Universal germline genetic testing catches missed cancer risks in older patients

Bottom line: Universal germline genetic testing of nearly 40,000 patients with solid tumors detected a substantial proportion of inherited gene variants that would have been missed by the standard germline testing approach that excludes those over age 50.

Journal in which the study was published: Cancer Discovery, a journal of the American Association for Cancer Research (AACR).

Authors: Zsofia K. Stadler, MD, and Luis A. Diaz, Jr., MD, FAACR are the two co-corresponding authors. At Memorial Sloan Kettering Cancer Center Stadler serves as the clinical director of the Clinical Genetics Service, and Diaz is the head of Solid Tumor Oncology.

Background: Germline genetic screening can identify whether a patient with cancer has inherited genetic alterations in a gene or genes that are implicated in cancer. These inherited genetic alterations, known as germline pathogenic variants, can cause predispositions to cancer in people who carry them. Germline pathogenic variants can be used to flag cancer risk in patients' family members, and the presence of certain germline pathogenic variants can also potentially guide patients' treatments.

However, germline screening is typically performed on patients with cancer who are younger than 50 years old, explained Stadler.

She said that the logic for the age cutoff in germline screening is the assumption that patients with average- or late-onset cancers are less likely to have cancers caused by inherited pathologic variants than patients with early-onset cancers.

"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. "As opposed to using an arbitrary cutoff such as age 50, we hypothesized that universal germline genetic testing would give us valuable insight into all patients regardless of age and potentially facilitate more testing for patients' family members who may also carry hereditary cancer risk."

How the study was conducted and results: The research team performed germline genetic testing in all 39,184 patients with solid tumors, regardless of age, at the Memorial Sloan Kettering Cancer Center by using the MSK-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay, which tested for 94 germline pathogenic variants using DNA isolated from patients' blood or saliva.

Overall, 16.3% of all patients harbored at least one of these germline pathogenic variants. The researchers found that, if they had limited the number of patients who had pathogenic variants to those under age 50-the typical age cutoff for germline genetic sequencing-they would have excluded 4,601 patients with pathogenic variants (72% of all patients with pathogenic variants).

Stadler and colleagues also examined the prevalence of pathogenic variants across early-, average-, and late-onset cancers. Rather than using the standard definition of early-onset cancer as cancer that develops before age 50 regardless of cancer type, they classified patients' cancer cases as either early-, average-, or late-onset based on the distribution of age at onset for each cancer type. They defined early-onset as occurring earlier than one standard deviation less than the cancer type's mean age at onset; correspondingly, they defined late-onset as occurring greater than one standard deviation above the cancer type's mean age at onset. Average-onset cancers were defined as occurring within one standard deviation of the mean age of onset for the cancer type.

Using this classification, they found that the prevalence of pathogenic variants was 18.4% among the early-onset population, 15.6% among the average-onset population, and 12.3% among the late-onset population.

High-penetrance pathogenic variants-variants that are more likely to produce the pathogenic effect with which they are associated-occurred in 9.1% of patients with early-onset cancers, 5.5% of those with average-onset cancers, and 2.6% of those with late-onset cancers. The prevalence of moderate-penetrance variants in patients with early-, average-, and late-onset cancers was 3.3%, 3.4%, and 2.5%, respectively. Taken together, high- and moderate-penetrance pathologic variants, which carry potential implications for cancer treatment strategies, occurred in about 9.7% of all patients, according to Stadler.

Authors' comments: The prevalence of pathogenic germline variants among older patients, especially high- and moderate-penetrance variants, suggested that a uniform cutoff for genetic screening at age 50 was insufficient, said Stadler. The study, she added, 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," said Diaz. "Our manuscript shows that relying on age at diagnosis misses a substantial proportion of patients with germline pathogenic variants and provides strong support for moving toward universal germline genetic testing in patients with cancer."

Doing so, Stadler added, would give clinicians insights into the patient's cancer that could guide treatment, and it would also allow for a greater use of cascade testing: the process of testing the patient's relatives to identify whether they might also harbor the same pathogenic variants.

"Unfortunately," Stadler said, "cascade testing remains one of the most underused opportunities in cancer prevention. Once a hereditary cancer predisposition variant is identified in one patient, testing relatives becomes highly targeted and informative, yet only a minority of eligible relatives currently undergo testing."

Study limitations: A limitation of the study was that it was conducted at a single major tertiary cancer center. Additionally, certain cancers were over- or underrepresented, and the cohort was predominantly of European and Ashkenazi Jewish ancestry.