Broad Testing for Multiple Genes Benefits Patients With Cancer, Relatives


Researchers conducting broad next-generation sequencing discovered more actionable variants in patients and families than they would have otherwise; they did so by using a universal approach, rather than sticking with clinical guidelines.

Universal multigene panel testing was linked with increased detection of actionable, heritable variants beyond what one would expect to find using targeted genetic testing based on current cancer guidelines, according to a study published late Friday in JAMA Oncology.

The multicenter cohort study, conducted at 3 Mayo Clinic cancer facilities as well as a community oncology practice, found that 1 in 8 patients had a pathogenic germline variant (PGV), half of which would not have been found if using guidelines alone. In addition, for the nearly 30% of patients with a high-penetrance variant, the findings led to a change in treatment.

The study sought to examine the incremental yield of pathogenic and likely PGVs using a broad universal testing strategy for those with a genetic predisposition to cancer, compared with a targeted strategy based on clinical guidelines the association of universal genetic testing with clinical management, and the proportion of families who would undergo free cascade family variant testing (FVT).

FVT may be conducted in relatives of a patient with cancer even when they are asymptomatic; it is currently recommended for certain breast and ovarian cancers as well as Lynch syndrome. But studies have shown uptake of the testing is poor, even when it is low cost or no cost, amid concerns about confidentiality and insurance barriers.

Most of the estimates regarding the prevalence of germline cancer susceptibility have come from patient registries, genetic testing companies, and high-risk cancer clinics. This has probably created a referral and ascertainment bias, the authors said, and there is a paucity of data that compares the prevalence of germline findings in patients with cancer unselected by practice guidelines.

Using universal screening, the 2984 patients in this study, all with solid tumors, were not chosen based on cancer type, disease stage, family history of cancer, ethnicity, or age. They were receiving care between April 1, 2018, and March 31, 2020, and had sequencing performed using the Invitae Multi-Cancer Panel next-generation sequencing platform. At the time of the testing, it analyzed 83 genes (it now analyzes 84 genes).

A PGV was considered incremental if it was detected based on the universal testing approach in this study and would not have been identified in targeted testing endorsed by published guidelines for specific tumors (from the guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics).

The mean (SD) age of the patients was 61.4 (12.2) years, and more than half (53%) were male. The breakdown for stage of disease was:

  • 535 patients (18.6%) with stage 0/I disease
  • 477 (16.7%) with stage II disease
  • 593 (20.7%) with stage III disease
  • 1257 (43.9%) with stage IV disease

A family history of cancer in a first-degree relative was reported in 1019 patients (34.1%).

PGVs were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes.

The 6 most common PGVs were found in BRCA1 and BRCA2, 66 (2.2%); monoallelic MUTYH, 50 (1.7%); CHEK2, 47, (1.6%); Lynch mismatch repair genes, 29 (1.0%); and ATM, 31 (1.0%). Variants of uncertain significance were found in 1415 patients (47.4%).

A total of 192 patients (6.4%) had incremental findings that would not have been found by phenotype or family history–based testing criteria based on clinical guidelines. This represents 48.4% of the 397 patients with PGVs. Of these 192 patients, 35 (18.2%) carried high-penetrance PGVs.

And of the 149 patients with a high-penetrance PGV, 42 (28.2%) had therapy changes based on the discovery. The changes included need for surgery (18), targeted therapy (21), or enrollment in a clinical trial (2).

Only younger age of diagnosis was associated with presence of PGV.

Just 70 patients (17.6%) with PGVs had family members take the no-cost cascade FVT. The FVT process included an online video that described the risks and benefits of genetic testing. Of the 176 relatives tested, 79 (45%) had positive results.

Even without the expense of the test, the authors noted that there was low acceptance of the offer for testing

“This study offers significant insight into the performance of multigene panel testing and has broad implications for its wide clinical implementation and acceptance in oncology practice," they wrote.


Samadder NJ, Riegert-Johnson D, Boardman L, et al. Universal genetic testing vs guideline-directed targeted testing in hereditary cancer syndrome. JAMA Oncol. Published online October 30, 2020. doi:10.1001/jamaoncol.2020.6252

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