Katherine L. Nathanson, MD

Refining breast cancer risk assessment by examining moderate risk genes and common inherited gene variations in families with a high risk of breast cancer.

Impact

The most common hereditary risk factors are mutations in the BRCA1 or BRCA2 genes, but these account for only 5 to 10 percent of inherited breast cancers. There are additional breast cancer risk genes, though mutations in these genes are not as potent as BRCA mutations. Dr. Nathanson’s studies have demonstrated the frequency of mutations in high and moderate penetrance genes, their distribution around the world, and the penetrance and risk of cancers associated with these mutations. Her team is utilizing novel methods of gene sequencing to assess mutations and variants in multiple genes associated with increased risk of breast cancer. The results of their studies will lead to a better understanding of hereditary breast cancer, specifically, the factors that increase the risk of breast cancer in those patients with negative standard genetic testing results. Their long-term objective is to ensure that more patients and their family members benefit from advances in breast cancer surveillance and therapeutics.

Progress Thus Far

Dr. Nathanson and her team have shown that women with breast cancer and a second primary cancer have an increased likelihood of carrying an inherited mutation in a cancer susceptibility gene and should be eligible for genetic testing regardless of the age of breast cancer diagnosis. Her team launched a study of very high-risk women with early-onset breast cancer to identify what drives their risk of breast cancer, who should be offered genetic testing, as well as the genes that should be included on multi-gene panels. Dr. Nathanson is working with multiple large consortia to precisely delineate the role specific gene variants play in breast cancer risk. Her studies also aim to assess how “variants of uncertain significance” in known breast cancer susceptibility genes contribute to this risk.

What’s next

Dr. Nathanson and her colleagues will continue to characterize the pathogenic variants in known and novel breast cancer susceptibility genes that can be correlated to an increased risk of the disease. In addition, analysis of the data they have collected from high-risk women—those with both early onset breast cancer and multiple family members with breast cancer—is ongoing to identify the drivers of risk in the absence of mutations in known predisposition genes. Her studies will be used to develop and refine models to yield accurate estimates of breast cancer risk and minimize inconclusive genetic testing results to provide greater benefit for patients and their families.