Multicenter study of prospective ctDNA surveillance in high-risk HR-positive, HER2-negative early breast cancer

Detection of circulating tumor DNA (ctDNA) during adjuvant endocrine therapy (ET) for hormone receptor positive HER2-negative early breast cancer (HR+ HER2- EBC) is associated with recurrence, with potential to direct switcches in adjuvant treatment. The multicenter TRAK-ER study enrolled patients with high-risk HR+ HER2- EBC who underwent 3-monthly ctDNA surveillance for up to 3 years during adjuvant ET. High-risk included ≥ 4 involved lymph nodes, tumor > 5 cm; or 1-3 involved lymph nodes with additional high-risk features. Upon ctDNA detection, patients have staging scans and in the absence of radiological recurrence, are randomized to receive palbociclib plus fulvestrant or standard ET. ctDNA analysis was performed using a tumor informed assay. By September 2025, 1133 patients were registered, 928 had panels designed, and 912 started ctDNA surveillance, including results from 5810 tests (median 7 per patient). ctDNA detection rate was 5.0% in the first test, and 1.3% in subsequent tests(p<0.001). Patient level detecton rate was 12.0%, with 1.1% of patients having a clinical recurrence without priorctDNA detection. Detection positively associated with nodal burden (p<0.001) and grade (p=0.04) and negatively associated with increasing time from surgery (p=0.01). Estimated cumulative ctDNA detection rate at 5 years post-surgery was 23.7%. In patients with ctDNA detected on the first test, 65.9% had radiological recurrence, compared to 26.6% in patients first detected on subsequent tests (p<0.001). The authors conclude that these results inform implementation of ctDNA surveillance in HR+ HER2- EBC.