Abstract PS3-07-17: Circulating tumor DNA predicts relapse in early ER positive breast cancer

Abstract Introduction: Early hormone receptor positive breast cancer is treated with surgery followed by adjuvant systemic therapy, including chemotherapy and endocrine therapy. Recent studies have reported the added benefit of CDK4/6 inhibitors in the adjuvant setting in high-risk patients. Despite the high risk of relapse in patients for whom these drugs are currently indicated, the relapse free benefits are very small. There is a need for a better method to determine more precisely the prognosis of these high risk ER+ breast cancer patients. Circulating tumor DNA (ctDNA) offers promise for real-time, personalized monitoring of cancer. Tumor bespoke ctDNA assays have been shown to accurately predict tumor relapse. In our Q-CROC-03 and TRICIA trials we validated the prognostic value of ctDNA in early triple negative breast cancer. We now present our first results of serial ctDNA testing in patients with early ER+ breast cancer in the adjuvant setting. Our aim was to detect relapse in early breast cancer patients at least 9-12 months prior to clinical relapse. Methods: Plasma samples were collected post-operatively in 35 patients with mostly stage II/III ER+ breast cancer every 3-12 months up to 5 years after surgery. We performed a case-control study in which 14 patients with relapse were compared with 21 patients without relapse. Serial plasma samples were analysed in the 2 years prior to relapse in relapsed patients and up to 5 years post-operatively in non-relapsed patients. Patient-specific digital PCR assays (5/patient) were designed in-house using somatic tumor mutations identified by whole exome sequencing. Fractional abundance (cFA) was corrected by subtracting the fractional abundance of each variant in normal control plasma. Negative cFA were labeled zero (negative). Results: We determined an optimal threshold of cFA of 0.015% detected in at least 2 of the 5 variants to consider the sample ctDNA positive (ctDNA+). The median time to relapse was 35 months. 12 of 14 (86%) relapsed patients were ctDNA+ compared to 6 of 21 non-relapsed patients in at least one time point. Patients with negative ctDNA (ctDNA-) had a relapse-free survival (RFS) of 88% compared to 19% in ctDNA+ patients (p = 0.003, HR = 0.16 (95% CI = 0.05 to 0.4)), a negative predictive value (NPV) of 88%, sensitivity of 86% and specificity of 71%. When examining only samples collected between 6-18 months after surgery, ctDNA- patients reached an RFS of 90% compared to 21% in ctDNA+ patients (p0.0001, HR = 0.08 (95% CI = 0.02 to 0.3)), reaching a NPV of 90%, sensitivity of 83% and specificity of 86%. Moreover, the mean cFA of tested variants in relapsed patients was over 10-fold higher than that of non-relapsed patients. The cFA of tested variants in relapsed patients increased with each time point, whereas in non-relapsed patients the fractional abundance in tested variants decreased with each time point. We were able to detect relapses in ER+ breast cancer patients for a median of 21.6 months (range 4.9 -53.3) prior to clinical relapse. Conclusion: Circulating tumor DNA (ctDNA) is a strong predictive biomarker for relapse in ER+ breast cancer patients following surgery. Our results show that detectable ctDNA predicts relapse with a lead-time of nearly 2 years offering a substantial lead time for potential intervention. Citation Format: M. Basik, A. Klemantovich, R. Talia, L. Josiane, L. Cathy, A. Aguilar-Mahecha. Circulating tumor DNA predicts relapse in early ER positive breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-17.