Postmenopausal hormone therapy and breast cancer: What is the problem? Peter Kenemans
Maturitas 51 (2005) 75–82 Postmenopausal hormone therapy and breast cancer: What is the problem? Peter Kenemans Department of Obstetrics and Gynaecology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Received 22 October 2004; received in revised form 25 January 2005; accepted 31 January 2005 Abstract Observational studies provide evidence that breast cancer risk is increased with long-term oral use of postmenopausal estrogen replacement therapy (ET). Various large cohort studies have shown that the addition of a progestogen in combined hormone replacement therapy (EPT) increases this risk further. Prospective, randomized controlled trials have confirmed this for the continuous combined regimen. So, why not tell our patients, “Stop using ET and EPT, it is dangerous to your health!”? The answer is: there are too many problems to allow such an oversimplified, definite statement. What is the problem? There is more than one! The problems are as follows: • There are many observational studies, but these are not consistent in their results. • Relative risk increases, if any, are small and thus often statistically non-significant. • Observational studies have inherent biases that cannot be corrected for; therefore evidence should come from randomized clinical trials (RCTs). • There are no RCTs that provide evidence as to the breast cancer risk with ET, compared to EPT in the same study population. • In the three large RCTs available, the populations studied are: not representative, too old and without climacteric complaints, and therefore lacking any indication for postmenopausal hormone therapy (HT). • The data obtained thus far do not apply to non-oral routes, neglect the difference in progestogens, and do not address tibolone, a valuable alternative to classical HT in Europe. • And finally, are these epidemiological findings biologically plausible? Can estrogens cause breast cancer and why then does the Women’s Health Initiative (WHI) RCT not find this? And how can the addition of a progestogen increase the ET risk further as progestogens are pro-apoptotic and down-regulate estrogen receptors as well as local estrogen biosynthesis? In conclusion, we have a problem as we cannot formulate any general advice that holds for the majority of European postmenopausal women due to lack of consistency, lack of biological plausibility, and lack of relevance of randomized clinical trial data to our daily practical work. So, we have a problem and not a firm basis for undisputable statements. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Breast; Breast cancer; Estrogens; Progestogens; Proliferation; Apoptosis E-mail address: kenemans@vumc.nl. 0378-5122/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2005.02.017 76 P. Kenemans / Maturitas 51 (2005) 75–82 1. Introduction Postmenopausal hormone replacement therapy (HT) carries both benefits and risks [1]. The problem is, what to tell our European climacteric patients about breast cancer risk with hormone use, when counseling them about postmenopausal hormone therapy? The problem is we cannot tell them anything for sure, as the evidence available is either biased [2] (the observational studies, like the MWS [3]) or obtained in the wrong population which is also too old [4] like in the randomized clinical trial (RCT) of the Women’s Health Initiative (WHI) [5]. The lesson learned from the cardiovascular diseaseHT issue is unequivocal: we cannot rely on (even consistent) favorable evidence from observational studies, not even when supported by consistent favorable surrogate endpoint data. The evidence should come from prospective randomized placebo-controlled clinical trials [6]. As to breast cancer risk, these RCTs are sparse [7–9] and not representative for our European climacteric women who are looking for symptom relief. These RCTs moreover do not address many of the European preferences such as transdermal or intranasal application, the medicated intrauterine device or the use of alternative drug options, like tibolone. Thus, there are no RCT data on 50–60-year-old European women who use micronized estradiol alone or in combination with one of the many (but different) progestogen options that are available in addition to medroxyprogesteron acetate (MPA), and who mostly prefer to use this via a nonoral, transdermal or intranasal route, or who prefer to use tibolone based on preclinical and mammographic data [10–13]. And, finally, there is the issue of biological plausibility, which should provide the basis for all epidemiological interpretations. Estrogens are not strong mutagenic genotoxic carcinogens, but do seem to be generally regarded as being able to cause clinically detectable breast cancers [14]. This is because estrogens could cause new tumors as they bring the epithelial breast cell into incessant mitotic activity, thereby inducing unrepairable DNA replication errors and thus mutations. Thus, in addition to growth stimulation of already existing occult tumors, estrogens also initiate or cause new breast cancers. How then can we explain that the best available evidence, the WHI RCT, does not find any risk increase with estrogen-only therapy (ET) [9]? In order to define in more detail what the real problem is, the following questions will be addressed: 1. Is exposure to estrogens a risk factor for breast cancer? 2. Do estrogens cause new breast cancers? 3. Does the addition of a progestogen influence breast cancer risk? 4. Are tumors under HT different and less aggressive? 5. Are there transatlantic differences? 2. Is exposure to estrogens a risk factor for breast cancer? Classical risk factors for breast cancer include female gender, higher age group and positive family history. In addition, many of the risk factors involved in breast cancer are hormonal in nature [15] (see Table 1). Breast cancer is considered a hormone-sensitive tumor and prevention and treatment strategies make use of anti-estrogen drugs like SERMs (tamoxifen, ralofixene), real anti-estrogens (fulvestrant) and aromatase inhibitors [16]. In general, prevention of contra-lateral breast cancer and of recurrences (activation of dormant metastases) in breast cancer patients aims to maximally reduce the exposure of breast epithelial cells to estrogens. In summary, on the basis of both epidemiological as well as clinical data, it is highly plausible that prolonged exposure to estrogens would induce breast cancer risk, and thus result in more breast cancers in an ET population. Table 1 Hormonal risk factors for breast cancer Risk factor High risk group Low risk group RR Age at menarche Age at menopause Oophorectomy Serum E2 BMI Bone density Breast density <12 years >55 years – High >30 High High >14 years <45 years <35 years Low <23 Low Low 1.5 2.0 3.0 3.0 2.0 3.0 6.0 Modified after Clemons and Goss (2001) [15]. P. Kenemans / Maturitas 51 (2005) 75–82 The problem is that the best available evidence, that of the WHI RCT [9] does not find any increased risk with long-term ET use (RR: 0.77; 95% CI: 0.59–1.01). And various recent observational studies also failed to find an increased breast cancer risk with ET use. This is true, both for cohort studies [17–20] as well as for case control studies [21–23]. 3. Do estrogens cause new breast cancers? Do estrogens induce new breast cancers, and if so, how many extra cases per year of estrogen exposure can we attribute to estrogen use? When we find tumors in ET users, are these newly induced tumors or only occult tumors that show up earlier as a result of accelerated growth through estrogeninduced proliferation? This is a relevant question for two reasons. First, it would surely make a difference to our patients, namely a tumor that would not be there at all without estrogen use is emotionally certainly different from an occult pre-existing tumor that would show up anyhow, but now only earlier and possibly in a less aggressive form (this is not certain, see later). And, second, if no more new tumors were to be induced, but only accelerated growth, finally there would be no more tumors in the total cohort when taken over a longer time period (e.g. 30 years). If so, after the peak, there would be a dip in breast cancer incidence within this population. If this is true, all calculations of attributable extra breast cancer cases per woman year of exposure would be wrong, as there would not be any extra cases of breast cancer over all. Breast carcinogenesis is best described by a multistep genetic progression model [24] (see Table 2, that Table 2 Multistep genetic progression model Step 1 Step 2 Step 3 Step 4 Step 5 Mutational activation of oncogenes coupled with inactivation of tumor-suppressor genes To become invasive: further mutations in at least four or five genes (chronological order less important) Tumor growth Additional mutations required for metastasis Genetic alterations over time and under (chemo) therapy (dedifferentiation, clonal selection) Modified after Kenemans et al. (2004) [24]. 77 discerns arbitrarily five different steps within the progression model). In each of the different steps of the model estrogens could play a role, as long as estrogen receptors are still present within the cell. If estrogens can induce new tumors, they would have to induce a mutation in either step 1 or step 2 of the model. Generally, estrogens are considered to be only weak genotoxic carcinogens [14], too weak to really play a role in direct DNA damage in ET users (see Fig. 1A). However, incessant estradiol-driven mitotic activity could result in an accumulation of DNA replication errors, which if left unrepaired could induce relevant carcinogenic mutations (see Fig. 1B) [25]. However, most probably, most breast cancers detected under ET are not induced, but growth stimulated (step 3, see also Fig. 1C), with the theoretical advance to being detected before step 4 (dissemination and the forming of metastasis) occurs (see also later). Whether ET is likely to increase lifetime risk for breast cancer in users (so, really more new tumors in the population), or only likely to increase short term breast cancer risk (by accelerated growth of clinically occult tumors) is an important difference. This question has not been addressed thoroughly in epidemiological studies looking at breast cancer risk with ET use. The question still has not been answered, and thus the issue has not been settled. The problem is, that as long as we do not know the answer to this question, all estimates as to extra cases of breast cancer per years of ET exposure are unreliable. Estimates derived from short-term studies (less than 10 years) do not allow for the correct prediction of excess cases over a much longer period. The conclusion is: estrogens probably induce new tumors as well as promote the growth of occult preexisting tumors. The problem is we do not know the proportion in which these two phenomena happen, so we cannot realistically calculate how many extra breast cancer cases are attributable to ET use. The large Million Women Study [3] found five extra breast cancer cases per 10,000 woman-years of ET use. The only available randomized control trial [9] found seven breast cancer cases fewer per 10,000 woman-years of ET use, which is biologically implausible and shows the lack of consistency between studies. So, what do we tell our patients? ET causes breast cancer? Or ET does not cause breast cancer, and it might be even protective? 78 P. Kenemans / Maturitas 51 (2005) 75–82 Fig. 1. Hormone dependent carcinogenesis. This figure depicts in a cartoon-like fashion the three possible hypothetical roles estrogens could play in the carcinogenesis of breast tumors (modified after Kenemans and Bosman, 2003) [25]. (A) Tumor initiation by genotoxic agents. Estradiol acts here as a genotoxic mutagenic carcinogen. The International Agency for Research on Cancer (IARC, Lyon) has classified estradiol as a weak carcinogen, as estradiol (via its catechol metabolites) can cause free-radical mediated DNA damage to epithelial breast cells. (B) Tumor initiation by incessant mitotic activity. Estradiol acts here as a tumor initiator, resulting from incessant mitotic activity, leading to accumulation of unrepaired replication DNA damage with subsequent damage to the tumor suppressor genes and impairment of DNA repair and apoptosis mechanisms. (C) Accelerated growth of pre-existing tumors. Estradiol acts here as a late stage tumor promoter via estrogen receptor mediated proto-oncogene activation and subsequent mitotic activity and proliferation, leading to accelerated growth of pre-existing clinically occult tumors. DNA: normal intact genome. DNA* : genome with “oncogenetic” mutations. 4. Does the addition of a progestogen influence breast cancer risk? Many observational studies have addressed the issue of breast cancer risk increase with EPT use (Table 3). The largest study on breast cancer risk with HT use (based on over 50,000 breast cancer cases), the Lancet re-analysis [32], concluded that there was no evidence of marked differences in relative risk of breast cancer between estrogen-only therapy and combined treatment with estrogens and progestogens. P. Kenemans / Maturitas 51 (2005) 75–82 79 Table 3 Breast cancer risk with different regimens of postmenopausal HT in the same population (long-term use) Study Study type Number of cases RRa ET RR scEPT RR ccEPT Reference Magnusson (1999) Ross (2000) Chen (2002) Newcomb (2002) Weiss (2002) Porch (2002) Olsson (2003) Li (2003) MWS (2003) Stahlberg (2004) Bakken (2004) Case-control Case-control Case-control Case-control Case-control Cohort Cohort Case-control Cohort Cohort Cohort 3345 1897 1995 5298 1870 411c 556 975 9364 244 624 2.18b 1.06 1.84b 1.34b 0.81 0.99 0.58 1.20 1.32b 1.96b 1.0 1.89 1.38b 1.62b 1.57 1.00 1.04 1.44 2.10b 2.12b 1.94b 2.2b 2.89b 1.09 1.85 1.54b 1.54b 1.82b 3.13b 2.20b 2.40b 4.16b 3.2b [26] [21] [27] [28] [22] [19] [20] [23] [3] [29] [47] a b c Relative risk, where applicable OR (Odds Ratio) or HR (Hazard Ratio). Significantly different from non-users. Including 73 in situ cancers. The same group of investigators concluded in a second study, the Million Women Study [3] (based on only 3202 breast cancer cases), that EPT had a significantly larger risk for breast cancer (RR: 2.0; 95% CI: 1.91–2.04), than ET (RR: 1.30; 95% CI: 1.22–1.38). Recent, mostly large, observational studies, looking within the same population at breast cancer risk, have indeed found that the addition of a progestogen increases the breast cancer risk further. When looking at the results of 10 large observational studies, which looked at the breast cancer risk with the three different regimens of HT available in the same population, there is a slight trend to a higher risk with continuous combined EPT, when compared to sequentially combined HT (see Table 3). Randomized controlled trials, like the HERS [7] and the WHI [8] confirmed a significantly increased risk seen with continuous combined, although relative risks found are much lower than those reported in the Million Women Study [3]. HERS [7] found a RR of 1.27, WHI [8] found a RR of 1.24. However, in the populations in which these risk estimates were obtained, no data were available as to the risk with ET. The WHI ET trial [9] that found a RR of 0.77 for ET was done in a highly similar, but different population because of the need to look only at hysterectomized women. Overall, the impression that the addition of progestogen would increase breast cancer risk compared to that seen with estrogens alone is justified. However, the problem is that this is hard to explain on the basis of breast cell biology [33–45]. Breast cell homeostasis is generally believed to result from the balance between proliferation and apoptosis. Cell proliferation is stimulated by estrogens, while progestogens are known to down-regulate estrogen receptor alpha and thus would counteract proliferation [25,33]. Further, it is known that in breast tumors local production of estradiol occurs within the tissue [34]. The maintenance of estradiol levels in tumors is independent of circulation blood levels, as most intratissue estradiol is derived from in situ biosynthesis. Progestogens in general are known to down-regulate local estradiol biosynthesis by influencing enzymatic pathways within breast cancer tissue. One would expect that in this sense, tumor growth acceleration by estrogens would also be hampered. Finally, estradiol is known to induce an anti-apoptotic pathway via Bcl-2 [35], while progestogens are known to stimulate apoptosis [36,37]. In conclusion, the action of a progestogen on the estrogen-induced cellular mitotic activity is claimed by some [36,38] to be antagonistic and by others [39,40] as synergistic. The data are highly complex, conflicting and confusing [41–44]. The problem is we do not know how progestogens in vivo influence human breast cells via their two known receptor isoforms PR-A and PR-B, which have different physiological functions via differential gene regulations. At this moment, it seems that only four genes are uniquely regulated via PR-A, while 65 genes are uniquely regulated by PR-B and only 25 by both receptors [45]. Furthermore, we do not know whether or not the various clinically different progestogens might also 80 P. Kenemans / Maturitas 51 (2005) 75–82 influence breast cancer risk in a different way. There are indications that different progestogens have different effects on the breast [26,29,31]. Moreover, it is not known which of the two combined regimens, sequentially combined or continuous combined, carries the greater risk. The problem is that a clear consensus regarding type of regimen and type of progestogen cannot be reached on the basis of existing data. 5. Are tumors under HT different, and less aggressive? A multitude of studies have reported that breast cancer tumors appearing in HT users are more often well differentiated, smaller and less likely to spread to the axillary lymph nodes [25,46]. However, not all studies found this. Most importantly, the WHI RCT [8] reported that tumors in the users group were more advanced (more often axillar node involvement and slightly larger). It had been long thought that HT users would possibly increase their risk for relatively mild breast tumors in addition to an unchanged baseline risk for aggressive tumors, the combination of which would explain the better prognosis seen in many of the users. This was also suggested by the authors of the large collaborative group reanalysis [32] that stated that excess tumors under HT were more localized in nature. However, the Million Women Study [3] found the opposite, explaining the increased mortality from breast cancer seen in this study. In conclusion, the evidence is conflicting as to whether or not tumors detected under HT are (in general) less aggressive and have a better prognosis than those developing without hormones. The problem is, what can we tell our patients? 6. Are there transatlantic differences? This is an intriguing question. Are there transatlantic differences with regard to drugs used in HT or in population characteristics that might influence risk? Obesity is one of the most important risk-modifying factors that might modify the risk for breast cancer when using HT. Lean, non-HT users have lower concentrations of sex hormones compared to more obese women and might increase their breast cancer risk when starting HT more than obese HT users would do. This has indeed been found in various studies [3,18,26,32]. There are indications that obese women were overrepresented in the American randomized controlled trials when compared to average early postmenopausal women in Europe. It could also be argued that the estrogen used in US studies, mostly conjugated equine estrogens, may incur a different risk than the estrogens preferentially used in Europe like micronized 17- estradiol (see Table 4). Although there seems to be a trend with a higher significant risk increase with the European estrogen, this certainly is not proven at all. It might be a good point to evaluate further. Some studies that looked at different estrogens reported finding no significant differences, like for instance the MWS [3]. Most American studies used medoxyprogesteronacetate (MPA) as the drug of choice for the progestogen to be added to estrogens in combined HT. In Europe, the choice of progestogens used is much Table 4 Breast cancer risk with long-term ET: transatlantic differences? USA (CEE)a RRb Reference Europe (17 estradiol) RRb Reference Schairer (2000) Ross (2000) Chen (2002) Newcomb (2002) Weiss (2002) Porch (2002) Li (2003) WHI (2004) 1.1 1.1 1.8c 1.3c 0.8 1.0 1.2 0.8 [18] [21] [27] [28] [22] [19] [23] [9] Persson (1999) Magnusson (1999) MWS (2003) Olsson (2003) Stahlberg (2004) Fournier (2005) 1.1 2.2c 1.3c 0.6 2.0c 1.1 [17] [26] [3] [20] [29] [31] a b c CEE: conjugated equine estrogens. Relative risk, where applicable OR (Odds Ratio) or HR (Hazard Ratio). Significantly different from non-users. P. Kenemans / Maturitas 51 (2005) 75–82 81 Table 5 Breast cancer risk with long-term EPT: transatlantic differences? USA (MPA)a RRb Schairer (2000) Ross (2000) Chen (2002) Newcomb (2002) Weiss (2002) Porch (2002) Li (2003) HERS (2002) WHI (2003) 1.4c a b c 1.1c 1.6c 1.5c 1.4c 1.8c 2.2c 1.3 1.2c Reference [18] [21] [27] [28] [22] [19] [23] [7] [8] Europe (other progestogens) RRb Reference Persson (1999) Magnusson (1999) MWS (2003) Jernstr¨om (2003) Stahlberg (2004) Fournier (2005) 1.7c [17] [26] [3] [30] [29] [31] 2.4c 2.2c 2.2c 2.7c 1.3c MPA: medroxyprogesterone acetate. Relative risk, where applicable OR (Odds Ratio) or HR (Hazard Ratio). Significantly different from non-users. wider and this is reflected in the European studies where testosterone-derived progestogens constitute the majority of progestogens used. 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