Navigating Skepticism and Unanswered Questions of ctDNA in Breast Cancer

Although the oncology community is buzzing with the potential of circulating tumor DNA (ctDNA) to revolutionize breast cancer care, many experts are urging a measured approach. For every patient finding “peace of mind” in a negative blood test, there is a physician grappling with the “what now?” of a positive one.

Dr. Demetria Smith-Graziani, an assistant professor and medical oncologist at the Winship Cancer Institute of Emory University and a member of the CURE advisory board, highlights that despite the “liquid biopsy” hype, the field is navigating a complex landscape of professional skepticism, financial risk and “molecular anxiety.”

The ‘stage 4’ standard versus the ‘early stage’ unknown

A critical distinction often lost in the excitement over ctDNA is the difference between its use in metastatic disease and its use in early-stage surveillance. According to Smith-Graziani, the medical community views ctDNA through two very different lenses.

In the metastatic (stage 4) setting, ctDNA is increasingly becoming a standard tool. “We isolate the circulating tumor DNA, and we look at those mutations to see if [patients] are candidates for certain targeted therapies,” she explains. This replaces the need for invasive tissue biopsies to identify mutations like ESR1 that guide treatment changes.

However, for early-stage patients (stages 1 to 3), the utility of ctDNA is still firmly in the “research” phase, experts who spoke with CURE argue. Although the technology can detect microscopic fragments of cancer DNA in the blood, the clinical consensus on what to do with that information is far from settled. Dr. Alexis Ann LeVee, a breast medical oncologist and CURE advisory board member, echoes this caution: “Right now, we don’t quite know how to act on these positive ctDNA test results.”

The ‘lead time’ dilemma: Detection without prevention?

One of the most significant sources of skepticism revolves around the concept of “lead time.” Updated results from the CHIRP study presented in 2025 at the American Society of Clinical Oncology Annual Meeting showed a median lead time of 1.4 months. To a patient, this sounds like a head start; to many oncologists, it represents a period of profound uncertainty.

“What we don’t yet know is how can we then prevent that recurrence from happening?” asks Smith-Graziani. The fundamental question is whether starting treatment earlier based on a blood test actually improves long-term survival. LeVee notes that, “traditionally, studies have not shown that earlier detection of metastatic disease in asymptomatic patients improves long-term overall survival.”

Without proof that early intervention changes the ultimate outcome, many providers are hesitant to subject patients to the toxicities of more aggressive treatment paths prematurely.

The accuracy gap: False positives and negatives

The scientific community also maintains a healthy skepticism regarding the negative predictive value of current assays. In a perfect world, a negative ctDNA test would be a 100% guarantee that cancer is gone. In reality, the numbers tell a different story.

Smith-Graziani points to recent data regarding response to neoadjuvant therapy (treatment given before surgery) among patients with triple-negative and HER2-positive breast cancer. Researchers hoped that clearing ctDNA from the blood would be a 90% accurate predictor of a “pathologic complete response” (the total disappearance of cancer at the time of surgery). “It was more like 50% to 60%,” Smith-Graziani notes. “It wasn’t really as predictive as they thought.”

This gap in sensitivity means a negative test could provide false reassurance, leading a patient to believe they are in the clear when residual disease remains. “Might patients be falsely reassured? Might they get a positive result and now have this anxiety ... but we don't have something we can do about it?” Smith-Graziani asks.

Direct-to-consumer risks and ‘molecular anxiety’

Perhaps the most pressing concern for clinicians is the rise of direct-to-consumer testing. Because these tests are commercially available, patients are increasingly ordering them independently of their treatment team.

Smith-Graziani warns that receiving these results without a clear clinical plan can lead to “molecular anxiety,” a state where a patient knows they are at high risk for recurrence but has no standard-of-care options to mitigate that risk. “That can be heavy for some people,” she says, emphasizing that she recommends patients have a “long discussion with their oncologist about the limitations” before pursuing such testing outside of a trial.

The financial toxicity factor

Beyond the psychological burden lies a significant financial one. Because ctDNA testing for early-stage surveillance is not yet part of the National Comprehensive Cancer Network (NCCN) guidelines, insurance companies are reluctant to cover it.

“In a world where cancer care is so expensive at every step of the way, you really have to think about what you’re adding,” Smith-Graziani says. Without guideline support or Food and Drug Administration approval for specific surveillance indications, patients may face steep out-of-pocket costs for tests they receive as frequently as every three months. This “financial toxicity” adds another layer of risk to a technology that has yet to prove its lifesaving value in the early-stage setting.

Professional ‘circumspection’ and the path forward

This hesitance is not limited to academic researchers; it is felt across the medical community. Dr. Sucharu Prakash, Medical Director of Quality Services for Texas Oncology, admits that “doctors are circumspect” and can be “slow to adopt new technology.” He notes that he often receives “pushback” from colleagues who argue that if a technology is not in the NCCN guidelines, it shouldn’t be routinely offered.

“We don’t want to wait for five more years and keep this technology from patients,” Prakash argues, but he acknowledges that the data must “mature” before widespread adoption is responsible.

For Smith-Graziani, the conclusion is clear: For patients with early-stage breast cancer, ctDNA is currently a tool for the laboratory, not the standard clinic.

“I’m very much a fan of ctDNA being a part of a clinical trial because there [are] still so many questions in the standard-of-care setting,” she says. For patients curious about the technology, her advice is rooted in transparency: understand the uncertainty, weigh the financial cost, and, whenever possible, participate in the research that will eventually turn these “unanswered questions” into lifesaving protocols.