Posted October 29, 2018
Josef Penninger, M.D., IMBA - Institute of Molecular Biotechnology, Vienna, Austria

Women who carry mutations within their Breast Cancer 1 (BRCA1) gene have a total lifetime risk of up to 85% for developing breast cancer. The risk of developing breast cancer begins at age 25 and continues to rise every year thereafter. Current preventative options for these women are limited to prophylactic mastectomy, an extremely invasive procedure, and/or intensive screening and monitoring, all of which carry detrimental physical and psychosocial side effects. Therefore, alternative preventative measures for these women are needed to improve their quality of life.

Aside from its well-established role in DNA damage control, BRCA1 protein has also been shown to play a role in breast development, at which time it modulates differentiation of mammary luminal epithelial cells (the cells that give rise to the majority of all diagnosed breast cancers) and controls the expression and activity of estrogen receptor and progesterone receptor. Independently, researchers have also shown that receptor activator of nuclear factor ?B (RANK) and its ligand (RANKL), which normally modulate bone homeostasis, play a role in the formation of the lactating breast during pregnancy and are controlled by progesterone levels in the body. Epidemiological studies have shown that progesterone titers and serum levels of RANKL are elevated among BRCA1 mutation carriers. Knowing that both BRCA1 and RANK/RANKL influence breast development and are affected by hormones, it was important to examine whether RANK/RANKL influenced cancer development in BRCA1 mutation carriers.

With a Fiscal Year 2011 Breast Cancer Research Program Innovator Award, Dr. Penninger sought to assess the role of RANK/RANKL in BRCA1 mutation-driven breast cancers and determine whether inhibition of RANK/RANKL signaling would provide a protection against the development of tumors. In a Cell Research publication, Dr. Penninger showed that high RANK and RANKL protein expression could be found in 70.4% and 59.1% of BRCA1 mutation carrier breast cancer tumor samples, respectively. Moreover, high levels of RANK could be found in the earliest tumor lesions detectable in BRCA1 mutation carriers. To determine whether inhibition of RANK/RANKL would influence the development of BRCA1 mutation-driven breast cancer, Dr. Penninger genomically and pharmacologically inhibited RANK/RANKL. Using BRCA1 mutation carrier mouse models, genomic inhibition of RANK in mammary epithelial cells was found to not only delay the onset of breast cancer, but it also reduced the incidence and attenuated the progression of tumorigenesis. Using the US Food and Drug Administration (FDA) approved RANKL inhibitor, denosumab, to pharmacologically inhibit RANKL, the number of pre-neoplastic lesions that developed were dramatically reduced in BRCA1-mutant mice. After 1 year of treatment, remarkably, only 7% (1 out of 13) of BRCA1-mutant mice showed evidence of tumors, whereas 82% (9 out of 11) of control-treated mice developed breast tumors.

Results from Dr. Penninger's study supported the initiation of a randomized, double-blind, placebo-controlled Phase III clinical trial set to open in November 2018 aimed at determining whether the preventative effects of denosumab (XGEVA�) are effective in preventing breast cancer in BRCA1 mutation carrier women (https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-002505-35/AT). This multi-center clinical trial is being sponsored by the Austrian Breast and Colorectal Cancer Study Group with support from Amgen, Ltd., and includes 15 sites across 3 continents, including the National Cancer Institute and Harvard Medical School in the United States. The study aims to recruit 2,918 patients between the ages of 18 and 64 who harbor a mutation in BRCA1 and have not yet been diagnosed with breast cancer. Patients will be randomized and receive either denosumab or placebo, and the time to the development of breast cancer will be evaluated to determine whether denosumab reduces the risk of any breast cancer (invasive or ductal carcinoma in situ [DCIS]) from developing.

Denosumab was originally developed and received FDA approval to be used for the treatment of postmenopausal osteoporosis and later to prevent skeletal-related events in patients with solid tumors. In clinical studies, denosumab was found to be well-tolerated by patients even when given over an extended period of time. Since receiving FDA approval, it has been administered to thousands of patients worldwide. Therefore, should this Phase III clinical study demonstrate that denosumab can reduce the risk of development of breast cancer in BRCA1 mutation carriers, it would be a feasible strategy that could be rapidly incorporated into clinical practice as the first drug that could be administered to prevent breast cancer development in BRCA1 mutation carrier patients, thus sparing them from having to obtain a prophylactic mastectomy.

Dr. Josef Penninger and team

Publications:

Sigl V, Jones LP, and Penninger JM. 2016. RANKL/RANK: From bone loss to the prevention of breast cancer. Open Biology 6(11):160230.

Sigl V, Owusu-Boaitey K, Joshi PA, et al. 2016. RANKL/RANK control BRCA1 mutation-driven mammary tumors. Cell Research 26(7):761-774.

Link:

Public and Technical Abstracts: Novel Approaches to Breast Cancer Prevention and Inhibition of Metastases

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