Several measures of growth and development across a woman's life course are associated with breast cancer risk. In particular, early age at menarche and tall stature have been associated with increased breast cancer risk,[1,2] pointing to an important exposure window in early childhood and adolescence. These associations may be mediated systemically through the insulin-like growth factor (IGF) or sex steroid pathways and thereby impact on the breast parenchyma. Mammographic breast density is the white radiographic appearance of epithelial and stromal tissue on a mammogram and women with increased mammographic density (MD) for their age and body mass index (BMI) are at significantly higher risk for breast cancer.[4,5] Breast cancer and MD share common predictors, such as parity and use of hormone therapy, suggesting that the effect of these factors on breast cancer risk may be mediated, at least partly, through MD. Age and BMI, a measure of weight for body size (weight/height2 in kilograms/metres2 [kg/m2]), are exceptions to this consistency and negatively confound the association between MD and breast cancer risk.[7,8] That is, the true risk factor is MD adjusted for a woman's age and BMI. There is also consistent evidence of an inverse association between pubertal body adiposity and adult MD.[9–11] Further, there is growing evidence that MD could mediate the inverse association of childhood BMI with breast cancer risk in pre-menopausal women.[9,12] However, the associations of age at menarche and adult height, both of which are known breast cancer risk factors, with MD are less consistent and not well understood.
A recent review of pubertal mammary gland development as a determinant of adult MD summarizes the inconsistent reports of the association between age at menarche and MD. Half of the studies showed a positive association, and the other half showed either a negative or null association with MD. The review also highlights the importance of adjustment for anthropometric measures when evaluating associations between age at menarche and MD, as increased body adiposity is associated with earlier pubertal development; hence, the association between age at menarche and MD is potentially dependent on childhood weight. Similarly, inconsistent results have also been observed between MD and height. MD in adult women has been positively associated with both adult height[13,14] and childhood height in some studies, whilst no association has been observed in other studies.[9,16]
In the present study, we therefore examined associations of age at menarche and adult height with two measures of MD, per cent density (PD) and dense area (DA), in the International Consortium of Mammographic Density (ICMD). This international study pools data from 11,755 women from 22 countries spanning all continents worldwide, with centrally measured MD and a common core set of epidemiologic data. An important consideration when investigating the independent effects of any outcome on MD in an international study is the influence of population groups and ethnicity on observed associations. For example, age at menarche and adult stature tend to be positively correlated within populations, because an early menarche is followed by an earlier timing of the maximal height velocity and thus final adult height is shorter.[17,18] Across populations, however, these correlation structures may differ if growth and development are associated with decreasing age at menarche and with increasing adult height. These factors are taken into consideration in the present study. The diversity of ethnicities and of growth and development patterns in the ICMD enhances exposure heterogeneity and allows examination of the consistency of associations across populations.
Breast Cancer Res. 2022;24(49) © 2022 BioMed Central, Ltd.
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