Background: Both germline and somatic genetic testing are well-established tools for precision medicine in cancer patients. Sequencing of a tumor detects somatic variants which can be used to inform therapy and can also detect germline variants, but with important limitations. As such, these tests can fail to report clinically actionable germline events.
Methods: We retrospectively analyzed a cohort of 2,023 cancer patients with previous tumor sequencing results who were receiving germline testing for cancer predisposition genes. Indications for germline testing included: tumor findings of potential germline origin, treatment guidance or surgical planning, and personal/family history. High and moderate risk pathogenic and likely pathogenic germline variants (PGVs) were analyzed.
Results: Overall, 30.5% (n=617) of patients harbored a PGV, most of which could have treatment implications. PGVs were prevalent across cancer types, genes, and patient age. Importantly, 8.1% of PGVs (50) were not reported by tumor sequencing as either somatic or germline findings. Among patients with PGVs, 11.2% (69) had their PGVs identified only after presenting with a second, possibly preventable, primary malignancy. Variants were often observed in patients with cancers not strongly associated with their germline finding, such as lung cancer and CNS tumors.
Conclusions: As a follow-up to tumor sequencing, germline tests can inform clinical management decisions. Current guidelines and tumor testing approaches capture many, but not all, of these germline findings, reinforcing the utility of both expanded germline reflex testing, as well as germline analysis independent of tumor sequencing in appropriate patients.