Comment on: Exploring the utility of ctDNA testing in high-risk breast cancer patients in a community setting: case series

To the Editor,

We read with great interest the article “Exploring the utility of ctDNA testing in high-risk breast cancer patients in a community setting,” published in Therapeutic Advances in Medical Oncology (July 2025). The authors describe a longitudinal ctDNA monitoring strategy using a tumor-informed assay and serial plasma collections over 5 years in 72 high-risk patients, most of Asian or Pacific Islander origin. Testing was performed every 3–6 months using a PCR-based assay with a variant allele frequency detection limit of 0.01%. Notably, ctDNA positivity preceded radiologic recurrence in six cases and informed treatment decisions in others, although the study also documented false negatives and unrelated findings to the original disease. ¹

We commend the authors for contributing real-world data to this evolving field. A key strength is the focus on underexplored scenarios—such as management of oligometastases, adherence surveillance, and potential selective estrogen receptor degraders (SERD) switching.

We agree that ctDNA is a promising tool for disease monitoring. In early-stage disease, studies such as I-SPY2, MONARCH-E, and Nguyen et al. demonstrated its prognostic value, while in advanced disease, SERENA-6 explored its role in guiding treatment based on molecular rather than radiologic progression.^{2 –5}

Building on the important contribution of the authors, we would like to share a series of reflections that may enrich the ongoing discussion within the scientific community. First, the study underscores major challenges in ctDNA implementation, particularly the need for greater methodological standardization. Assay design and sensitivity are critical. Recent data suggest that tracking structural variants may enhance sensitivity without compromising specificity. ⁶ The I-SPY2 trial used a personalized assay targeting up to 16 patient-specific mutations from whole-exome sequencing. ² Nguyen et al. ⁴ tracked 1–9 mutations from a panel of 95 cancer-related genes using multiplex PCR. To expand access, alternative biomarkers—such as circulating and tumor miRNA profiles—may offer predictive value in early-stage disease at lower cost. ⁷

Second, histologic subtype appears to influence ctDNA dynamics, as recently demonstrated by Foldi et al. ⁸ in metastatic invasive lobular carcinoma, where ctDNA complemented imaging, particularly in subtypes where FDG-PET may exhibit reduced sensitivity.

Third, ctDNA may contribute to more personalized treatment strategies. For instance, in selected triple-negative breast cancer cases—such as tumors smaller than 2 cm with high tumor-infiltrating lymphocytes and negative ctDNA—treatment de-escalation in the neoadjuvant or adjuvant setting could be considered. In such scenarios, the integration of ctDNA with emerging molecular classifiers may further support individualized clinical decisions. ⁹

Defining the impact of ctDNA on survival and quality of life will require large-scale prospective studies, many of which are already underway. Within these studies, implementation science is key—we must address fundamental questions such as: who should be tested, when to initiate testing, how frequently to monitor, when to stop, and how to interpret the results. As emphasized by Agostinetto and seen in the SERENA 6 trial design, optimal timing for ctDNA surveillance and intervention remains unresolved.^5,10

Finally, patient anxiety, cost, and discordant findings matter. Wong et al. showed that inconsistencies between ctDNA and clinical/radiologic findings can cause emotional distress. Interpretation must integrate imaging and clinical context with systematic assessment of patient-reported outcomes and quality-of-life measures.

We appreciate this valuable contribution and support further rigorous research in this area.