Postmenopausal hormone therapy and cancer risk

International Congress Series 1279 (2005) 133 140 www.ics-elsevier.com Postmenopausal hormone therapy and cancer risk P. Kenemans*, R.A. Verstraeten, R.H.M. Verheijen Department of Obstetrics and Gynaecology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Abstract. Postmenopausal Hormone Replacement Therapy has been implicated in the development of four frequent female tumors: endometrial cancer, breast cancer, ovarian cancer and colorectal cancer. Estrogens are only weak genotoxic, mutagenic carcinogens, but could induce tumors by way of accumulation of incessant DNA replication damage. While estrogen (only) hormone replacement therapy (ERT) increases the risk of endometrial carcinoma and probably of ovarian carcinoma, ERT seems to be neutral for the breast and colorectal cancer. With combined estrogen progestagen replacement therapy (HRT), there is no increased risk of endometrial cancer nor of ovarian cancer. The risk of breast cancer, however, is slightly increased with long-term use. Colorectal cancer risk is probably reduced with combined HRT use. Data are only available for oral use; for transdermal, intranasal and other use no data are available. D 2005 Elsevier B.V. All rights reserved. Keywords: Estrogens; Progestagens; HRT; Cancer risk; Breast cancer 1. Introduction In postmenopausal women the risk of cancer increases with age [1]. Breast cancer is the most common malignancy in women. Worldwide, endometrial carcinoma is the second most common gynecological cancer after breast carcinoma, while ovarian cancer is the main cause of death among the gynecological malignancies. Colorectal cancer is the most frequent neoplasm among non-smoking women in the Western world, and in the United States it is the third highest cause of death after lung and breast cancers, respectively. * Corresponding author. E-mail address: Kenemans@vumc.nl (P. Kenemans). 0531-5131/ D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2005.01.004

134 P. Kenemans et al. / International Congress Series 1279 (2005) 133 140 Endogenous as well as exogenous sex hormones have been implicated in the development of these four frequent tumors. 2. Endometrial cancer The large majority of endometrial carcinomas is hormone dependent. Both in premenopausal and in postmenopausal women, prolonged unopposed estrogen stimulation plays a major role. As shown in a meta-analysis by Grady [2], the overall relative risk (RR) of developing endometrial cancer for ever-users of estrogenonly hormone replacement therapy (ERT) was doubled compared with never-users. The same analysis showed a risk increasing over time with duration of ERT use. For patients who stop their estrogen-only replacement therapy, the increased risk persists for many years (at least 5 years) after the treatment. A number of additional factors are recognized which may increase the risk of endometrial cancer in ERT users. The excess risk may be larger in lean women, non-smokers and in women that never used oral contraceptives. The addition of a progestogen, the combined hormone replacement therapy (HRT), substantially reduces the risk of developing endometrial cancer [2]. However, the use of a sequential regimen for long periods of treatment has generated some worries and doubts. An American study of women treated with sequential HRT reported an increased risk (RR 2.5, 95% CI 1.1 5.5) for periods of use longer than 5 years, even when a progestagen was used 10 days or more each month [3]. The importance of adequate progestogen combination length in offering sufficient endometrial protection was shown in another American study [4]. Women treated with a sequential HRT regimen with progestogens for at least 10 days per month (10 up to 21 days/month) did not show any significant increase in endometrial cancer risk (RR 1.1, 95% CI 0.8 1.4). Various observational studies show that continuous combined regimens provide sufficient endometrial protection or even might reduce the risk of endometrial cancer [4 6]. Also prospective, randomized trials like the Hers study [7] and the Women s Health Initiative (WHI) study [8] provide evidence as to the neutrality of a continuous combined regimen on the endometrium. In summary, for non-hysterectomized women, unopposed estrogen use greatly increases the risk of endometrial cancer. This risk is greatly reduced by combining a progestogen with the estrogen in a sequential regimen. The continuous use of a progestogen may even reduce the risk of endometrial cancer [5]. 3. Ovarian cancer Ovarian cancer cells express various types of sex hormone receptors. In a review of the available evidence on ovarian cancer, Drew et al. [9] showed that the results from studies on ovarian cancer with HRT are discordant. While unopposed estrogen therapy may increase risk, many studies with combined estrogen/progestogen show no increased risk of developing ovarian cancer [9]. Also, two meta-analyses [10,11] and two observational studies [12,13] do not indicate a strong positive correlation between HRT and ovarian cancer. The role of HRT duration on risk is still debated. In a meta-analysis by Garg et al. [10], the use of HRT for more than 10 years was associated with a slight risk increase (RR 1.15, 95% CI 1.05 1.27), whereas

P. Kenemans et al. / International Congress Series 1279 (2005) 133 140 135 Coughlin et al. [11] did not report any correlation between HRT use and incidence of ovarian cancer (RR 1.1, 95% CI 0.9 1.3). Great uncertainty surrounds the conclusion from studies that have analyzed ovarian cancer mortality in relation to HRT. In fact, an earlier study [14] did not observe any increase in mortality among women using HRT, while the higher mortality observed among women treated for more than 10 years in a recent study [12] caused great astonishment. Relative risk for former use was 1.59 (95% CI 1.13 2.25) and for current use 2.20 (95% CI 1.53 3.17). Despite the remarkable number of cases considered and the noteworthy observational period (14 years) of this American study, data on HRT use for more than 10 years in this trial was derived from only 66 cases of ovarian cancer. In conclusion, it would seem that high-dose ERT for many years would increase the risk for ovarian cancer. There is no evidence that modern combined use would increase the risk for ovarian cancer. 4. Breast cancer Many known risk factors for breast cancer are hormonal in nature. A reanalysis of over 90% of the world literature on the relationship between estrogen use and breast cancer published in the Lancet in 1997 reviewed 51 epidemiological studies with over 52,000 women with breast cancer and over 108,000 women without [15]. This reanalysis shows that in women who use hormones breast cancer risk increases from the basal individual risk by 2.3% for each year of HRT use. The same applies for a delay in onset of menopause. Annual breast cancer risk increases by 2.8% for each year of delayed menopause [15]. Fig. 1 shows the absolute increase in risk of breast cancer as taken from the Lancet reanalysis. In North America and Europe, the cumulative incidence of breast cancer between the ages of 50 and 70 years in HRT never-users is about 77 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who Cumulative incidence per 1000 women 90 80 70 60 50 40 30 20 10 0 89 never use use for 5 years 83 79 use for 10 years 77 use for 15 years 45 50 55 60 65 70 75 Age (years) Fig. 1. Estimate of increase in cumulative number of breast cancer per 1000 post-menopausal women using hormone replacement therapy for 0, 5, 10 and 15 years, respectively, all having started at age 50. Modified after Beral et al. [15], with permission.

136 P. Kenemans et al. / International Congress Series 1279 (2005) 133 140 began HRT use at 50 and used it for 5, 10 and 15 years are estimated to be 2, 6 and 12, respectively. This excess risk reduces after HRT use ceases and largely disappears after 5 years [15]. Cohort studies on breast cancer risk with long-term use show a difference in breast cancer risk between ERT and combined HRT regimens. There appears to be a negative effect of addition of a progestogen compared with estrogen alone [16 23]. Case control studies analyzing the difference in breast cancer risk between unopposed estrogen use and combined HRT give the same picture [24 28]. There is a negative effect of estrogen progestogen combinations on the breast compared with estrogen alone. Studies [19 22,24 29] analyzing the difference of breast cancer risk between unopposed estrogen (ERT) and the two forms of combined HRT in the same population seem to indicate that, in general, the effect of continuous combined regimens on the breast might be stronger than that of sequential combined regimens (Table 1). Data from the two prospective, placebo-controlled studies [7,30] showed a RR of approximately 1.25 among women treated with continuous combined HRT; the increase in risk became significant for HRT use longer than 4 years [30]. The increase in risk of breast cancer with HRT use seems to be restricted to lean women (BMIb25.0). Overweight postmenopausal women have already achieved the maximum hormone-related risk increase due to their endogenous production of estrogens, and HRT use is not increasing this risk further [15,18]. In the reanalysis [15], use for 5 years and over did not increase risk in women with a BMI of 25 and over (RR 1.02), however, it did in women with a BMIb25 (RR 1.52). The Million Women Study, the MWS [20], is a retrospective cohort study of 1,084,110 British women aged 50 to 64 years participating in the National Breast Cancer Screening Programme that was set up to investigate the effects of various patterns of use of HRT on incident and fatal breast cancer. In this trial, current use of HRT was associated with an increased risk of both incident as well as fatal breast cancer; the effect was substantially greater for estrogen progestogen combinations (RR 2.0 (95% CI 1.9 2.1)) than for ERT (RR 1.3 (95% CI 1.2 1.4)). Table 1 Breast cancer risk with different regimens of postmenopausal HT in the same population Study Study type Number OR ERT OR schrt OR cchrt Reference of cases Magnusson (1999) case-control 3345 2.18 a 1.89 2.89 a [24] Ross (2000) case-control 1897 1.06 1.38 a 1.09 [25] Chen (2002) case-control 1995 1.84 a 1.62 a 1.85 a [26] Newcomb (2002) case-control 5298 1.34 a 1.57 1.54 a [27] Weiss (2002) case-control 1870 0.81 1.00 1.54 a [28] Porch (2002) cohort 411 b 0.99 1.04 1.82 a [19] Olsson (2003) cohort 556 0.58 c 1.44 c 3.13 a,c [21] Li (2003) case-control 975 1.20 2.10 a 2.20 a [29] MWS (2003) cohort 9364 1.30 a 2.12 a 2.40 a [20] Stahlberg (2004) cohort 244 1.96 a 1.94 a 4.16 a [22] a pb0.05. b Including 73 in situ cancers. c Hazard rate.

P. Kenemans et al. / International Congress Series 1279 (2005) 133 140 137 The MWS is a very large study with 3202 breast cancer cases in 285,987 current hormone users. However, this does not compensate for the suboptimal observational design of the study, with a substantial detection and enrollment bias [31 33]. In the MWS, current continuous combined HRT use was associated with a larger risk increase for breast cancer (RR 2.12) than for sequential combined estrogen progestogen use (RR 2.40). Remarkably, risk increases were observed after just 1 year s exposure, and had almost disappeared 1 year after treatment discontinuation. In contrast to the recent data of the WHI [35], the patients included in the ERT arm of the MWS showed a significant increase in breast cancer risk, while the WHI found a non-significant decrease in risk (RR 0.77 (95% CI 0.59 1.1). In contrast to the more increased relative risk observed in combined estrogen progestogen users in the MWS (RR 2.40), the relative risk increase with continuous combined treatment as found in the prospective randomised WHI trial (after 5.2 years of use) was only 24% (RR 1.24 (95% CI 1.01 1.54)). So the MWS has probably overestimated potential risks. Thus, in contrast to prospective, randomised trials like Hers [7] and WHI [30,35], the MWS [20] shows a substantial overestimation of the relative risk for breast cancer, both for that with ERT [35] as well as that with HRT [7,30]. 5. Colorectal cancer Many cohort and case control studies have reported a substantial reduction in colorectal cancer risk among women using HRT. Such a positive outcome varies from 20% to 40% and is higher among women who have recently used hormones [36,37]. A meta-analysis that specifically addressed the relationship between HRT and colon cancer showed that recent use (either at the time of assessment or within the previous year) was associated with an RR of 0.67 (95% CI 0.59 0.77) of developing this malignancy [36]. Protection was limited to recent users. In another meta-analysis on 20 studies [37], the overall RR among ever users was 0.8 (95% CI 0.74 0.86) and 0.66 (95% CI 0.59 0.74) for current HRT users. This protective effect of HRT significantly decreased after stopping treatment. Clinical controlled studies like HERS [7] and WHI [8] studies confirm the protective role of combined HRT on colorectal cancer. In the WHI trial [8], the incidence rate of colorectal cancer in treated women was significantly reduced by 37% (RR 0.63 (95% CI 0.43 0.92)). In terms of absolute excess risk per 10,000 person years, attributable to continuous combined HRT use, this means six fewer colorectal cancers, but 8 more breast cancers. Remarkably, in the WHI [35] ERT use did not reduce colon cancer risk (excess risk per 10,000 person years: 1 case), but did reduce breast cancer risk (7 cases less per 10,000 person years). The overall results of the trial show that there was neither an increase in relative risk of total cancer in HRT users (RR 1.03, 95% CI 0.90 1.17), nor in total mortality (RR 0.93 (0.82 1.18)). The fact that postmenopausal hormone use does not increase mortality had been shown earlier in large cohort studies [38 41].

138 P. Kenemans et al. / International Congress Series 1279 (2005) 133 140 Table 2 Mortality in HT users Studies All causes Myocardial All cancers Breast cancer Colon cancer Reference infarction Hunt et al. 0.56 0.41 0.70 0.76 [38] (1990) (0.47 0.66) (0.20 0.61) (0.55 0.85) (0.45 1.06) Sturgeon 0.7 0.7 0.8 0.7 0.8 [39] et al. (1995) (0.7 0.8) (0.6 0.9) (0.7 0.9) (0.5 1) (0.6 1.3) Schairer 0.77 0.61 0.85 0.72 0.87 [41] et al. (1997) (0.73 0.81) (0.55 0.69) (0.78 0.92) (0.58 0.89) (0.62 1.18) Grodstein [40] et al. (1997) Current use 0.58 (0.52 0.64) 0.35 (0.25 0.49) 0.67 (0.59 0.76) 0.77 (0.59 1.00) Past use 1.00 (0.92 1.08) 0.84 (0.67 1.05) 1.01 (0.90 1.01) 0.80 (0.62 1.03) RR (95% CI) in cohort studies with at least 200 deaths in HT users. Table 2 represents the relative risk of mortality demonstrated in cohort studies using ERT/HRT, in which at least 200 deaths were recorded in ever-users. Overall, in terms of mortality, the results with ERT/HRT are beneficial [38 41]. 6. Discussion and conclusion In summary, data available on combined HRT and cancer show no effect on endometrial cancer, possibly a reduced risk with continuous combined HRT, a potential increased risk of ovarian cancer (mainly found with ERT, not with HRT), an increased risk of breast cancer with combined HRT, and a protective effect against developing colon cancer. Data available on other types of cancer show no effect or conflicting data. The majority of data available on HRT and breast cancer come from over 60 observational studies [34] and 3 randomized trials [7,30,35] using mostly conjugated equine estrogens via the oral route. These studies provide evidence that either no or a very small increase in the risk of breast cancer appears with current long-term use of combined HRT. It is not clear whether there is a difference in risk with sequentially combined versus continuously combined HRT. Little information is available from prospective randomized trials using different types and doses of estrogen or progestogen, and different routes of administration. It is therefore inappropriate to consider all HRT as being the same. The future of HRT lies in individualization of therapy for each patient. References [1] R. Yancik, L.A. Ries, Cancer in older persons. Magnitude of the problem how do we apply what we know? Cancer 74 (1994) 1995 2003. [2] D. Grady, et al., Hormone replacement therapy and endometrial cancer risk: a meta-analysis, Obstet. Gynecol. 85 (1995) 304 313. [3] S.A. Beresford, et al., Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women, Lancet 349 (1997) 458 461.

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