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Polygenic Risk Score, Family History Refine Breast Cancer Risk Assessment in CHEK2 Mutation Carriers

NEW YORK – Some carriers of germline variants in the gene CHEK2 appear to be at high risk for breast cancer, though additional genetic and family history data may be needed to find those cases and refine their risk estimates, according to investigators at Memorial Sloan Kettering Cancer Center, Myriad Genetics, and elsewhere.

In a presentation at the American Society of Clinical Oncology annual meeting on Friday, held virtually this year, MSK medical oncologist Mark Robson outlined his team's work to estimate breast cancer risk in women with pathogenic germline CHEK2 variants by bringing in additional polygenic risk score (PRS) and personal or family history data.

Past studies suggest that nearly 1 percent of individuals tested using a hereditary cancer panel carry pathogenic variants in CHEK2, Robson explained, noting that around 65 percent of those pathogenic variants represent the same European founder deletion.

Overall, pathogenic CHEK2 mutations are thought to coincide with a moderate risk of breast cancer — in the 23 to 28 percent lifetime risk range — he explained, though that risk appears to be dialed up or down depending on broader genetic risk factors, an individual's family history, and certain environmental exposures.

For their new study, Robson and his colleagues set out to get a more refined look at breast cancer risk in women with pathogenic CHEK2 germline changes by incorporating the so-called Tyrer-Cuzick model, which captures some relevant genetic, personal, and family history clues, and by bringing in information from the 86 SNPs that make up Myriad's riskScore — a validated test based on low-penetrance variants that have been shown to modify breast cancer risk.

"The goal of the work is to develop a comprehensive risk prediction model to more precisely estimate risk by incorporating both the 86-SNP polygenic risk score and the Tyrer-Cuzick model for women who carry these rare variants," Robson said.

Starting with data for nearly 355,429 women of European ancestry who had undergone multigene panel testing for hereditary cancer risk, the team focused in on participants carrying pathogenic changes in CHEK2. While the median age was similar in women with or without pathogenic CHEK2 variants, Robson noted that those with the CHEK2 mutations were more prone to breast cancer diagnoses and also more likely to have multiple first degree relatives with the disease.

Among the 4,286 women with pathogenic CHEK2 variants, for example, 1,583, or 37 percent, were diagnosed with breast cancer. Across the group of 351,143 women who did not have mutations in CHEK2 or other breast cancer-related genes, meanwhile, breast cancer was diagnosed in 83,257 individuals, or 24 percent.

When they took a closer look at factors that might affect CHEK2-related risk models, including the specific pathogenic variant at hand, the researchers found that both pathogenic CHEK2 variants and a breast cancer-related PRS tended to coincide with a family history of breast cancer.

That prompted them to come up with a risk assessment strategy that took the riskScore and Tyrer-Cuzick model into account without "double-counting" information from any of these sources, Robson explained.

The team applied that combined risk assessment tool to data from another 459 women with pathogenic CHEK2 variants, classifying nearly one-quarter as low risk group for breast cancer, with a remaining lifetime risk of the disease coming in below 20 percent. Nearly 64 percent appeared to have moderate breast cancer risk, while the remaining 12 percent fell into a high-risk group that appeared to have a remaining lifetime breast cancer risk that exceeded 50 percent.

Robson cautioned that the results so far only represent women who had already been referred for hereditary cancer testing, and noted that more work is needed to understand polygenic risk of breast cancer in non-European women, as well as other risk factors not yet captured in the data.

Even so, he and his colleagues concluded in their abstract that "comprehensive risk assessment could inform individualized decision-making and may lead to improved targeting of screening and prevention strategies" for women carrying pathogenic CHEK2 variants.

"Individual patients [with pathogenic CHEK2 variants] may fall along a wide spectrum of risk that's influenced by many factors," Robson explained. "Some women have a risk that may not necessarily be sufficient to warrant increased surveillance, whereas other women fall into categories of risk that are high enough to warrant consideration of preventive surgery similar to that consideration given for BRCA mutations."

In a statement, Nicole Lambert, president of Myriad Oncology, Myriad Women's Health, and Myriad International, said these and other data presented at the ASCO meeting from studies using the Myriad riskScore test "will support a broader launch of riskScore to even more women in the coming year, with more personalized information and the unique ability to modify carrier risk through a clinically validated tool."