Genetic Risk Assessment for Breast Cancer Using Multi-gene Panel Testing

By Mariam AlHilli, MD

On June 13, 2013, the U.S. Supreme Court made a landmark decision that broke the monopoly on BRCA1 and BRCA2 gene testing held by Myriad Genetics. Testing for BRCA1 and BRCA2 alone and in combination with other genes is now available through several companies.

Traditionally, individuals susceptible to hereditary cancers were screened based on history and offered testing for mutations in a single gene or a set of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). Today, advances in next-generation sequencing allow simultaneous testing for multiple genes associated with hereditary cancers.

Multi-gene panel testing

Multi-gene panel testing encompasses tests for a wide range of mutations, including:

• Mutations in homologous recombination (HR) (BRCA1/2, ATM, BARD1, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D)
• Mismatch repair genets (MLH1, MSH2, MSH6, PMS2 and EPCAM)
• Breast cancer susceptibility genes (CDH1, PTEN, STK11, TP53)
• Other cancer susceptibility genes

This is a highly cost-effective and time-effective method for the simultaneous evaluation of multiple genes. It has allowed for the identification of 40 to 50 percent more individuals with hereditary cancer gene mutations than is possible testing for BRCA1 and BRCA2 alone. However, these tests have some noteworthy limitations.

• Multi-gene panel testing is more likely to detect rare variants of unknown significance or novel variants with unknown pathological or clinical significance.
• There are limited data on the degree of cancer risk associated with each gene identified or the age-adjusted risks attributable to the genes.
• There are no guidelines on the management of many deleterious mutations identified.
• It is unclear if these individuals would benefit from risk-reduction strategies.

Multi-gene panel testing for gynecologic cancers

Women with BRCA1 mutations have a 65 to 85 percent risk for breast cancer and a 39 to 46 percent risk for ovarian, fallopian tube and primary peritoneal cancers by age 70.

Similarly, women with BRCA2 mutations have a 45 to 85 percent risk of breast cancer and a 10 to 27 percent risk of ovarian cancer by age 70.

Mutations in other genes, including BRIP1, RAD51D and RAD51C, have been described to be associated with a 10 to 15 percent lifetime risk of ovarian cancer.

Approximately 20 to 25 percent of ovarian carcinomas are thought to result from a hereditary predisposition. While BRCA1 and BRCA2 genes are responsible for the vast majority of hereditary ovarian cancers, several other genes within the HR pathway have been shown to contribute to a similar phenotype. Patients with these phenotypes have a better prognosis and clinical response to platinum therapies. In addition, they are likely to benefit from targeted therapies (PARP inhibitors) that exploit defects in the HR pathway.

Current guidelines issued by the National Comprehensive Cancer Network and the Society of Gynecologic Oncologists recommend genetic counseling and testing for all women with ovarian cancer, regardless of age or family history.

In addition, patients with a history consistent with hereditary breast and ovarian cancer should be given the option of pursuing panel testing when other cancer types are present in the family, rare syndromes are being considered or the results would influence medical management.