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Levels of a blood protein may be linked to an increased risk of breast cancer among BRCA carriers, study finds

Spring 2017

A BRCA mutation and low levels of osteoprotegerin (OPG) increases breast cancer risk four-fold

Joanne Kotsopoulos, PhD
Joanne Kotsopoulos, PhD, the lead author.

WCH scientists have found that women with a BRCA1 mutation who have low levels of a protein called osteoprotegerin (OPG) in their blood are at a higher risk of breast cancer, but doctors may be able to reduce their risk by using a drug that is al­ready approved to treat osteoporosis, called denosumab.

WCRI Scientist Joanne Kotsopoulos, PhD, conducted the study with collaborators including Senior Scientist Dr. Steven Narod.

The researchers found that women with a BRCA1 genetic mutation and low levels of OPG in their blood were four times more likely to develop breast cancer than those with high levels of OPG. This suggests that doctors may be able to determine breast cancer risk more precisely using a blood test that measures OPG levels.

In the body, the protein OPG binds to a molecule called RANKL as part of a path­way that helps keep bones strong. Emerg­ing evidence suggests that this pathway may also play an important role in breast cancer development. Denosumab is a drug used to prevent osteoporosis by targeting this same pathway and thus mimics the behaviour of OPG. With growing evidence that the same pathway is related to breast cancer, scientists are starting to investigate denosumab as an option to prevent breast cancer for women at a very high risk. For example, a 2016 study in mice, published in Nature Medicine, showed that denosum­ab could prevent some tumours from grow­ing in breast tissue. Since BRCA mutation carriers have lower OPG levels, this may be of particular relevance for this high-risk population.

BRCA mutation carriers have a 60 per cent risk of breast cancer in their lifetime, compared with a 10 per cent risk in the general population. Their best option for preventing cancer are limited to a prophy­lactic double mastectomy.“Giving high-risk women less invasive prevention options for breast cancer is one of the most important goals of our research,” Kotsopoulos says. “These findings could point us toward the first viable drug for breast cancer preven­tion, which would make a huge difference for women making tough decisions about their risk.”

Dr. Narod says that his team will investigate denosumab in larger studies. “Denosumab is a safe drug that many women are al­ready taking. If we show that it is effective for preventing breast cancer, more high-risk women will have a potentially life-saving option without resorting to surgery.”

This is the first study of the relationship between OPG levels and breast cancer risk in women. The researchers measured OPG levels in 206 women with a BRCA1 or BRCA2 mutation, or both, and followed them over an average of 6.5 years. During the study, 18 women developed breast cancer, most of whom had low levels of OPG in their plasma.

The study was published in the journal Oncotarget.

This research is an example of how WCH is contributing to a healthier, wealthier, smarter Ontario.

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