Exogenous and endogenous hormones, mammographic density and breast cancer risk: can mammographic density be considered an intermediate marker of risk?

Elevated mammographic density measures are a well-established, relatively strong risk factor for breast cancer development. A systematic review of prospective cohort studies and cross-sectional studies strikingly establishes parallels between the associations of combined postmenopausal estrogen and progestin replacement therapy with, on the one hand, mammographic densities and, on the other hand, breast cancer risk. Other parallel observations were the inverse associations of both mammographic density and breast cancer risk with the selective estrogen receptor modulator tamoxifen, and direct associations with prolactin. Paradoxically, however, high mammographic density has been found associated with higher risks of both estrogen- and progesterone-receptor positive (ER+/ PR+) and negative (ER-/PR-) breast cancers, while hormone replacement therapy (HRT) use, but also circulating (blood) levels of androgens, estrogens, and prolactin appear to be associated more specifically to the risk of ER+ tumors. The effects of aromatase inhibitors and gonadotropin-releasing hormone agonists on breast density, as well as on breast cancer risk, still require further investigation. Regarding circulating levels of insulin-like growth factor (IGF)-I or IGFBP-3, studies did not show fully consistent relationships with mammographic density measures and breast cancer risk. In view of these various findings, it is impossible, at present, to propose mammographic density measures as an intermediate risk-related phenotype, integrating the effects of exogenous and/or endogenous hormones on the risk of developing breast cancer.