Women who have inherited genes linked with breast cancer may have a markedly altered risk depending on whether it has already developed in close family members, according to research that could help tailor decisions about their future care.
The study, in JAMA Oncology, demonstrates the complex interplay between genetics, family history, and other environmental or behavioral risk factors in determining risk.
The findings may help provide women carrying predisposing genes, their physicians and genetic counselors with personalized estimates of breast cancer risk to make clinical decisions regarding prevention and screening.
“Our prediction model provides a useful framework for conveying tailored risk information simply and identifying women who may receive enhanced benefit from specific intervention strategies because they expect to be at elevated risk of incident breast cancer,” reported Katie O’Brien, PhD, from National Institute of Environmental Health Sciences in Durham, North Carolina, and colleagues.
Pathogenic variants of genes known to predispose people to breast cancer have varying impacts depending on the affected gene and specific mutation.
O’Brien and co-workers examined how risk could be affected by having a first-degree family member with a breast cancer, which in itself is a strong predictor of risk and represents a mixture of genetic traits and shared environmental and behavioral exposures.
To do this, they accessed information from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, which genotyped tens of thousands of U.S. women with and without breast cancer for 12 established breast cancer predisposition genes.
The team combined this information with nationally representative survey data and cancer and mortality statistics across the U.S. to calculate breast cancer risk associated with predisposing variants in seven genes with established links to breast cancer.
A total of 67,692 women were included, including 33,841 who were diagnosed with breast cancer. Pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 pathogenic variants showing evidence of variation according to family history.
Women with a pathogenic variant and a first-degree family history—identified as a mother, sister, or daughter who had breast cancer—had an estimated 22.5% risk of breast cancer by the age of 50 years and a 51.2% risk between the ages of 50 and 80 years.
This compared with an estimated 9.4% risk by the age of 50 and 29.7% risk between ages 50 and 80 years in women with a pathogenic variant but no family history.
Absolute risks were markedly much higher for women with a pathogenic variant in PALB2 if they had an affected first-degree relative.
After accounting for pathogenic variants, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% in women with no pathogenic variants and no family history to 35.5% in carriers of the PALB2 pathogenic variant who had a family history of breast cancer.
Among women who have not been diagnosed with breast cancer by the age of 50 years, the cumulative risk of breast cancer by the age of 80 years ranged from 11.1% in women with neither pathogenic variants nor a family history to 70.5% for PALB2 carriers with a family history.
The team also determined risk estimates for specific subgroups defined by race and ethnicity or by categories of potentially modifiable risk factors, such as obesity, hormone therapy use, and alcohol consumption.
The researchers acknowledge that they did not have information on prophylactic surgery such as mastectomy, oophorectomy, or chemoprevention.
Nonetheless, they conclude: “Altogether, these estimates may provide guidance for individually tailored screening and prevention strategies, including more targeted prevention efforts for women with specific [pathogenic variants] and breast cancer family history.”
