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

Abstract

Abstract Background 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. Methods The study participants were 4,108 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 square root transformed tissue metrics and epidemiological factors were investigated using multivariable linear regression models. Results 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 (-0.04 to -0.013); P<0.001] with ESP peaks at 30-40 years and 60-70 years among pre- and post-menopausal women, respectively. ESP was higher among gravid than nulligravid women [β (95%CI)= 0.19 (0.08-0.30); P<0.001], increasing with increasing number of live births (P-trend <0.001). A positive family history of breast cancer was associated with higher ESP [β (95%CI)= 0.13 (0.02-0.25); P=0.02]. Further, overweight [β (95%CI)= 0.18 (0.06-0.30); P=0.004] or obese [β (95%CI)= 0.33 (0.21-0.44); P<0.0001] women had higher ESP than those with normal body mass index (BMI), while Black women had higher ESP than White women [β (95%CI)= 0.13 (0.01-0.26); P=0.03]. Conclusion Our findings provide strong epidemiological evidence on the potential role of joint variations in stromal-epithelial tissue composition in the etiopathogenesis of breast cancer and underscore the need for further research into how exposure-tissue interactions shape breast cancer development and etiologic heterogeneity.