Prospectively Randomized, Placebo-Controlled Phase 3 Study to Determine the Effect of Denosumab on Breast Cancer Prevention in BRCA1 Mutation Carriers
Abstract
In Europe and the USA, more than 1.3 million women are estimated to carry a germline mutation in the BRCA1 or BRCA2 genes. These women have up to 87 percent lifetime risk of developing breast cancer, with tumors usually developing at an early age. Currently, prophylactic surgery is the only proven procedure that significantly reduces breast cancer risk, and this is can be associated with postoperative complications and a suboptimal cosmetic outcome. Medical prevention, if effective, could present a non-invasive alternative to mastectomy, but would need to be started relatively in early adulthood and has potentially to be offered beyond menopause. This strategy could also buy time for women considering prophylactic mastectomy. There is accumulating evidence that the RANK/RANKL signaling pathway plays a pivotal role in breast tumorigenesis, particularly in the development of BRCA1-mutated tumors. Targeting the RANK pathway has been shown to attenuate breast epithelial proliferation in vitro and in vivo, and to profoundly reduce mammary tumor formation in mouse models. In addition, since BRCA germline (gBRCA) mutations confer an increased risk for ovarian cancer, the vast majority of gBRCA women undergo prophylactic bilateral salpingo-oophorectomy (PBSO) at a young age. This has been shown to reduce ovarian cancer risk, but can significantly compromise bone, sexual and potentially cardiovascular and cognitive health. Many women who undergo PBSO therefore receive some kind of osteoprotective therapy. Current medical breast cancer prevention strategies for gBRCA mutation carriers involve the use of tamoxifen or aromatase inhibitors, which - at least in the case of aromatase inhibitors - may further compromise bone health.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1155751
Entities
People
- Benjamin Leder
- Geoffrey Lindeman
- Hang Lee
- Joy Tsai
- Judy E. Garber
- Marie Wood
- Sarah-jane Dawson
Organizations
- Dana–Farber Cancer Institute