ctDNA in Breast Cancer: The Journey to Clinical Utility With Ben Park, MD, and Jasmin Hundal, MD, MS, MPH

Early detection and precision treatment are transforming the landscape of breast cancer care. At the 2024 San Antonio Breast Cancer Symposium (SABCS), Dr. Ben Park, Professor of Medicine and Director of Precision Oncology at Vanderbilt School of Medicine, served on a panel exploring updates in liquid biopsy in breast cancer, including the role of circulating tumor DNA (ctDNA) in detecting minimal residual disease (MRD) and predicting recurrence.

In this interview with Fellows Forum member Dr. Jasmin Hundal, he shares takeaways from the panel for oncology fellows looking to understand the clinical utility and ongoing challenges in the field.

The Role of ctDNA in Early Detection

Dr. Park began by emphasizing the biological basis of ctDNA. All cells, including cancer cells, shed DNA into the bloodstream. Cancer-specific DNA can harbor mutations and structural variants distinct from normal cell-free DNA, making ctDNA a surrogate marker for early detection of disease recurrence.

Over the past 15 years, significant advances have been made in detecting ctDNA. Yet while these tools can identify patients at risk for relapse, challenges remain in translating these findings into improved clinical outcomes.

Clinical Validation Versus Clinical Utility

One of Dr. Park’s key messages was the distinction between clinical validation and clinical utility. Clinical validation confirms that a test measures what it claims to measure, but utility determines whether it changes patient outcomes. “I think that’s really important because I see clinic patients coming for second opinions when a lot of ctDNA is being detected,” noted Dr. Hundal. “They get imaging, and we don’t see any disease on imaging. They still have that ctDNA, but we don’t know where it is. Do we change treatment? Do we just observe? There’s not much data on that right now.”

For ctDNA, a positive MRD result is highly predictive of relapse. However, there is no definitive evidence yet that intervening early based on ctDNA positivity can cure more patients. Trials are ongoing to determine if changing therapy in response to ctDNA can improve outcomes, especially in early-stage breast cancer.

Patient Conversations and Ethical Considerations

For fellows encountering patients interested in ctDNA testing, Dr. Park offered practical guidance. While ctDNA tests are available commercially, their limitations must be carefully communicated. Dr. Park described the emotional burden of receiving a positive ctDNA result with no visible disease on imaging. Patients may perceive it as a “ticking time bomb” without a clear treatment path. Fellows should balance patient autonomy with transparency about the test’s current limitations, including financial toxicity and lack of definitive therapeutic options.

“Patients always ask me, ‘if this were you, what would you do’?” Dr. Park mentioned. “As a scientist, I want data, even if I know it may be a fait accompli that this means I’m going to have metastatic disease at some point. But that’s just me, so I’m transparent with patients. I’ve had patients who, once I’ve explained it them, say they want to order it. We’re in a gray zone right now; we don’t know what the right thing is.”

Current Research and Unanswered Questions

Dr. Park and his team are optimistic about the future utility of ctDNA. Ongoing trials, such as those conducted through the Translational Breast Cancer Research Consortium, aim to address questions of both validation and utility. With over five years of follow-up, these studies will provide critical data on ctDNA’s predictive power and role in clinical decision making.

Dr. Park noted, “The biggest unmet need in my mind is the question: is this patient cured or not? Are we undertreating when we shouldn’t be, or are we overtreating?” This question, particularly relevant in breast cancer, where overtreatment remains a concern, highlights an opportunity for innovation in biomarker research.

Key Takeaways for Fellows

1. Understand the biology of ctDNA: ctDNA is a promising surrogate marker for recurrence, but no test is perfect. Current commercial platforms lack sufficient negative predictive value to confirm cure
2. Communicate thoughtfully with patients: Be transparent about the limitations, emotional impact, and financial considerations of ctDNA testing
3. Engage in research to solve unmet needs: Identifying whether a patient is cured remains a central challenge in oncology. Fellows can play a pivotal role in advancing this field

As Dr. Park concluded, the journey from validation to utility is long, but the field is advancing rapidly. For fellows, staying engaged with these innovations will be critical in shaping the future of precision oncology.

About the Speakers

Ben Park, MD, is a Professor of Medicine and the Director of Precision Oncology at Vanderbilt School of Medicine. He is also the Donna S. Hall Chair in Breast Cancer, the Co-Leader of the Breast Cancer Research Program, the Associate Director for Translational Research at Vanderbilt-Ingram Cancer Center. Dr. Park’s research aims to find a cure for all types of breast cancer by investigating mutated and altered genes responsible for the development and progression of breast cancer, as well as genes that lead to drug resistance. 

Jasmin Hundal, MD, MS, MPH, is a second-year Hematology/Oncology Fellow at the Cleveland Clinic in Cleveland, Ohio. Previously, she completed her Internal Medicine Residency at the University of Connecticut. Dr. Hundal’s main area of interest is the overlap between cardiometabolic health and cancer, particularly for breast cancer patients and survivors. Outside of work, she enjoys traveling, cooking, and hiking.