The Current and Future Utility of ctDNA Testing in Breast Cancer

ctDNA Testing in Breast Cancer

Community oncologists Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, hosted a panel discussion on the role of ctDNA in breast cancer for the Oncology Brothers podcast Clinical Insights series. The pair were joined by three breast cancer experts: Matthew Kurian, MD, of St. Elizabeth Healthcare; Wassim McHayleh, MD, of AdventHealth; and Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care.

In cancer care, ctDNA describes small, free-floating DNA fragments that solid tumor cells shed into the bloodstream during their lifecycle or as they break down. Recent technological advancements have allowed oncologists to isolate and analyze these DNA fragments, which can provide valuable information for tumor detection, monitoring, molecular profiling, and treatment response tracking. Currently, ctDNA has been established as a prognostic biomarker across cancer types, but its utility in guiding treatment decisions is still unclear in many populations, including breast cancer. 

ASCO Guideline Recommendations

A few weeks before the panel discussion, the American Society of Clinical Oncology (ASCO) Guidelines committee published updated recommendations for ctDNA testing in solid tumors and lymphoma based on a systematic review of currently available data. According to the guideline authors, available evidence moderately supports using ctDNA testing to identify tumor genetic alterations as first assessment or when tissue-based testing is not feasible or would take too long. Although tissue-based testing for genetic alterations should be performed if ctDNA testing is negative or inconclusive. 

Outside of identifying alterations, ctDNA testing should only be offered alongside standard-of-care tests if the results can inform a specific, evidence-based action or if there is uncertainty with standard assessments. However, at the time of publication, the authors found very limited scenarios where ctDNA testing has clear evidence of clinical utility beyond genetic profiling, and they overall discouraged testing for other populations outside of clinical trials. “While there is a large volume of evidence showing a correlation between ctDNA findings and prognosis, there is very limited evidence around what, if any, action should be taken in response to those results,” the guideline authors wrote.

Notably, the guideline authors strongly recommended against using ctDNA as a replacement for any other form of testing, or using fractional, percentage, or concentration-based ctDNA or total cell-free DNA concentration assessments as a surrogate measure of disease burden.

Current Utility and Future Potential of ctDNA in Breast Cancer

Although evidence for clinical utility of ctDNA testing in breast cancer is still uncertain, testing is performed outside of clinical trials in both academic and community settings, said Dr. Kurian. The panel discussants shared how they approach ctDNA testing in their practices. As of today, ctDNA is particularly helpful as a follow-up to inconclusive imaging or findings, Dr. Teplinsky said. Concerning but uncertain imaging findings that coincide with positive ctDNA increases the level of suspicion and may prompt additional imaging and potentially earlier intervention, particularly for high-risk subgroups like TNBC. 

Importantly, ctDNA shedding varies by breast cancer subtypes, with TNBC exhibiting the most shedding and hormone receptor (HR)–positive breast cancer exhibiting the least, Dr. Kurian said. As a result, ctDNA testing may be less applicable for HR–positive populations. Trials are exploring whether ctDNA assessment in these higher-shedding subtypes can function as a surrogate for pathologic complete response, but data are not yet available, Dr. Kurian said.

Looking forward, ctDNA has a variety of potential utilities for breast cancer treatment decisions. Several trials are exploring ctDNA testing after neoadjuvant therapy and surgery to guide escalation or de-escalation of adjuvant therapy. In addition, ctDNA testing could serve as the basis for earlier intervention if there are signs of recurrence. There is even the possibility that ctDNA testing could replace routine mammograms for lobular histologies, Dr. McHayleh said. However, all these possible utilities need to be validated in clinical trials

Discussing ctDNA With Patients

Although the value of ctDNA testing is still not clear, more patients with breast cancer are aware of and requesting testing. Until trials validate specific treatment decisions based on ctDNA results, oncologists must manage patient expectations when incorporating ctDNA testing. For instance, patients who have positive ctDNA after completing standard therapy may expect additional intervention that is not currently indicated. Conversely, patients with negative ctDNA may question the necessity of continuing adjuvant therapy, or may hope to pause therapy until ctDNA appears. As a result, oncologists need to be prepared to discuss the current utility and limitations of ctDNA testing and to interpret test results with patients. 

Key Takeaways

In closing the discussion, the doctors all agreed that using ctDNA in practice today should be a shared decision with patients. Dr. Kurian emphasized that oncologists need to be acquainted with the current data, and added that patients should be referred to ctDNA trials to help establish evidence-backed treatment algorithms, particularly those with ctDNA positivity after standard therapies. Dr. Teplinsky summarized that ctDNA is valuable for select populations today, but more time is needed to determine its overall utility in breast cancer. Similarly, Dr. McHayleh advised that ctDNA testing both now and in the future should be reserved for high-risk patients whose prognosis and treatment options are less certain than low-risk patients.