Genetic testing has become an increasingly important tool in oncology. Patients with a personal or family history of breast or ovarian cancer are currently the most common users of such tests.1 Traditional genetic testing historically included the sequential analysis of single and generally well-described genes involved in heritable cancers, such as BRCA1 or BRCA2.2 More recently, technological advances have led to the development of multigene panels and next-generation sequencing (NGS), allowing for the analysis of multiple genes at one time. Although there are considerable advantages to this approach, there are also many challenges.

Single-Gene Testing

Single-gene testing is typically conducted when a family or personal history of disease is highly suggestive of involvement with a single or a small set of genes.2 An advantage of single-gene testing is that because the target gene is usually well described, test results are typically easily interpreted and there are often established clinical practice guidelines or standards of care associated with a pathogenic variant. Patients also typically receive pretest and post-test genetic counseling to help them understand the potential implications of their test results.

Multigene Analysis

A major limitation of single-gene testing is that it only provides information about 1 gene, and thus, misses any other potential deleterious gene variants. Multigene panels identify pathogenic mutations in about 9% of patients with or at risk of a hereditary cancer.1 A study of 10,030 consecutive hereditary cancer NGS tests identified at least 1 pathogenic or likely pathogenic variant in 9% of cases; nearly half of these variants were in genes with moderate or unknown cancer risk.1 Similarly, pathogenic mutations have been identified in approximately 9% to 10% of patients at risk of developing hereditary breast or ovarian cancer.3,4 Similarly, several studies have identified pathogenic mutations harbored by patients who were negative for BRCA1/2 mutations. A study of 127 patients who underwent multigene testing after a prior standard genetic test found that 7% had a pathogenic mutation; 42% of patients who were rescreened were found to have variants of uncertain significance (VUS) that were not detected through initial screening tests.5 Another study of 122 patients undergoing retesting found that 11% harbored pathogenic mutations — of which, 85% were actionable, according to published guidelines.6 Clinical management was changed in approximately 64% of patients who had actionable mutations as a result of retesting.

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Multigene testing comes with several challenges. Numerous laboratories now conduct multigene panels and NGS, many with their own unique panels.7 As a result, selecting a laboratory with an appropriate panel that is also captured by a patient’s insurance coverage can be challenging.

Because approximately half of the pathogenic mutations that are identified by multigene panels are of moderate to unknown risk, the clinical utility of the information provided by multigene analysis is unclear.7 Not all mutations warrant a change in clinical management, and inexperience or uneducated interpretation of test results can lead to inappropriate treatment decisions. An increasing number of referrals for prophylactic surgery — many as a result of low- to moderate-penetrance pathogenic mutations — have been reported. Many of the referrals were attributed to a misunderstanding of test results.8