DNA methylation–based liquid biopsy for longitudinal monitoring of treatment response in metastatic breast cancer.

Abstract

e15051 Background: Treatment response in metastatic breast cancer patients is currently monitored with CT-scans every 3-6 months leaving many patients on ineffective therapies while their disease progresses. The methylation DETEction of Circulating Tumour DNA (mDETECT) assay is a targeted DNA methylation-based Next Generation Sequencing liquid biopsy designed to detect cancer specific DNA methylation patterns. The mDETECT breast cancer assay targets 58 hypermethylated regions across the genome, assessing over 400 CpG sites. The assay has been designed to detect all subtypes of breast cancer, and is quantitative for molecules of methylated DNA. As a tumour and treatment agnostic assay with compact sequencing requirements (2 million sequencing reads per sample), mDETECT is ideal for frequent disease monitoring. The mDETECT breast cancer assay has shown 93% sensitivity at 100% specificity for TNBC and has a limit of detection of 0.025%. Methods: We are conducting a prospective multi-centre observational cohort study to monitor metastatic breast cancer patients using the mDETECT liquid biopsy as they undergo treatment. Metastatic breast cancer patients are eligible regardless of subtype or treatment and are followed through treatment changes. 20mL of blood was collected at each standard of care blood draw for up to 3 years. Plasma was extracted from patient blood draws and assessed using the mDETECT assay. To date, 128 participants have been enrolled, generating over 700 longitudinal blood sample timepoints (1-22 timepoints per patient). Patient’s longitudinal samples were assessed for their response to treatment and monitored over time for disease progression. Results: This initial analysis focuses on fifteen patients who were followed with standard of care blood draws throughout their treatments until death. Results show decreasing mDETECT levels during initial treatment response indicating response or partial response to treatment. In multiple patients, increasing mDETECT levels were observed prior to treatment change, radiological disease progression, and death. In some patients, the final timepoints before death showed a dramatic increase in both plasma cell free DNA levels and mDETECT determined circulating tumour DNA levels, consistent with advancing disease. Conclusions: These findings demonstrate the potential of methylation-based longitudinal monitoring of treatment response for metastatic breast cancer patients, a key clinical need given the large number of available therapies and complex treatment sequence decisions to be made. Longitudinal DNA methylation trajectories measured by mDETECT reflect treatment response and rising disease burden in metastatic breast cancer, suggesting a potential role for earlier identification of ineffective therapies and more timely treatment decision-making.