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Primary prevention of breast cancer: state of the art in 2012
Fabienne Liebensa*, Birgit Carlya, Pino Cusumanob, Virginie Lienarta, Serge Rozenberga a ISALA Breast Unit and Prevention Center, OBGYN department, CHU Saint Pierre, Brussels, ULB-VUB. bBreast Unit, CHC Saint Joseph and CHU Sart Tilman, Liège, ULg *Corresponding author: Fabienne Liebens MD, ISALA Breast Unit and Prevention Center, CHU Saint Pierre, 290 rue Haute, 1000 Bruxelles. Received: 18.09.2012 Accepted: 14.12.2012 Published: xx.04.2013 Abstract
Breast cancer is the most frequent cancer in women and the first cause of mortality linked to malignancies. In
Belgium the mortality rate is 1 on 4 being amongst the highest across EU countries. Despite huge progress in
screening and treatment, cancer remains a plague in the developed world. As a consequence urgent efforts are
needed to foster primary prevention. All women should be encouraged to decrease alcohol consumption, to
control body weight, to exercise, to avoid uncontrolled hormone treatments and to follow healthy lifestyle
thereby reducing cardiovascular risk and diabetes. They should also be informed on the benefits of long lasting
breastfeeding and early pregnancy. More accurate primary prevention allows defining for each woman her
personal risk profile. Indeed undisputed progress has been made nowadays in identifying properly high risk
women likely to benefit from tailored preventive intervention.

Keywords: breast cancer, risk factors, primary prevention
P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. Organisation (WHO) defined primary prevention as "all activities designed to Cancer is a frequent disease reduce the instances of an illness in a affecting one man out of three and one population and thus to reduce, as far as woman out of four before age 75 (1). For possible, the risk of new cases appearing". the year 2008, 59.996 new malignancies of According to the European expert group any type have been diagnosed in Belgium. for cancer prevention, screening is a Breast cancer (BC) is the one most valuable method to limit cancer but as much as possible primary prevention representing more than one third of all should be preferred (4). One also female cancers. About 9 600 women are acknowledges that prevention strategies hit annually, meaning another Belgian can only be successful if addressing health woman every hour (2). The mean age of issues considered being at high risk by the diagnosis is 61 years. However 25% will general population. Furthermore validated occur before age 50. This disease risk factors should have been identified represents the first cause of cancer fatalities in our female population. In 2008, prerequisites apply to BC. 2 329 deaths were recorded meaning that A limited proportion of BC (5- one out of four women still dies from BC. 10%) are linked to genetic predisposition These unfortunate figures for Belgium requiring specific diagnostic approaches, correspond to an annual age standardized preventive strategies and follow up incidence rate of 143.6 per 100 000 women measures. Except this rare situation, the in contrast to the European average causes favoring BC are multi-factorial. fluctuating far lower, closer to 106 (2). Nevertheless recent advances suggest that Nonetheless in all developed countries the a tailored risk pattern should be defined for number of new cases increases by 1-2% annually. In 20 years time (1984-2003) the parameters are quantifiable today and one incidence has levelled off in some has to recognize that some of these can be countries like the United Kingdom substantially reduced. reaching 51% (3). BC is also a disease affecting man: in Belgium about 85 cases RISK FACTORS LINKED WITH BC
are diagnosed each year. Despite important progress in NON MODIFIABLE FACTORS screening and treatment, BC remains an epidemiological plague in developed The incidence of BC varies with age. Incidences are usually lower in burden and the financial cost linked to the women below age 40. Figures increase treatment of overt disease, important thereafter and reach their highest values efforts are urgently needed in the field of and plateau after 70. A family history primary prevention. The World Health influences the level of risk depending on

P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. the degree of family relationship with the without atypia, ductal or lobular atypical sick parent(s) (mother, sister, daughter), hyperplasia and in situ cancer. Ductal or their age at occurrence of the disease and lobular atypical hyperplasia lesions are their number (see Table 1). Between 5 and 10% of BC occur in a genetic context and performed for diagnostic purposes. Their are transmitted on the autosomal dominant frequency has increased in the last decade mode. Namely two different major genes (6). A personal history of BC also have been identified; BRCA1 and BCRA2 increases the risk to develop a second (localized respectively on chromosome 17 cancer in the other breast. Women who and 13). They account for the majority of underwent radiation therapy involving the hereditary cancer forms. Other genes their breast(s) before the age of 30 are also also play a role but at a lesser extent at higher risk. Such situation mostly (BCRA3, p53, PTEN, ATM). In families concerns young women irradiated on the displaying the BCRA1 gene the lifetime chest for Hodgkin disease. risk of developing BC before age 70 varies between 56 and 87%. For ovarian cancer FACTORS LINKED TO REPRODUC- the risk ranges between 16 and 60%. A TIVE LIFE AND HORMONE USE biopsy finding of an „intra-epithelial neoplasia‟ (IEN) increases the risk of BC. Several factors will increase the Such entities include a number of risk of BC: early menarche, (relative risk mammary proliferations like hyperplasia RR: 1.3; menarche < 12 versus >15 years); Table 1. Non modifiable risk factors of Breast Cancer (BC)
P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. no or late childbearing (RR: 1.7-1.9; and differentiation. For instance, in nulliparity or first parity above 30 versus overweight or obese individuals, an first parity below 20); late menopause (RR: increase of several endogenous hormones, 1.2-1.5; menopause above 55 versus before growth factors and cytokines has been described. The excess of fat tissue combining estrogens and progesterone increases insulin resistance. The resulting chronic hyperinsulinism facilitates IGF-1 Nevertheless the impact of these factors on production inducing cell proliferation. On BC risk remains low. Inversely long lasting the other hand obesity also induces a breastfeeding is protective factor chronic inflammatory state via increased (decreased risk of 4, 3% per feeding year) blood levels of pro-inflammatory factors facilitating cell proliferation. These pro- MODIFIABLE FACTORS interleukin 6 (IL-6), C-reactive protein (CRP) and leptin. Obesity also induces research in cancer (IARC) evaluates that increased blood levels of estrogens 25% of BC are due to overweight and resulting from the aromatization of sedentary lifestyle (8). A number of androgens in fat tissues. The current global epidemiological surveys indicate that trends towards a dramatic increase in women exercising 3-4 hours weekly overweight and obesity seem to parallel a decrease their risk by 30-40% compared to significant decrease in physical activity in their non-active counterpart. Overweight the overall population. Such behaviors will and obese women display an increased risk after menopause; this increase can be as incidence (9). For women already suffering high as 250%, being directly correlated to from BC one should stress that their way the weight excess. Alcohol consumption of life could influence their healing. A equal or higher than 2 daily glasses also study exploring the contribution of several increases the risk both before and after modifiable risk factors - excluding those linked to reproductive life - demonstrates definitively established, some studies that 21% of BC mortality worldwide can indicate that diet (rich in animal fat and be attributed to alcohol consumption, carbohydrates but low in fruit, vegetables overweight and lack of physical activity. In and fibers) could also play a role as a risk addition, the contribution of modifiable factors to BC risk in unaffected women is Several biological mechanisms are highest in high-income countries (27%) and the most significant factor is between modifiable risk factors and BC. overweight/obesity. These are mostly mechanisms interfering intermediate-income with carcinogenesis via cell proliferation proportion of BC linked to these risk P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. factors decreases to 18% and exercise is estrogens and several in vitro studies are the one contributing most (10%) (11). currently conducted. Such products are Finally breast density has been recently called "endocrine disruptors". Examples recognized as one of the strongest independent risk factor of BC apart from age and genetic mutations (12). Breast density (BD) is that proportion of breast polychlorobiphenyls occupied by radiological dense tissue released during incineration or burning of reflecting breast tissue composition. Dense coal and petrol, bisphenol A (BPA) used in areas represent fibro glandular, when non plastic and resins and also parabens dense areas correspond to fatty tissue. preservatives used in cosmetics and Although the mechanisms by which BD deodorants (14). In the short term it will be affects BC risk are not well understood, an impossible to determine with certainty estimated 16% of all BC have been linked which role these agents play effectively. to breast densities higher than 50%. This implies that among all known BC risk MODELS ESTIMATING THE RISK
factors BD has the greatest population OF BREAST CANCER
attributable fraction. Unlike most other risk factors for BC, BD can be modified by In recent years important progress hormonal agents, suggesting that it may be has been made in identifying women likely a biomarker for preventive interventions in to benefit from primary preventive high risk women (13). interventions and/or from tailored or personalized screening approaches. Several BREAST CANCER AND ENVIRON- models estimating the risk have been proposed but none considers all possible contributing factors. Existing models do As a concept the environment not allow predicting with 100% certainty which woman will or will not develop BC. biological agents one person will be Moreover none allows finding out which exposed to during life. Pesticides, X-rays, woman will benefit from drug prevention. electromagnetic fields, cosmetics, cleaning Nevertheless such tools represent very agents… The list is long of threatening valuable means to establish thresholds agents having a possible link with cancer. above which preventive therapies can be Nowadays research is facing in this respect discussed. Most used models are those more questions than answers. Indeed any developed by Gail, Tyrer- Cuzick, Claus, BCRApro, and Cough (15). Some of these models make it possible to determine the challenging to establish. A number of probability of carrying a BRCA1-2 genetic chemicals are being investigated since their mutation. This may be helpful before biological properties mimic those of advising genetic testing. Several studies P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. are currently validating the integration of prevention for unprotected medicinal BD measurement in the risk appraisal. products already available as generic High risk women are those running a risk between 20-25% or higher to develop BC during life time or showing a TAMOXIFEN (TABLE 2) risk between 4-8% at 10 years. One should remember that the overall risk for any Tamoxifen is a selective estrogen woman during her whole life ranges receptor modulator (SERM). In the adjuvant setting, patients with hormone sensitive BC treated with tamoxifen show PREVENTIVE MEDICATIONS
a 50% risk reduction of contralateral BC. This finding has led to use tamoxifen for Based on solid scientific evidence, primay prevention in high risk women. three drugs have demonstrated an effect in Based on four powered double blind preventing BC in high risk women. These randomized placebo controlled studies, drugs are tamoxifen, raloxifene and tamoxifen (20 mg) given during 5 years exemestane. Preliminary investigations has decreased the risk of hormonal suggest a possible similar effect for receptor positive BC by 43%. This drug lasofoxifen and arzoxifen. Promising does not prevent the occurrence of malignancies. Tamoxifen also protects against osteoporosis but increases the risk Molecules like aspirin or other non steroid of phlebitis and pulmonary embolism (RR anti-inflammatory agents, anti COX-2, 1.9 : CI 1.4-2.6), cerebro-vascular bleeding retinoids and several food supplements (RR : 1.59) and endometrial cancer (RR : show limited effect and are in their early 2.4: CI 1.5-4.0). Updates of these studies development phase (15). have been recently published and confirm reimbursed by our social security system but only for osteoporosis and cardio- reduction of 38% compared with placebo vascular diseases. Such possibility is after 6-10 years of surveillance). Moreover currently not foreseen for BC. In the US, side-effects decrease after stopping the FDA has granted a preventive indication therapy (15). One can define cohorts of for tamoxifen and raloxifene. In contrast, women in which the advantage of drug in Europe such preventive indication has prevention will outweigh the risk of drug not been agreed. It seems very unlikely (thrombo-embolism, that the current situation will evolve. Big cancer). Such women are those displaying Pharma does not see any financial atypical hyperplasia or in situ malignancies advantage in extending the indication to and particularly if they are premenopausal.

P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. Table 2. Summary of the main BC prevention studies

For postmenopausal women the benefit is
effect, low incidence of thrombo-embolic highest if the risk of endometrial cancer is events) suggests that it could represent the discarded (e.g women having undergone first choice for postmenopausal high risk RALOXIFENE (TABLE 2) EXEMESTANE (TABLE 2) Exemestane belongs to the groups investigated in the preventive setting in 3 of aromatase inhibitors, the enzyme studies (Table 2). In two trials the metabolizing androgens in estrogens in medication was tested in a group of women several target organs including breast. In at high risk of developing diseases other adjuvant setting for women suffering from than cancer (cardio-vascular disease or BC, this therapeutic class seems more osteoporosis). In the third study, raloxifene effective than tamoxifen in reducing the and tamoxifen were compared head to risk of developing contralateral BC (15). head in women at high risk of BC. The risk These aromatase inhibitors do not cause decreased by 23% and by 38% in the the gynaecologic or thrombo-embolic raloxifene group and the tamoxifen group effects seen with tamoxifen. However they respectively. This difference was not increase the risk of bone fracture, statistically significant. The lowest toxicity arthralgia and possibly cardio-vascular profile of raloxifene (no endometrial events. Exemestane has recently shown its P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. preventive efficacy in post menopausal women attending our Breast Unit (Liebens women included in a large double blind F et al. Abstract 129, 8th European Breast randomized placebo controlled study. A Cancer Conference 2012). Most of these 65% reduction of hormone receptor women belong to the high income positive BC was demonstrated after a median follow up of 3 years (RR: 0.35; recruitment bias, their knowledge of their 95% CI 0.18-0.70). Another aromatase risk is quite limited and not sufficient to inhibitor (anastrazole) is currently under allow making decisions likely to modify investigation and the recruitment phase of their own risk profile. The majority of the study (IBIS 2) is closed. women questioned do not appraise correctly the risk factors they could act on WOMEN'S VIEWS AND EXPECTA-
like alcohol consumption, physical activity or weight control. Moreover two third imply stress as one of the most important A modern and efficacious approach risk factor when no study has ever shown of BC primary prevention supposes active any direct causal link with BC. Adequacy participation of women. Their behavior of knowledge could well be linked to age. depends on their understanding of the risk However appropriateness of understanding they run. Indeed the way they perceived differs quite widely depending on the risk the risk and their understanding of the factor considered. For instance women danger of dying from cancer seems far aged between 40-59 years are better aware from reality. Numerous studies conducted of the importance exercise than women in Europe and the US have revealed that less than 40 or more than 60. Not about 9 out of 10 women do not evaluate surprisingly women with a family history correctly their risk of developing BC. The are better informed of risk factors on which majority have very limited knowledge they could act. The higher the education concerning the risk factors they are level, the higher the overall knowledge. eventually exposed to (16). As of today we Curiously patients referred by a GP do not do not have data concerning the knowledge score better for any question whatever the and attitudes of the Belgian female risk factor considered. More worrying 85% population concerning primary prevention of women participating in the survey had of BC. However such information is no idea at all of risk factors linked to BC. paramount before deciding prevention Concerning their willingness to take strategies since some modifiable factors medications or undergo surgery in high risk situations, these women would simply rely on the advice of their GP. One has to replacement therapy or poor weight know that as of today the medical control). Moreover specific drug therapies education does not offer any targeted could be offered to high risk women. A information on how the risk of BC should recent survey was conducted in 1000 be screened and managed in high risk P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. populations. Most women would be will benefit from any primary preventive interested to participate in research approach or might not be willing to follow programs aimed at identifying new it. However doctors have nowadays preventive agents if they would be offered effective tools in hands. The earlier the any potential personal benefit. On the other intervention in the causal cascade the hand half of them (47%) would participate longer the effects in reducing the risk and anyway if the benefit would serve other eventually decreasing the occurrence of women. Unfortunately a single clinical BC. In parallel huge efforts are needed to trial in the field of primary prevention is inform women on the modifiable risk currently running in Belgium. On top this factors, to educate the medical profession study is limited to menopausal women. In in evaluating individual risk, to foster contrast several dozens of clinical trials clinical research in the field of primary sponsored by industry are being conducted prevention. Public health efforts are also but only aim at establishing new costly required to develop consistent preventive therapies to treat, not to prevent BC. Our actions in parallel to mass screening. survey confirms the lack of knowledge within a high income Belgian population In 2012 breast cancer is the leading concerning their risk of developing BC. In cause of female mortality due to cancer this context it seems unlikely that these and one of the most feared diagnoses by women can make adequate choices and women in this country. Today we master take appropriate decisions in order to better knowledge and have in hands improve their risk profile. effective tools to reduce a risk endangering half of the population. Expectation would CONCLUSION
suffer no excuse. What are we waiting for? In order to fight effectively BC, the role of prevention needs first to be recognized and acknowledged. Prevention seems a better alternative than therapy of overt disease. Nowadays major progress has been made and allows identifying more accurately those women at highest risk who could benefit most from preventive interventions. It is of crucial importance to establish the level of risk modifiable by surgery, drug therapy, behavioral changes and possibly tailored screening. Primary prevention strategies should be evaluated on an individual basis taking into account the general health state. Not all women P Belg Roy Acad Med Vol. 2:.100-109 F. Liebens et al. LIST OF REFERENCES

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