# The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families

## TL;DR

Adding genetic risk scores, lifestyle factors, and breast density improves breast cancer risk classification for women in families with a CHEK2 gene mutation.

## Contribution

This study shows that integrating polygenic risk scores and additional risk factors refines breast cancer surveillance recommendations in CHEK2 mutation families.

## Key findings

- Adding PRS311 reclassified 34.5% of heterozygotes and 35.6% of non-carriers in surveillance categories.
- Including breast density further shifted risk classifications in 23.1% of heterozygotes and 27.8% of non-carriers.
- Most heterozygotes moved to less intensive surveillance, while non-carriers needed more intensive monitoring.

## Abstract

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families.

In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups.

The surveillance advice was reclassified in 20 (34.5%) heterozygotes and 21 (35.6%) non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 11 (20.0%) heterozygotes and 8 (15.1%) non-carriers; and a sub-analysis showed that adding breast density on top shifted another 9 (23.1%) heterozygotes and 5 (27.8%) non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance.

The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

•Lifetime breast cancer risk in unaffected CHEK2 heterozygotes and familial non-carriers was calculated using CanRisk.•Risks ranged from 22.1 to 51.7% in heterozygotes and 10.7–31.0% in non-carriers based on family history alone.•Adding PRS311 caused the largest shift in risk prediction, followed by breast density and questionnaire-based risk factors.•Risk stratifications were similar among distant relatives, not supporting modified cascade screening in CHEK2 families.

Lifetime breast cancer risk in unaffected CHEK2 heterozygotes and familial non-carriers was calculated using CanRisk.

Risks ranged from 22.1 to 51.7% in heterozygotes and 10.7–31.0% in non-carriers based on family history alone.

Adding PRS311 caused the largest shift in risk prediction, followed by breast density and questionnaire-based risk factors.

Risk stratifications were similar among distant relatives, not supporting modified cascade screening in CHEK2 families.