Somatic Profiling Prospectively Guides Germline Genetic Testing in Patients with Mutations in High-Risk Cancer Predisposition Genes

Approximately 15% of patients with advanced cancer have an inherited predisposition to malignancy, as revealed by germline genetic testing of unselected patients with cancer.^1,2 Despite this genetic predisposition, over one-third of patients who carry a pathogenic germline variant do not qualify for genetic testing based on current clinical testing guidelines.^3–10 Many patients with cancer undergo molecular profiling of their tumor using commercial next-generation sequencing (NGS) laboratories. Most of these laboratories perform tumor-only somatic sequencing without matched germline sequencing analysis, even though variants identified in tumor-only sequencing could be of germline origin.¹¹ In a study of over 2300 patients whose tumors were profiled, 3.5% were referred for genetic counseling and testing based on the profiling results, and 1.6% were referred based on other concerns.¹² Of these, 74% had confirmed germline pathogenic variants.

Of note, FDA approvals for targeted therapies depend on identification of pathogenic genetic variants that could be only within the tumor or in a patient's germline and often in genes that predispose to inherited forms of cancer.^13–15 In addition to therapeutic implications for the individual, supplementing somatic sequencing with germline testing may reveal familial pathogenic variants, which would extend benefits to family members by informing them about the risk of disease and its prevention or early detection.¹⁶

For these reasons, supplementing the current practice of somatic sequencing with germline testing of genes associated with hereditary predisposition to cancer would improve the current treatment of cancer and inform on the risk of future cancers.¹² The rapid expansion of NGS into routine clinical practice makes it feasible to integrate these 2 approaches to identify variation in both the cancer and inherited genomes, both of which are clinically important and informative for the treatment and monitoring of patients with cancer.¹⁷ Currently, there are clinical trials that include targeted therapy for patients whose tumors or germline findings show deficiency in the DNA damage repair pathways including mutations in 1 of the mismatch repair genes (MLH1 [Lynch syndrome], MSH2, MSH6, or PMS2) and clinical indications in homologous recombination deficiency genes (BRCA1 and BRCA2 [hereditary breast and ovarian cancer syndrome]).^18–21 In addition, the FDA approved use of talazoparib in combination with enzalutamide for patients with prostate...