The more researchers learn about breast cancer susceptibility genes, the more personalized treatment can become, said Fergus J. Couch, PhD, who presented the AACR Outstanding Investigator Award for Breast Cancer Research on Friday, December 9, during the San Antonio Breast Cancer Symposium. Women with one or more first-degree female relatives with a history of breast cancer have a two-fold increased risk of developing breast cancer, and those risks continue to escalate with the number of affected family members and whether those family members were diagnosed at a young age or with bilateral disease. 

By analyzing these families, researchers identified the BRCA1 and BRCA2 breast cancer susceptibility genes, and further work has shown that pathogenic variants can result in the truncation of these proteins. Genetic study results are a mainstay of research and have identified genetic mutations associated with moderate and high risks of breast cancer in up to 5% of population-based breast cancer cases and 35% of high-risk families, providing personalization of underlying breast cancer risk for all women, he said.

Truncated proteins coupled with a small number of pathogenic missense variants “have been associated with 55%–65% lifetime risk of breast cancer in the general population and up to 85% lifetime risks among women with a strong family history of the disease,” he said. Conversely, very little is known about the influence on cancer risk of rare variants of uncertain significance (VUS). 

Couch’s work at the Mayo Clinic Cancer Center and the Center for Individualized Medicine concentrates on identifying the inherited genes and mutations that predispose people to breast cancer. He leads two large consortia on the topic—Consortium of Investigators of Modifiers of BRCA1/2 and Triple-Negative Breast Cancer Consortium.

BRCA1 and BRCA2 are not the only genes that result in a predisposition to breast cancer, he noted.

  • Moderate-risk mutations (relative risk between 2.0 and 5.0)
    • CHEK2
    • ATM
  • High-risk mutations (relative risk greater than 5.0)
    • PALB2
  • High-risk mutations (associated with hereditary gastric cancer, Cowden, Peutz-Jeghers, and Li-Fraumeni syndromes)
    • CDH1
    • PTEN
    • STK11
    • TP53

Unfortunately, the risk associations have not yet been firmly established or are weakened by very broad confidence intervals. Yet gene panel screening for hereditary cancer gene mutations has become an integral component of medical management for high-risk families and individuals with triple-negative breast cancer. Ongoing research is attempting to better quantify and qualify breast cancer risk in the general population as well as high-risk families. The studies “are expected to identify the subset of panel genes that are associated with increased risk of breast cancer or breast cancer subtypes and to establish more accurate risks of breast and other cancers,” he said.

Although thousands of VUS in BRCA1 and BRCA2 have already been identified through clinical testing and many more in BRCA1, BRCA2, and other predisposition genes are being identified through panel-based genetic testing and tumor sequencing studies, patients have not been able to benefit from enhanced risk assessment, prevention, or clinical management.

Previous studies attempted to classify VUS as neutral or pathogenic, and more recent studies have established the utility of validated functional assays for VUS assessment. Hundreds of BRCA1 and BRCA2 VUS have been reclassified by commercial testing laboratories or by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles consortium that serves as the expert review panel for variants in these genes for the ClinVar and BRCA Exchange. 

Genome-wide association studies have also identified several common genetic variants associated with breast cancer risk. Although the majority of the 179 known breast cancer variants are associated with estrogen receptor- (ER-) positive breast cancer, 21 of these show specific associations with ER-negative or triple-negative (ER-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer. The variants account for just under 20% of the familial relative risk of breast cancer.

On the upside, Couch explained that numerous studies have established that polygenic risk scores derived from these risk variants can improve individualized risk assessments in women who are at increased or reduced risk of breast cancer and modify risks of breast cancer among BRCA1 and BRCA2 mutation carriers.