Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Abstract

Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration–approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.

Comparison of Germline Genetic Testing Before and After a Medical Policy Covering Universal Testing Among Patients With Colorectal Cancer

“…22,23 The value of universal GGT testing has been questioned by some based on the number of low-penetrance genes or recessive alleles included in multigene panels. 24 However, the classification of variants as pathogenic or likely pathogenic in the multigene panel used in the current study and others 2,16 is consistent with the rigorous variant interpretation criteria proposed by the American College of Medical Genetics and Genomics. 25 The National Comprehensive Cancer Network provides recommendations for patients with findings in low-penetrance or recessive alleles, including, at a minimum, family history evaluation and subsequent endoscopic surveillance.…”

“…Increased financial burden is often raised as an argument against universal testing, yet this argument is contradicted by cost analyses of Lynch syndrome screening in the US and Europe . The value of universal GGT testing has been questioned by some based on the number of low-penetrance genes or recessive alleles included in multigene panels . However, the classification of variants as pathogenic or likely pathogenic in the multigene panel used in the current study and others is consistent with the rigorous variant interpretation criteria proposed by the American College of Medical Genetics and Genomics .…”

The Evolution of Genetic Testing from Focused Testing to Panel Testing and from Patient Focused to Population Testing: Are We There Yet?

“…Population testing would not require a family history evaluation and would be simpler to implement across oncology and nononcology specialties. 18 Universal testing would help with uptake of genetic testing which we know is already underutilized. We can look at testing rates among cancers where the NCCN recommends testing for all cases.…”

Saturation-scale functional evidence supports clinical variant interpretation in Lynch Syndrome

“…The eventual reclassification rate for VUS in LS and other hereditary cancer genes is modest, reaching only ~25% [11,12]. The difficulty of resolving these VUS stands as one of the most persistent barriers to the utility of broader genetic testing for LS genes [13].…”