Early breast cancer is treated with curative intent. Surgery removes visible disease, and adjuvant therapy addresses microscopic spread. Yet recurrence still occurs — sometimes years after treatment completion. This pattern suggests that biologically active residual tumor cells can persist below the threshold of radiologic detection, raising the question of whether circulating tumor DNA (ctDNA) can reveal what imaging cannot.
Prognostic Validity Across Biological Subtypes
Before addressing the question of intervention, it is important to recognize the strength of the prognostic signal. Early mutation-tracking studies established that ctDNA detection after curative-intent therapy can precede clinical relapse (Garcia-Murillas et al., Sci Transl Med 2015). Subsequent longitudinal analyses in high-risk hormone receptor–positive early breast cancer have confirmed the strong association between ctDNA detection and subsequent distant recurrence (Lipsyc-Sharf et al., J Clin Oncol 2022).
In triple-negative breast cancer, particularly among patients with residual disease following neoadjuvant therapy, ctDNA positivity has consistently been associated with subsequent relapse (Chen et al., 2017; Radovich et al., 2020). Studies incorporating serial sampling during systemic therapy further indicate that ctDNA persistence or clearance correlates with pathologic response and long-term outcomes.
Across these settings, detectable ctDNA after curative-intent therapy is strongly associated with recurrence, particularly when persistence is confirmed on serial testing. Given these observations, the central uncertainty is no longer whether ctDNA predicts recurrence, but whether acting on that information alters clinical outcomes.
Biological Heterogeneity and Trial Design
The c-TRAK TN trial, published in Annals of Oncology (2022), was the first prospective attempt to initiate therapy based on ctDNA positivity in early triple-negative breast cancer. High-risk patients were monitored using tumor-informed assays and, upon ctDNA detection, randomized to pembrolizumab or observation. The trial highlighted limitations in the timing of intervention. A significant proportion of ctDNA-positive patients were found to have radiologically detectable metastatic disease at the time of molecular relapse, narrowing the potential window for therapeutic interception. Enrollment into the intervention phase was therefore limited, and the study closed early because of feasibility challenges.
These findings suggest that the interval between molecular relapse and overt metastatic disease may vary across biological subtypes. This observation underscores the importance of considering tumor biology when designing MRD-guided strategies rather than applying a uniform approach across early breast cancer populations.
The DARE study represents a biologically informed evolution in trial design. Conducted in high-risk HR+/HER2– early breast cancer, it evaluates whether detection of ctDNA using tumor-informed assays during ongoing adjuvant endocrine therapy should prompt therapeutic escalation. Patients with molecular evidence of relapse are randomized to additional systemic treatment or standard care, directly testing whether treatment escalation at the time of molecular relapse influences disease trajectory. The study is ongoing, and clinical outcome data are awaited.
Analytical Validity, Clinical Validity, and Clinical Utility
Recent reviews have framed the evaluation of ctDNA within a structured biomarker framework that distinguishes analytical validity, clinical validity, and clinical utility. Analytical validity addresses whether the assay can be measured reliably and reproducibly. Clinical validity considers whether molecular detection predicts recurrence. Clinical utility, however, addresses a different question — whether acting on that information improves patient outcomes.
In early breast cancer, analytical performance and prognostic association are increasingly well supported. Whether molecular detection should guide treatment decisions remains an open question. ctDNA has reshaped our understanding of recurrence by rendering minimal residual disease measurable rather than theoretical. It provides a valuable opportunity to observe relapse biology before clinical manifestation. Yet oncology has repeatedly shown that earlier detection of recurrence alone does not necessarily translate into improved clinical outcomes.
The central task now is to determine whether molecular detection can meaningfully inform therapeutic decision-making. Ongoing randomized trials will clarify whether intervention at the time of ctDNA positivity alters the natural history of disease. Until such evidence emerges, ctDNA remains a powerful prognostic tool whose ultimate role in guiding treatment is still being defined.
Can ctDNA Reveal Disparities in Breast Cancer Treatment?
Circulating tumor DNA analysis is increasingly used not only to detect molecular relapse but also to explore broader biological and clinical questions in breast cancer. A study analyzing ctDNA from more than 1,300 patients with estrogen receptor–positive, HER2-negative metastatic breast cancer investigated potential racial disparities in genomic alterations and targeted treatment patterns.
Written by Marine Rushanyan, MD
FAQ
Can ctDNA detect breast cancer recurrence earlier than imaging?
Several studies have shown that circulating tumor DNA detection can precede radiologic or clinical recurrence by several months. This “molecular lead time” suggests that plasma tumor DNA analysis may identify relapse earlier than conventional monitoring methods. However, whether earlier detection through liquid biopsy approaches ultimately improves patient outcomes remains under investigation.
Is molecular relapse testing currently used in routine clinical practice for early breast cancer?
At present, circulating tumor DNA (ctDNA) monitoring for minimal residual disease is not standard practice in most clinical guidelines. Although the prognostic value of this approach is increasingly supported by research, its clinical utility—meaning whether acting on molecular detection results improves outcomes—has not yet been conclusively demonstrated in randomized trials.
What are the limitations of ctDNA testing in early breast cancer?
Despite its promise, circulating tumor DNA testing faces several limitations. These include variability between assay platforms, uncertainty about optimal testing intervals, and the lack of definitive evidence showing that molecular relapse–guided treatment improves survival or prevents metastasis.
What future role could ctDNA play in breast cancer management?
If ongoing clinical trials demonstrate clinical benefit, circulating tumor DNA monitoring could eventually help personalize surveillance strategies and guide earlier therapeutic intervention in patients with molecular relapse. For now, this approach remains an important research tool that may reshape how recurrence risk is assessed in early breast cancer.