Mammographic Density as a Mediator for Breast Cancer Risk: Pooled Analysis of Four Population-Based Case-Control Studies on Women with Screening Mammograms before Age 50.

BACKGROUND

Multiple risk factors influence breast cancer risk, but the role of percent mammographic density (PMD) in mediating these associations remains unclear.

METHODS

In this pooled analysis of women who had screening mammograms before age 50 years, we assessed whether PMD mediates associations between reproductive, structural, and lifestyle factors and breast cancer risk. Causal mediation analysis was used to estimate direct and indirect effects and the proportion mediated by PMD.

RESULTS

PMD partially mediated 29% of the association between breast calcifications and breast cancer risk, with a natural indirect effect odds ratio (ORNIE) of 1.16 [95% confidence interval (CI), 1.04-1.30; P = 0.009]. A history of breast biopsies was marginally associated with increased risk (P = 0.083), with 83.1% of this effect mediated by PMD (ORNIE = 1.28; 95% CI, 1.11-1.49; P = 0.001). PMD mediated 48.6% of the reduced risk among parous versus nulliparous women (ORNIE = 0.76; 95% CI, 0.65-0.90; P = 0.001). No significant mediation by PMD was observed for first-degree family history of breast cancer, age at first live birth, or smoking. Adult body mass index showed inconsistent mediation with opposing direct and indirect effects, reducing breast cancer risk via lower PMD but increasing risk through density-independent pathways, yielding a null total effect.

CONCLUSIONS

Our findings highlight PMD's important role as a mediator in linking certain reproductive and structural factors to breast cancer risk in younger women, offering insights into early-onset breast cancer.

IMPACT: This underscores PMD's potential as both a biomarker and a target for risk prediction and prevention.