Host, reproductive, and lifestyle factors in relation to quantitative histologic metrics of the normal breast

Emerging data indicate that variations in quantitative epithelial and stromal tissue composition and their relative abundance in benign breast biopsies independently impact risk of future invasive breast cancer. To gain further insights into breast cancer etiopathogenesis, we investigated associations between epidemiological factors and quantitative tissue composition metrics of the normal breast.

The study participants were 4108 healthy women ages 18-75 years who voluntarily donated breast tissue to the US-based Susan G. Komen Tissue Bank (KTB; 2008-2019). Using high-accuracy machine learning algorithms, we quantified the percentage of epithelial, stromal, adipose, and fibroglandular tissue, as well as the proportion of fibroglandular tissue that is epithelium relative to stroma (i.e., epithelium-to-stroma proportion, ESP) on digitized hematoxylin and eosin (H&E)-stained normal breast biopsy specimens. Data on epidemiological factors were obtained from participants using a detailed questionnaire administered at the time of tissue donation. Associations between epidemiological factors and square root transformed tissue metrics were investigated using multivariable linear regression models.

With increasing age, the amount of stromal, epithelial, and fibroglandular tissue declined and adipose tissue increased, while that of ESP demonstrated a bimodal pattern. Several epidemiological factors were associated with individual tissue composition metrics, impacting ESP as a result. Compared with premenopausal women, postmenopausal women had lower ESP [β (95% Confidence Interval (CI)) = -0.28 (- 0.43, - 0.13); P < 0.001] with ESP peaks at 30-40 years and 60-70 years among pre- and postmenopausal women, respectively. Pregnancy [β (95%CI) _{vs nulligravid} = 0.19 (0.08, 0.30); P < 0.001] and increasing number of live births (P_-trend < 0.001) were positively associated with ESP, while breastfeeding was inversely associated with ESP [β (95%CI) _{vs no breastfeeding} = -0.15 (- 0.29, - 0.01); P = 0.036]. A positive family history of breast cancer (FHBC) [β (95%CI) _{vs no FHBC} = 0.14 (0.02-0.26); P = 0.02], being overweight or obese [β (95%CI) _{vs normal weight} = 0.18 (0.06-0.30); P = 0.004 and 0.32 (0.21-0.44); P < 0.001, respectively], and Black race [β (95%CI) _{vs White} = 0.12 (- 0.005, 0.25); P = 0.06] were positively associated with ESP.

Our findings revealed that cumulative exposure to etiological factors over the lifespan impacts normal breast tissue composition metrics, individually or jointly, to alter their dynamic equilibrium, with potential implications for breast cancer susceptibility and tumor etiologic heterogeneity.