Circulating tumor DNA dynamics in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer assessed using an ultrasensitive tumor-informed assay.

BACKGROUND: Circulating tumor DNA (ctDNA) in early breast cancer (EBC) is prognostic for distant relapses. The ctDNA dynamics in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative EBC, which is considered low-shedding, are challenging to track. We used an ultrasensitive assay to detect molecular residual disease (MRD) and its association with recurrence in this subtype. PATIENTS AND METHODS: Patients with stage II-III HR-positive/HER2-negative EBC were assessed for MRD, in which ctDNA concentrations were measured in serial plasma samples at varying intervals using a whole-genome sequencing tumor-informed assay and the association of ctDNA dynamics with disease recurrence was examined. RESULTS: Twenty-six patients had provided two or more serial plasma samples and had a tumor suitable for DNA sequencing. The median follow-up time was 5.0 years from surgery (range 2.3-10.8 years). Patient-specific ctDNA assays with a median detected ctDNA concentration of 70.2 p.p.m. (interquartile range 14.9-757.0) were designed to test 118 plasma samples (2-9 samples per patient). Eleven patients (42%) had MRD at one or more time points, including preoperative, and 58% of ctDNA detections were in the ultrasensitive range (<100 p.p.m.). Six patients (23%) experienced distant recurrence, consistent with expectation for this subtype within 5 years of follow-up, all of whom had MRD before clinical recurrence (100% sensitivity), with a median lead time of 1.5 years (range 1.0-2.5 years). All 15 patients who remained persistently MRD-negative and 5 patients who experienced ctDNA clearance while receiving oncological treatment remained recurrence-free throughout follow-up. CONCLUSION: Using an ultrasensitive assay, we found that all patients who experienced distant relapse had MRD detected before clinical detection, with a median lead time of 1.5 years. We observed a strong correlation of ctDNA dynamics with oncological outcomes, with 100% sensitivity of the assay for distant relapse.