Epidemiology of breast cancer: an environmental disease?

APMIS 109: 321-32,2001

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Copyright 0 APMIS 2001

APUUS ISSN 0903-4641

Epidemiology of breast cancer: an environmental disease? Review article

ANNIE J. SASCO

Unit of Epidemiology for Cancer Prevention, International Agency for Research on Cancer, and Institut National de la Santk et de la Recherche Midicale, Lyon, France

Sasco AJ. Epidemiology of breast cancer: an environmental disease? Review article. APMIS 2001;

Breast cancer is the leading cancer site in women, both in the developed and the developing world. Incidence rates are increasing in many countries, although, in some, mortality may be stable or slightly decreasing. Geographical differences exist, with high rates of disease in North America, North Europe and Oceania, intermediate rates in South and Central America as well as South and East Europe, and low rates in Africa and Asia. Most of the literature reports that genetic inherited factors account for less than 5% of cases, although some authors advance higher figures, up to about 10%. Risk factors for breast cancer are related to the reproductive life of women: early menarche, nulliparity or late age at first birth, late menopause, diet and physical exercise, as well as hormonal factors, be they endogenous (high levels of free or not bound to SHBG estrogens) or exogenous (long-term use of oral contraceptives or menopausal hormone replacement). The present review does not aim to be exhaustive and fully comprehensive, or to present in detail domains currently well known and accepted by all. On the contrary, it modestly wishes to highlight potentially controversial conditions which could in the future be recognized as new risk factors.

Key words: Breast cancer; environment; epidemiology; hormones.

Annie J. Sasco, Unit of Epidemiology for Cancer Prevention, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France. e-mail: [email protected]

109:321-32.

Breast cancer, which for centuries has been described by clinicians as the classical cancer of women, is the present-day concern of women all over the world, first as an epidemic which plagues them, but also as a possible pathological marker of general exposures to hormones and more generally to endocrine disrupters, likely to have an impact on the human species as well as on wildlife and our planet.

In this paper, we first review the descriptive epidemiology of breast cancer, evaluating the burden of disease and death for women in the world, looking at current and past figures of absolute numbers and rates of the disease, con-

Received March 19, 2001. Accepted March 29, 2001.

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trasting mortality and incidence trends. Then we review etiological epidemiology7 searching for risk and preventive factors, briefly distin- guishing direct factors from what would better be viewed as susceptibility states, and finally we propose a synthesis corresponding to the crucial need we are facing at the dawn of the XXIst century to explain the evolution of this disease and to search for new clues as to its etiology, among which the environment clearly stands.

DESCRIPTIVE EPIDEMIOLOGY

As its name indicates, the objectives of descriptive epidemiology are to quantify the burden of disease and death, to describe its geography and

EPIDEMIOLOGY OF BREAST CANCER

to evaluate trends over time, either measured in secular periods or for individuals in terms of age. As disease experience may be modified by treatment, care has to be taken to distinguish mortality from incidence.

World breast cancer burden The most recently published estimates for

mortality refer to the year 1999 with 467 000 deaths attributed to breast cancer for women in the world, representing 1.7% of all female deaths (1). In terms of absolute numbers, the figure is now higher for countries with a low or middle income, where 252 000 such deaths occurred, as compared to high income countries with 160000 deaths. Yet, the percentage of deaths due to breast cancer in women is still higher in the latter countries, at 2.0%, than in the former, at 0.5% (2).

In terms of incidence, estimates for 1997 amount to 895 000 new breast cancer cases worldwide, with 505 000 in the developed and 390 000 in the developing world. Therefore, breast cancer now ranks first among cancers in

women in the whole world and not only in the Western world (3).

Geographical epidemiology According to the cancer incidence rates pub-

lished by population-based cancer registries, zones with a high risk of breast cancer can clearly be distinguished, with world age-standardized estimated national incidence rates greater than 80 new cases per 100 000 women- years. They correspond to North America (USA and Canada), Australia, New Zealand and some countries in Europe, but also selected countries elsewhere, such as for example Uruguay in South America (4). Examining ac- tual data from population-based cancer registries rather than national estimates, among the 30 highest rates can be counted 20 registries from North America, one from South America (Montevideo), 2 from Israel and 5 from Eur- ope. The only one from Africa is for Euro- peans in Zimbabwe (Harare), and from Oceania the registry of Hawaii for Hawaiians (Fig. 1). In contrast, among the 30 lowest

Zimbabwe, Harare:Europ. US, LA:Non Hisp. White US, SENon Hkp. Whlte

US, Hawaii : White US, Connecticut : White

Uruguay, Montevideo us. Seattle

us. DetroitWhite US, SEER:Whte

Israel: Jews born in Israel us, Atlantll:White

Israd:Jerm born in Am. w Eur. US, New 0lleans:White

US, New Mer:Non Hisp. White US, CenL Calif.:Non HIsp. Whlte

France, Wre us, Iowa

US, New 0rieans:White us, c0nnectiCUt:Biack

Canada, Britlsh Colombia US, Hawaii:Hawalian

us, sF:Black UK, Oxford

us, LABiack US, Detroit:aiack

France, Haut-Rhin Franca, Wmult

Malta The Netherbnds US, SEER:Biack

I I

0 10 20 30 40 50 60 70 80 90 100 110 120 130

New cases per 100 OOO woman-years

Fig. 1. Population-based cancer registries with the 30 highest world-age-standardized incidence rates of female breast cancer.

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Peru, Trljiiio

France, la R6union *N8 =

Costa Rica US, New Mexico:Amer. lndbn

India, Bombay Japsn, Nw=M

Ecuador, Quito China, ShM@ Poland, Kielce China, Tianjin Japan, Osaka India, Madm

Japan, Yamagata US, MKoraan

lamaimon Jaws India, Bangalore

Uganda, Kvadondo Zimbabwe, Haram:Afrkw

Japan. %a India, TdMndNm

Vlet Nam, Hanoi India. Karunagappaily malland, Chlang Mai

China, Wong Mali, Bamako A i m S e ( H

India, Barshi, Paranda & Bhum Thailand, Khon Kam

Kom, K q w h a

I

0 10 20 30 40 50 60 70 80 90 100 110 120 130 New cases per 100 OOO woman-years

Fig. 2. Population-based cancer registries with the 30 lowest world-age-standardized incidence rates of female breast cancer.

rates, 5 are from Africa, 18 from Asia and Is- rael, 3 from South America, 2 from Eastern Europe and 2 from the United States of Amer- ica (American Indians in New Mexico and Koreans in Los Angeles, California) (Fig. 2) (5).

Potential explanations for these large geographical differences may either be genetics or lifestyle and environment. In the past, the only way to distinguish these influences was to study migrant populations. In this regard, the study of Chinese migrating from the People’s Republic of China to Hong-Kong and then the United States of America showed that it took more than one generation and often more than two to progressively move towards the high rates of breast cancer of Caucasian American women compared to the very low rates of Chinese women in China (6).

Temporal epidemiology Time in epidemiology may either be debed

as calendar period or for a given individual as age.

Over time, the world breast cancer burden has

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increased steadily with an almost doubling of the annual number of estimated new cases over a 20-year span, the increase being seen both in the developed as well as the developing countries (Fig. 3) (7-9). Even when considering, as is more appropriate, rates rather than absolute figures, and thereby correcting for ageing of the population as well as differences in age struc- tures across countries, most cancer registries of the world still exhibit increases in breast cancer incidence. In the period 1975-1990, the largest increases, greater than 1% and sometimes 5% per year, are exhibited by registries previously having low rates of disease, mostly in Asia and Africa, as well as in some parts of Europe. In contrast, the smallest increases, in general under 0.5% per year, are usually seen in places previously having high rates, mostly in North America and Europe. The picture is particularly clear when we look at the youngest age groups, below 45 years of age (5, 10). Even in countries like the USA, for the period 1975-1994, the average annual change for white women was 1.4% and for black women 1.8% (1 1).

For a given individual, it can be stated that


E 1000000 1 - B 'Developed' world

6

V m 'Developing' world

= m

2 500000 0 s

.- 4 d - 5

Z %

f " l . v

! - 5

0 0 - c

1980 1985 1990 1991 Year

Fig. 3. World breast cancer burden over time.

the major risk factor of breast cancer, and cancer in general, is age. The vast majority of breast cancers appear among women older than 50 years of age. Yet such a distinction on the basis of age is crude, as for breast cancer ageing is not the sole intervening event. It is also necessary to consider what is most relevant from a physiopa- thological point of view, namely menopausal status. Particularly worrying are the increases seen among women under 45 years of age (5, 10).

A note on mortality versus incidence rates Most of what has been described above re-

lates to incidence rates. If we look at mortality rates instead, the picture for selected countries is now slightly less gloomy, with falling rates for example in the United Kingdom and in the USA (12). Even in countries such as France, where large increases in incidence rates are still seen, mortality rates have remained almost stable for the last 20 years (1 3). The discrepancy between mortality and incidence comes from better treatment, earlier diagnosis and screen- ing. For example, the impact is clearly seen in changes observed in survival in Europe (14, 15). This, of course, represents good news for women, but from an etiological as well as a public health point of view, the most relevant information derives from increases in incidence rates.

ETIOLOGICAL EPIDEMIOLOGY

The search for risk and, more recently, preventive factors for breast cancer is the raison dztre of epidemiological research, especially when the aim is prevention. The so-called recognized risk

factors belong to several domains: genetics, reproductive and hormonal life, diet, physical exercise, and a few selected specific exposures. Yet, much is still unknown and the proportion of breast cancers that cannot be readily explained by the risk factors just listed most probably ex- ceeds the ones that can. The present review does not aim to be exhaustive and fully comprehensive, or to present in detail domains currently well known and accepted by all. On the contrary, it modestly wishes to highlight potentially controversial conditions which could in the future be recognized as new risk factors. There- fore, the space devoted to each group of items is not proportional to their quantitative import- ance in terms of relative or attributable risk, but rather to our current ignorance and the questions that must be asked if we want to progress.

Genetics and family history The most notable discoveries of the last 20

years regarding the etiology of breast cancer concern genetics. The roles of BRCAl and BRCA2 in the etiology of the disease are now much better understood and quantified. These gene mutations are only responsible for a tiny fraction of all breast cancers, much less than 10% overall, but they do confer on the women affected a considerable life-time risk, estimated most often at between 50 and 80% compared to the general population with a risk of under 10% (16, 17). Other mutations of greater public health, as compared to clinical, interest are likely to be found in the coming years, possibly through elucidation of the etiological roles of other genetic conditions, in particular heterozy- gotic states of more common conditions, such as ataxia telangiectasia. Well before the genetics

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of breast cancer was known, familial risk was already recognized, with many syndromes having been described, of breast cancers alone, breast and ovarian cancers associated, or also other malignancies (1 8).

Reproductive life For almost half a century now and even

longer if we refer to the pioneering work of Lane-Claypon (19), events of reproductive life have repeatedly been considered as risk factors for breast cancer in women. Cancer of the breast occurs more frequently among women who had an early menarche, remain nulliparous, or even if parous have few children with a late age at first and possibly subsequent births. In- fertility per se appears as a risk factor for breast cancer, as possibly does lack of breastfeeding. Finally, a late age at menopause increases the risk of breast cancer.

The first modern epidemiological studies on this topic were mostly done in the 1970s with the help of hormone determinations. Recent studies in general still confirm the effects of age at menarche or pregnancy history (20). The uni- fying hypothesis behind the effects on breast cancer risk of reproductive events relates to hormonal influences, in particular estrogens. Their role is crucial not only in cancer initiation and promotion (21), but could also possibly be used for prevention (22). Hormones and reproductive life closely interact not only in the occurrence of disease but also in the development of the mammary gland and the susceptibility to car- cinogenesis (23).

Lifestyle The most important element to consider

under this heading is diet. High intake of fruits and vegetables is probably associated with a slightly reduced risk of breast cancer. In contrast, there is convincing evidence that rapid growth and greater adult height, reflecting in part the total food intake in early years, are associated with an increased risk (24). Similarly, a high body mass, also linked to a high total caloric intake, or at least an intake not counter- balanced by caloric expenditure, is a risk factor for postmenopausal breast cancer. Total fat as well as saturated animal fat possibly increases the risk (25). Similar conclusions have been reached by the UK Department of Health (26).

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Of particular interest, also in the context of what follows, is an evaluation of the impact of meat consumption on cancer occurrence. Meat consumption is possibly associated with an increased risk of breast cancer. This statement is based on the fact that three out of eight prospective studies reported an increased risk of breast cancer with higher meat intake. A meta- analysis of seven cohort and case-control studies found a relative risk of 1.5, later con- b m e d in several other case-control studies not included in this combined analysis. Red meat was more frequently cited as a risk factor and, in fact, diets rich in poultry possibly had no links with breast cancer risk (25). A further review published one year later shows even clearer trends. Out of 20 case-control studies carried out in countries with different meat consumption levels, 17 observed higher risks associated with higher total meat, red meat or processed meat intake, although only 11 studies were statistically significant. One study found a nonstat- istically significant reduced risk associated with higher meat consumption, one found no association, and all others had increased relative risks ranging from 1.1 to 3.5. Among 10 cohort studies, one found no association and the other 9 had estimates above one but statistically significant in only 5 . Values of relative risks ranged from 1.2 to 2.4. In four cohort studies, a grad- ing effect associated with the number of meat servings per week was described. The conclusion of that review was that there is considerable and consistent evidence that higher meat consumption, particularly red or fried/browned meat, is associated with a higher risk of breast cancer (24). Although the role of N-acetyltrans- ferase genetic polymorphisms was considered to mediate the risk of breast cancer in relation to meat consumption, this was not supported by the results of a traditional case-control study (27) nor of a nested case-control study (28).

Alcohol consumption has been shown to be associated with breast cancer risk. Based on a 1997 review, 11 cohort and 36 case-control studies have examined this issue. Evidence shows an increased risk of breast cancer for consumption of alcohol and alcoholic drinks (29). In a meta-analysis of 38 studies, a dose- response was found related to number of drinks per day, including consumption in the low range (30).


In contrast with alcohol, the evidence on smoking and breast cancer remains somewhat inconclusive. For a long time, tobacco was viewed as an anti-estrogen and thereby a protective factor against breast cancer (31). Smokers on average reach menopause some 2 years earlier than nonsmokers and early menopause is associated with reduced risk of breast cancer. More recent studies, in contrast, have incriminated passive smoking as a risk factor for breast cancer (32) and thereby rekindled interest in the subject of smoking and breast cancer. Smoking tobacco may indeed turn out to be a risk factor, but the effect will be dependent on N-acetyl transferase 2 genetic polymorphisms (33). De- spite studies in genetically predisposed women which found a reduced risk of breast cancer among smokers (34), methodological limi- tations precluding the distinction of factors af- fecting survival rather than occurrence should make us cautious with regard to reaching de- finitive conclusions.

Physical activity has been the subject of a thorough review with respect to its effect on breast cancer. Out of a total of 21 studies then available, 15 suggested a reduced risk of breast cancer associated with physical activity, with a greater effect for women who are slim, parous and premenopausal. Four studies did not find an association and two found an increased risk (35). The relationship seems clearer for occupational activity than for leisure-time or nonoc- cupational activity (36). A recent study did not find that specific periods had a greater impact on recreational physical activity (37), whereas one would have been led to suspect a preferen- tial effect of peripubertal activity linked to breast susceptibility (23).

Exposure to specijic agents: physical, chemical, biological and others

Only limited data are available on specific exposures in relation to breast cancer. The best known and studied refer to radiation. Long- term follow-up of women exposed to the Hiro- shima or Nagasaki nuclear explosions indicates an increased risk of breast cancer, in particular for women having been exposed around puberty, at the time of breast development (38). Similarly, exposure as a result of treatment and surveillance of tuberculosis, is associated with risk (39). More recently, exposure to electro-

magnetic fields has been evaluated. Occu- pational cancer mortality for cancers of the breast, as well as other hormone-related cancers in women, has been found elevated in women employed in the telephone industry (40). Risks may be higher in premenopausal rather than postmenopausal women (41). Even residential exposure has been incriminated in a Swedish study, with very high risk for premenopausal, estrogen-positive tumors (42).

Specific exposures to chemicals have been evaluated in studies of mortality. Suggestive as- sociations were found for styrene, several or- ganic solvents, such as methylene chloride, car- bon tetrachloride, formaldehyde, as well as for several metals, metal oxides and acid mists (43). These data contrast somewhat with the long held view that risk of breast cancer was mostly a social class phenomenon, with higher risk for executives, administrative and clerical workers (44). Systematic reviews on occupation and breast cancer are still few (45) and much work remains to be done. This also applies to as yet to be conducted studies to evaluate the potential impact of unemployment or other sources of stress.

Based on animal experience, a viral hypothesis has been put forward. In mice, a retrovirus, the murine mammary tumor virus, is a recognized cause of mammary tumors, transmitted with milk from mother to daughters. Exposure in humans is known to occur, yet no evaluation of risk has ever been carried out (46). Another viral candidate is the Epstein-Barr virus, although data from the USA are not particularly supportive (47). This would be better studied in populations where inflammatory breast cancer is frequent, for example in North Africa. Other potential viral candidates remain to be investi- gated.

Hormones and endocrine disrupters Since the 1960s, numerous studies have been

conducted on the influence of hormones on breast cancer risk. Estrogens, female hormones par excellence, have been measured in various body fluids, urine, blood, and more recently breast tissue, either tumorous or in the vicinity of tumors. Estrogens in the body exist in several forms, estradiol, estrone and estriol being the three main ones. Differences in levels of these hormones exist from country to country and

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have been linked to different risks of breast cancer. Women with high levels of estrogens, in particular free estrogens, not linked to the sex-hormone-binding globulin, have long been recognized as being at a high risk of cancer development (48). This demonstrates that even in the absence of exogenous hormones, risk of cancer is influenced by the endogenous hormonal milieu. In fact, future cancer risk is in part also determined by conditions of exposure in utero. The preventive effect of gravidic toxe- mia is recognized (49) and since the 1950s studies have incriminated high birth weight as a risk factor for cancer and in particular for breast cancer (50). Similarly, a very recent study concluded that, among twins, the risk of breast cancer may be affected by the type of twinning (dizygotic versus monozygotic) and sex of the dizygotic twin (51).

Exogenous hormones have been evaluated for carcinogenicity in humans using the IARC Monographs programme, for some of them several times and most recently in 1999 (52-55).

More than 10 cohort and 50 case-control studies have assessed the relationship between use of combined oral contraceptives and risk of breast cancer. The evidence suggests a small increase in the relative risk of breast cancer especially among current and recent users, which is, however, unrelated to duration of use and type or dose of preparation, and may be partly linked to detection bias (55). Data on injectable progestogen-only contraceptives come from two case-control studies and a pooled analysis of original data. Relative risks vary between 1.0 and 1.3, and are not statistically significant (55).

In contrast, information on the relationship between postmenopausal estrogen therapy and risk of breast cancer is available from many epidemiological studies. A pooled analysis of the original data from 51 of these studies and a review of data from 15 cohort and 23 case-control studies showed that in the majority of the studies there is a small increase in risk with longer duration of use in current and recent users (55). Separate information on the effects of use of postmenopausal estrogen-progestogen therapy was provided in only a minority of the studies on the risk of breast cancer. The results of nine cohort and five case-control studies that did include such information and the findings of a pooled analysis of the original data from

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these and other studies indicate that the increased relative risk observed with long-term use of postmenopausal estrogen-progestogen therapy is not materially different from that for long-term use of estrogens alone (55) .

If evidence for other cancer sites, in addition to the breast is also considered, as well as evidence from experimental animals, several hormonal compounds belong to categories of carcinogens for humans. In group 1 (carcinogenic to humans), one finds diethylstilbestrol(53, 54), postmenopausal estrogen therapy ( 5 9 , nonster- oidal estrogens (53, 54), steroidal estrogens (53, 54), combined oral contraceptives ( 5 9 , sequen- tial oral contraceptives (53, 54) and tamoxifen (56). In group 2A (probably carcinogenic to humans), one finds androgenic anabolic steroids (54). In group 2B (possibly carcinogenic to humans) , we have medr ox yproges terone acetate (53, 54), progestins (53, 54), postmenopausal estrogen-progestogen therapy (55) , progestin - only oral contraceptives (55). Finally, in group 3 (not classifiable as to carcinogenicity to humans), one finds clomiphene citrate (53, 54), estradiol mustard (52), toremifene (56) and dro- loxifene (56).

Some data implicate a polymorphism in catechol-o-methyl transferase (COMT) in breast cancer risk. Methylation by COMT is an important pathway for inactivation of catechol estrogens. The allele encoding low-activity COMT may be a contributor in particular to postmenopausal breast cancer (57), although this was not confirmed by another study (58). In fact, menopausal status, as well as weight, may modify this association (59). Even physical exercise and training have an impact on 4-hydroxy catechol estrogen metabolism (60).

The knowledge currently available on the carcinogenicity of hormones as well as on the impact in various disease risks of small variations, remaining within the physiological range, as may occur in utero or at other susceptible life periods, helps us provide answers to exceedingly difficult questions, such as for example the potential impact on human health of hormone residues in bovine meat and meat products, re- sulting from the use in beef, as growth pro- moters, of natural hormones (17p estradiol, tes- tosterone, progesterone) or synthetic compounds (zeranol, trembolone acetate, melengestrol acetate). Of course, no study is


available, nor more importantly is ever likely to be available, where two strictly identical populations are compared, one consuming meat from hormone-treated animals and the other consuming exactly the same types and quantities of similarly prepared and cooked meat but from animals not having been treated with hormones for growth-promotion purposes, the allocation between the two groups being decided by ran- domization. Therefore, we can only rely on in- direct evidence. From an etiological point of view, we can also rely on studies conducted on vegetarian populations. The overall cancer risk and, in particular, breast cancer risk is generally lower among non-meat eaters. The evidence is more marked in North America than in Europe (25, 29). Finally, better knowledge of the hormone receptors, a and p, with more accurate information on their functions would also be helpful. Genotoxic effects, independent of the hormonal receptors, have been recognized for metabolites of the parent compounds. These essentially concern catechol estrogens and corresponding quinones, in particular 4-hy- droxylated derivatives (61). An international symposium on “Estrogens as endogenous carcinogens in breast and prostate” was recently reported in Monograph 27 of the Journal of the National Cancer Institute (62). Papers demon- strating the developmental basis of breast cancer (63) are of specific relevance, as well as the carcinogenic role of oxidative metabolites of estrogens (64), the possibility of obtaining DNA adducts and mutations (65), the recognition of the huge variability in tissue-specific synthesis and oxidative metabolism (66), the role of conjugation (67) and genetic polymorphisms (68), and finally the role of estrogen-receptor-me- diated processes (69). All this points towards the possibility of the coexistence of several pathways in the development of the breast and later on breast cancer, involving both hormonal endocrine events and genotoxicity.

Over the last 10 years, there has been increasing concern regarding the potential risks linked to exposures, not only to hormones, but to arti- ficial products, mimicking hormonal activities. This has led to the concept of xenohormones, largely represented so far by xenoestrogens. The exact role they play is still unknown. Most of the epidemiological studies available so far deal with various pesticides, essentially organochlor-

ides, which remain in the environment for a long period of time and the residues of which may be found in adipose tissues of various species, including humans (70). Old studies, mostly dealing with polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE), found higher levels in cancer cases compared to controls (71), as did a nested case-control study which looked at estrogen-receptor-positive cases (72). Yet other studies were negative, in particular for specific population groups, such as Asian women in the USA (73). Three studies even found that levels of organochloride residues were lower among cases than among controls (7676). One of these studies was conducted in Mexico, a country where DDT was still in use (74). Specific products may carry a higher risk than others (77). Such could be the case for diel- drin (78), which could also play a role not only for occurrence of cancer but also for survival (79). Yet, exact quantification of the risk remains to be done on a larger scale. For the time being, many consider these links as speculative and unfounded (80) or as markers of susceptibility (81). Similarly, studies on the role of phta- lates and other contaminants in plastics remain to be done, at least in epidemiological terms.

A note on risk versus vulnerability factors The major problem when discussing effects of

exposure to low levels of hormones is that many questions remain unanswered regarding the identification of all metabolites, mechanisms of action, and knowledge of all effects. Whether hormones are true “causes” of cancer or crucial agents in the causal pathway is not known. Yet, we may wonder from the point of view of prevention how relevant this is. If one excludes radiation and inherited mutations which can easily be seen as direct carcinogens for the breast, all the other so-called risk factors regarding, in particular, reproductive life may better be considered as vulnerability factors. Having an early menarche, a late menopause, or no pregnancy will render the woman more susceptible to other potential contributing factors, such as alcohol or exogenous hormones and possibly xenoestrogens (82).

The other important aspect is that besides de- fining individual susceptibility in terms of genetic background, metabolic profile and sex, there is a crucial need to better define time win-

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dows of exposure. Vulnerability periods correspond to in utero life, as well as prepubertal period both for girls and boys. In women, per- imenopause may also be particularly relevant.

CONCLUSION

Only a small proportion of all breast cancers can currently be explained by traditional risk factors, leaving most of the recent and worldwide increases in incidence unsolved. Given the crucial role of the hormonal pathway in the occurrence and development of tumors, better knowledge of the determinants of endocrine events such as puberty and fertility is needed. Too much is still unknown and yet too little is studied with respect to the etiology of breast cancer, in particular premenopausal disease. We need to assess the impact of continuous, low- level, yet cumulative exposures over a lifetime. In the mean time, the precautionary principle (83) should, whenever possible, be enacted to prevent unnecessary exposures, notably at specific periods of vulnerability.

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DISCUSSION

Elsebeth Lynge (Copenhagen, Denmark) What is known about the interaction between genes and the environment in women known to be carriers of BRCAl or 2?

Annie Susco (Lyon, France) Colleagues at the International Agency for Research on Cancer are studying that aspect of interaction of gene and environment at present. There are other large studies looking at the populations of women carrying BRCA 1 or BRCA 2, including EORTC studies. The influence of taking exogenous oestrogens, of physical exercise and of diet in changing the risk of developing breast cancer will be assessed among these women who are starting with a very high background incidence. We do not have a comprehensive picture in a large population because many countries will need to be involved in recruiting a sufficiently large cohort for analysis. There is one controversial result concerning BRCA l women and smoking in which there was a reduced incidence of breast cancer amongst smokers in that specific population, but there are criticisms about the design of that study. The study group was limited to survivors of breast cancer and that may have introduced bias because incident cases were not used as a starting point.

Jose Russo (Philadelphia, USA) It was en- couraging to hear that you emphasise the im- portance of puberty as a susceptible window for environmental exposure. Do you recommend any interventional measures that could apply to pubertal girls in an attempt to protect them from developing breast cancer?

Annie Susco At the present time, given our

state of knowledge, we can only recommend general health promotion such as avoiding obesity and taking much physical activity. This can be achieved by consuming an adequate diet to maintain a good energy balance. Avoiding obesity will prevent early puberty except in pathological conditions, and late puberty re- duces the risk of breast cancer. In my opinion, delaying puberty in girls by drug therapy or hormonal manipulation should be avoided because we do not know the longterm consequences.

Sabine de Muinck Keizer-Schrama (Rotter- dam, The Netherlands) What is the biological explanation for the increase in breast cancer re- lating to alcohol consumption even at low levels?

Annie Sasco A dose-response effect has been seen in a meta-analysis indicating higher risk due to higher dose of alcohol (Longnecker, Cancer Causes Control 1994;5:73-82). This may be due to the impact of alcohol on the liver, and its effect on changing metabolism, which may have consequences on the hormonal pathways, perhaps by enhancing oestrogens. We also know that alcohol itself has a carcinogenic effect in humans, but usually at much higher doses than is seen for breast cancer. We often hear that low levels of alcohol are good for our health, especially in the cardiovascular system, but there is less beneficial cardiovascular effect in women than in men, and women have the added risk of breast cancer. Perhaps we should not be pro- moting even moderate amounts of alcohol in women.

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Manolis Kogevinas (Barcelona, Spain) There are a few studies comparing women with breast cancer in low incidence countries and high incidence countries, and there is a difference in the distribution of oestrogen receptor (ER) and progesterone receptor positive tumours. In the USA, there are a higher proportion of ER +ve cases. Is receptor positivity related to the aetiology?

Annie Sasco I do not know of any study which has assessed ER status world wide, and we know very little on the aetiology of breast

cancer in Africa. The incidence of breast cancer among young women is not negligible in North Africa. These women tend to have many children at an early age, which should be protective according to data from Western countries. The North African incidence may be associated with a virus such as the Epstein Barr Virus (EBV), which is in keeping with animal models of the murine mammary tumour viruses. The African tumour is more frequently an inflammatory type of breast cancer, which suggests differences from Western Countries.

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Documents

Epidemiology of breast cancer: an environmental disease?