Breast cancer: a lifetime disease?

Age-related risk factors and opportunities for prevention

Jaak Ph. Janssens, Magda Vandeloo
European Cancer Prevention Organization
Klein Hilststraat 5 – B-3500 – Hasselt – Belgium
Tel: +32 11 275734
Fax: + 32 11 283677
Janssens.ecp@skynet.be

Abstract

Almost 95 per cent of the common epithelial cancers are related to lifestyle.  Breast cancer is not different.  As a leading cause of death in women and doubling in incidence over the last 40 years, less than 10 per cent have a hereditary background.  Exposure to estrogens is the main established causal factor.  Other important determinants are early menarche, increased length/weight, obesity, lack of physical exercise, late first full-term pregnancy (FFTP), nulliparity, late age at menopause and hormonal substitution.  If it comes to prevention, recognition and management of these factors is imperative.

Adults have few possibilities to change cancer risk.  Nutrition high in animal fat, postmenopausal hormonal replacement therapy and alcohol have been frequently cited to cause a slight but significant risk increase in several well conducted studies.  These factors can be avoided but the effects are expected to be modest.  Anti-estrogens and aromatase inhibitors may also decrease risk and give a reasonable additional preventive alternative for high risk groups.  Although most epidemiological observational studies point to nutritional and hormonal factors, case-control and cohort studies do not.  Children however are largely excluded from these studies.

Attention to the lifestyle of children in relation to subsequent risk for breast cancer is a relatively recent line of research.  Breast cancer seems to originate almost entirely in childhood at the very onset of breast development when the organ is most vulnerable.  All mixtures of direct and indirect risk factors might constitute intermediaries between lifestyle, childhood milestones, estrogen exposure and breast cancer.  Of particular importance is menarche that confers a life-time influence on risk.  But is cancer prevention feasible by modulation of menarche?  We studied 1146 healthy girls between birth and the age of 13 with regular clinical evaluations and extended questionnaires.  Lifestyle and growth milestones were correlated with early puberty and menarche and subsequently compared them to established breast cancer risk determinants.  46.7 % of the girls reached their menarche during the study.  Uni- and multivariate analyses, investigating the most important variables of the period from birth to menarche, show clear evidence that lifestyle factors, including nutrition, do have an effect on both breast development and menarche.  Childhood obesity, lack of physical activity, high glycemic carbohydrate consumption, parental factors, and history of mononucleosis are among the strongest determinants that influence the onset of puberty and menarche.  Consequently, impact on breast cancer risk might be expected.  Certainly when the observed determinants for menarche prove to be known breast cancer risk factors as well.

When breast cancer originates during childhood and the disease becomes apparent in middle-aged women, there appears a large window of opportunity to conquer the disease by adequate prevention strategies.  The adoption of intermediary risk biomarkers is imperative to select high risk groups and to guide preventive strategies before the disease becomes overt and in a period where cancer risk can still be modified.  The search for these factors and their validation is becoming another priority.

Conclusion:

Estrogen exposure and other mutagenic agents can have their highest metabolic impact during early breast development and might be considered as susceptibility initiating factors.  These factors, together with age at onset of puberty and menarche, are manageable i.e. can be modified by changing lifestyle in children.  Later in life, breast cancer causation is less proven, less important and expected to be restricted to promotion and inhibition.  Here, preventive policies based on established intermediary risk biomarkers measured before the disease becomes clinical need priority.  Altogether, breast cancer is most likely a life-time menace with various windows of opportunity for prevention and treatment.

The burden of breast cancer

Breast cancer is among the most lethal forms of cancer in the world affecting one out of 8 women in the Western Countries.  An estimated 1 million cancers will be identified yearly.  About 500 000 new and existing patients will die from the disease.  There is ample evidence that breast cancer around the world reflects similar diseases with regard to causation, biological behavior and response to treatment[1].  Previously a malady of Western countries, breast cancer is now everywhere.  Asia, Africa, Eastern Europe and Latin America have all seen their caseloads spike.  By 2020, 70 % of all breast cancer cases worldwide will be in developing countries.

The global differences in survival from breast cancer reflect closely the diagnostic opportunities of local health care systems.   In countries where the access to diagnosis are to the state of the art, survival from breast cancer is beyond 80 and even close to 90 %.   If breast cancer services are not available the number of patients detected with curable cancers is inferior to 50 %.  A cancer detected when 5 cm in diameter has a cure rate of 50 % in contrast: a 1 cm cancer over 80 %.  There is no treatment available that can offer more chances for cure than early detection.  Consequently, efforts should be increased towards early detection.

Although incidence rates (all races combined) are substantially higher for women age 50 and older, approximately 23 to 50% of breast cancers are diagnosed in younger women because those women represent 73% of the female population[2].  Age-specific incidence rates increase rapidly until age 50 for all ethnic groups, and then continued to increase more slowly for Western countries.  Incidence rates plateau for other areas like Japan.  Age-specific incidence rates reflect bimodal (early-onset and late-onset) breast cancer populations, whereas Japan has primarily an early-onset age distribution[3].  Using data from the Geneva Cancer Registry, research groups found that in 2002-2004, breast cancer incidence in women aged 25-39 years increased by 46.7% per year, which surveillance or detection bias may not fully explain[4].

Before the age of 24, breast cancer is extremely rare.  After that age, the number of patients is increasing steeply up to the age of 50; then the curve decreases (red line in Figure 1).  This can give the impression that breast cancer is a disease of young to middle aged women.  In a sense that is true for the clinical part of the disease.  But when it comes to cancer prevention, it means that the origin of the disease must be explored primarily before the age of 24 i.e. at puberty and adolescence.

Before the first breast cancers appear, the target organ – the breast – makes a remarkable entrance in the life of a woman.  Unlike all the other organs, the breast are not present before puberty.  At that time they start an immense growth in the first few years to become one of the largest organs in the body.  At menarche, growth declines and makes place for differentiation and maturation.  The development stops already some years later, around the age of 25 or at FFTP, to change in an apoptotic process that involutes the parenchyma as can be seen in sequentional mammographies.  The involution continues until almost all parenchyma disappears after menopause.  It is an astonishing observation to see that the first clinical breast cancers appears when the breasts start the involutionary process.

Origin of breast cancer

The familial predisposition is truly the most important risk factor for breast cancer.  The majority of hereditary breast and/or ovarian cancer cases are caused by germ line mutations of the susceptibility breast cancer genes: BRCA1 and BRCA2.  Both are responsible for a large part of the familial breast and ovarian cancer syndromes[5],[6]. A child born with a germ line mutation in the BRCA1 has 70 to 80 per cent life time risk.  For BRCA2, the penetration is less but still amounting to almost 60 per cent.  However, not even 5 to 10 per cent of the breast cancer patient population has a germ line gene mutation[7].

In previous decennia there has been a considerable research towards lifestyle factors that can explain the geographical and temporal variability in breast cancer.  Human migration studies and laboratory animal work show that food (e.g. alcohol), hormonal medication and reproductive practices (cultures) are related to risk[8].  Recent cohort-and case control studies however are less convincing, probably because in these epidemiological studies only adults were included[9].  Indeed, limited attention was given to children.  This is remarkable because recognized risk determinants relate to early life; at the time of breast development and before involution.

The hypothesis that breast cancer originates mainly from lifestyle factors and considering that the causation precedes clinical disease, attention has to be drawn to the period in life before breast cancer becomes evident.  Immediately, the pubertal period and the target organ, the breast, comes into focus.  Apoptotic failures combined with estrogen exposure seem to create breast cancer.  Failure to apoptosis is likely be induced by early menarche and late FFTP when the maturation of the breast remains incomplete.  Cancer might be related to an incomplete maturation of the breast that is induced by an early full term pregnancy.  The longer the period between menarche and FFTP, the more immature elements seem to remain from which cancer can originate.

Numerous scientific data support the hypothesis that the susceptibility for cancer originates during the organogenesis of the breast.  For example, children undergoing thoracic radiation are extremely at risk for developing breast cancer later in life with odds ratios amounting to 40 when irradiation takes place early after the start of breast growth[10].  Early removal of the ovaries on the other hand decreases effectively the breast cancer risk[11].  Clearly, the growing breast is the susceptible organ for genetic damage.  This is in a sense comparable to the embryo and fetus during pregnancy.  The genetic damage might remain clinically silent for years depending on promoting and inhibiting factors that relate again to lifestyle and environment.

Where the window of induction of cancer susceptibility is closely related to the breast development, the oncogenic factors are rather speculative.  Estrogen exposure is known to be the most important risk factor and depends on many other factors.  Other genotoxic factors like radiation, chemicals, viruses and others might be considered as well.  Early menarche, late first full term pregnancy (FFTP), increased height and weight, are recognized as important determinants for breast cancer[12].  They influence the estrogen exposure directly or indirectly.  Even menarche is under influence of factors of which many are already known to have a relationship with cancer risk.  Cancer prevention studies should therefore focus on estrogen exposure and the factors during childhood, that can influence directly and indirectly this exposure.  Our research group concentrated mainly on the influence of lifestyle, environment and other determinants of early puberty and menarche and how they relate to estrogen exposure and cancer risk.

Estrogen exposure

There is ample evidence that exposure to estrogens, whether endogenous or exogenous, is the main determinant of breast cancer risk.  Long term exposure to estradiol increases the risk in a variety of animal species.  It is likely to be the case in women as well[13].  Estrogens have a dual stroke: the direct hormonal action and the genotoxicity.  Metabolic products, mainly the catechol estrogens (CE), are toxic to DNA.  The prevailing theory proposes that estrogens increase the rate of cell proliferation by stimulating estrogen receptor (ER)-mediated transcription and thereby the number of errors occurring during DNA replication.  Estrogens behave different depending on their binding to the estrogen receptor and the relative binding properties to ER alpha and beta.  Diethylestradiol (DES) for example is a strong ligand for the ER alpha and causes high estrogen activity.  Ethinylestradiol, the main compound in the contraception pills, behaves similar to the natural estradiol.  Estriol is much less active for the breast where it can even be considered as an anti-estrogen.

An alternative hypothesis proposes that estradiol can be metabolized to quinone derivatives which can react with DNA and then remove bases from DNA through a process called depurination[14].  Error prone DNA repair then results in point mutations.  DES metabolization for example causes high production of quinone derivatives.  Ethinylestradiol give much less genotoxic products in comparison with natural 17-beta-estradiol.  Mammary tumor development is primarily initiated by metabolism of estrogens to 4-CE and, then, to CE-3,4-quinones[15], which may react with DNA to induce oncogenic mutations.  Phyto-estrogens in general seem to form more 16-catecholestrogens that results in far less quinone production.  Soy products are even able to change estradiol metabolism to less toxic CE[16].

These two relatively independent processes, increased cell proliferation and genotoxic metabolite formation, act in an additive or synergistic manner to induce cancer.  If correct and as a correlate, aromatase inhibitors could block both processes whereas anti-estrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than use of anti-estrogens.

Childhood risk factors

Little is known about the sequence of endocrine developmental and maturation events early in life.  Early puberty, breast development and menarche might give the impression to follow a natural occurring process determined by a biological clock that, once initiated, turns on a rather independent process of senological and gynecological development and maturation[17].  However, the age at menarche looks affected by nutrition also because ovulation and menstruation need a critical weight.  The attainment and maintenance of ovulatory cycles demands a minimal degree of body fat: from 17 to 22 % of total weight.  The sooner this weight is attained, the earlier a regular bleeding pattern is to be expected.  The data comes largely from countries with a large variation in energy intake i.e. developing countries.  Conversely, children with an intense physical life, like ballerinas and young athletes, appear to have a retarded menarche.  Thus the biological clock, causing the endocrine events and puberty to initiate, might indeed be influenced by sociocultural, environmental and nutritional factors that alter the timing of the involved neuroendocrine mechanisms.  If known breast risk related lifestyle factors might change pubertal milestones as well, then prevention strategies could be developed as early as in childhood with a lifetime protection.

The time between early puberty and menarche could even be more crucial than the time between menarche and FFTP for modulating the cancer risk.  Before menarche, estrogens are the leading hormone to influence breast tissue.  After menarche, progestins come into play.  The time lag between the onset of early puberty and FFTP could therefore also be vital in cancer risk.  This period is far less studied probably because the exact time of pubic hair appearance or initiation of breast development is rather poorly remembered by women in interviews later in life.  In addition, early puberty and age at menarche are probably not regulated by the same mechanisms.  Nutritional factors for example can have different impacts on breast development and menarche making the interval between them variable and interesting for cancer prevention purposes.

Puberty in girls starts with the appearance of secondary sex characteristics, e.g. breast development, pubic hair growth, body hair appearance and changes in body contours.  The age at first menstruation or menarche, which on the average occurs roughly two years later, is not the end of pubertal development.  Instead, it represents a turning point allowing new hormones as progesterone to be secreted in the plasma.  The secretion of these new hormones coincide with a declining growth speed of the breasts and stimulation of pubertal maturation.

As mentioned before, early menarche, late FFTP, increased height and weight, are recognized as important determinants for breast cancer.  Both earlier menarche and adult tallness are markers of increased risk[18].  Earlier menarche in the Western hemisphere is usually associated with earlier onset of hyperinsulinaemia, and numerous case-control studies report that fasting hyperinsulinaemia too is a marker of increased breast cancer risk[19].

In Western populations the mean age of girls at menarche has fallen from about 16 to 13 since the beginning of the previous century.  For a woman who had menarche at the age of 12 the risk increase for breast cancer is 1.6 times higher compared to a woman who had menarche after the age of 13.  A one-year decrease in age at menarche is estimated to increase breast cancer risk by at least 10%[20].

The explanation why menarche has such a powerful influence on breast cancer risk is the exposure to estrogens.  Children with a menarche before the age of 12 have twice the endogenous estrogen exposure compared to children with a menarche after the age of 13[21].  This significant difference in plasma concentration might be boosted or reduced by other dependent and non-dependent factors.  One of the best known is the sex hormone binding globulin that binds free estrogens and hereby protects the body from direct estrogen activity.  SHBG is decreased in obese infants.  Hence, for the same total plasma concentration, the exposure to free estrogens is higher in obese infants.

In view of the importance of pubertal development and breast cancer risk and the possible influence of lifestyle factors on pubertal development, our observational study was initiated to correlate known breast cancer lifestyle risk factors with breast development and menarche.  The main significant variables are discussed in this chapter and relate to Table 1 & 2.

Table 1: variables predicting for early puberty
Independent variables
Parameter earlier puberty
P-value
Univariate analysis
Higher weight mother begin pregnancy
0,001
More chemicals at home (3 to 6 years )
0,008
More chemicals at home (6 to menarche)
0,002
Having mononucleosis (3 to 6 years)
0,001
More high carbohydrate drinks (3 to 6 years)
0,028
More high carbohydrate drinks (6 to menarche)
0,052
More mixed drinks (6 to menarche)
0,042
Higher length in relation class
< 0,001
Higher Weight Length Index
< 0,001
Higher skin thickness
0,014
Larger waist & hip contour
< 0,001
Multivariate analysis
Larger hip contour
< 0,001
Mononucleosis (3 to 6 years)
0,003
Less sport (hours – 3 to 6 years)
0,074

 

Table 2: Variables related to menarche
Independent variable
Parameter earlier menarche
P-value
Univariate analysis
Small length father & mother
0,010 (0,044)
Higher weight mother begin pregnancy
0,002
Lower education father & mother
0,005
Outside country of birth of father & mother
< 0,001
Lower length at birth
0,086
Early breast growth (3 to 6 years)
0,007
Less self made vegetables (0 – 3 years)
0,041
Less sport
0,013
Higher length in relation class
< 0,001
Higher Weight Length Index
< 0,001
Higher skin thickness
0,043
Larger waist & hip contour
< 0,001
Multivariate analysis
Forward Backward
Lower length father
0,060           0,054
Lower length mother
0,028           0,034
Larger hip contour
0,025           0.020
Outside country of birth father
0,036           0.052
Less breast feeding
0,017           0,009
Higher length in relation class
< 0,001
Higher Weight Length Index
< 0,001

Weight & Length

Overweighed and tall girls have an earlier menarche and earlier onset of puberty.  This finding is in line with previous studies[22],[23],[24].  It is known that the age at menarche is influenced by nutrition because ovulation and menstruation need a critical weight.  The sooner this weight is acquired, the earlier a regular bleeding pattern starts.  The weight is similar for early and late maturing girls[25].  Malnutrition and low body fat, or an altered ratio of lean mass to body fat seemed to delay the adolescent spurt and to retard the onset of menarche.  Between the ages of 5 to 8, there is a progressive increase in adrenal androgen production, leading to an increase in plasma dehydroepiandrosterone and the dehydroepiandrosterone sulphate.  This increase in adrenal androgens precedes that of gonatropins and gonadal steroids and plays a role in pubertal somatic growth, pubic and axillary hair growth, oily skin and acne[26].

Significant correlations were seen between national food consumption data and child growth: between cancer incidence and age-specific stature, weight and triceps skin fold thickness[27].  Early menarche, increased height and weight are recognized as important determinants for breast cancer. Both earlier menarche and adult tallness are markers of increased cancer risk.  However, above average weight at age 12 can be inversely associated with risk of postmenopausal breast cancer[28].

In our Belgian population we observed an association between the length at birth and later age at menarche.  This finding is in accordance with other studies[29] but somewhat in conflict with the hypothesis that taller girls predict for higher risk of breast cancer.  The influence of this parameter might be overruled by others later in child life as for example childhood obesity[30].  Data that conflict with ours indicate earlier menarche in taller girls at birth[31].  A recent cohort study indicated that size at birth may be the etiological relevant factor in premenopausal breast cancer[32].

Parental factors

Higher weight of the mother at the onset of pregnancy predicts for earlier breast development and menarche.  This can be related to birth weight.  Higher weight of the mother indeed predicts for higher birth weight[33],[34].  Tall fathers and mothers have daughters with later menarche in our series.  This is in line with other studies21.  Higher education of father and mother predict for later breast development and menarche in our dataset.  This is in contrast with others[35],[36],[37].  While considering that most literature is coming from developing countries, this suggest that other relating factors overrule in Western Countries.  The notion of education in developing countries can push children into obesity compared to lower class children.  In Western countries the opposite seems to play.  As the social status differences decrease, the difference observed in menarche disappeared in urban areas of developing countries[38].  In general, a lower education level is associated with increased cancer risk[39].  This might be not totally relevant to breast cancer and depends again on the country of origin.

Lifestyle variables that reduce age at menarche may contribute to the rising risk of breast cancer diagnosed after age 40, whereas earlier-onset cancers may be characterized by a distinct pathogenesis[40].  Advanced paternal and maternal age predicts for increased risk for early premenopausal breast cancer and identifies a novel population group at increased risk[41],[42],.

Environmental toxins

Home chemicals induce earlier onset of puberty in our study.  This is another new finding since up to know there was no connection known to breast development and menarche.  Breast cancer risk is known to be related to exposure to chemicals during juvenile life.[43],[44].  DDT exposure in young women predicts for breast cancer.  This has been observed in a prospective, nested case-control study where exposure to p,p’-DDT early in life related to increased breast cancer risk[45].

Carbohydrate metabolism and energy intake

Nutrition high in carbohydrates provokes later menarche while low energy foods tend to induce earlier menarche.  While this observation was totally unexpected, the best explanation was that girls with an already higher BMI switched their nutrition towards lower energy foods as a compensation for drinks.  Girls that consumed more soft drinks had an earlier onset of puberty.  Although the relation indicated drinks instead of food, the results might be relevant considering the high intake of carbohydrate drinks in youngsters[46].  Of particular concern are the soft drinks.  Some children obtain more than 50 per cent of daily calories from soft drinks.  Soft drinks increase insulin which is a reputable tissue growth factor.  Children with even a small increase in body mass index produce significantly more insulin compared to lean children.  These dietary factors can cause direct growth abnormalities in the breast during early puberty.

Four meta-analyses and literature reviews have concluded that a positive association exists between circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) as markers of insulin resistance and breast cancer risk for premenopausal but not postmenopausal women.  Recently, a large prospective study reported an association with IGF-I and IGFBP-3 concentration for late premenopausal breast cancer as well.  In a case-cohort study, IGF-I and IGFBP-3 were positively associated with breast cancer risk in older women but not in younger women[47].  Diabetes mellitus has been associated with breast cancer.  Type 2 diabetes was observed among 19% of Hispanics and 9% of non-Hispanic Whites but was not associated with breast cancer in either group in another study.  Gestational diabetes was inversely associated with breast cancer in both ethnic groups, especially when first diagnosed at age < or =35 years.  In this study, diabetes was not associated with breast cancer overall, although the inverse association with gestational diabetes warrants further investigation[48].

Breast Feeding

Breast feeding in our study group predicted for a later age at menarche.  This might not be the only beneficial effect.  It reduces overweight in children[49] and is inversely associated with breast cancer risk[50],[51],[52].

Physical activity

Sporting girls have a later menarche although there was no relationship with onset of puberty.  This can be explained by sporting activities being started at around 6 to 8, an age that is too late to influence puberty but in time to influence menarche.  It was already known that hard physical work or intensive physical activity at young ages delays menarche[53],[54],[55].  Physical activity has been found to be associated with decreased risk of breast cancer[56] in postmenopausal women in the majority of epidemiologic studies, but the association is inconsistent in premenopausal women.  A Scandinavian group studied the effect of physical activity at various ages on the incidence of breast cancer.  Compared to inactive women, women with higher levels of physical activity at enrollment had a similar risk of incident breast cancer.  Physical activity at age 30 or at age 14 also did not afford any significant protection from breast cancer, nor did a consistently high level of activity from younger ages to enrollment[57] suggesting that physical activity can be more important at premenarcheal ages and that the effect can be overruled by other risk factors.

Infant diseases

Mononucleosis between 3 to 6 years induces earlier breast development probably because this infection is related with a prolonged period of low physical activity.  Particles of the Epstein-Barr virus are often found in breast cancer.  EBV is an ubiquitous human herpes virus associated with lymphoid and epithelial tumors, including breast cancer[58].  Research on this topic is highly warranted

Window opportunity for prevention

The efficacy of early breast cancer prevention and detection programs seems to be mainly influenced by the awareness of breast cancer risk knowledge among healthy women.  78.8% are well aware of breast cancer in general terms. However incidence or risk factors were poorly understood.  Only one-third of the population correctly estimates the incidence of breast cancer; 95% understands breast cancer in the familial history as a risk factor, but only 57% the age risk.  37.1% of women thinks hormonal contraceptives are risk factors while 35.9% points to hormonal replacement therapy in particular for women above 40 years. Recommendations for the improvement of cancer prevention programs include targeting understanding of lifetime risk of breast cancer, age as a risk factor, survival from breast cancer and hormonal causal factors. There is a need to separately address the perceptions of women depending on age, social status and educational levels[59].  The finding that risk factors are already present at early life is largely unknown.

Given that the peak of clinical breast cancer appearance is between 50 and 60 years of age and that breast cancer susceptibility induction is at early puberty, a fairly large window of opportunity of nearly 50 becomes available.  First measures can be taken to prevent children from cancer induction.  Some direct measures can be undertaken to protect children like exposure to toxins during breast development.  In an era of increased medical imaging one could protect children from high radiation exposures imposed by CT scanning whenever possible.  The choice for less toxic methods like ultrasound and magnetic resonance should be encouraged in early puberty.  High energetic food and drinks, in particular soft drinks, ought to be avoided as much as possible.  The huge variety of food products available should make this measure feasible.  Increase in physical activity is another evident way for prevention.  In addition, both nutrition and physical activity are not only important for cancer prevention but have a larger impact on many diseases and conditions.  Decreasing the exposure to estrogens might be feasible as well during puberty by nutrition and physical activity.

But the largest impact might come from the identification of risk biomarkers and polymorphisms that could be monitored for prevention strategies and identification of high risk groups.  If childhood factors cause DNA derangements that cause breast cancer risks, the will remain detectable in the next years before breast cancer becomes overt.  These biomarkers can be direct gene expression tests or products[60] but might be indirect as well like breast density.  The identification at young ages makes it possible to steer prevention implementation policies and activities.  Crucial in the latter type is the detection damaged genes or gene product expression as early as before the age of 20.  These intermediate risk genes might be useful in determining risk groups for secondary prevention.  In addition, risk markers might have an important role in disease management as well.  They might show the way of how cancer emerged and the pathways that were necessary to derange the cellular metabolism.  Consequently, therapeutic strategies might be designed upon data from this gene profiling.

Epidemiologic models used for cancer risk prediction, such as the Gail model, are validated for populations undergoing regular screening but often have suboptimal individual predictive accuracy.  Risk biomarkers from tissue samples and body fluids may be used to improve predictive accuracy based on the Gail or other epidemiologic models and, to the extent that they are reversible, and to assess response in phase I-II prevention trials.  Common intermediate risk biomarkers include high mammographic breast density, premalignant lesions[61], intra-epithelial neoplasia, and cytomorphology with associated molecular markers such as Ki-67 and hormonal metabolic products.  Protein biomarkers suitable for the prevention of breast cancer must be extremely sensitive, easily detectable and highly correlated with the disease.  They should also be expressed in the reversible phase of carcinogenesis.  Among the large number of candidate tumor-associated proteins, those related to the estrogen/chorionic gonadotropin/insulin pathway seem to be of most interest because these can be causally implicated.  They presumably are the first to express differently and are open to hormonal treatments.  The biomarkers that give information on membrane receptor-modulated signal transduction should be considered as well.  Up to now, only tamoxifen has shown some preventive activity, suggesting that the estrogen pathway is useful indeed.  Fenretinide and recombinant human chorionic gonatotropin (hCG) are also promising[62].  But the financial requirements and the very long assessment periods largely prevent current research.  This is precisely why research need to give priority to molecular biology research that identifies intermediate markers.  There is widespread belief that advanced proteomics together with increased informatics can provide specific combinations of disease-related expression profiles that could identify high-risk groups with much more reliability and that allows monitoring preventive strategies[63].

 

Table 3: breast cancer risk biomarkers
Assessment
Type   of intermediary risk biomarker
Ref
Questionnaire
Gail like Models
[64],[65],[66]
Radiology
Mammographic breast density
[67]
Radiology
MRI risk factors
[68]
Tissue
Intra-epithelial neoplasia
[69],[70],[71],[72]
Tissue
Ki-67 , Prog Recpt A, ER resp prot expression
[73],[74]
Tissue
Gene profiling
[75],[76]
Tissue
Catechol estrogen metabolism
[77]
Tissue
Parity induced genes
[78]
Plasma
IGFs, IGFBP-3, C-peptide polymorphisms
[79],[80],[81]
Plasma
Plasma phyto-estrogens
[82],[83]
Plasma
Adiponectin
[84]
Plasma
Prolactin
[85]
Plasma
N-acetyl transferase polymorphism
[86]

Most of the intermediate risk biomarkers in breast cancer are related to tissue components i.e. premalignant lesions.  The assessment of these markers is less evident compared to non-invasive techniques.  However, new tissue acquisition techniques become increasingly available[87] leading to improved sample quality (specific to the lesion of interest), better patient tolerance and affordable applications.

Conclusion

Breast cancer is a devastating disease that is increasing and spreading worldwide.  Actual treatment is curing between  50 and 90 per cent depending on the stage at diagnosis and available therapeutic resources.  Since almost half of the patients cannot be cured there is a plea for prevention and early detection.

For prevention, focus must be set at childhood were susceptibility induction takes place due to toxic influences during formation of the breast.  Exposure to estrogens add another gene toxicity and will be extended during the whole puberty and early adult lives.  Modulation of estrogen exposure is feasible in children and sets the basis of preventive measures.  Susceptibility to breast cancer should be identified early in adult life in the search for women at increased risk.  The same biomarkers might be useful in the evaluation of preventive strategies and even in early treatment options.  Clinical breast cancer, mainly a disease of middle-aged women, is a life time disease when it comes to prevention, early detection and treatment.

Acknowledgments

This work on children has been possible by the exquisite support of nurses, data managers, researchers and colleagues of the University of Hasselt and the Limburg Oncological Center in Belgium.  The manuscript was handled by the Working Group on Hormone Related Cancer of the European Cancer Prevention Organization that supported financially most part of the projects.

 

 

 

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