Broad Genetic Testing Uncovers Additional Risk Variants in Cancer Patients, Study Finds

NEW YORK – Universal genetic testing could identify more cancer patients with pathogenic risk variants, potentially changing treatment approaches for some, a new analysis has found.

Germline genetic testing to assess inherited risk for cancer is typically offered to a subset of patients meeting certain personal and family cancer history criteria. But through its Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) study, the Mayo Clinic sequenced nearly 3,000 cancer patients for around 80 cancer susceptibility genes and found that more than 1 in 8 patients harbored germline pathogenic variants associated with increased cancer risk. The researchers reported on Friday in JAMA Oncology that they wouldn't have identified half of these patients with pathogenic variants if they had tested patients according to current guidelines.

For 42 patients these findings led to changes in their treatment, suggesting that a broad germline genetic testing strategy among cancer patients could help personalize therapeutic management.

"This targeted treatment would have been lost if the patients had not received genetic testing," first author Niloy Jewel Samadder, a gastroenterologist and hepatologist at Mayo, said in a statement. Samadder also presented the findings at the virtual American Society for Human Genetics conference this week.

The researchers enrolled more than 3,000 patients with solid cancers into their prospective, multi-site study. The patients underwent germline sequencing using Invitae's Multi-Cancer Panel, which included 83 genes at the start of the study and increased to 84 genes in July 2019. 

Overall, 397, or 13.3 percent, of the 2,984 patients in the final cohort harbored at least one pathogenic genetic variant. Most commonly, those pathogenic genetic variants were in BRCA1 and BRCA2, but also in MUTYH, CHEK2, the Lynch syndrome-associated mismatch repair genes, and ATM. 

The incidence of germline pathogenic genetic variants varied by tumor type, occurring in 7.3 percent of melanoma patients and in up to 20.6 percent of ovarian cancer patients. While the presence of a pathogenic genetic variant did not vary by cancer stage, it did vary by patients' age at diagnosis, with younger cancer patients more likely to have a pathogenic genetic variant.

But some of these variants would have been missed if the researchers adhered to genetic testing guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, or the American College of Medical Genetics and Genomics, the researchers reported. They used the guidelines to determine whether genetic testing would have been indicated for each patient in their study and which genes likely would have been tested.

Based on that, they determined that if testing had been guided by those criteria, pathogenic genetic variants in 192 patients would have been missed, representing 48.4 percent of the 397 patients in the cohort with pathogenic genetic variants.

"Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients," paper co-author Robert Nussbaum, who is also chief medical officer at Invitae, said in a statement. "All cancer patients should have access to complete genetic information that can guide their care and inform their families' health." 

For more than a quarter of the patients with a pathogenic variant in high-penetrance genes, test results led to a change in their treatment. Twenty-one patients then received a targeted therapy, while 18 had surgery and two enrolled in a clinical trial.

Patients' positive results for pathogenic genetic variants can have ramifications for their family members, but the uptake of cascade testing is often low. The researchers of the INTERCEPT trial considered that test cost may be one factor contributing to the low uptake and offered follow-on variant testing to the relatives of affected patients for free. Of the patients with pathogenic genetic variants, 17.6 percent had family members who underwent follow-on testing within three months and nearly half had positive results.