Prospectively Randomized, Placebo-Controlled Phase 3 Study to Determine the Effect of Denosumab on Breast Cancer Prevention in BRCA1 Mutation Carriers
Abstract
In this proposal, we will address the overarching challenge: To prevent breast cancer. Which patients will this research help and how will it help them? Women who carry a faulty BRCA1 gene who have a high (~50%-80%) lifetime risk of developing breast cancer. Moreover, when tumors arise, the majority (~70%) are clinically aggressive “triple-negative” tumors. Currently, the only effective strategy for reducing their breast cancer risk is prophylactic mastectomy, which reduces risk by about 90%. We propose to examine whether denosumab, a well-tolerated medication already approved to treat bone loss (osteoporosis) or cancer that has spread to bone, can prevent breast cancer in BRCA1 mutation carriers, or at least delay breast cancer onset so that preventive mastectomy can be deferred. What are the potential clinical applications, benefits and risks? Denosumab is an agent approved to reverse bone loss. If it also safely reduces the risk of breast cancer in women with a BRCA1 mutation, it could be offered to thousands of women carrying a BRCA1 mutation, enabling them to at least defer mastectomies with some confidence, if they so desire. The risks are related to the drug, which can cause mild pain under the skin when administered, and can transiently lower blood calcium. Use of calcium and vitamin D minimizes this risk. At higher doses than will be used in this study, long-term use of denosumab has rarely been linked to hip and vertebral fractures and a jaw condition (“ONJ”), attributed to altered bone turnover. When these occur, they are usually reversible. What is the projected time it may take to achieve a patient-related outcome? The definitive results of the randomized Phase III prevention trial will not be achieved during the 4 years of the grant period. However, we propose to examine health-related quality of life after 12 and 24 months of study drug in women in the US, UK, and Australia (English-speaking, because of the instruments used for the assessments). We plan to assess quality of life, cancer worry by allocation perception, risk perception, and by intention to have prophylactic surgery, controlling for age and menopausal symptoms; to assess the Impact of Events scale, and to assess menopause symptoms using the Green Climacteric Scale. Because enrollment will take place over the first 30 months of the trial, outcome data will be analyzed and available to share in the fourth year of the project. What is the likely impact of this study on ending breast cancer? At completion of the funding period, we should have important information about the effects of Denosumab versus placebo on circulating markers, quality of life, bone and breast tissue of women with a BRCA1 mutation, and we will have an important repository of coded (de-identified) blood, digital images (mammograms, MRI scans), tumor and normal breast tissue for further investigation. At completion of the BRCA-P trial, the randomized placebo-controlled trial of Denosumab versus placebo for women with germline BRCA1 mutations, we will have shown that Densoumab either does or (less likely) does not reduce the risk of developing breast cancer in this population. If successful, the trial will offer young women an option that will allow them to defer or, ultimately, perhaps avoid bilateral mastectomies for breast cancer risk reduction. This would be a remarkable option for this very high-risk group of women, who are currently burdened with the knowledge of their breast cancer risk and undesirable strategies to reduce it.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910780
Entities
People
- Judy Garber
Organizations
- Dana–Farber Cancer Institute
- United States Army