Under the traditional paradigm of genetic testing in cancer, the role of germline testing was to assess for the inherited risk of cancer, whereas the role of tumor testing was to determine therapeutic selection. Parallel tumor-normal genetic testing uses simultaneous genetic testing of the tumor and normal tissue to identify mutations and allows their classification as either germline or somatic. The increasing adoption of parallel testing has revealed a greater number of germline findings in patients who otherwise would not have met clinical criteria for testing. This result has widespread implications for the screening and further testing of at-risk relatives and for gene discovery. It has also revealed the importance of germline testing in therapeutic actionability. Herein, we describe the pros and cons of tumor-only versus parallel tumor-normal testing and summarize the data on the prevalence of incidental actionable germline findings. Because germline testing in patients with cancer continues to expand, it is imperative that systems be in place for the proper interpretation, dissemination, and counseling for patients and at-risk relatives. We also review new therapeutic approvals with germline indications and highlight the increasing importance of germline testing in selecting therapies. Because recommendations for universal genetic testing are increasing in multiple cancer types and the number of approved therapies with germline indications is also increasing, a gradual transition toward parallel tumor-normal genetic testing in all patients with cancer is foreseeable.
Trial registration: ClinicalTrials.gov NCT04214067.