Long-term effects of tibolone on mammographic density. Key Words: Tibolone, mammographic density, long-term use

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1 FERTILITY AND STERILITY VOL. 82, NO. 5, NOVEMBER 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. MENOPAUSE Long-term effects of tibolone on mammographic density Deborah Bruce, M.B.Ch.B., a Jillian Robinson, R.N., a Sarah McWilliams, M.R.C.P., F.R.C.R., b Mamatha Reddy, M.R.C.P., b Ian Fentiman, M.D., c and Janice Rymer, M.R.C.O.G., M.D. a Guy s Hospital, London, United Kingdom Objective: To investigate the long-term effect of tibolone on mammographic density. Design: Open-label, nonrandomized study. Setting: Academic research environment. Patient(s): Postmenopausal women. Intervention(s): Tibolone was administered orally, mammograms were performed annually. Main Outcome Measure(s): Mammographic density according to the Wolfe classification, performed by two independent radiologists, both of whom were blinded to treatment group. Result(s): No statistically significant differences were found between the two groups in baseline demographic data. There were no statistically significant differences in mammographic density between the control and active groups at baseline or at 10 years. Conclusion(s): This pilot study shows that tibolone does not adversely alter the mammographic density of the breasts over 10 years of treatment. (Fertil Steril 2004;82: by American Society for Reproductive Medicine.) Key Words: Tibolone, mammographic density, long-term use Received July 30, 2003; revised and accepted March 18, Reprint requests: Deborah Bruce, M.B.Ch.B., Camelot, Blundel Lane, Stoke D Abernon, Cobham, Surrey KT11 2SN, United Kingdom (FAX: ; debs_bruce@ hotmail.com). a Menopause Research Unit. b Department of Radiology. c The Breast Unit /04/$30.00 doi: /j.fertnstert Breast cancer is the most common and most feared malignant disease, excluding skin cancer, in women in all developed countries (except for Japan), as well as in the Caribbean, Micronesia/Polynesia, northern Africa, South America, and western Asia. The incidence is increasing and currently accounts for 20% of all female cancers. In the United Kingdom, it is estimated that one in nine women will develop breast cancer during their lifetime. Despite the contributions of mammography to decreasing breast cancer mortality in recent years, the reduction in mortality from breast cancer that results from screening mammography has been shown to be largely confined to women 50 years of age. Data from five randomized Swedish trials (Malmo, Kopparberg, Ostergotland, Stockholm, and Gothenburg) were analyzed in an overview (1). There was a consistent reduction in deaths from breast cancer in those invited for screening compared with those not invited in all five studies. The greatest effect was seen in those aged years at the time of randomization (relative risk 0.71), whereas those aged years showed a nonsignificant mortality reduction of 13%. No effect on mortality was seen among those aged years until 8 years after randomization. One proposed explanation for the seeming lack of efficacy of screening in younger women is the higher density of their breast tissue, which makes accurate interpretation of the mammogram difficult (2). In addition, longitudinal studies have found that mammographic density is an independent risk factor for breast cancer; furthermore, the degree of risk associated with mammographic density is greater than that associated with almost all other known breast cancer risk factors (2). Concerns have arisen regarding the possible association of breast cancer and hormone replacement therapy (HT). The largest metaanalysis to date, which included more than 90% of the world s literature (3), concluded that HT does increase the risk of developing 1343

2 breast carcinoma and that this risk increases with increasing duration of HT use. Once HT is stopped this risk decreases, and it largely disappears by 5 years after stopping. Recent findings from the Women s Health Initiative study showed an increased incidence of invasive breast cancer during HT (4). These results were for the conjugated equine estrogen plus medroxyprogesterone acetate arm of the trial; the estrogen-only trial is still in progress, and results are awaited. There has been a suggestion that there might be a beneficial effect of HT on the type of tumor present because no increase in mortality has been observed (5). There has been considerable interest in recent years concerning data on different hormone combinations and changes in breast density as ascertained by mammography (6) and whether this compromises the ability to identify a significant pathologic change. A double-blind, randomized, placebocontrolled study performed to investigate this effect is the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial (7), and this confirmed that HT (estrogen or estrogen and one of three possible progestin regimens) increased breast tissue density on mammograms, compared with placebo. Numerous longitudinal observational studies have shown that HT use reduces the sensitivity of mammographic screening; however, the magnitudes of these effects are unknown (8, 9). The extent of the changes observed in mammographic density with HT use seems to depend on the selected HT regimen (10, 11). The results of all of these studies make it very difficult to give advice to women at high risk of developing breast cancer or with a personal history of breast cancer. Tibolone is a synthetic nor-steroid with tissue-selective estrogenic, progestogenic, and androgenic properties. It is metabolized into three main metabolites: the -4 isomer and the 3- and 3- hydroxy metabolites. Each metabolite has different individual binding to the estrogenic, progestogenic, and androgenic receptor. Studies have shown that tibolone has an effect at the level of the breast different from that of conventional HT: it does not seem to stimulate breast tissue and might have an inhibitory effect on the growth of breast tumor cells in humans in vitro and in animals (12), in addition to slowing down the proliferation rate and increasing differentiation and apoptosis (13). Estradiol is the main factor supporting the growth and evolution of breast cancers, and one of the pathways involved in the transformation of E 2 is the sulfatase pathway, which transforms E 2 sulfate to E 2 (14, 15). Tibolone and its metabolites have also been shown to be very potent inhibitors in the conversion of estrone sulfate to E 2 in the hormone-dependent breast cancer cell (14, 15). Various studies to date have also suggested that tibolone might not increase mammographic density (11, 16, 17). However, the studies reported to date have concerned relatively short periods, of 1 to 2 years. This article reports the results of a phase II study on the effects of tibolone on mammographic density over 10 years treatment. MATERIALS AND METHODS At the outset of this study, 113 postmenopausal women were recruited over an 18-month period, primarily with the aim of investigating the effects of tibolone on bone metabolism. These subjects were originally recruited from hospital clinics and by self-referral. Institutional review board approval was obtained from Guy s Ethics Committee, Guy s Hospital, London. The groups were matched for age, weight, and time since last menstrual period. Because of the ethical problems of allocating women to a placebo in a long-term study for the prevention of osteoporosis, women were allowed to choose whether or not they wanted to take HT. Fifty-eight women chose the tibolone group (2.5 mg daily), and 55 women who did not wish to take HT were followed as voluntary controls. At the 10-year visit, 32 women re- TABLE 1 Demographic data Tibolone (n 22) Control (n 10) Mean SD Mean SD P value Age at menarche (y) Age at menopause (y) Age at start of study (y) No. of live births No. of miscarriages Breast-fed children (%) Past use of combined oral contraceptive pill (%) Race (Caucasian) (%) Family history of breast cancer (%) Past history of breast cancer (%) Bruce. Tibolone and mammographic density. Fertil Steril Bruce et al. Tibolone and mammographic density Vol. 82, No. 5, November 2004

3 FIGURE 1 A comparison of the mammograms, classified by two independent radiologists according to the Wolfe grading system, of the tibolone and control groups at baseline and after 10 years of treatment. None of the changes observed were significant, P.05. Bruce. Tibolone and mammographic density. Fertil Steril mained in the tibolone group and 28 women in the control group. Permission was obtained to use the mammograms from these subjects. Mammograms from visits at 0, 1, 6, 8, and 10 years, in 22 women taking tibolone and 10 women from the control group, were retrospectively reviewed by two independent radiologists. The radiologists were blinded to the treatment group of the women. Each mammogram was assigned a grade according to the Wolfe classification (18). The Wolfe classification was used because previous published studies have also used this classification, and thus we would be able to compare our results with those from other published reports. The Wolfe classification is as follows: N1: Parenchyma composed primarily of fat, with at most small amounts of dysplasia. No ducts visible. P1: Parenchyma chiefly fat, with prominent ducts in the anterior portion of up to one quarter of the volume of the breast. Also can be a thin band of ducts extending into a quadrant. P2: Severe involvement, with prominent duct pattern occupying more than one quarter of the volume of the breast. DY: Severe involvement with dysplasia. Often obscures an underlying prominent duct pattern. The system used in the United States is the Breast Imaging Reporting and Data System (BIRADS), adopted by the American College of Radiology, but this is very similar to the Wolfe classification. The BIRADS system is described below: 1. The breast is almost entirely fat. 2. There are scattered fibroglandular densities that could obscure a lesion on mammography. 3. The breast is heterogeneously dense. This might lower the sensitivity of mammography. 4. The breast is extremely dense, which lowers the sensitivity of mammography. Organon Laboratories sponsored the original study. Organon Laboratories has sponsored D.B., J.Ro., and J.Ry. to attend national and international meetings for further education. Sandoz, Novartis, Merck Sharpe & Dome, and Schering Pharmaceuticals have supplied similar sponsorship. RESULTS A commercial statistical package was used to analyze the data (SigmaStat; SPSS, Chicago, IL). The data were found to FERTILITY & STERILITY 1345

4 have a normal distribution, so an unpaired t-test was used. There were no statistically significant differences found between the two groups in baseline demographic data, including age of menarche, age at menopause, number of live births, breast-feeding, or personal or family history of breast cancer (Table 1). There were no statistically significant differences in mammographic density class between the control and the active groups at baseline or at 10 years, when assessed by two independent radiologists. When radiologist 1 reviewed the mammograms, only one woman in the tibolone group changed mammographic class (DY to P2), and no one in the control group changed class. When radiologist 2 reviewed the data, one woman from the tibolone group changed class (P1 to P2), and one woman from the control group changed mammographic class (P2 to P1). These changes were not significant. These results are illustrated in Figure 1. DISCUSSION Tibolone has been shown to effectively relieve estrogendeficient symptoms, such as hot flushes and night sweats (19), in addition to providing estrogenization of the lower genital tract (20). Numerous studies have been performed that confirm that tibolone is an effective treatment to prevent postmenopausal bone loss (21 23). Tibolone is metabolized in situ within the endometrium into the -4 isomer, which has a specific progestogenic activity. This antagonizes estrogen at the level of the endometrium, thereby inducing an atrophic endometrium. Tibolone can therefore be classed as a period-free form of HT with high rates of long-term adherence that allows women to achieve the long-term benefits without cyclical bleeding (24). The effect of tibolone on breast density as determined by mammography has been investigated previously (11, 16, 17, 25). All of these studies showed that tibolone has minimal effect on mammographic density, in contrast to conventional HT, but all of these studies were performed over a relatively short period, of 1 to 2 years. This study shows that tibolone does not adversely alter the mammographic density of the breasts over 10 years of treatment. This study, however, does have limitations. First, it involves a relatively small number of women. This could skew the results, and clearly the results obtained from this study need to be confirmed in a larger study. Second, the potential impact of selection bias cannot be ignored, thus the results also need to be confirmed in a randomized, placebocontrolled study. Third, the Wolfe classification is subjective. However, the Wolfe classification is well known, easy to apply, and reproducible. Both of our radiologists are familiar with this classification because they are participating in the Medical Research Council trial, in which the Wolfe classification is also being used. In further studies a more rigid model with computer-aided density measurements could be used, but these have not been fully evaluated yet. If a larger randomized, placebo-controlled study were to be performed, it would be useful to include a direct comparison with estrogen alone and estrogen/progestogen combined therapy. However, this study suggests that tibolone seems to have minimal effect on mammographic density. This could be an advantage over conventional HT. This also could have positive implications in the ability to accurately interpret mammograms in women taking tibolone over the long term. References 1. Nystrom L, Rutqvist LE, Wall S, Lindgren A, Lindqvist M, Ryden S, et al. Breast cancer screening with mammography: overview of Swedish randomised trials [erratum in Lancet 1993;342:1372]. 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