ctDNA test may guide treatment de-escalation for older women with breast cancer

A circulating tumor DNA (ctDNA) test showed promise in identifying which older patients with estrogen receptor–positive breast cancer can safely forgo surgery in favor of hormone-blocking therapy alone, according to a prospective trial published in Clinical Cancer Research.

Priscilla F. McAuliffe, M.D., Ph.D., a breast surgical oncologist at UPMC Hillman Cancer Center, and an assistant professor of surgery at the University of Pittsburgh School of Medicine, and team enrolled 43 women aged 70 and older with ER-positive, HER2-negative, non-metastatic breast cancer who had opted for primary endocrine therapy rather than surgery. Using the Signatera ctDNA assay developed by Natera, Inc., the team tracked small fragments of tumor-derived genetic material in patients' blood over the course of treatment to determine whether those molecular signals could predict which patients were responding to endocrine therapy and which were not.

The findings suggest the answer is yes. Patients whose ctDNA was undetectable, either before starting therapy or after beginning treatment, were more likely to experience stable disease or tumor shrinkage. In contrast, patients with persistent ctDNA positivity at six months were at significantly higher risk of tumor progression, indicating a potential need for surgery or alternative treatment. Notably, ctDNA monitoring detected all five tumor growth or recurrence events ahead of standard imaging.

"We are learning that not every patient needs the same treatment based simply on their diagnosis, and instead, care should be right-sized for each individual," said McAuliffe in an article published on the University of Pittsburgh School of Medicine website.

Acording to a Natera news release about the study, pretreatment molecular residual disease (MRD) assessment identified 68% of patients (23 of 34) were MRD-negative and none experienced progression (100% negative predictive value). Among the 11 patients who tested MRD positive, 7 cleared their ctDNA after six months of primary endocrine therapy.

For managed care stakeholders, the study raises the prospect of a molecular tool that could help clinicians avoid unnecessary surgical interventions and their associated complications, including lymphedema, nerve damage, scarring and infection risk, in a patient population where competing comorbidities already complicate treatment planning. Older women with early-stage, hormone-responsive breast cancer represent a growing share of the oncology population, and tools that support appropriate de-escalation could reduce procedure-related costs and improve quality of life without compromising outcomes.

The trial's hybrid-decentralized design also offers a model for broadening clinical trial access. Blood samples were frequently collected from patients' homes through mobile phlebotomy, reducing the travel burden and enabling enrollment from UPMC Hillman network community oncology sites beyond the main academic center.

"We worked really hard to include patients outside the main academic center," said lead author Neil Carleton, M.D., Ph.D., a postdoctoral fellow at the University of Pittsburgh. "Making care more convenient for patients, including access to clinical trials, is a priority at UPMC Hillman Cancer Center."

Patient-reported data reinforced the clinical findings. When surveyed, more than 80% of participants said ctDNA results helped them feel more informed about their treatment decisions without increasing anxiety, suggesting the tool may support shared decision-making between clinicians and patients navigating the tradeoffs of surgical versus nonsurgical management.

The researchers cautioned that the study was small and that the findings are not yet ready for routine clinical application. Larger, confirmatory trials will be needed before ctDNA-guided surgical de-escalation could be incorporated into standard treatment pathways. The study was funded by the Hillman Cancer Center Developmental Pilot Program, the Shear Family Foundation and the National Institutes of Health.