• Joaquim Calaf i Alsina
• Antonio Cano Sanchez
10.1
Introduction
Lactation is a basic period in mammalian reproduction, and the breast, its function, and pathology have a very important place in medicine and society. In developed countries breast cancer is the most important issue, far more important than nonlactational galactorrhea; it is frequently related to infertility or unsuccessful breastfeeding and is a major health concern among women.
Breast cancer is the most common malignant tumor in women. It comprises 18% of all female cancers, before cervix (15%) and colon (9%) cancer. After lung cancer it is the most frequent malignancy resulting in death (Brinton and Devesa 1996). However, the incidence and mortality vary widely among countries. From 6 per 100,000 women/year in Japan to almost 30 in the UK. Studies in migrants show that the rates of breast cancer tend to be those of the host country within one or two generations and become different from those of the family members remaining in the country of origin. This suggests that nutritional and other environmental factors are more important than genetics.
Age is the most important risk factor. Both the incidence of the disease and related mortality increase with age, and there is a clear slowing after menopause (Fig. 10.1). This alone suggests a relationship between estrogen priming and the incidence of the disease. This is corroborated by the differences in incidence according to the duration of reproductive life. Early menarche or late menopause increases the risk of presenting a breast cancer, and having had an oophorectomy before age 35 lowers the risk of presenting breast cancer to 40% of that presented by women reaching natural menopause at around age 50. Other anthropometric factors like body weight or body mass index are negatively related to breast cancer incidence. Skin and fat tissue are major sites for aromatase, an enzyme converting androgenic precursors to estrogens, and consequently obese women are able to produce more estrogens. Obesity is also negatively related to circulating levels of sex hormone binding globulin (SHBG), a plasmatic protein that binds potent estrogens like estradiol, and thus leaving a higher percentage of circulating estrogens “free” to bind to estrogen receptors (ERs). Other risk factors identified, like socioeconomic group, alcohol consumption, and saturated-fat-rich diets, seem to act through an increase in the ability to produce estrogens.
Fig. 10.1. Age-specific incidence and mortality for breast cancer in United Kingdom. Reproduced with permission from McPherson et al. (2000)
With these evidences in mind the rationality of any attempt at blocking the access of an estrogen molecule to its receptor, and consequently diminishing the risk of breast cancer, seems justified. SERMs, a family of molecules characterized by their ability to bind to ERs with high affinity and competing with genuine estrogens, are in a preferential position to play this role. In fact tamoxifen, the first widely used SERM, has been the major tool for adjuvant therapy in early, ER(+) breast cancer and remains the only drug accepted for preventive intervention in high-risk women. In this battle against breast cancer SERMs have to find their place among new agents also able to minimize the estrogenic stimulation of the breast cell, normal or neoplastic, as aromatase inhibitors or “pure” ER antagonists.
In this chapter we will review the basic aspects of endocrine regulation of breast tissue growth and development. The relationship between genetics, estrogen exposure, and breast cancer risk will be discussed, and preclinical and clinical experience in the use of SERMS for both prevention and adjuvant treatment of ER-positive breast cancer will be reviewed and put in perspective.
10.2
Biology of Breast Development and its Endocrine Regulation
Mammary epithelium is very sensitive to hormonal stimulation. It is where proliferative events take place and where neoplastic transformation begins.
Crucial for the understanding of this process are the studies of Russo (Russo and Russo 1997), according to which any carcinogenetic action takes place in the less differentiated and highly proliferating areas of the breast.
Consequently, breast cancer develops as the result of the synergy between a foreign stimulating agent and an especially sensitive area of the mammary epithelium. According to Russo and coworkers (1992), the mammary ductal tree shows a clear regional specialization. From their studies it can be deduced that, from birth, the mammary gland enters in a continuous branching process giving rise to the lobules. Since this is a dynamic process, lobules can be found in different developmental stages that have been classified in four categories. Type 1 lobule, also called the terminal ductal lobular unit, is the less differentiated structure.
Type 1 lobules evolve into type 2 lobules by incorporating a higher number of ducts. During pregnancy all of them progress to type 3 lobules endowed with a highly dense duct branching system. Lactation is based on type 4 lobules, with an intense secreting activity that regresses to types 2 and 3 after weaning. After menopause the majority of these structures regress to type 1 (Russo et al. 1992). Consequently, pregnancy is a determinant factor for the development of type 3 and 4 lobules and, in nulliparae, type 1 is predominant. It is in this type of lobule where cancer develops more frequently. After age 50 the lobular composition of the breast tissue is predominantly composed of type 1 lobules in both nulliparae and early para women. However, the risk of developing a cancer is higher in nulliparae, and it is plausible that type 1 lobules from the former have a higher malignancy potential since they have never reached type 4 differentiation.
Explaining this higher tendency to malignancy are the observations of a higher proliferating activity in type 1 lobules, especially in nulliparae, and also a higher concentration of estrogen and progesterone receptors. According to this, the majority of the most common breast cancers arise from type 1 lobules, whereas type 2 lobules used to be the place of origin of atypical hyperplasias or in situ carcinomas. Type 3 lobules are the site offibro-adenomas or cysts (Wellings et al. 1975).
10.3
Framework of Breast Cancer Research
An integrated analysis of the biological, epidemiological, and clinical data recently available has led to a multitarget approach to the investigation of the origins of breast cancer (Wolman et al. 1997). This involves new knowledge in molecular genetics, cellular biology, and endocrine environment.
In the field of molecular genetics, several susceptibility genes for breast cancer have been identified. The genes involved in the regulation of development and differentiation of normal breast tissue and the role of their abnormality in the onset of a tumor are crucial in the understanding of the disease. The isolation of the proteins regulated by these genes open new approaches for tumoral research (McPherson et al. 2000).
Two genes, BRCA1 and BRCA2, have been identified and are present in a relevant proportion of high-risk families. They are located in the long arms of chromosomes 17 and 13, respectively. They are large genes allowing for multiple mutations at different positions and thus making the detection of genetic abnormalities in a given patient technically and time demanding. P53 and PTEN are genes associated with rare familial syndromes including breast cancer, but, together with other unknown genes, they are also involved in an increase in risk above the general population level. They are probably rather common and account for a substantial part of the genetic contribution to breast cancer (Black 1994).
A second element in breast cancer genesis is cellular biology. The availability of cellular models able to reproduce the development of a breast cancer allows the study of the sequential morphologic changes and to test the impact of different manipulations of factors modifying the progression of the disease.
In this field two models contribute especially to the advance of research: the culture of primordial mammary cells, able to grow even as a xenograft, and the transgenic mouse. The mouse hyperplasic alveolar node is the most advanced model of preneoplastic breast tissue. It is a focal lesion related to situations known to be at high risk of developing breast cancer. It has been used to investigate the role of chemical carcinogens, viruses, hormones, and growth factors in its progression to a malignant tumor.
A third basic element is the micro environment of the tumor. The tumoral cells are surrounded by other cellular and acellular components and establish with them a paracrine relationship that determines the ability of the tumor to grow and create metastasis. Relevant in this sense are the members of the family of IGFs and the proteases, cytokines, or factors regulating tumoral angiogenesis like vascular endothelium growth factor. Also very important in clinical terms are the evidences of the high aromatase concentrations in the tumor itself and in the surrounding benign areas, assuring a local contribution of high levels of estrogens to tumor growth (Santner et al. 1997).
Finally, estrogen-dependent tissues are all related by the endocrine information system where the messengers are estrogenic molecules. As has already been mentioned, any modification, positive or negative, in the availability of estrogen to the mammary breast cells has an impact on the future risk of breast cancer. This opens new and interesting research lines in methods to diminish breast tissue estrogenic priming and thus diminish the risk of presenting the disease.
10.4
Relationship Between Estrogens and Breast Cancer
10.4.1
Endogenous Estrogens
The origin of a malignant tumor is a random genetic mutation leading to the loss of mitotic control by the cells. Normal cells experience mutations regularly, and they are necessary mechanisms of adaptation that are strictly controlled. Malignant transformation, however, means a loss of control and a chaotic, uncontrolled growth.
The factors inducing and maintaining mutations leading to malignant growth can be distinguished as inducers or promoters. The former are the genuine carcinogens giving rise to genomic modification, whereas the latter maintain and amplify the lesion. However, both roles can be interconnected. Estrogens, as naturally occurring substances, do not fulfill the criteria of a carcinogen but exert a proliferative effect leading to continuous cellular divisions, a risk situation for the appearance of mutations. The errors, appearing during the process of DNA replication, are corrected by a complex repair system in which cellular proteases and specific genes like P53 are involved.
If the effectiveness of this repair system is overcome by the intense proliferating rate induced by estrogens, a number of abnormally mutated cells will continue to divide and give rise to a malignant tumor, making estrogens both inducers and promoters (Fig. 10.2) (Ames and Gold 1990).
Based on this concept of correlation between high replication rate/high persistent mutation risk, Pike et al. (1983) formulated the hypothesis of “breast tissue age” and developed a mathematical model to predict the effects of exposure to ovarian hormones. This model incorporates reproductive and endocrine items related to breast cancer and is able to predict the relative risk of individual situations with results that are very close to those observed in clinical trials. According to this hypothesis, both the years of exposure and the circulating serum levels of estrogens are associated to short-term breast cancer risk in postmenopausal women (Toniolo et al. 1995).
Consequently, any life event related to an increase in breast tissue exposure to estrogens leads to a higher risk of developing a cancer. Thus early menarche or late menopause increases the risk of presenting a cancer, whereas long periods of hypoestrogenic amenorrhea or early oophorectomy decreases the risk as compared to the general population. Obesity implies a larger amount of skin and fat, both tissues rich in aromatase, the enzyme that converts androgens to estrogens. At the same time high body mass index is an independent factor diminishing the hepatic secretion of sex hormone binding globulin (SHBG), a transport protein binding both to testosterone and estradiol and limiting its bioavailability (McTiernan et al. 2003). Thus, in obese postmenopausal women the peripheral production of estrogens is higher as compared to lean ones, and those estrogens are more available to the ER. This leads to a higher breast cancer incidence (Endogenous Hormones and Breast Cancer Collaborative Group 2003).
Fig. 10.2. Breast epithelial cells can evolve into a malignant ones either as a consequence of the functioning of the repair system or after repeated replication favored by estrogens. Both mechanisms can coexist and act synergistically
Conversely, circumstances reducing estrogen production such as exercise, reduced alcohol intake, or low-fat diet decrease the risk (Chlebowski et al. 1999; McTiernan et al. 2004). The role of smoking remains controversial because mutagenic substances present in tobacco smoke can cause DNA damage, but current smoking can have an antiestrogenic effect by interfering in estrogen metabolism (Manier et al. 2004). In summary, any anthropometric or behavioral circumstance increasing endogenous production of estrogens and consequently higher circulating concentrations increases the likelihood of presenting a breast cancer in the future.
10.4.2
Exogenous Estrogens
The consequences of the administration of substances with estrogenic activity on brest cancer incidence are probably different before and after menopause. During reproductive age the concentrations of estrogens during the spontaneous cycle or in some anovulatory situations like polycystic ovary syndrome change from woman to woman and cycle to cycle. With the administration of hormonal contraception the synthetic steroids contained in contraceptive preparations block the ovarian function and replace the endogenous hormones. In these circumstances the circulating concentrations of estrogens are relatively homogeneous and not necessarily higher than those present during the natural cycle. At the present time several cohort studies have failed to show any increase in breast cancer among users of hormonal contraception (Marchbanks et al. 2002).
After menopause the exogenous hormones just add to those produced through peripheral metabolization of androgens and mean an increase in estrogen availability to breast epithelium. Until recently the evidences on the effect of hormone therapy (HT) after menopause came from observational or cohort studies. In 1995 an evaluation of this topic among the participants of the Nurse’s Health Study (Colditz et al. 1995) detected a small increase in the risk of presenting a breast cancer after the use of HT, either estrogens alone or combined with progestins, for more than 5 years. A reanalysis of the data published in 51 studies comparing the information from 52,705 cases of breast cancer with 108,411 controls (Collaborative Group on Hormonal Factors in Breast Cancer 1997) confirmed an increase in risk among users of HT.
In recent years two large-sample, prospective, double-blind, randomized trials have been performed to evaluate the usefulness of HT as a tool for secondary (Heart and Estrogen/Progestin Replacement Study, HERS) or primary (Women’s Health Initiative, WHI) prevention of cardiovascular disease in postmenopausal women (Grady et al. 2002; Rossouw et al. 2002; Anderson et al. 2004). HERS randomized 2763 postmenopausal women with coronary disease to receive a combination of conjugated equine estrogens (CEE) 0.625 mg/dplus 2.5 mg medroxyprogesterone acetate or placebo. Two thousand three hundred twenty-one surviving HERS participants consented to continue the 4-year placebo-controlled period with a subsequent open-label observational study for 2.7 years. It totalized a 6.8-year followup period. Breast cancer was one of the outcomes evaluated in the study, and after nearly 7 years of treatment the difference between hormone and placebo group was insignificant even if the incidence was slightly higher in the treated group (RH = 1.27; 95% CI = 0.84-1.94) (Hulley et al. 2002).
WHI had two different arms. One included postmenopausal women with intact uterus randomly assigned to receive daily (Rossouw 2002). A parallel study randomized postmenopausal hysterectomized women to receive either placebo or 0.625 mg/d of CEE. The two studies included a total of 27,347 women. The study with nonhysterectomized women was interrupted prematurely, after a mean of 5 years of treatment, because health risks exceeded benefits. Among them an increase in invasive breast cancer was observed in the treated group up from the fourth year of treatment (HR = 1.24 95% CI= 1.01-1.54) with the intent of treating analysis (Fig. 10.3). When a sensitivity analysis was performed excluding the events in nonadherent women, the observed effect was slightly higher (HR = 1.49) with the possibility of an earlier appearance of the effect. Unlike what had been observed in previous studies (Holli et al. 1997), where tumors were slightly larger (1.7 cm [1.1] vs.1.5 cm [0.9]), tumors have been diagnosed at a more advanced stage compared to those in the placebo group and were similar in histology (Chlebowski et al. 2003).
Fig. 10.3. Effect of daily treatment with CEE + MPA on breast cancer incidence as compared to placebo. WHI study, nonhysterec- tomized women. Reproduced with permission from Chlebowski et al. (2003)
The part of the study involving hysterectomized women was also interrupted in February 2004 after nearly 7 years of treatment because there was no protective effect on the risk of heart disease, but the risk of stroke increased at the same rate as for the estrogen plus progestin combination.
It is important to note that the invasive breast cancer rate was 23% lower in the CEE group than in the placebo group (26 vs. 33 cases per 10,000 woman- years) approaching statistical significance (HR = 0.77 95% CI = 0.50-1.01). These results do not support the previously quoted hypothesis on the effects of estrogen exposure and breast cancer incidence, but some aspects must be taken into account. The majority of studies have found a higher effect of HT on breast cancer incidence when progestins were associated to estrogens. At the same time a high percentage of hysterectomized women are also oophorectomized and, consequently, the endogenous contribution of androgen precursors for aromatization is limited to adrenal secretion. Thus these results do not override the general advice of limiting postmenopausal estrogen (Fig. 10.4) administration to symptomatic women at the lowest effective dose (Anderson et al. 2004).
Fig. 10.4. Effect of daily treatment with CEE alone on breast cancer incidence as compared to placebo. WHI study, hysterectomized women. Reproduced with permission from Anderson et al. (2004)
10.5
Pharmacological Blockade of Estrogen Receptors:
The Concept of Chemoprophylaxis
The evidence for a negative effect of estrogen exposure on breast cancer risk raises automatically the idea of minimizing the risk by diminishing the binding of estrogens to their receptors. Oophorectomy has been the first measure to show effectiveness in improving the evolution of advanced breast cancer. This alternative was challenged by the discovery of molecules able to bind to ERs competing with estrogens. The substances were called “antiestrogens” and shown to be at least as effective as surgery without invasive measures (Buchanan et al. 1986; Ingle et al. 1986).
The evidence that tamoxifen was able to exert estrogenic effects on several tissues like the bone (Love et al. 1992) opened the door to the concept of SERMs, which is explained in detail in Chaps. 2 and 3 of this book. The mechanisms of action of these substances on ERs is explained in detail in Chap. 3. However, it is pertinent to comment on some special aspects of its action on mammary cancer cells. IGF-1 is a key element in growth control of malignant breast cells through endocrine and paracrine pathways. Tamoxifen and its active metabolite are able to inhibit IGF-1-stimulated growth (Jordan 1994), modulate the expression of IGFBPs (Lee and Yee 1995), reduce the autocrine secretion of IGFs (Huff et al. 1988), and reduce both the plasmatic levels (Colletti et al. 1989) and the receptor population (Freiss et al. 1990) of IGF-1.
Fig. 10.5. Drugs can impair the estrogenic stimulation of the mammary cell in different ways: 1. Increasing SHBG hepatic secretion and diminishing the amount of free bioavailable hormone. 2. Inhibiting the activity of aromatase and blocking the conversion of weak androgens to estrogens. 3. Pure antiestrogens, like fulvestrant, compete with estrogens to bind to the receptor and blocks its ability to influence on nuclear action. 4. SERMs bind to the receptor but influences selectively on cellualar action depending on the tissue. (A = androgens, E = estrogens, ER = estrogen receptors, SHBG = sex hormone binding globulin)
Tamoxifen has pioneered the field of primary and secondary chemopreven- tion of breast cancer, which has been followed by second- and third-generation SERMs and alternative approaches as aromatase inhibitors or “pure antiestrogens”, as will be explained below (Fig. 10.5).
10.5.1
Tamoxifen as Adjuvant Therapy in Early ER(+) Breast Cancer
Tamoxifen has been widely used in the adjuvant treatment of invasive breast cancer associated to surgery and chemotherapy. It has been shown to be effective in preventing new contralateral tumors and local or peripheral recurrences (Nolvadex Adjuvant Trial Organization 1983; Cuzick and Baum 1985; Abe et al. 1998). The overview comprised 37,000 women from 55 randomized trials and included events occurring more than 5 years after randomization. The effects of tamoxifen administration in cases with a low or zero level of ER measured in the primary tumor (about 8000 women) appeared to be small, and consequently analysis of recurrence and total mortality have been restricted to patients with ER(+) tumors or untested (around 30,000 cases altogether). Both recurrence and mortality reductions over approx. 10 years of followup had a clear significant trend toward greater effect with longer treatment. After 1,2, and 5 years of adjuvant treatment, recurrences were reduced by 21,19, and 47% and mortality by 12, 17, and 26%, respectively. Even if the relative reduction in mortality was similar for both node-negative and node-positive patients, the absolute mortality reductions were greater in node-positive women. The proportional reductions in contralateral breast cancer were 13, 26, and 47%, respectively, for the aforementioned periods of treatment (Fig. 10.6).
Toremifen is a SERM considered a tamoxifen analog characterized by one chlorine atom and is approved for first-line treatment of metastasic breast cancer in postmenopausal women who have tumors that are either ER(+) or of unknown status. In a 3-year face-to-face study with tamoxifen, there were no significant differences between both drugs. The number and profile of adverse events are also similar. Experience with toremifen is limited and far from that accumulated with tamoxifen.
Until recently tamoxifen has been the gold standard for adjuvant therapy in ER(+) early breast cancer. Recent information from controlled trials comparing tamoxifen to aromatase inhibitors has challenged this idea. More research is needed to establish the respective roles of the two families of substances in the hormonal management of breast cancer (Chlebowski et al. 2002).
Fig. 10.6. Reduction in the risk of recurrence obtained with the administration of 20 mg/d of tamoxifen and subdivided by nodal status. Reproduced with permission from Abe et al. and the Early Breast Cancer Collaborative Group (1998)
10.5.2
Tamoxifen in Primary Prevention of ER(+) Breast Cancer
Since SERMs are able to block (estrogen-dependent) malignant mammary cell growth, it is logical to deduce that its administration to healthy women should prevent the progression from premalignant to malignant epithelial cells. The administration of tamoxifen to different groups of high-risk women has produced relevant information on the advantages and inconveniences of such an approach (Chlebowski et al. 1999).
The most relevant study is the Breast Cancer Prevention Trial (BCPT, NSABP-P1) (Fisher et al. 1998). Initiated in the USA by the National Surgical Adjuvant Breast and Bowel Project, this study recruited 13,388 women considered at high risk for breast cancer based on Gail’s probability algorithm (Gail et al. 1989).
The women were randomized to receive either tamoxifen (6681) or placebo (6707) for 5 years. However, the trial was stopped prematurely because the findings provided strong evidence of a reduction in breast cancer with tamoxifen therapy. The results have been released and made available at http://cancertrials.nci.nih.gov. These are the first available data supporting the hypothesis that breast cancer can be pharmacologically prevented in an at-risk female population. The administration of tamoxifen was effective in reducing by 69% the annual rate of ER(+) tumors, both invasive and in situ, but was ineffective in reducing the occurrence of ER(-) neoplasias (Young 1999).
This prevention was evident in all risk category groups included in Gail’s score and with any previous history of breast lesions (atypical hyperplasia, lobular carcinoma in situ, etc.) (Fig. 10.7).
Three other studies were conducted to investigate the preventive potential of tamoxifen. One in Italy (Veronesi et al. 1998), one at the Royal Marsden Hospital, United Kingdom (Powles et al. 1998), and a multicentric international study (IBIS 2002). The British study was the smallest in size (2471 participants) but concentrated on women with a high incidence of family history and consequently presented a higher number of breast cancers. The Italian trial included only women with previous hysterectomy and, accordingly, around 50% had also undergone bilateral oophorectomy. The family risk was low: only 15% had a first-degree relative affected by breast cancer. Both European studies permitted concurrent HRT, and 26% of the participants in the British trial received HRT while on study and 42% had “ever received” HT for menopausal symptoms. Neither of the studies showed any positive effect of the treatment with tamoxifen on the incidence of breast cancer. Reasons for this lack of effect can be different for each trial.
The Italian study included low-risk women, especially as concerns the aspects expected to be protected by tamoxifen, and the sample was too small to show differences with the placebo group. The compliance has been reported to be very low since only 149 women completed the expected 5 years of treatment. Two recently published subanalyses of the Italian trial focus on two especially high-risk subgroups: HRT users (Veronesi et al. 2002a) and those fulfilling precise risk criteria for breast cancer (Veronesi 2002b). Both subanalyses show significant protection from tamoxifen administration. As the authors point out, “Tamoxifen’s effect appears to be restricted to women who are predicted to be at high risk of the hormone-dependent form of breast cancer. If it proves to be true the same reduction in the absolute numbers of breast cancer could be obtained by restricting treatment to the reduced women at high risk and thus improve the cost effectiveness of the intervention”.
Fig. 10.7. Effect of tamoxifen administration on incidence of invasive (left panel) or noninvasive (rightpanel) breast cancer. Reproduced with permission from Fisher et al. and other National Surgical Adjuvant Breast and Bowel Project Investigators (1998)
The results obtained in the UK trial are more difficult to explain. Since the sample was basically composed of rather young women (62% younger than 50 years old) with increased risk by family history (96% with a first- degree relative affected), it can be postulated that the origin of the majority of cancers was probably more genetic than hormonal. Furthermore, there is no information on the receptor status of the tumor detected in both placebo and treated group.
The IBIS-I study was promoted by the UK Coordinating Committee for Cancer Research and supported by the Imperial Cancer Research Fund. A group of 7152 high-risk women were selected according to criteria related to familial cases of breast cancer, previous atypical biopsies, and parity. The most important group was that of women with two or more first- or second-degree relatives with breast cancer. For this group the yearly frequency of breast cancer, in the absence of any intervention, was calculated to be 7.50 per 1000 women. This proved to be accurate since the actual frequency in the placebo group was 6.74 per 1000, not significantly different from that projected. The study took place predominantly in the UK, Australia, and New Zealand, with testimonial participation of some European countries (Spain, Ireland, Finland, Italy, Belgium, and Switzerland).
After median followup of 50 months a risk reduction of 32% in the tamoxifen-treated group has been observed. This protection was independent of age, degree of risk, and previous or actual use of HRT. The most striking outcome of the study has been the significant increase in the death rate of all causes in the tamoxifen group as compared to that receiving placebo (25 vs. 11 cases). The increases correspond to cancers other than breast cancer (only four deaths were due to breast cancer, two in each study group), pulmonary embolism other vascular causes, and cardiac deaths. The variety of causes of death and the lack of an increase in overall frequency suggests that this may be a chance finding excepting thromboembolic events, which will be discussed in detail later. This increase in overall mortality in the treated group raises the issue of the cost-benefit of these interventions. If the number of breast cancers has been lower than expected, and the reduction in the number of new cases is at the cost of unexpected deaths, the appropriateness of the treatment has to be carefully evaluated. The editorial introduction at the moment of the IBIS publication was entitled “Chemoprevention of breast cancer: a promising idea with an uncertain future” (Kinsinger and Harris 2002). A summary of the data on prevention trials is presented in Table 10.1.
Table 10.1.
|
Trial |
Sample size |
Women/years of followup |
Cancers/1000 women/year |
|
|
Placebo |
Tamoxifen |
|||
|
BCPT |
13.388 |
46.858 |
6.6 |
3.6 |
|
Powles |
2.471 |
12.355 |
5.0 |
4.7 |
|
Veronesi |
5.408 |
20.731 |
2.3 |
2.1 |
|
IBIS |
7.152 |
29.967 |
101 |
69 |
10.5.3
Drawbacks of Tamoxifen as a Preventive Agent
The estrogenicity of tamoxifen at several levels brings both advantages and inconveniences. Among the former we have already mentioned bone quality and vaginal proliferation. However, the inconveniences, especially endometrial polyps and cancer and thrombotic events, are important enough to avoid the systematic use of this drug as a preventive agent except with well-identified high-risk patients. Thus a careful cost-benefit analysis is needed.
A recent review by Cuzick et al. has pooled the information generated by the four randomized prevention trials mentioned above (Cuzick et al. 2003). The observed reduction in breast cancer incidence was 38%, in good agreement with what was expected from the individual trials. When analyzing according to ER status, there was no reduction in the incidence of ER(-) tumors, and a reduction of 48% was observed in the incidence of ER(+) cancers. These figures clearly confirm that tamoxifen can reduce the risk of ER(+) breast cancer.
The rates of endometrial cancer were increased in the tamoxifen group in all trials. The consensus relative risk was 2.4 (1.5-4.0) in the prevention trials, and the hazard ratio was 3.4 (1.8-6.4) in the adjuvant studies. The risk increase is seen almost exclusively after 50 years of age, and the information available suggests that the cancers detected in the tamoxifen-treated women are not of worse prognosis than those detected in the general population. The endometrial action of tamoxifen seems to be exerted mainly through the IGF system rather than by direct binding to ERs. Tamoxifen decreases the synthesis of IGFBPs and potentiates the tisular activity of IGF-1 through tyrosine phosphorylation (Kleinman et al. 1996) (Fig. 10.8).
Besides cancer, tamoxifen induces benign changes in the endometrial and subendometrial structures, which induce a burden of unnecessary examinations (ultrasound, hysteroscopy, biopsy etc.) and surgery (D&Cs, hysterectomies) due to misleading or false positive ultrasonographic reports (Dijkhuizen et al. 1996). Since the absolute incidence of the disease is low and frequently manifested by abnormal bleeding, the American College of Obstetricians and Gynecologists recommends limiting the endometrial examination of tamoxifen users to those presenting with abnormal bleeding. This situation makes very suitable the availability of new agents devoid of endometrial activity.
Fig. 10.8. Hazard ratio of presenting an endometrial cancer as the consequence of treatment with tamoxifen or raloxifene (MORE study). Reproduced with permission from Cuzick et al. (2003)
Tamoxifen users present also a doubling incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) (118 vs. 62 cases). This increase is similar to that seen with HRT. There are some aspects of this side effect that should be commented on to improve the management ofwomen eligible for tamoxifen treatment and at risk for DVT (Goldhaber 2005). In the subanalysis of the Italian study (Decensi et al. 2005), the venous thromboembolism definition included DVT, PE, and superficial phlebitis. Most of the VTE that the authors reported were, in fact, cases of superficial phlebitis, whereas the admitted definition of venous thromboembolism excludes this entity. Such conceptual differences, together with differences in age and background characteristics between the four studies, can explain the diversity in the incidences observed.
It is interesting to note that in IBIS, where the rate of thromboembolic events was about 2.5 times higher in the tamoxifen group, the majority of the events took place within 3 months of major surgery or after long-term immobility. Twenty of 25 such events were in women in the tamoxifen group. This is why the authors strongly suggest discontinuing tamoxifen before any surgery or longstanding immobility and providing appropriate antithrombotic measures. The treatment should not be restarted until full mobility is restored.
Fig. 10.9. Hazard ratio of presenting a venous thomboembolic event as the consequence of treatment with tamoxifen or raloxifene (MORE study). Reproduced with permission from Cuzick et al. (2003)
The Italian study subanalysis identifies as independent predictors of VTE: age > 60 years, height > 165 cm, and diastolic blood pressure > 90 mm. Also relevant is the association between high global cardiovascular risk scores and VTE incidence. This means that there is a correlation between arterial and venous risks, and consequently prevention of arterial complications will also mean lower venous risk (Decensi et al. 2005; Goldhaber 2005) (Fig. 10.9).
Considering the information presented, tamoxifen does not appear to be suitable for breast cancer prevention. Further studies are needed to reduce risks and increase efficiency either by reducing the dose or identifying those women likely to gain the highest benefit (Powles and Chang 1997). Meanwhile, new agents emerge as alternatives with similar or higher protective effects and fewer or different side effects (Fabian and Kimler 2005; Cuzick 2005).
10.6
Raloxifene and Breast Cancer
Raloxifene is a SERM devoid of stimulating effects on the uterus as is known from the initial studies (Delmas et al. 1997). Eliminating one of the major concerns raised by the experience gained with tamoxifen studies, both in prevention and adjuvant treatments, puts raloxifene in a place of privilege to be a rational alternative agent. At the same time it improves bone density, prevents osteoporosis and vertebral fracture, and reduces cardiovascular events in a subset of high-risk patients (Silverman et al. 2004). The evidences on the effects of raloxifene on the uterus are explained in detail in Chap. 10 of this book.
Experimental studies showed antitumoral effects of raloxifene in different in vitro preparations and animal models. Raloxifene has been able to inhibit the mitogenic effect induced by estrogens on ZR-75-1 cells, an estrogen responsive human breast cancer cell line (Poulin et al. 1989). In a well-accepted rat model of breast cancer induced by nitroso-methyl urea (NMU) raloxifene significantly suppressed the development of breast tumors and acted synergistically with 9 cis-retinoic acid (Anzano et al. 1996).
10.6.1
Clinical Studies
The strongest clinical information on the effects of raloxifen on breast cancer risks emerges from the MORE study. As a reminder, this study included 7705 osteoporotic women randomized either to placebo (2576) or raloxifene (5129), either 60 or 120 mg. Mammographic evaluation was optative during the first year but mandatory at the second, third, and fourth years. At the six-month followup controls the patients were asked about any mammary event, and in the case of surgery or biopsy the mammograms, pathological reports, specimens, and ER special staining slides were reviewed by an independent board for adjudication. There were no differences in family history between the placebo and the treated group, and no specific evaluation of breast cancer risk factors has been made.
From the first evaluations a positive effect of raloxifene tratment on the incidence of breast cancer was detected (Cummings et al. 1999). During the 4 years of treatment 79 breast cancer cases were detected and 77 of them were confirmed by thereviewboard. Inthe placebogroup 44 caseswereidentified, of which 39 were invasive, whereas in the raloxifene-treated group 33 cases were detected and 22 were invasive. The differences between both groups appeared progressively and tended to increase over time. This means a relative risk of 0.38 (IC: 95% 0.24-0.58) or, in other words, a reduction in the incidence of breast cancer of 68%.
Absolute risks can better reflect the clinical importance of the protective effect. In the placebo group the incidence was 5.3 cases per 1000 woman-years, while in the treated group only 1.9 cases per 1000 woman-year were diagnosed. If we only take into account invasive cancers, the figures would be 4.7 and 1.3, respectively, meaning a relative risk of 0.28 or a decrease of 72% (Cauley et al. 2001).
These encouraging results, similar to those observed with tamoxifen in the BP-1 study, lead to the design of CORE (Continuing Outcomes Relevant to Evista) with the primary objective of investigating the effect of four additional years of raloxifene treatment on the incidence of invasive breast cancer. In fact, the study was the continuation of MORE in a slightly reduced subset with a change in the primary endpoint. A final group of 4011 participants of MORE agreed to continue in CORE. They continued with the same assignment, raloxifene or placebo. Consequently, 1286 received placebo and 2725 raloxifene. The active treatment was 60 mg/d raloxifene because it is the dose approved for the prevention and treatment of osteoporosis and because the two dosage groups in MORE (60 and 120 mg/d) had similar reductions in the incidence of breast cancer. All participants had a bilateral mammogram within the year of enrollement and 2 and 4 years thereafter. The process of adjudication by an independent review board was similar to that implemented for MORE.
During the 4 years of the trial 61 cases of breast cancer were reported and confirmed. Of these, 30 were in the placebo group (28 invasive) and 31 were in the raloxifene group (24 invasive). This means a 59% reduction in the incidence of invasive breast cancer in the raloxifene group as compared with women receiving placebo (2.1 vs. 5.2 cases per 1000 woman-years; HR = 0.41, CI = 0.24 to 0.71). Only nine intraductal, noninvasive breast cancers were detected, seven in the raloxifene group and two in the placebo group. The treatment with raloxifene reduced the overall incidence of breast cancer by 50%. The results obtained in this second treatment period are very similar to those observed in MORE.
Considering all 7705 MORE participants from the moment of the initial randomization to the end of their participation in either MORE or CORE, a total number of 121 breast cancers were adjudicated, 56 cancers in the raloxifene group and 65 in the placebo group. Of these 58 in the placebo group (4.2 cases per 100 woman-years) and 40 in the raloxifene group (1.4 cases per 1000 woman-years) were invasive. Consequently, raloxifene induced a 66% reduction in the incidence of invasive breast cancer compared with the placebo group (HR = 0.34,95% CI = 0.22-0.50) (Martino et al. 2004b) (Fig. 10.10).
Fig. 10.10. Cumulative incidence of invasive breast cancers during 8 years of treatment either with raloxifene (dotted line) or placebo (solid line) Reproduced with permission from Martino et al. (2004)
10.6.2
Estrogen Receptor Status
It is also important to note that, as happened with tamoxifen, this decrease in risk concentrated exclusively in ER(+) tumors. ER status was determined for 88 cases, and 75% of these were considered positive. The decrease in risk induced by raloxifene administration during the total 8 years of MORE plus CORE reached 76% of the invasive ER(+) cases, compared with the placebo group (0.8 vs. 3.2 cases per 1000 woman-years; HR = 0.24; 95% CI = 0.15 to 0.40). There was no influence of the raloxifene treatment on the incidence of ER(-) invasive tumors (0.53 versus 0.51 cases per 1000woman-years;HR = 1.06;95%CI = 0.43 to 2.59). This confirms the hypothesis that raloxifene exerts its protective effect through its binding to breast cell ERs, avoiding the proliferative effect of estrogens to take place. Consequently ER(-) tumors cannot be influenced by the presence of raloxifene in the blood, and no difference in its incidence should be expected between placebo and treated groups (Cauley et al. 2001) (Fig. 10.11).
Fig. 10.11. Annual incidence rate per 1000 woman-years of followup for invasive breast cancers over the 8 years of CORE according to ER status. Reproduced with permission from Martino et al. (2004a)
10.6.3
Estrogen Circulating Levels and Raloxifene Protection
The hypothesis of protection based on the competition of raloxifene with estrogens for the occupation of ERs implies the need for circulating estrogens to compete with. For the same reason the higher the concentrations of estrogens circulating, the higher the expected risk of presenting an ER(+) breast cancer and, consequently, the higher the protection offered by the administration of a SERM. The validity of this hypothesis has been tested both in MORE and CORE.
Lippman et al. (2001) determined the basal serum estradiol levels of 7290 women participating in MORE at the moment of enrollement. The samples were analyzed in a central laboratory with a low-sensitivity radioinmuno analysis (RIA) allowing for discrimination only between samples containing more or less than 12 pmol/L. The incidence of invasive breast cancer was clearly higher among women in the placebo group, with values higher than 12 pmol/L. The number of cancers was similar in the treatment group irrespective of the estradiol concentrations. Thus the effect of raloxifene treatment was also more evident in the group of women with the higher estrogen levels.
Using a more sensitive RIA, but studying the same population, Cummings et al. (2002b) were able to discriminate between undetectable concentrations and those lower than 5,6 to 10, and more than 10 pmol/L. In the placebo group the incidence of invasive breast cancer increased according to increases in the concentrations of circulating estradiol detected. As expected, the raloxifene- treated group presented the same incidence of breast cancer, irrespective of circulating levels of estradiol at recruitment, reflecting the ability of raloxifene to compete with any postmenopausal level of circulating estradiol. Since the incidence was higher in the high estrogen group, the degree of protection was also more important in these patients.
Finally, Martino et al. (2004a) analyzed the cases from MORE and CORE together using the basal data analyzed by Cummings et al. (2002). Participants were divided into three groups: those with baseline levels of < 5 pmol/L (N = 3655), 5-10pmol/L (N = 983), or > 10pmol/L (N = 2652). The incidence of invasive breast cancer cases was significantly reduced by 75% (HR = 0.25, 95% CI = 0.14-0.47; ARR = 46 cases per 10,000 woman-years) in the raloxifene group compared to placebo in women with serum estradiol > 10 pmol/L.
In those with serum estradiol concentrations of 5-10 pmol/L, invasive breast cancer incidence was reduced by 67% (HR = 0.33, 95% CI = 0.13-0.84; ARR = 40 cases per 10,000 woman-years) in the raloxifene group compared to those receiving placebo. In women with serum estradiol levels < 5 pmol/L, the 48% reduction in invasive breast cancer incidence for the raloxifene group compared to placebo was not significant (HR = 0.52, 95% CI = 0.26-1.06; ARR =11 cases per 10,000 woman-years). However, the interaction test showed that the magnitude of reduction in breast cancer incidence with raloxifene was independent of estradiol level (interaction p = 0.317).
These figures lend support to the hypothesis that raloxifene prevents the progression of breast cancer by blocking the binding of estrogens to specific intracellular receptors and allows for the suggestion that the detection of relatively high estrogen concentrations can be a criterion for selecting women in which a pharmacological intervention would be cost-effective. This is not an easy task since the usual clinical RIA systems are not sensitive enough to discriminate among the very low estradiol levels circulating in postmenopausal women (Stanczyk 2002). However, this is technically feasible, and specific RIAs could be set up if such a selection system were shown, by prospective randomized studies, to be clinically useful (Cummings 2002b) (Fig. 10.12).
Fig. 10.12. Effect of raloxifene on the risk of invasive breast cancer at different serum estradiol levels evaluated in two different studies. Elaborated from Lippman et al. (2001) and Cummings et al. (2002a)
10.6.4
Bone Density and Effect of Raloxifene on the Breast
All women included in MORE met criteria for osteoporosis defined as a lumbar spine or femoral neck bone mineral density (BMD) T score equal to or less than 2.5 or as the presence of a radiographic vertebral fracture. These women are considered to be at lower risk for breast cancer than women with normal BMD since this parameter could partially reflect a woman’s lifetime exposure to estrogens (Zhang et al. 1997). After the start of MORE, NHANES III criteria standardizing total hip BMD measurements became available allowing part of the MORE population to be recategorized as having osteopenia and the rest as being osteoporotic.
Delmas and coworkers (2005) have analyzed the impact of raloxifene treatment on breast cancer incidence over the 8 years of MORE plus CORE depending on the classification of the participants as osteopoenic or osteoporotic. For women assigned to placebo, more cases of invasive and ER(+) invasive breast cancers were reported in the osteopenic than in the osteoporotic group.
In postmenopausal women with osteopenia, 8 years of raloxifene, compared with placebo, was associated with a 65% lower incidence of invasive breast cancer and 78% lower incidence of ER(+) invasive breast cancer. In postmenopausal women with osteoporosis, 8 years of raloxifene, compared with placebo, was associated with a 69% lower incidence of invasive breast cancer and a 71% lower incidence of ER(+) invasive breast cancer. As mentioned previously, raloxifene performed better in protecting from ER(+) cancers, and consequently this effect was more evident in the osteopenic group, expected, according to the hypothesis, to have a higher estrogenic priming along reproductive life. Even if this reanalysis has the limitation of being based on a post hoc classification, according to new conventional criteria, it gives indications of the correlation between bone density and breast cancer risks and suggests that what is true for osteoporotic patients could also apply to women with normal BMD (Fig. 10.13).
Fig. 10.13. Effect of raloxifene on invasive breast cancer incidence by ER status in postmenopausal women with osteopenia or osteoporosis. Reproduced with permission from Delmas et al. (2005)
10.6.5
Other Conditions Related to Raloxifene Protection
Several secondary analyses have evaluated the effect of raloxifene as compared to placebo after stratifying for different factors known to be related to invasive breast cancer incidence as age, family history, Gail score, or previous exposure to hormone treatment for menopausal symptoms. Martino et al. (2005a) stratified MORE + CORE participants according to age (< 65 and ≥ 65 years). The participants older than 65 had a 77% increase in the risk of presenting an invasive breast cancer vs. those < 65 years (hazard ratio 1.77, 95% CI = 1.01, 3.12). The invasive breast cancer rates were 29.6 and 51.0 per 10,000 woman- years in the age categories < 65 and ≥ 65 years, respectively. The absolute risk reduction (ARR) was 17.1 cases per 10,000 woman-years for the group younger than 65 years and 35.6 cases per 10,000 woman-years for those older than 65 years. Therapy by age group interaction was not significant (p = 0.43), and consequently raloxifene risk reduction was independent of age group.
As previously mentioned, HT is considered to increase risk for invasive breast cancer. The ability of raloxifene to reduce breast cancer risk was evaluted after MORE (Lippman 2001; Johnell et al. 2004) and has been evaluated recently with a consideration of all the breast cancer cases diagnosed after MORE + CORE (Purdie et al. 2004). Previous HT use was reported by 2235 women and no previous HT use by 5447 women. In these women, the overall reduction in invasive breast cancer incidence for the 8 years of MORE plus CORE was 66% (HR = 0.34; 95% CI = 0.22-0.50). In the placebo group the incidence of invasive breast cancer was 2.7% in those with prior HT use compared to 2.1% in those with no prior use (p = 0.279). In women with a history of prior HT use, raloxifene significantly reduced invasive breast cancer incidence by 71% (HR = 0.29; 95% CI = 0.14-0.59) compared to placebo. In women with no prior exposure to HT, a 64% reduction in incidence of invasive breast cancer was found in those receiving raloxifeneX (HR = 0.36; 95% CI = 0.22-0.59). The magnitude of risk reduction with raloxifene did not differ irrespective of the previous exposure to HT (interaction p = 0.618).
Another prespecified secondary analysis addressed the effect of raloxifene administration after stratifying by previous family history (FH) of breast cancer defined as breast cancer occurring in a first-degree relative (Martino et al. 2005b). The group with FH included 949 participants, whereas 6569 did not have FH. Raloxifene decreased the risk for invasive breast cancer in both groups, but this decrease was higher in the group with family history: HR =0.11; (95% CI = 0.03-0.38) vs. HR = 0.42 (0.27-0.66) for the group without FH. Expressed in terms of absolute risk reduction (ARR), raloxifene avoided 72 cases per 10,000 woman-years in the FH group vs. 21 cases in the group with no FH (p = 0.04). Thus, compared with placebo, raloxifene significantly reduced the incidence of invasive breast cancer both in those postmenopausal osteoporotic women with and those without a FH of breast cancer, but this reduction was significantly greater in women with a FH.
As discussed in the preceding section, osteoporotic women are known to be at lower risk for invasive breast cancer. However, the incidence detected in the study was not lower than that expected for a similar general population. The breast cancer incidence rate for the placebo group in the CORE trial was 5.4 cases per 1000 woman-years, slightly higher than the 4.4-4.5 observed for a similar age group population as reported by the National Cancer Institute’s Surveillance, Epidemiology and End Results Program (Kikuchi et al. 1997). Thus the CORE participants were not at lower risk for breast cancer despite having osteoporosis. To explain this situation Cauley and coworkers (2004) analyzed the basal risk for breast cancer as evaluated according to Gail’s score (Gail et al. 1989).
Of the 5213 MORE participants included in the CORE primary analysis, 3996 had a Gail risk assessment; 2718 received 60 mg/d raloxifene and 1278 received placebo during CORE. The mean 5-year breast cancer risk for all women in CORE was 1.94, and 54% met the Gail criteria for breast cancer high risk (Gail’s score > 1.67%). In the placebo group, the rate of invasive breast cancer was 2.7 times higher in the high-risk group than the low-risk group (p = 0.034). In the total cohort, there were 45 adjudicated cases of invasive breast cancer: 21 (0.8%) in the raloxifene group vs. 24 (1.9%) among those receiving placebo (HR = 0.42, 95% CI = 0.23, 0.75; p = 0.002 vs. placebo). In the high-risk group there were 31 cases of invasive breast cancer, 13 in the group receiving raloxifene (0.9%) and 18 (2.7%) in the pacebo group (HR = 0.33, 95% CI = 0.16,0.67). Even if the protective effect was three times higher in the high-risk group, there was no significant difference in the effect of raloxifene between those patients at low and those at high risk of breast cancer based on the Gail model (interaction p = 0.28) (Fig. 10.14).
Fig. 10.14. Effect of raloxifene on incidence of invasive breast cancer after stratifying for risk evaluated with Gail’s score. Redrawn from Cauley et al. (2004)
10.6.6
Raloxifen as a Breast Cancer Preventive Agent
In 1999 the American Society of Clinical Oncology working group on breast cancer risk reduction strategies concluded that “it was premature to recommend raloxifene use to lower the risk of developing breast cancer outside of a clinical trial setting” (Chlebowski et al. 1999). Five years later the amount and quality of information has increased significantly. The results obtained in the CORE study prove that what was true for a 5-year treatment with tamoxifen in BP1 can persist for at least 8 years with raloxifene. The most relevant lesson learned from all tamoxifen prevention trials is that the degree of protection is closely related to the risk profile of the participants. Even in osteoporotic women, CORE included a significant amount of high-risk women irrespective of the evaluation system used (age, family history, Gail’s score, or estrogen levels), which probably explains the high degree of protection offered by raloxifene. Even not reaching significance, raloxifene always performed better in these high-risk subgroups. Consequently, more refined and updated scores than Gail’s, including biological data such as estradiol levels, would decrese the number of women to treat (NNT) to avoid a new case. Such an evaluation should be considered in future strategies for breast cancer prevention.
On the other hand, efforts have to be made to reduce the major side effect shared by both tamoxifen and raloxifene: thromboembolism (Cuzick et al. 2003). This could be achieved through a careful selection of women at risk (Goldhaber 2005) and concomitant administration of preventive treatments like low-dose aspirin. At the present time tamoxifen is not the answer (Powles and Chang 1997) since for apparently similar protective effects it has similar venous effects and significant increase in endometrial cancer risk as compared to raloxifene. We have to wait for the results of STAR (Wickerham 2003), an ongoing breast cancer study comparing the ability of tamoxifen and raloxifene to reduce the incidence of breast cancer in postmenopausal women at high risk, and RUTH (Mosca 2001), a prospective, double-blind, randomized study comparing raloxifene an placebo in both secondary prevention of cardivascular disease and risk reduction of breast cancer in postmenopausal women. In the meantime we have to keep in mind that, for menopausal women with osteoporosis and increased breast cancer risk, raloxifene is a reasonable choice to treat osteoporosis and also reduce the risk of breast cancer (Kalidas et al. 2004).
10.7
New Perspectives
At the present time SERMs are the only alternative for pharmacological primary prevention of ER(+) breast cancer. Only a small percentage of the eligible women agree to enter into such a process, the most important reason being the uncertainty about the risk/benefit ratio. Consequently, new research aims to find substances or strategies maintaining the preventive ability at the level of the breast and bone and without the negative impact on venous thrombosis or uterine cancer (Fabian and Kimler 2005).
There are evidences showing that lower daily doses of tamoxifen, between 1 and 5 mg, can obtain antiproliferative effects on in situ or small invasive cancers similar to those observed with the usual dose of 20 mg (Decensi et al. 2003). If that proves to be true with respect to the protective effect in primary prevention, it would probably allow skipping the negative effects on endometrium and coagulation, both dose related.
New SERMS are in different development stages. Lasofoxifene has been shown to have positive effects on bone and lipid metabolism without negative impact on uterine growth (Ke et al. 1998). There is a large-sample, prospective, randomized clinical trial in progress in which breast cancer, together with fracture prevention, is one of the main outcomes.
Bazedoxifene has also demonstrated in experimental studies its ability to inhibit the growth of ER(+) tumors in mice and rats in the absence of uterotrophic effects (Greenberger et al. 2001). At the present time bazedoxifene’s ability to counteract the estrogenic effects of CEE at the levels of both breast and endometrium is being tested in a multicentric study comparing calcium + vitamin D to bazedoxifene with and without a low dose of CEE in mild symptomatic postmenopausal women.
Arzoxifene, a third-generation SERM, has demonstrated in experimental, preclinical, and presurgical studies its ability to inhibit tumoral proliferation and prevent bone loss. A randomized trial of arzoxifene vs. placebo has been initiated in late postmenopausal women to evaluate its preventive effect on breast cancer and vertebral fractures.
All these new SERMs will be challenged by the emerging alternative in prevention: aromatase inhibitors (Santen et al. 2001; Cuzick 2005). Data from adjuvant trials suggest that these substances could be more efficient than tamoxifen in preventing new ER(+) cancers without the drawbacks of endometrial cancer and thromboembolic risks. However, they increase bone turnover and induce bone mineral loss leading to the need for coadministering an antire- sortive agent. Two large studies, IBIS II and MAP3, are now in the recruitment period to evaluate the preventive effect ofanastrazole and exemestane, respectively. IBIS II will also consider the coadministration of a bisphosphonate in case of initial low bone mass, and MAP3 will associate colecoxib to exemes- tane during the first 3 years in a subgroup of 5100 high-risk postmenopausal women.
When the results of these studies and STAR are made available, the choice between the two alternatives will likely be very complex. Decisions will be influenced by the profile of the women, the importance of the different (bone and breast) risks, and additional risk factors. With quality evidences available, wise clinical judgment will be made on a case-by-case basis.
References
1. Abe O, Abe R, Enomoto K et al. and the Early Breast Cancer Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 351:1451-1467
2. Ames BN, Gold LS (1990) Too many rodent carcinogens: mitogenesis increases mutagenesis. Science 249:970-971
3. Anderson GL,LimacherM,Assaf AR et al. (2004) Effects of conjugated equine estrogens in postmenopausal women with hysterectomy. J Am Med Assoc 291:1701-1712
4. Anzano MA, Peer CW, Smith JM et al. (1996) Chemoprevention of mammary carcinogenesis in the rat: Combined use of Raloxifene an cis-retinoic acid. J Natl Cancer Inst 88:123-125
5. Black DM (1994) The genetics of breast cancer. Eur J Cancer 30a:1957-1961
6. Brinton LA, Devesa SS (1996) Etiology and pathogenesis of breast cancer. Epidemiologic factors. Incidence, demographics and environmental factors. In: Harris JR, Lippman ME, Morrow M, Hellman S (eds) Diseases of the breast. Lippincott-Raven, Philadelphia, pp 159-168
7. Buchanan RB, Blamey RW, Durrant KR et al. (1986) A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol 4:1326-1330
8. Cauley JA, Norton L, Lippman ME et al. (2001) Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treat 65[2],125-134
9. Cauley JA, Martino S, Barrett-Connor E et al. (2004) Effect of raloxifene on invasive breast cancer incidence in postmenopausal women stratified by Gail risk assessment: results of the Continuing Outcomes Relevant to Evista (CORE) trial. Abstract 1018. American Society of Clinical Oncology
10. Chlebowski RT, Collyar DE, Somerfield MR et al. (1999) American Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene. J Clin Oncol 17:1939-1955
11. Chlebowski RT, Col N, Winer EP et al. (2002) American Society of Clinical Oncology Technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 20(15):3328-3343
12. Chlebowski RT, Hendrix SL, Langer RD et al. (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. J Am Med Assoc 289:3243-3253
13. Colditz GA, Hankinson SE, Hunter DJ et al. (1995) The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Eng J Med 332:1589-1593
14. Collaborative Group on Hormonal Factors in Breast Cancer (1997) 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
15. Colletti RB, Roberts JD, Devlin JT et al. (1989) Effect of tamoxifen on plasma insulinlike growth factor I in patients with breast cancer. Cancer Res 49:1882-1884
16. Cummings SR, Eckert S, Krueger KA et al. (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial. J Am Med Assoc 281(23):2189-2197
17. Cummings SR, Duong T, Kenyon E et al. (2002a) Serum estradiol level and risk of breast cancer during treatment with raloxifene. J Am Med Assoc 287:216-220
18. Cummings SR (2002b) Measurement of serum estradiol levels in postmenopausal women. J Am Med Assoc 288:451
19. Cuzick J (2005) Aromatase inhibitors for breast cancer prevention. J Clin Oncol 23:1636-1643
20. Cuzick J, Baum M (1985) Tamoxifen and contralateral breast cancer. Lancet ii:282
21. Cuzick J, Powles T, Veronesi U et al. (2003) Overview of the main outcomes in breast- cancer prevention trials. Lancet 361(9354):296-300
22. Decensi A, Robertson C, Viale G etal. (2003) A randomized trial of low dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 95:779-790
23. Decensi A, Maisonneuve P, Rotmenz N et al. (2005) Effect of Tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 111:650-656
24. Delmas P, Cauley JA, Burshell AL et al. (2005) Breast cancer risk reduction over 8 years in postmenopausal women with osteopenia or osteoporosis receiving raloxifene. Bone 36:S436-7
25. Dijkhuizen FPHLJ, Brolmann HAM, Oddens BJJ etal. (1996) Transvaginalultrasonog- raphy and endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Maturitas 24:45-50
26. Early Breast Cancer Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 351:1451-1467
27. Endogenous Hormones and Breast Cancer Collaborative Group (2003) Body mass index, serum sex hormones and breast cancer risk in post menopausal women. J Natl Cancer Inst 95:1218-1226
28. Fabian CJ, Kimler BF (2005) Selective estrogen receptor modulators for primary prevention of breast cancer. J Clin Oncol 23:1644-1655
29. Fisher B, Constantino JP, Wickerham DL et al. and other National Surgical Adjuvant Breast and Bowel Project Investigators (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371-1388
30. Freiss G, Rochefort H, Vignon F (1990) Mechanisms of 4-hydroxytamoxifen antigrowth factor activity in breast cancer cells: alterations of growth factor receptor binding sites and tyroxine kinase activity. Biochem Biophys Res Commun 919-926
31. Gail MH, Brinton LA, Byar DP et al. (1989) Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81:1879-1986
32. Goldhaber SZ (2005) Tamoxifen, preventing breast cancer and placing the risk of deep vein thrombosis in perspective. Circulation 111:539-541
33. Grady D, Herrington D, Bittner V et al. for the HERS research group (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and
Estrogen/progestin Replacement Study follow-up (HERS II). J Am Med Assoc 28:49-57
34. Holli K, Isola J, Cuzick J (1997) Hormone replacement therapy and biological aggressiveness of breast cancer. Lancet 350:1704-1705
35. Huff KK, Knabe C, Linsey R (1988) Multihormonal regulation of insulin-like growth factor-1-related protein in MCF-7 cells. Mol Endocrinol 2:200-208
36. Hulley S, Furberg C, Barret-Connor E et al. (2002) Noncardiovascular disease outcomes during 6.8 years of hormone therapy. J Am Med Assoc 288:58-66
37. IBIS (2002) First results from the international Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 360:817-824
38. Ingle JN, Krook JE, Green SJ et al. (1986) Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastasic breast cancer. J Clin Oncol 4:178-185
39. Johnell O, Cauley JA, Kulkarni PM et al. (2004) Raloxifene reduces risk of vertebral fractures and breast cancer in postmenopausal women regardless of prior hormone therapy. J Fam Pract 53:789-796
40. Jordan CV (1994) Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer Res Treat 31:41-52
41. Kalidas M, Hilsenbeck S, Brown P (2004) Defining the role of raloxifene for the prevention of breast cancer. J Natl Cancer Inst 96(23):1731-1733
42. Ke HZ, Paralkar VM, Grasser WA et al. (1998) Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus, and body composition in rat models. Endocrinology 139:2068-2076
43. Kinsinger LS, Harris S (2002) Chemoprevention of breast cancer: a promising idea with an uncertain future. Lancet 360:813-814
44. Kleinman D, Karas M, Danilenko M (1996) Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction of IGF binding proteins. Endocrinology 137:1089-1095
45. Lee AV, Yee D (1995) Insulin-like growth factors and breast cancer. Biomed Pharma- cother 49:415-421
46. Lippman ME, Krueger KA, Eckert S et al. (2001) Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with Raloxifene therapy in the multiple outcomes of Raloxifene evaluation study participants. J Clin Oncol 19(12):3111-3116
47. Love RR, Mazess RB, Barden HS et al. (1992) Effects of tamoxifen in bone mineral density in post menopausal women with breast cancer. N Engl J Med 326:852-856
48. Manier J, Johansson R, Lenner P (2004) Smoking is associated wtith post menopausal breast cancer in women with high levels of estrogens. Int J Cancer 112:324-328
49. Marchbanks PA, Mc Donald JA, Wilson HG et al. (2002) Oral contraceptives and the risk of breast cancer. N Engl J Med 27(346):2025-2032
50. Martino S, Cauley JA, Barrett-Connor E et al. (2004a) Continuing outcomes relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 96(23):1751-1761
51. Martino S, Powles T, Cauley JA et al. (2004b) Effect of raloxifene on incidence of invasive breast cancer in postmenopausal women stratified by baseline serum estradiol: results of the Continuing Outcomes Relevant to Evista (CORE) trial. San Antonio Breast Cancer Symposium
52. Martino S, Disch D, Dowsett S, Mershon J (2005a) Effect of raloxifene on invasive breast cancer incidence in postmenopausal women stratified by age (< 65 and > 65 years) Abstract: ASCO Annual Meeting
53. Martino S, Disch D, Dowsett S, Mershon J (2005b) Raloxifene and Breast Cancer Risk Reduction based on Breast Cancer Family History. Abstract. ASCO, San Francisco
54. McPherson K, Steel CM, Dixon JM (2000) ABC of breast cancer: Epidemiology, risk factors and genetics. Br Med J 321:624-628
55. McTiernan A, Rajan KB, Tworoger S et al. (2003) Adiposity and sex hormones in post menopausal breast cancer survivors. J Clin Oncol 21:1961-1966
56. McTiernan A, Rajan KB, Ulrich CM et al. (2004) Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Res 64:29232928
57. Mosca L, Barrett-Connor E, Wenger NK et al. (2001) Design and methods of the Raloxifene Use for the Heart (RUTH) study. Am J Cardiol 88:392-395
58. Kikuchi Y, Hirata J, Kita T, Imaizumi E et al. (1997) SEER cancer statistics review. National Cancer Institute Bethesda, MD
59. Nolvadex Adjuvant Trial Organization (1983) Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer; interim analysis at four years by Nolvadex Adjuvant Trial Organization. Lancet i:257-261
60. Pike MC, Krailo MD, Henderson BE (1983) “Hormonal” risk factors, “breast tissue age” and the age incidence of breast cancer. Nature 303:767-769
61. Poulin R, Merand Y, Poirier D et al. (1989) Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells. Breast cancer Res Treat 14:65-76
62. Powles TJ, Chang J (1997) Chemoprevention of breast cancer: why is tamoxifen not the answer? Endocrine-related cancer 4:135-139
63. Powles T, Eeles R, Ashley S (1998) Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomiz,sed chemoprevention trial. Lancet 352:98-101
64. Purdie D, Cauley J, Disch D et al. (2004) Effect of raloxifene on incidence of invasive breast cancer in postmenopausal women having a history of prior hormone therapy use: results of the CORE trial Abstract. European Society of Medical Oncology (ESMO), Vienna
65. Russo J, Rivera R, Russo IH (1992) Influence of age and parity on the development of the human breast. Breast Cancer Res Treat 23:211-218
66. Russo J, Russo IH (1997) Role of differentiation in the pathogenesis and prevention of breast cancer. Endocrine-Rel Cancer 4:7-21
67. Rossouw JE, Anderson GL, Prentice RL et al. (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative
68. Santner SJ, Pauley RJ, Tait L (1997) Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. J Clin Endocrinol Metab 82:200-208
69. Santen RJ (2002) To block estrogen’s synthesis or action: That is the question. J Clin Endocrinol Metab 87(7):3007-3012
70. Santen RJ, Pinkerton J, McCartney C (2001) Clinical review 121: Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. J Clin Endocrinol Metab 86(1):16-23
71. Silverman SL, Delmas PD, Kulkarni PM (2004) Comparison off racture, cardiovascular event, and breast cancer rates at 3 years in postmenopausal women with osteoporosis. J Am Geriatr Soc 52(9):1543-1548
72. Stanczyk FZ (2002) Measurement of serum estradiol levels in postmenopausal women. J Am Med Assoc 288:450-451
73. Toniolo PG, Levitz M, Zeleniuch-Jacquotte N (1995) A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 87:190-197
74. Veronesi U, Maisonneuve P, Costa A (1998) Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352:93-97
75. Veronesi U, Maisonneuve P, Sacchini V et al. (2002a) Tamoxifen for breast cancer among hysterectomised women. Lancet 359:1122-1124
76. Veronesi U, Maisonneuve P, Rotmenz N et al. (2002b) Italian randomised trial among women with hysterectomy: tamoxifen and hormone dependent breast cancer in high- risk women. J Natl Cancer Inst 94:160-165
77. Wellings SR, Jensen HM, Marcum RG (1975) An atlas of subgross pathology of 16 human breasts with special reference to possible precancerous lesions. J Natl Cancer Inst 55:231-275
78. Wickerham DL (2003) Tamoxifen’s impact as a preventive agent in clinical practice and an update of the STAR trial. Recent Results Cancer Res 163:87-95
79. Wolman SR, Heppner GH, Wolman E (1997) New directions in breast cancer research. FASEB J 11:535-543
80. Young RL (1999) Selective estrogens and breast tissue. Am J Managed Care 5(Suppl 3):S180-S189
81. Zhang Y, Kiel DP, Kreger BE et al. (1997) Bone mass and the risk of breast cancer among postmenopausal women. N Engl J Med 336:611-617