycle two, day one, that is prognostically better,” Dr. Vasan says. But what happens when ctDNA reappears later remains unclear.

This uncertainty becomes even more challenging in the minimal residual disease setting — after neoadjuvant therapy, surgery, and adjuvant treatment. If ctDNA turns positive at that point, the field has no solid consensus.

“What do we do if those patients turn ctDNA positive?” he asks. “Do we change therapy? Keep everything the same? Intensify screening?”

These are open questions, and researchers are actively designing targeted studies to answer them.

A Future Built on Better Signals — and Better Interpretation

For now, ctDNA remains a powerful tool to extract information on the cancer, but it does not always provide a clear direction. A positive result is a meaningful warning. A negative result is helpful but not definitive. Dr. Vasan emphasizes that the field is still learning how best to act on these signals.

What’s certain is that ctDNA is already reshaping how clinicians detect resistance, understand recurrence risk, and design the next generation of breast cancer trials and treatments.