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Originally published as JCO Early Release 10.1200/JCO.2005.04.7332 on February 20 2007 © 2007 American Society of Clinical Oncology. Postmenopausal Hormone Therapy and Changes in Mammographic Density
From the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Radiology, Addenbrooke's Hospital, Cambridge Breast Unit; and Medical Research Council Dunn Human Nutrition Unit, Cambridge, United Kingdom Address reprint requests to Carla H. van Gils, PhD, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Mail-drop Str 6.131, PO Box 85500, 3508 GA Utrecht, the Netherlands; e-mail: C.vangils{at}umcutrecht.nl
Purpose Hormone therapy (HT) use has been associated with an increased breast cancer risk. We explored the underlying mechanism further by determining the effects of HT on mammographic density, a measure of dense tissue in the breast and a consistent breast cancer risk factor. Patients and Methods A total of 620 HT users and 620 never users from the Dutch Prospect–European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 175 HT users and 161 never users from the United Kingdom EPIC–Norfolk cohort were included. For HT users, one mammogram before and one mammogram during HT use was included. For never users, mammograms with similar time intervals were included. Mammographic density was assessed using a computer-assisted method. Changes in density were analyzed using linear regression. Results The median time between mammograms was 3.0 years and the median duration of HT use was 1 year. The absolute mean decline in percent density was larger in never users (7.3%) than in estrogen therapy users (6.4%; P = .22) and combined HT users (3.5%; P < .01). The effect of HT appeared to be high in a small number of women, whereas most women were unaffected. Conclusion Our results suggest that HT use, and especially estrogen and progestin use, slows the changes from dense patterns to more fatty patterns that are normally seen in women with increasing age. Given that it is postulated that lifetime cumulative exposure to high density may be related to breast cancer risk, a delay in density decline in HT users potentially could explain their increased breast cancer risk.
The use of hormone therapy (HT), in particular the combination of progestins with estrogens, has been reported to increase breast cancer risk,1-3 but the exact mechanism behind this observed increased risk is still unclear. Exogenous hormones may play a role in the genesis of breast cancer through an increase in breast cell proliferation.4,5 This increase may be shown by an increase in mammographic density, which is determined by the relative amounts of connective tissue, epithelial tissue, and fat in the breast. High mammographic density has been associated with a three- to six-fold increase in breast cancer risk.6,7 The degree of mammographic density is dependent on several factors such as the number of children, body weight, and a woman's age. High mammographic density is usually seen in young women, whereas density decreases with age and shows a larger decline around menopause.8 Several studies have suggested that this accelerated decrease does not occur in some women who use HT for climacteric complaints. Some have reported that HT use has been suggested to lead to a statistically significant increase in mammographic density among some women.9-19 Three randomized, double-blind, placebo-controlled trials have been reported that determined the change in density with a quantitative method.17-19 Freedman et al17 found a 2-year increase of 1.2% for estrogen therapy (ET) use compared with a decrease of 1.3% for no hormone use, which was statistically significant. The study by Greendale et al18 found an increase of 1.17% in percent density for the ET group, which was not statistically significantly different from the decrease of 0.07% for the placebo group. The three combined HT groups all showed a statistically significant increase in percent density (range, 3.08% to 4.76%) compared with the placebo group. McTiernan et al19 reported a 6.0% increase in percent density in the first year and a 4.9% increase in the second year for the combined HT group, which differed statistically significantly from the 0.9% decrease in the first year and the 0.8% decrease in the second year for the placebo group. Two recent observational longitudinal studies, also using a quantitative measurement method, found evidence that the use of HT leads to a delay in decline of breast density over the years20 (C.M. Vachon, personal communication, June 2006). In one of these studies, a distinction was made between different types of HT use, and it was found that combined ET and progesterone therapy resulted in a significant delay in the decline of breast density compared to no HT use (the difference in decrease per decade is 3.3%). Estrogen only was also associated with a significantly lower decrease, but to a much smaller extent than combined HT (the difference in decrease per decade is 1.6%). We aimed to determine the effects of HT use on changes in mammographic density using an objective and quantitative density measurement method.
Study Population Women were selected from the Prospect-European Prospective Investigation into Cancer and Nutrition (EPIC; NL)21 and the EPIC-Norfolk (UK)22 study, a Dutch and a United Kingdom cohort, both participating in the European Prospective Investigation into Cancer and Nutrition.23 Between 1993 and 1997, participants had a medical examination and completed lifestyle and food frequency questionnaires.24,25 At the end of the inclusion period, 17,357 women were included in NL and 16,744 women were included in UK. All participants provided written or oral informed consent and the studies were approved by the local ethical committees. Approximately 5 years after recruitment, participants from both cohorts completed a follow-up questionnaire. In addition to questionnaire data, consecutive mammograms were available through the regional breast cancer screening programs. The baseline as well as the follow-up questionnaire was used to obtain information on HT use, defined as the use of hormones for menopausal complaints. Both questionnaires comprised questions on the age at which a woman started and stopped using HT. HT users were defined as those women who reported at either the baseline or the follow-up questionnaire that they had ever used HT. Never HT users were defined as those women who reported at both questionnaires that they never used HT. Information on the type of HT regimen was gathered through the questionnaire and by registration of medication boxes, which women were asked to bring to the breast screening examination. Ever HT users were eligible if one screening mammogram before HT use and a second mammogram during HT use could be obtained. Never HT users were matched to HT users on year of mammogram, duration of interval between mammograms, and year of birth. Women were excluded when they used oral contraceptives at the first mammogram or when they were diagnosed with breast cancer before or within 2 years of the second mammogram because oral contraceptives or the presence of a tumor may influence mammographic density. For the present analysis, 620 HT users and 620 never HT users age 49 to 69 years were selected from NL, and 175 HT users and 161 never HT users age 51 to 71 years were selected from UK.
Mammographic Density Analysis After the films were digitized using a laser film scanner (Lumiscan 50 [Lumisys/Eastman Kodak Co, Rochester, NY] for NL, and Lumiscan 85 [Lumisys] for UK), mammographic density was quantified using a computer-assisted method based on gray levels in the digitized mammogram.27 We present results on both the relative and absolute amount of mammographically dense tissue, which we refer to as percent density and dense area, respectively. The mammograms from NL and UK were read by the same observer (F.v.D.) in sets of 68 (UK) and 70 (NL) images composed of both the first and second mammogram from 34 or 35 women in random order. To assess the reliability of the reader, two library sets of 68 (UK) and 70 (NL) images were made, which consisted of randomly chosen mammograms. The library set was incorporated in the study set and read several times by the blinded reader. Images in the library set were ordered randomly every time they were read to prevent the observer from recognizing this set. An average intraclass correlation coefficient of 0.88 (range, 0.82 to 0.93) for dense area and 0.94 (range, 0.91 to 0.95) for percent density was reached between repeated readings. These results are comparable to previous studies using the same method.27
Data Analysis The absolute change in percent density and dense area was compared between never HT users, ET users, combined HT users, and tibolone users by linear regression analysis because the outcomes were approximately normally distributed. To determine the change, mammographic density at the second mammogram was used as the outcome variable and mammographic density at the first mammogram was included as a covariate in the first adjusted model. The mean mammographic density at the second mammogram was calculated from this model, and the change in density was computed by subtracting the mean mammographic density at the first mammogram from this number for the different HT users and never HT users separately. In the second adjusted model, in addition to type of HT use (no HT use, ET use, combined HT use, or tibolone use) and density at first mammogram, age, body mass index, age at menarche, parity/age at first full term, menopausal status, family history of breast cancer, previous oral contraceptive use, smoking, alcohol consumption, physical activity, and study population were included as covariates. The interaction between HT use and study population was investigated by adding the product term to the linear regression model. Given that the product term was not statistically significant, all analyses were performed for both cohorts together. In addition, we examined whether the effect of HT use was stronger among those who used more than 1 year than among those who used HT 1 year or less. All analyses were performed with SPSS version 12.0 (SPSS Inc, Chicago, IL).
The median time between the first and the second mammogram was 3.0 years (range, 1 to 11 years). The median duration of HT use up to the second mammogram was 1 year (range, 1 to 7 years). Table 1 lists the distribution of breast cancer risk factors at baseline according to HT use. Percent density at the first mammogram was lower for never HT users (37.0%) than for ET users (39.3%) or combined HT users (46.1%). Similarly, the dense area at the first mammogram was lower for never HT users (40.6 cm2) than for ET users (45.9 cm2) and combined HT users (50.8 cm2). A total of 74.8% of never users, 80.7% of ET users, and 45.0% of combined HT users were postmenopausal. Never users less often used oral contraceptives in the past (63.4% v 66.7% and 73.1%) and less frequently consumed alcohol (31.2% v 37.9% and 41.5%) compared with ET users and combined HT users.
The absolute change in percent density as well as dense area was normally distributed for HT users and never HT users. The range of percent density change in HT users was between –32.2% and 28.3%, whereas the interquartile range was between –12.6% and 3.1%. In never HT users the range was between –33.9% and 26.0%, whereas the interquartile range was between –17.2% and 0.2%. For 570 (71.7%) of the 795 HT users, the type of HT preparation was known. The absolute change in percent density as well as dense area for the different types of HT use are shown in Table 2. The mean decline in percent density between the first and the second mammogram was 7.3% for never HT users compared with 6.4% for ET users (P = .22), 3.5% for combined HT users (P < .01), and 7.1% for tibolone users (P = .85). Similarly, the decline in dense area was 9.5 cm2 for never HT users compared with 6.8 cm2 for ET users (P = .01), 5.6 cm2 for combined HT users (P < .01), and 8.0 cm2 for tibolone users (P = .42). Adjustment for other potential confounders did not change these results materially.
When the effect of duration of HT use was investigated, the difference in percent density change between short-term users (  1 year) and nonusers was 0.4% (P = .56), whereas this difference was 3.7% (P < .01) among long-term users (> 1 year) versus nonusers. Similarly, the difference in dense area change for short-term users was 2.5 cm2 (P = .02) and for long-term users was 4.2 cm2 (P < .01; data not shown).
In this large prospective study, HT users showed a smaller decrease in mammographic density during a median period of 3 years than never HT users. The effect seemed to be more marked in combined HT users than in ET users. Longer use of HT (> 1 year) appeared to have a larger effect on mammographic density than shorter use ( 1 year). Most women in our study, however, used HT for a relatively short time and we could not evaluate true long-term use of HT (ie, more than 5 years). To appreciate these findings, some issues need to be addressed. In this study, mammographic density was determined with an objective and quantitative method, which only few studies in literature have used to measure density change. Instead of an increase in density in the HT users, as is shown by the randomized trials,17-19 we observed a significant delay in the decline of breast density in this group compared with the nonusers. This effect was more pronounced in women who used combined HT than in women who used ET. Our findings are in line with two recent observational longitudinal studies, also using a quantitative measurement method20 (C.M. Vachon, personal communication, June 2006). Several explanations are possible for these differences between the randomized trials and observational studies. First, the number of years between the first and the second mammogram may differ. A period of 1 or 2 years between both mammograms was taken for all participants in the clinical trials, whereas the median time between both mammograms in our cohorts was 3 years (range, 1 to 11 years). When the interval between mammograms is larger, it is more likely that the conversion from dense patterns to more fatty patterns that is normally seen in women with increasing age has already started, and that the change measured at the second mammogram is a combination of this process and the effect of HT on mammographic density. When the effect of this process during the years is larger than the effect of HT, overall a decrease in density will be measured. Second, observational studies are more prone to confounding by indication, which is prevented by randomization in controlled trials. Obviously, the HT users in observational studies have been prescribed HT because of alleviation of their menopausal complaints, which are supposedly caused by a decrease in endogenous estrogen levels.29-31 For this reason, among HT users, women with low estrogen levels and hence lower breast cancer risk could be over-represented compared with the nonusers group. Another possibility is that HT use has been contraindicated for women known to be at high risk for breast cancer (eg, because of a family history of breast cancer). This too might have caused the HT group a priori to have a lower breast cancer risk than the nonusers. A difference in the direction of the effect (delay of decrease v increase in density) may be the result, if, for example, HT users in trials, compared with those in observational studies, have higher estrogen levels at the start of the studies. Starting the use of HT may then possibly result in estrogen levels that are on average higher than those in HT users in observational studies. In both scenarios of confounding by indication described above, a dilution of the harmful effect of HT on the breast tissue would be the result, leading to conservative effect estimates in observational studies. We used self-reported data for ages at start and stop of HT use and mammograms were selected accordingly. Any mistake in answering these questions may have caused misclassification. However, we believe that this misclassification, if present, is nondifferential, and thus has led to an underestimation of the effect. Another limitation is the lack of information about the duration of effect of HT use. Studies on HT use and breast cancer risk suggest that the increase in breast cancer risk in current HT users is not present in past HT users.1,32 Studies on HT use and mammographic density have also reported that the effect on mammographic density is no longer seen when HT use is discontinued.12,33 The exact period of time that is needed before the risk or effect has returned to its original level is not yet known, and it would be of great clinical interest to investigate this. The breast density measurement method that we used in this study is highly reproducible and is the most widely used method to study breast density. However, a drawback of this two-dimensional method is that differences in breast positioning and compression may influence the relative and absolute amount of breast density observed. This makes it very difficult to measure changes over time because differences in positioning and compression may occur. This problem should be solved in the near future with the development of digital volumetric measurements of breast density based on digital mammography.34 Despite the limitations of the current two-dimensional method, leading to random measurement error, we were still able to observe a small but statistically significant difference between users and nonusers of different types of hormone replacement therapy. Therefore, it can be expected that a more precise method will reveal larger differences between these groups. Although not yet proven, it is conceivable that a delay in the decline of breast density over the years may translate to a higher breast cancer risk. The prevailing hypothesis is that cumulative exposure to mammographic breast density (meaning the number of years that a woman has high breast density) could reflect the cumulative exposure to hormones and growth factors that stimulate cell division in breast stroma and epithelium, and could be an important factor underlying the age-specific breast cancer incidence in the population.20,35 This hypothesis follows the model of Pike et al,36 which proposes that the rate of breast tissue aging is the relevant measure for describing the age-specific incidence of breast cancer. Maskarinec et al20 recently showed that the age-specific breast cancer incidence and cumulative percent breast density show very similar increases by age. According to this hypothesis, a slower decrease in density in HT users, meaning a longer duration of exposure to high density, could potentially lead to a higher breast cancer risk in HT users compared with nonusers.
The authors indicated no potential conflicts of interest.
Conception and design: Fränzel J.B. van Duijnhoven, Petra H.M. Peeters, Carla H. van Gils Provision of study materials or patients: Petra H.M. Peeters, Ruth M.L. Warren, Sheila A. Bingham, Carla H. van Gils Collection and assembly of data: Petra H.M. Peeters, Ruth M.L. Warren, Sheila A. Bingham Data analysis and interpretation: Fränzel J.B. van Duijnhoven, Petra H.M. Peeters, Ruth M.L. Warren, Sheila A. Bingham, Paulus A.H. van Noord, Evelyn M. Monninkhof, Diederick E. Grobbee, Carla H. van Gils Manuscript writing: Fränzel J.B. van Duijnhoven, Petra H.M. Peeters, Ruth M.L. Warren, Sheila A. Bingham, Paulus A.H. van Noord, Evelyn M. Monninkhof, Diederick E. Grobbee, Carla H. van Gils Final approval of manuscript: Fränzel J.B. van Duijnhoven, Petra H.M. Peeters, Ruth M.L. Warren, Sheila A. Bingham, Paulus A.H. van Noord, Evelyn M. Monninkhof, Diederick E. Grobbee, Carla H. van Gils
We thank Norman Boyd, MD, DSc, and Martin Yaffe, PhD, for their support with the computer-assisted software. We thank Robert Luben and Bernard Slotboom for selecting the study populations, and Iqbal Warsi, Joke Metselaar-van den Bos, Bert Rodenburg, and Jelmer Hoefakker for collecting the mammograms.
published online ahead of print at www.jco.org on February 20, 2007. Supported by the Dutch Cancer Society Grant No. UU 2002-2716. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Collaborative Group on Hormonal 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 350:1047-1059, 1997[CrossRef][Medline] 2. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 3. Chlebowski RT, Hendrix SL, Langer RD, et al: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA 289:3243-3253, 2003 4. Clarkson TB, Appt SE, Wood CE, et al: Lessons to be learned from animal studies on hormones and the breast. Maturitas 49:79-89, 2004[CrossRef][Medline] 5. Hofseth LJ, Raafat AM, Osuch JR, et al: 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 84:4559-4565, 1999 6. Boyd NF, Byng JW, Jong RA, et al: Quantitative classification of mammographic densities and breast cancer risk: Results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87:670-675, 1995 7. Byrne C, Schairer C, Wolfe J, et al: Mammographic features and breast cancer risk: Effects with time, age, and menopause status. J Natl Cancer Inst 87:1622-1629, 1995 8. Boyd N, Martin L, Stone J, et al: A longitudinal study of the effects of menopause on mammographic features. Cancer Epidemiol Biomarkers Prev 11:1048-1053, 2002 9. Christodoulakos GE, Lambrinoudaki IV, Panoulis KP, et al: The effect of various regimens of hormone replacement therapy on mammographic breast density. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
