Universal germline genetic testing of nearly 40,000 patients with solid tumors revealed that standard age-based screening cutoffs miss a substantial proportion of inherited gene variants linked to cancer risk.
Genetic screening in oncology traditionally relies on age as a gatekeeper under the assumption that average- or late-onset cancers are less frequently driven by inherited pathogenic variants. A major study examining nearly 40,000 patients with solid tumors upends that premise.
Memorial Sloan Kettering Findings on Age Cutoffs
As Stadler pointed out, roughly 9.7% of all patients displayed high- and moderate-penetrance pathologic variants overall, which could potentially impact therapeutic approaches for cancer. Stadler indicated that the occurrence of pathogenic germline variants in older individuals—particularly those of high and moderate penetrance—demonstrated that a standard age threshold of 50 for genetic screening is inadequate. The study demonstrated the value of universal germline genetic testing, regardless of age. Hereditary cancer can occur at any age, and we should move toward a new standard in which genetic testing is considered for every patient diagnosed with cancer, regardless of age, noted Diaz.
“The current standard practice is, in many ways, a gatekeeper for genetic testing. Our study aimed to assess how much inherited cancer risk we miss when we rely too heavily on age at diagnosis,” said Stadler.
Zsofia K. Stadler, MD, clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center
Stadler clarified that germline screening utilizes an age threshold based on the premise that individuals diagnosed with average- or late-onset cancers possess a lower probability of harboring inherited pathologic variants compared to those with early-onset malignancies. On the other hand, individuals who possess these inherited genetic changes, designated as germline pathogenic variants, can develop an increased susceptibility to cancer.
While the presence of specific germline pathogenic variants may assist in directing patient therapies, these same variants also serve to alert family members about their own cancer vulnerability. However, germline screening is typically performed on patients with cancer who are younger than 50 years old, as Stadler explained.
Implications for Commercial Panel Testing and Guidelines
Medical professional organizations have developed guidance on genetic testing criteria based on personal and family histories. However, many individuals with cancer-predisposing pathogenic germline variants remain unidentified.
Delayed Genetic Testing Limits Preventative Cancer Care
Through hereditary cancer testing, people at elevated risk of developing cancer can be pinpointed, opening doors for proactive risk oversight, preventative measures, targeted therapy approaches, and family cascade testing. Countless people affected by hereditary cancer syndromes fail to receive genetic testing until post-diagnosis—even when their family backgrounds satisfy screening guidelines—triggering forfeited chances for preventative surgery alongside postponed diagnosis, refined treatment plans, and cascade testing.
Earlier research indicates that between 10% and 48% of cancer survivors carry pathogenic variants within cancer-associated genes that failed to satisfy standard testing benchmarks, while panels endorsed by guidelines might miss certain hereditary cancer syndromes. Highlighting established clinical utility, these findings reveal that testing criteria concentrate genes linked to specific cancer syndromes, thereby validating the application of multicancer panels even for patients who satisfy just one set of screening parameters.