Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of several cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist only in a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast-derived cfDNA using a breast-specific DNA methylation signature.

We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples).

Pretreatment breast cfDNA was detected in patients with localized disease with a sensitivity of 80% at 97% specificity. High breast cfDNA levels were associated with aggressive molecular tumor profiles and metabolic activity of the disease. During neoadjuvant chemotherapy, breast cfDNA levels decreased dramatically. Importantly, the presence of breast cfDNA towards the end of the chemotherapy regimen reflected the existence of residual disease.

We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.