Why are older adults, particularly post-menopausal women, at an increased risk for breast (cancer)?

Why Old Age Increases Breast Cancer Risk

Advanced age is the single most important risk factor for breast cancer, with incidence rates climbing steeply throughout life—approximately 45% of all breast cancer deaths occur in women aged 65 and older, and mortality rates increase from 86 deaths per 100,000 women aged 65-69 years to 200 deaths per 100,000 women aged 85 years and older. 1, 2

Primary Mechanisms of Age-Related Risk

Cumulative Hormonal Exposure

• Older age represents decades of cumulative exposure to estrogen and progesterone, which continuously stimulate cell division in breast tissue 3, 4
• This prolonged hormonal stimulation increases the probability of DNA replication errors and malignant transformation over time 4
• Postmenopausal women with elevated serum estradiol or testosterone levels have 2-3 times greater breast cancer risk 2

Beyond Simple Mutation Accumulation

• While somatic mutations do accumulate with age, this alone is insufficient to explain the steep age-dependent increase in breast cancer incidence 5
• Age-related changes in the breast tissue microenvironment corrupt the tumor-suppressive activity of normal tissue 5
• Aging imposes age-specific epigenetic changes that alter gene expression, creating cellular phenotypes associated with cancer susceptibility 5

Age-Specific Tumor Biology in Older Women

Paradoxically Favorable Characteristics

• Older women tend to develop less aggressive tumors with longer sojourn times (mammographically detectable preclinical phase) 1
• The prevalence of poorly differentiated (Grade 3) tumors decreases with advancing age 1
• Hormone receptor-positive tumors become more prevalent in older age groups 1
• For any given tumor size, the likelihood of axillary lymph node involvement is lower in older women compared to younger women 1

Critical Caveat

• Despite these more favorable tumor characteristics, breast cancer remains potentially lethal at any age, and larger tumor size is still associated with higher nuclear grade, greater nodal involvement, and poorer outcomes regardless of patient age 1
• Older women actually have higher mortality from early-stage breast cancer than younger women, likely due to competing comorbidities and treatment-related factors 1

Clinical Implications for Risk Assessment

Quantifying Age-Related Risk

• The 5-year breast cancer risk varies dramatically with age: from 0.4% for a 40-year-old woman with no risk factors to 6.0% for a 49-year-old woman with several risk factors 1
• About 25% of breast cancer cases occur before age 50, while less than 5% occur before age 35, demonstrating the steep age gradient 3
• The median age of breast cancer diagnosis in the United States is 60 years 1

Polygenic Risk Remains Relevant in Older Age

• A 313-variant polygenic risk score independently predicts incident breast cancer in women aged 70 years and older (hazard ratio per standard deviation = 1.4) 6
• Women in the top quintile of polygenic risk have over two-fold higher risk than those in the lowest quintile, even in this older age group 6

Screening Performance in Older Women

Superior Mammography Effectiveness

• Mammography sensitivity is actually higher in women aged 65 and older (81%) compared to younger age groups: 78% for ages 50-64,77% for ages 40-49, and only 54% for women under 40 1
• Positive predictive value and biopsy yield are comparable or better in older women 1

Important Screening Considerations

• For women aged 70 years or older with stage I estrogen receptor-positive breast cancer who undergo lumpectomy with negative margins and are likely to complete 5 years of endocrine therapy, omission of radiation therapy can be considered, though this increases local recurrence risk (10% vs. 2% at 10 years) without affecting overall survival 1

Competing Risks in Older Women

• Screening decisions in older women must balance breast cancer risk against competing risks of death from comorbid conditions and limited longevity 1
• Primary endocrine therapy should be reserved only for patients who are not surgical candidates with predicted life expectancy less than 5 years 1
• Older patients enrolled in adjuvant chemotherapy trials derive similar disease-free survival and overall survival benefits compared to younger patients, but experience increased risk of side effects and treatment-related mortality 1