Background: 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. Patients and methods: We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples). Results: 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. Conclusion: We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.
Bibliographical noteFunding Information:
This work was supported by grants from the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, the Alex U. Soyka Pancreatic Cancer Fund, the Israel Science Foundation , the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Kahn Foundation (to YD), the Israel Cancer Association and the Personalized Medicine Grant 2018-2020 of the Ministry of Science and Technology (Israel). No grant numbers are applicable. YD holds the Walter and Greta Stiel Chair and Research grant in heart studies.
© 2019 The Authors
- DNA methylation
- breast cancer
- circulating cell-free DNA