SAN ANTONIO – Inhibition of Receptor Activator of Nuclear Factor-kappa B ligand (RANKL) may represent a promising approach to reduce the risk for developing breast cancer in BRCA1 mutation carriers, a study presented at the 2016 San Antonio Breast Cancer Symposium (SABCS) has shown.1

“Studies have recently demonstrated the emerging role of progesterone signaling in BRCA1-associated cancer,” said Geoffrey J. Lindeman, BSc, MBBS, PhD, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. “Augmented expression of progesterone have been observed in breast tissue from BRCA1 mutation carriers and BRCA1-deficient mice.”

Since RANKL appears to be a key effector of progesterone signaling to stem/progenitor cells in mice, researchers sought to determine if the progesterone/RANKL/RANK signaling pathway is relevant in human BRCA1 mutation-positive breast tissue.

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For the study, investigators explored the role of the RANK/RANKL pathway during the preneoplastic phase in freshly isolated (histologically normal) patient specimens from BRCA1 mutation carriers using various approaches.

Researchers found that RANK-positive cells were highly proliferative and displayed a highly abnormal DNA repair.

“RANK-positive signature correlated with basal-like cancers,” Dr Lindeman added. “Thus, RANK-positive progenitors represent a key target population.

Following a pilot study that showed treatment with denosumab, a RANKL inhibitor, reduced median Ki67 levels in BRCA1 carriers, researchers are currently developing a randomized, double-blind, phase 3 breast cancer prevention study. For the study, researchers plan to enroll more than 2900 BRCA1 and BRCA2 mutation carriers to receive denosumab or placebo for 5 years. The primary end point is breast cancer events.


1. Lindeman GJ, Nolan E, Vaillant F, et al. RANK ligand as a target for breast cancer prevention in BRCA1 mutation carriers. Paper presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.