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Menopausal Hormone Therapies: Their Effect on Mammographic Density and Breast Cancer Risk

Posted on: Tuesday, 11 October 2005, 03:00 CDT

By Santen, Richard

Abstract

Postmenopausal hormone therapy (HT) increases breast density, an effect that is rapidly reversed upon treatment discontinuation. Increased breast density is recognised to be a powerful risk factor for breast cancer. It is therefore important to know whether HT- induced changes in mammographic breast density can provide information about an individual's future risk of breast cancer; or whether an absence of any change in breast density following HT should be viewed as reassuring. Mammographic breast density therefore needs to be examined in further detail in order to better assess the risks of breast cancer in postmenopausal women and further individualize prescribing practices.

Keywords: Hormone therapy, breast cancer, mammographic density, estrogen, progestogen, tibolone

Introduction

It is known that menopausal hormone therapy (HT) increases mammographic breast density and that increased mammographic density is associated with an increased risk of breast cancer. The logical question therefore is whether HT increases the risk of breast cancer. The aim of this review is to present data concerning the effects of HT on breast tissue and to consider the practical significance of recent evidence showing an increased risk of breast cancer in women taking HT.

Effect of HT on breast density

A marked variation in the radiological appearance of the breast exists between individuals. This variation in mammographie density reflects differences in the relative proportion of fat and fibroglandular tissue. Fat is radiolucent and appears dark on the mammogram, whereas stroma and epithelial cells are radiodense and appear lighter.

It has been clear for some time that postmenopausal HT influences breast density, such that more current HT users have high mammographie density than non-users. Persson and colleagues evaluated the hypothesis that HT regimens have differential effects on mammographie density in a study involving 554 women who started HT after the first mammogram and were current users at the second mammogram and 554 women who had never received HT [1]. The results, which have been confirmed in many subsequent studies, showed that mammographie density increased significantly in women who received estradiol with cyclically (relative risk [RR]: 3.6; 95% confidence interval [CI]: 1.6-7.7) or continuously (RR: 12,4; 95% CI: 6.3- 24.4) combined progestogens, compared with unexposed women (Figure 1). A small increase in mammographie density was also seen in women who received estrogen alone, administered either orally, transcutaneously or vaginally.

Investigators have also compared the effect of tibolone - the first member of a unique class of compounds known as STEARs (Selective, Tissue Estrogenic Activity Regulators) - with that of continuous combined estrogen-progestogen therapy (ccEPT) on mammographie density. For example, in a double-blind, placebo- controlled study conducted in 166 women, mammograms were performed at baseline and after 6 months, and breast density was quantified according to the Wolfe classification and by the percentage of the breast that had a dense pattern [2]. An increase in mammographie density was much more common among women receiving ccEPT than among those receiving tibolone or placebo (Table I). The difference between ccEPT and placebo was highly statistically significant (p < 0.001), but treatment with tibolone did not differ significantly from placebo. This suggests that tibolone seems to exert little stimulation of breast tissue - a finding that is critical in terms of the results reported in the Million Women Study [3].

Although the randomized, placebo-controlled Women's Health Initiative (WHI) study did not assess breast density in a qualitative or quantitative manner, it did report on the frequency of abnormal mammograms associated with treatment [4]. An abnormal mammogram was denned as one that required recall. After one year, the percentage of women with abnormal mammograms was substantially greater in the ccEPT group (9.4%) compared with the placebo group (5.4%). This pattern continued for the duration of the study so that, overall, 31.5% of women in the ccEPT group and 21.2% in the placebo group had an abnormal mammogram. The differences at both time points were highly statistically significant (p < 0.001). This finding prompted investigators to conclude that abnormal mammography represents a newly identified risk of short-term hormone use and is likely to be related to an increase in mammographie density (Hendrix, S.L., personal communication).

Figure 1. Percentage of women with increase in mammographic density following exposure or non-exposure to HT [1].

Table I. Number (%) of women with an increase in mammographie density after 6 months of treatment with ccEPT, tibolone or placebo [2].

Another important issue concerns what changes at the histological level underlie these observed hormone-induced increases in mammographie density. Hofseth and colleagues carried out a cross- sectional observational study to examine the proliferative effects of treatment with estrogen therapy (ET) or EPT on tissue from benign breast biopsies from 86 postmenopausal women [5]. Breast epithelial density was significantly greater in women treated with ET (12%) or EPT (20%) compared with non-hormone users (5%). This indicates that one component of breast density relates to the percentage of breast tissue area occupied by the epithelium. Unpublished data from my group suggests that an increase in stroma is also associated with increased mammographie density. Hofseth et al. [5] also measured relative levels of cell proliferation in the ducts and terminal duct lobular units using the Ki67 antibody. The findings indicated that breast proliferation with EPT was localized to the terminal duct- lobular unit of the breast, which is the site of development of most breast cancers (Figure 2). Taken with other findings, these data provide substantial evidence that progestogens are mitogenic on the human breast when given long-term to postmenopausal women [6].

It should also be noted that the breast responds rapidly to HT cessation. Discontinuation of treatment has been shown to be followed by a very rapid decrease in mammographie density observable within two weeks [7]. This is probably the result of apotosis.

Effect of breast density on breast cancer risk

There is no doubt that increased breast density is a strong risk factor for breast cancer. Boyd et al. classified the level of mammographie density in 353 women, enrolled in the National Breast Screening Study, who had undergone biopsies [8]. As shown in Figure 3, there was a linear increase in the relative risk of breast cancer with increasing levels of mammographie breast density, so that women with mammographie density in more than 75% of the breast tissue had a more than 5-fold increase in their risk of developing breast cancer. This finding has been confirmed in a number of studies to date. In a recent review of 12 such studies using quantitative methods of assessment, the odds ratio for developing breast cancer for the most dense compared with the least dense categories ranged from 1.8 to 6.0, with the majority of studies reporting an odds ratio of at least 4.0 [9].

Figure 2. Percentage of Ki67-positive cells in the ducts and terminal duct lobular units of breast biopsies taken from women treated with EPT or ET and non-hormone users [5].

Figure 3. Relative risk of breast cancer in relation to mammographie density (Boyd classification) [8].

In addition, the effect of tamoxifen on mammographie breast density is consistent with the decrease in breast cancer risk associated with its use. After 12 months or more of treatment, the decrease in the proportion of women with dense breasts is quantitatively consistent with the reported reduction in breast cancer risk [10].

Possible explanations for this link between mammographie breast density and breast cancer risk include the presence of premalignant lesions, increased levels of growth factors and increased production of estrogen due to elevated aromatase activity.

Does HT increase the risk of breast cancer?

The most important question concerning postmenopausal hormone treatment today is therefore whether the effect of HT on mammographie density can provide us with information about an individual woman's future risk of breast cancer. In other words, does an HT-associated increase in breast density increase the individual's risk of breast cancer, or should an absence of any change in breast density following HT be viewed as reassuring in this regard? Unfortunately, this very important question has not been adequately addressed as yet.

The WHI study reported a hazard ratio of 1.26 (95% CI: 1.00- 1.59) for the effect of ccEPT on the risk of invasive breast cancer [4]. In addition, although the breast cancers in women receiving ccEPT were comparable in terms of grade, receptor status, histology and incidence of metastatic disease with those in women receiving placebo, they were significantly larger (1.7 vs 1.5 cm) and more often associated with positive lymph nodes (25.4% vs 16.0% of women). In contrast, data from earlier observational studies indicate that cancers in women given HT tend to be of a more favorable type, being more differentiated and more likely to have lobular features [11-13]. Better survival in HT users has also been repor\ted in observational studies [14,15]. No survival data are available from the WHI study.

If HT is causing breast cancer, one would expect to see a linear increase in the risk with the duration of therapy. This was indeed found in the collaborative re-analysis of 51 epidemiological studies, involving more than 50,000 women with breast cancer and more than 100,000 without, in which the relative risk increase per year was 2.3% (95% CI: 1.1-3.6) [16]. Evidence of linearity was also observed in an analysis of prior observational studies [17-19]. We utilised strict criteria to identify studies that we considered valid. These criteria included a sufficiently large number of women in the study with breast cancer (i.e., at least 1,500 women with breast cancer); women must have been current HT users or have stopped within the previous 4 years; women must have used HT for at least 4 years and the study must have compared ET with EPT [20]. As shown in Table II, there was a linear increase in the relative risk of breast cancer in all cases, with the increase in risk being greater with EPT than with ET. This increase in the risk of breast cancer with increasing duration of use, which does not vary substantially across studies, provides evidence for a causal relationship.

On the basis of what is known today, it would appear that progestogen adds to the long-term risk of breast cancer associated with estrogen use. This conclusion is based on mammographie breast density data, the rate of tissue proliferation in breast biopsies, and on the incidence of breast cancer in observational and large randomized controlled trials. However the practical significance of these findings needs to be considered carefully and in the context of relative versus absolute risk.

Data examining the risk of breast cancer from HT report relative risk statistics to determine statistical significance. This methodology provides substantial statistical power to detect the effects of these agents that might be quite small in magnitude. However, relative risk provides the ratio of breast cancer risk in women taking HT to those not taking HT - it takes no account of the actual frequency of breast cancer in the group under consideration. This is only assessable by determining the absolute risk by multiplying the usual rate of breast cancer in the group being considered by the relative risk. When this is done, the attributable risk in terms of breast cancer from EPT is minimal for short-term use, but may be substantial in the setting of long-term therapy.

Table II. Increase per year in the relative risk of breast cancer with ET and EPT in valid observational studies.

The increased risk with HT must also be put into the context of other biological and hormonal risk factors. For example, oophorectomy before the age of 40 reduces the risk of breast cancer by about two thirds, whilst postmenopausal weight gain, a late menopause, a late first birth and high bone density all markedly increase the risk (Figure 4). The increased risk seen with HT is therefore small compared with other factors.

Conclusion

Advances in the development of alternative means of managing the menopause make the decision-making process more complex. Where possible, treatments should be tailored to suit the needs and risk factors of the individual woman; the patient should be encouraged to share in the decision making process with her physician.

A first step in decision-making should be to determine the breast cancer risk. My feeling is that, for women whose risk of breast cancer is low, then the absolute risks associated with the use of HT for 5 years or less for the management of climacteric symptoms and urogenital atrophy are relatively low. In terms of women with an intermediate risk of breast cancer, then it makes sense to consider alternative treatments that do not affect mammographie breast density, such as tibolone or selective estrogen receptor modulators (SERMs) as appropriate. Those women at high risk of breast cancer are clearly candidates for tamoxifen treatment. As we go forward, I believe that mammographie breast density needs to be examined in further detail to better assess risk and further individualize prescribing practices.

Figure 4. Risk factors for breast cancer.

References

1. Persson I, Thufjell E, Holmberg L. Effect of estrogen and estrogen progestin replacement regimens on mammographie breast parenchymal density. J Clin Oncol 1997;15:3201-3207.

2. Lundstrom E, Christow A, Kersemaekers W, Svane G, Azavedo E, Soderqvist G, Mol-Arts M, Barkfeldt J, von Schoultz B. Effects of tibolone and continuous combined hormone replacement therapy on mammographie breast density. Am J Obstet Gynecol 2002;186:717-722.

3. Beral V, the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-427.

4. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-3253.

5. Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 1999;84:4559-4565.

6. Santen RJ. Risk of breast cancer with progestins: critical assessment of current data. Steroids 2003;68:953-964.

7. Harvey JA, Pinkerton JV, Herman CR. Short-term cessation of hormone replacement therapy and improvement of mammographie specificity. J Nat Cancer Inst 1997;89:1623-1625.

8. Boyd NF, Jensen HM, Cooke G, Han HL, Lockwood GA, Miller AB. Mammographie densities and the prevalence and incidence of histological types of benign breast disease. Eur J Cancer Prev 2000;9:15-24.

9. Harvey JA, Bovbjerg VE. Qualitative assessment of mammographic breast density: relationship with breast cancer risk. Radiology 2004;230:29-41.

10. Brisson J, Brisson B, Cote G, Maunsell E, Berube S, Robert J. Tamoxifen and mammographie breast density. Cancer Epidemiol Biomarkers Prev 2000;9:911-915.

11. Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study. JAMA 1999;281:2091-2097.

12. Bonnier P, Bessenay F, Sasco AJ, Beedassy B, Lejeune C, Romain S, Charpin C, Piana L, Martin PM. Impact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer. Int J Cancer 1998; 79:278-282.

13. Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J CHn Oncol 1998;16:3115-3120.

14. Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996;7:449-457.

15. Schairer C, Gail M, Byrne C, Rosenberg PS, Sturgeon SR, Brinton LA, Hoover RN. Estrogen replacement therapy and breast cancer survival in a large screening study. J Nat Cancer Inst 1999;91:264-270.

16. Collaborative Group on Hormone Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-1059.

17. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-491.

18. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332: 1589-1593.

19. Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I. Breast cancer risk following long-term oestrogen- progestin-replacement therapy. Int J Cancer 1999; 81:339-44.

20. Santen RJ, Pinkerton J, McCartney C, Petroni GR. Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. J Clin Endocrinol Metab 2001;86:16-23.

RICHARD SANTEN

University of Virginia, Charlottesville, USA

Correspondence: Richard Santen, University of Virginia, Charlottesville, USA.

Copyright CRC Press Jul 2005

Source: Gynecological Endocrinology

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