Elsevier

Maturitas

Volume 64, Issue 1, 20 September 2009, Pages 20-26
Maturitas

Review
Hormone therapy, mammographic density, and breast cancer risk

https://doi.org/10.1016/j.maturitas.2009.07.009Get rights and content

Abstract

Percent mammographic density (PMD) is a strong independent risk factor for breast cancer. The effects of age, parity and menopause on PMD are consistent with it being a marker of susceptibility to breast cancer. In this review, we describe the association of PMD with breast cancer, the biological plausibility of this association, and discuss the extent to which PMD meets the criteria for a surrogate marker for the effects of exogenous hormones on risk of breast cancer.

Combined hormone therapy is associated with a small increase in both PMD and the risk of breast cancer. However there is evidence that the associations of blood estradiol levels and HRT with breast cancer risk are independent of the association of PMD with risk, suggesting that different biological pathways may be involved. Tamoxifen, an anti-estrogenic drug, reduces both the risk of breast cancer and PMD, but the potential mediation of the effects of anti-estrogens on breast cancer risk by their effects on PMD has not yet been examined. Given the evidence that estradiol and PMD are independently associated with breast cancer risk, it seems unlikely that an effect of these agents on PMD mediates their effects on risk.

We thus find that the available evidence is insufficient to conclude that PMD can be used as a surrogate marker for the effect of exogenous hormones on breast cancer. Further research to examine the potential role of PMD as a mediator of the effects of other risk factors is required.

Introduction

In this paper we consider the potential role of mammographic density as a surrogate marker for the effects of exogenous hormones on risk of breast cancer. Mammographic density refers to variations in the radiological appearance of the breast illustrated in Fig. 1, and is usually expressed as the proportion of the total breast area occupied by dense tissue (PMD). As we discuss below, these variations in radiological appearance reflect differences in breast tissue composition, and are associated with differences in risk of breast cancer. PMD differs from other risk factors for the disease in a number of ways. The differences in risk of breast cancer associated with variations in PMD are larger than for almost all other risk factors, and the high-risk appearance of extensive PMD is common and may account for a substantial fraction of breast cancer [1], [2]. Further, unlike most other risk factors, PMD can be changed and is influenced by several other risk factors for the disease, including exogenous hormones.

Section snippets

Criteria for a surrogate marker

These observations raise the possibility that PMD might be a surrogate marker for breast cancer. A surrogate marker would allow prediction of the effects of an exposure or intervention on a disease outcome by observing the effects on the marker, which can thus be used instead of a disease endpoint in clinical trials [3]. A surrogate marker would be especially valuable in research on breast cancer prevention where, if breast cancer is the endpoint, large studies with long periods of observation

Mammographic density and breast cancer risk

In 1976, Wolfe described a method of classifying variations in the appearance of the mammogram comprised of four categories that were associated with different risks of breast cancer [6], [7]. The categories were designated N, for a breast comprised mainly of fat, DY for a breast mostly dense, and P1 and P2 for linear densities of different extents, indicating ‘ductal prominence’. Other methods of classifying breast density in current use include a Breast Imaging Reporting and Data System

Age, PMD and the incidence of breast cancer

The average level of PMD declines with increasing age (Fig. 3A), reflecting the age-related differences in breast tissue composition referred to above, while breast cancer incidence increases with age (Fig. 3C). This apparent paradox may however be resolved by reference to a model of breast cancer incidence proposed by Pike [41], that is based on the concept that the rate of ‘breast tissue exposure’, rather than chronological age, is the relevant measure for describing the age specific

Mammographic density as a potential surrogate marker of breast cancer

As summarized above, PMD has been repeatedly shown to be a strong independent risk factor for breast cancer, and thus meets the first of the three criteria for a surrogate marker referred to in Section 2. Further, PMD is also influenced by several exogenous hormones that are known to influence breast cancer risk. The second of the three criteria is thus also met for these hormones.

To date, however, none of the hormones that influence breast cancer risk have been shown to do so through their

Conflict of interest

The authors declare that they do not have any conflict of interest.

Provenance

Commissioned and externally peer reviewed.

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