Study Suggests All Patients Diagnosed With Cancer—Regardless of Age—Should Receive Genetic Testing

Identifying inherited gene variants can uncover hereditary cancer risk and guide treatment.

Sometimes, when a patient is diagnosed with cancer, genetic testing is offered to identify whether the patient has inherited genetic alterations; these are known as germline pathogenic variants, which can cause predispositions to cancer in people who carry them. Knowing whether a patient has germline pathogenic variants can flag cancer risk in family members, and certain variants can also guide treatment. However, this screening is typically performed on patients with cancer who are younger than 50 years old. A new study in the American Association for Cancer Research (AACR) journal Cancer Discovery found that this practice may miss most inherited cancer gene variants.

CHALLENGING THE CURRENT PRACTICE FOR GENETIC TESTING

Zsofia K. Stadler, MD

The study’s co-corresponding author, Zsofia K. Stadler, MD, who serves as clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center (MSKCC), 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 Dr. 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.

Dr. Stadler, alongside co-corresponding author Luis A. Diaz, Jr. MD, FAACR, head of Solid Tumor Oncology at MSKCC, and the research team performed germline genetic testing in all 39,184 patients with solid tumors, regardless of age, at the MSKCC 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.

MOST VARIANTS MAY BE MISSED WHEN EXCLUDING PATIENTS OVER 50

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 with pathogenic variants to those under age 50, they would have excluded 4,601 patients with pathogenic variants—in other words, 72% of all patients with pathogenic variants would have been missed.

Dr. Stadler and colleagues also examined the prevalence of pathogenic variants across early-, average, and late-onset cancers using the following definitions instead of the standard that considers under 50 to be early-onset cancers:

  • early: occurring earlier than one standard deviation below the cancer type’s mean age at onset;
  • average: occurring within one standard deviation of the mean age of onset for the cancer type; and
  • late: occurring later than one standard deviation above the cancer type’s mean age at onset.

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

The study demonstrated the value of universal germline genetic testing, regardless of age.

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, Dr. Stadler said. 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 Dr. 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, Dr. 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.”