Circulating breast-derived DNA allows universal detection and monitoring of localized breast cancer

Joshua Moss ¹ Aviad Zick ² Albert Grinshpun ² Einat Carmon ³ Myriam Maoz ² Bracha Lea Ohana ¹ Ofri Abraham ¹ Lili Germansky ² Benjamin Glaser ⁴ Ruth Shemer ¹ Beatrice Uziely ² Yuval Dor ¹

¹Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
²Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
³Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
⁴Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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 in only 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 detection and monitoring of breast cancer.