FORCE has a strong commitment to promoting research to benefit our community. We advocate for more research funding, educate people about available studies, and report findings back to our community.
by Lisa Rezende, PhD
BRCA mutation carriers have the option of taking drugs such as tamoxifen or raloxifene to reduce their risk of breast cancer; however many women opt for mastectomy rather than risk-reducing medication. The search for new drugs to reduce breast cancer risk has led to denosumab (Prolia®), a drug approved to treat osteoporosis. This drug works by blocking the RANKL protein, which is present in cells from BRCA1-mutated tumors, according to a study done in 2016 (see our XRAYS review). The study also found that RANKL inhibitors reduced the number of breast tumors in mice engineered to have no BRCA1 gene.
At his December presentation at the San Antonio Breast Cancer Symposium, Dr. Geoffrey Lindeman of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia presented data from experiments that used cells from people with BRCA1 mutations. His data suggested that growth of BRCA1 mutated cells could be controlled by RANKL inhibitors. Clinical trials looking at the use of denosumab to treat some breast cancer are ongoing. A phase III study of denosumab to reduce breast cancer risk in BRCA mutation carriers is expected to open next year.
PARP inhibitors are a class of drugs that target tumors with a certain type of DNA defect, such as those found in people with inherited mutations in BRCA. Two PARP inhibitors, olaparib (Lynparza®) and rucaparib (RubracaTM) are FDA-approved to treat certain BRCA-related ovarian cancers. Currently, no PARP inhibitors are approved to treat breast cancer. Dr. Hyo Sook Han of Moffitt Cancer Center presented results from the BROCADE 2 study, a phase II clinical trial that compared treating advanced breast cancer in BRCA-mutation carriers with either carboplatin and paclitaxel, a combination previously shown to be effective in BRCA mutation carriers, or with carboplatin, paclitaxel, and the PARP inhibitor veliparib. The study found a trend towards improved responses in people treated with veliparib: patients on veliparib and carboplatin/paclitaxel had a median of 14.1 months before their disease progressed (a measure known as progression-free survival), compared to 12.3 months for patients who took only carboplatin/paclitaxel. In terms of overall survival, patients who were given veliparib had a median overall survival of 28.3 months, compared to 25.9 months for those who did not. While these are interesting trends, the results did not reach statistical significance, and more time is needed to get an accurate measure of overall survival. In the meantime, BROCADE 3, a larger phase III study, is currently enrolling patients with mutations in BRCA1 or BRCA2 who have advanced breast cancer tumors.
Multi-gene panel tests are being used more often to identify mutations in many genes that are known or believed to increase cancer risk. Despite their widespread use, the extent of cancer risk and range of cancers associated with mutations in some of the genes found on these panels remains an active area of research. Dr. Fergus Couch and colleagues looked at data from over 38,000 white breast cancer patients who were diagnosed between 2012 and 2016 and had genetic testing through Ambry Genetics. By comparing the frequency of pathogenic mutations (those that cause disease) in patients and a previously characterized European control group, Couch and colleagues calculated breast cancer risks for many of these genes. They found that mutations in BRCA1, BRCA2, and PALB2 were associated with a high risk of breast cancer, while the risk associated with ATM, CHEK2, BARD1, RAD51D, and MSH6 (a gene associated with Lynch syndrome) was moderate. Mutations in BRIP1, NBN, RAD50, RAD51C, and MRE11A were not associated with increased cancer risk. FORCE will continue to follow research on these and other multigene panels and note any changes to national guidelines for risk management on our website.
Previous studies have shown that breast cancer diagnosis at a young age is associated with greater risk of recurrence and decreased overall survival. Dr. Diana Eccles and colleagues at the University of Southampton wanted to see if a mutation in BRCA1 or BRCA2 affected overall survival in young breast cancer patients. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH study), followed about 2,900 women diagnosed with breast cancer between the ages of 18 and 40. The study found no significant difference in survival of patients with and without BRCA mutations. A trend towards better survival for patients with BRCA mutations and triple-negative breast cancer was noted, but the result did not reach statistical significance. Samples from the study will be further analyzed for mutations in other genes that increase the risk of breast cancer in young women.