Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Abstract

Simple SummaryThe clinical utility of positive findings in DNA damage-repair (DDR) genes BRCA1 and BRCA2 for the treatment of patients with breast or ovarian cancer is well established. However, multigene panel genetic testing for patients with breast and ovarian cancer now commonly includes DDR genes in addition to BRCA1 and BRCA2, a number of which are considered moderate or low-risk genes. This study aimed to describe the clinical utility of positive results from genetic testing when the findings were in one of these other DDR genes. In a group of 101 women with positive findings in a cancer gene other than BRCA1 or BRCA2 (often in a DDR gene), nearly three-fifths (58%) had a clinical recommendation made based on their positive genetic test result and two-thirds (65%) had the clinician make recommendations for family members that may be at risk. This real-world data provides evidence that positive findings from genetic testing for moderate and low-risk genes, including DDR genes, can have clinical utility and can impact a patient’s clinical management.Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients’ family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.