Multigene Panel Tests in Breast and Ovarian Cancers
Orlando, FL—The National Comprehensive Cancer Network (NCCN) has provided guidance for the clinical management of genetic mutation carriers who are identified using multigene panels without endorsing the routine use of these tests outside of research and/or intensive counseling on the risks and benefits of their use.
In version 2.2017 of its guidelines on genetic/familial high-risk assessment for breast and ovarian cancers, the NCCN states that “patients who have a personal or family history suggestive of a single inherited cancer syndrome are most appropriately managed by genetic testing for that specific syndrome,” noting that multigene testing may be more efficient and/or cost-effective when more than 1 gene can explain an inherited cancer syndrome.
A profusion of commercial panel tests that includes intermediate- and low-penetrance genes followed a Supreme Court ruling tearing down intellectual property barriers (gene patents), paving the way for next-generation sequencing.
At the 2017 NCCN annual conference, Kenneth Offit, MD, MPH, Chief, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York City, presented the NCCN’s screening recommendations based on genetic test results.
“Everyone was concerned that we weren’t quite ready to do this, because these genes hadn’t been very well studied in a large population,” said Dr Offit. Soon after, investigators found that 20% to 30% of panel tests yield variants of uncertain significance, mainly in the form of missense and intronic changes, which have undefined clinical relevance.
“New guidelines are going to be risk threshold–based,” he said. For breast cancer screening, the American Cancer Society recommends magnetic resonance imaging (MRI) for women who have a ≥20% lifetime risk for breast cancer. The problem with lifetime risk is that different definitions of lifetime yield different outcomes, with the remaining lifetime risk always being higher for younger patients, Dr Offit said.
Population mammogram screening is generally accepted in the United States at age 45 years, when the 5-year risk for breast cancer is 0.94%.
Dr Offit and Mark E. Robson, MD, Clinical Director, Clinical Genetics Service, MSKCC, developed summary suggestions to stimulate discussion of the NCCN’s surveillance and screening recommendations for women with low- or moderate-penetrance genes uncovered by multigene panels.
They advised that screening moderate-penetrance mutation carriers begin when their risk reaches the level at which population screening is recommended, which would be age 40 years for women who are carriers of ATM, CHEK2, or NBN mutations, and age 30 years for those with PALB2 mutations.
The NCCN mirrored these recommendations in its most recent guidance, while stating that its guidance does not imply the endorsement for or against multigene testing for moderatepenetrance genes.
For example, for ATM, NBN, and CHEK2 mutations, the NCCN suggests an annual mammogram and consideration of a breast MRI with contrast starting at age 40 years. The age is lowered to 30 years for women with CDH1 or PALB2 mutation, who are at increased risk for lobular breast cancer. Women with BRIP1 mutation have an increased risk for ovarian cancer; therefore, according to the NCCN, risk-reducing salpingo-oophorectomy should be considered in this group at age 45 to 50 years.
The evidence for breast cancer risk in patients with RAD51C mutation is unknown or insufficient. In this group, the NCCN recommends risk counseling for the autosomal recessive condition in offspring and the consideration of risk-reducing salpingo-oophorectomy based on a sufficient lifetime risk for ovarian cancer.
RAD51D mutation is associated with unknown or insufficient evidence for breast cancer risk; however, according to the guidelines, the lifetime risk for ovarian cancer in carriers of this mutation “appears to be sufficient to justify consideration of risk-reducing salpingooophorectomy.”