A new multi-institutional study led by NIEHS researchers gives the most detailed U.S. estimates to date of how inherited genes and family history together affect a woman’s lifetime risk of breast cancer.

The researchers, as part of the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, pooled data from nearly 68,000 women across 13 studies. By combining genetic test results, family history, lifestyle factors, and national cancer statistics, the team calculated breast cancer absolute risk estimates for women with a variant in one of several “pathogenic” genes known to be strongly associated with breast cancer susceptibility — including BRCA1, BRCA2, PALB2, CHEK2, and ATM. Results were published Oct. 9 in JAMA Oncology.

“Our goal was to present population-based estimates of cumulative breast cancer risk for women with these pathogenic variants,” said Katie O’Brien, Ph.D., lead author and staff scientist in the NIEHS Epidemiology Branch. “We wanted to acknowledge how those risks vary not only by family history, but also by lifestyle and other factors, so women can make more informed decisions in consultation with their doctors.”

Why it matters

Breast cancer is the most common cancer among U.S. women after skin cancer. Each year, about 240,000 women are diagnosed and more than 40,000 die from the disease. Overall, 1 in 8 women (13%) will be diagnosed in their lifetime.

Researchers have long known that risk is shaped by both genetic and environmental factors. Some women carry gene variants that sharply raise risk, while others may have an elevated risk due to a family history of breast cancer. Until now, most published numbers have been depicted as relative risks or hazard ratios, statistics that are difficult for patients to translate into meaningful decisions.

“Women with these variants often want to know: What does this mean for me, in absolute terms?” O’Brien explained. “We tried to put the numbers in a framework that is both rigorous and simple enough to guide real-world decisions.”

How the study was done

To provide those more tangible estimates, the team combined three major data sources. The first data source was genetic and health information from nearly 68,000 women in the CARRIERS consortium, approximately half of whom were included because they had been diagnosed with breast cancer. All of the included women had previously provided data on their first-degree family history of breast cancer (e.g., a mother, sister, or daughter with the disease) and were genotyped to see if they had pathogenic variants in 12 known breast cancer genes. The second major data source was nationwide cancer incidence and mortality data. Lastly, the investigators incorporated data on lifestyle factors, such as alcohol consumption, body mass index, reproductive history, and hormone therapy use, from a sample that was representative of the general U.S. population.

Integrating these streams of information, the researchers calculated the cumulative probability of both young-onset (prior to age 50) and later-onset (ages 50-80) breast cancer. This approach allowed the team to generate absolute risk estimates that are directly applicable in clinical care.

Key findings

• Family history amplifies risk. Women carrying a pathogenic variant and reporting a first-degree family history of breast cancer had a 22.5% chance of diagnosis by age 50 and a 51.2% chance between ages 50-80. Without family history, the risk was significantly lower (9.4% by age 50; 29.7% between 50-80).
• Family history matters more for some genes. Although very rare, PALB2 carriers with a family history had some of the highest lifetime risk — up to 81% by age 80, which was similar to BRCA2 carriers with a family history. However, lifetime risk estimates for BRCA1 carriers was approximately 60% by age 80 whether they had a family history or not.
• Lifestyle factors matter. Alcohol use and menopausal hormone therapy use were linked to higher risks, particularly among PALB2 carriers. O’Brien noted that heavy alcohol consumption was associated with a 27% higher risk of breast cancer by age 50 among women with a first-degree family history and a pathogenic variant in PALB2.

Translating science into action

Although fewer than 1 in 50 women in the study carried a pathogenic variant, the findings may inform clinical decision-making for women at elevated risk.

• Screening choices — earlier or more frequent screening, with MRI as an option.
• Preventive measures — from lifestyle changes to prophylactic surgery.
• Personalized counseling — integrating genetic results with family history, lifestyle, and reproductive factors.

“Some women may feel comfortable managing a 20% risk with enhanced screening, while others may choose more aggressive preventive steps,” O’Brien said. “They may also make different decisions as they age, especially if their risk approaches 70% or 80%. This study helps put those decisions into context.”

Looking ahead

The authors emphasize that breast cancer risk is never determined by genes alone.

“Most chronic diseases are a combination of genetic and environmental factors,” O’Brien noted. “Not everyone with a BRCA1 or BRCA2 mutation will develop breast cancer. Other exposures, behaviors, and family history matter.”

NIEHS Epidemiology Branch Chief Dale Sandler, Ph.D., senior author of the study, underscored its significance.

“By translating rare genetic findings into population-based estimates, we are providing clinicians and women with tools they can actually use. This work moves us closer to personalized, evidence-based prevention.”

Future efforts may add more predictors — such as polygenic risk scores or breast density — to refine estimates further. For now, the authors say the results represent a major step toward making genetic information actionable in everyday medical care.