Educational Review

Hormonal and genetic risk factors for breast cancer

A. Clamp 
S. Danson 
M. Clemons
Department of Medical Oncology, Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada

Correspondence to: M. Clemons, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, T Wing, Toronto, Ontario, M4N 3M5, Canada

Introduction Hormonal risk factors Oestrogen and breast cancer

Genetic and familial factors Management of a positive family history Conclusion References

Keywords: Breast cancer, hormones, genetic, risk factors
Surg J R Coll Surg Edinb Irel., 1 February 2003, 23-31

Breast cancer is a major cause of female morbidity and mortality worldwide. In this review, we discuss the hormonal and genetic risk factors associated with breast cancer development and describe the currently available models for predicting an individual woman’s risk. We highlight three more sophisticated surrogate markers of life-time oestrogen exposure (plasma oestradiol, mammographic breast density, bone mineral density) and propose that these may be used to improve estimates of a woman’s absolute risk

INTRODUCTION
Despite the increased availability of screening mammography and the use of adjuvant systemic therapy, breast cancer remains a major cause of morbidity and mortality in women.¹ For clinicians involved with breast cancer patients and their families, two of the most commonly asked questions remain ‘why did I get breast cancer’? and ‘will my daughters get breast cancer’?

This review will overview those factors most commonly associated with breast cancer risk and the currently available tools for breast cancer risk assessment.

HORMONAL RISK FACTORS FOR BREAST CANCER
Traditionally, hormonal factors and oestrogen in particular, have been viewed as the main risk factors for breast cancer (Table 1).2 In vivo oestrogens can induce and promote mammary tumors and although the mechanisms for this remain unclear, there is evidence that both oestrogens and some of their metabolites may be directly genotoxic.^3,4,5 An alternative hypothesis is that breast tumour development is the consequence of excessive oestrogenic stimulation of an organ whose normal growth is under hormonal control.⁶ The consequence of this is progression from normal growth via hyperplasia to neoplasia. If this hypothesis holds true then breast cancer risk will at least, in part, be determined by the total cumulative exposure of breast tissue to bioavailable oestrogens.

OESTROGEN AND BREAST CANCER RISK
A number of factors that may reflect a woman’s life-time exposure to oestrogen have been linked to increased breast cancer risk in case control studies. These include early age at menarche and late menopause.^7-10  In addition, women with a first birth occurring before age 20 have about half the life-time risk of nulliparous women or of women delaying their first birth until age 30 years or later.^11-14

Three surrogate markers of life-time exposure to oestrogen (plasma oestradiol, breast density and bone mineral density) have come under scrutiny as they also provide further evidence for the role of oestrogens in breast cancer aetiology.

Plasma oestrogens
Defining the role of endogenous premenopausal oestrogen levels in breast cancer has been difficult.^12,15-18  However, elevations have been demonstrated in breast cancer patients and conversely low premenopausal serum oestradiol levels have been found in Asian populations at low risk of breast cancer.^15,19-23

The follow-up of the osteoporotic fractures study also showed a positive relationship between postmenopausal sex hormone levels among women and their subsequent risk of breast cancer.²⁴ Comparing extreme quartiles of oestrone levels, they observed a relative risk (RR) for breast cancer of 3.2 (95% CI; 1.4-7.0) for women in the highest quartile compared with those in the lowest quartile of postmenopausal oestrone levels.

Radiographic breast density
The radiological appearance of the female breast varies depending on the relative amount of fat, connective and epithelial tissues present. Mammographic pattern is associated with age and menopausal status, such that young, premenopausal women generally have breasts of greater radiodensity than do older, postmenopausal women.^25,26

The decline in mammographic density with increasing age, lower body weight and reduced number of live births suggests that the tissue changes responsible are under hormonal control.^26-30 Indirect evidence supporting this comes from studies that have shown a significant increase in breast density after commencing oestrogen replacement therapy.^31,32

Dense breasts are associated with a higher breast cancer incidence.^33-35 Prospective studies have generated relative risks for breast cancer of 4 to 5 between the highest and lowest categories of density.^29,35

Bone mineral density
Since oestrogens are important determinants of bone mineral density (BMD), several investigators have proposed that this may serve as a marker of cumulative oestrogen exposure in postmenopausal women.^36-38 Cauley et al (1996) prospectively demonstrated that increased BMD was significantly associated with an increased risk of subsequent breast cancer.³⁸ The RR was more than two-fold greater amongst women with BMD above the lowest quartile than among women with BMD in the lowest quartile. Zhang et al (1997), showed that the RR between extreme quartiles of bone density in their study population was 3.5 (95% CI, 1.8-6.8).³⁹ It is not surprising, therefore, that women with osteoporotic fractures have been shown to have a low risk of breast cancer.^36,37

Obesity
A consistent positive association between weight and breast cancer risk has been demonstrated in studies of postmenopausal women such that lean women have both lower oestrogen levels and lower age-specific incidence of breast cancer.^12,15 This finding reflects the fact that fat cells metabolise androgens to oestrogens. In postmenopausal women this results in raised levels of free oestradiol. Obesity also lowers SHBG levels resulting in an increased amount of bioavailable oestradiol. Conversely, several studies have reported reduced risk in obese premenopausal women.^8,40

A proposed mechanism to account for this dichotomy is that obese premenopausal women are more likely to have longer menstrual cycle lengths and a greater tendency for anovulatory cycles resulting in a lower net oestrogen influence on target breast cells.^8,41,42

Exogenous oestrogens
The role of exogenous sex steroids such as oral contraceptives (OC) and postmenopausal hormone replacement therapy (HRT) in breast cancer risk has been extensively reported. The hormonal effect of OCs on the breast is complex. They often cause protective anovulatory cycles, but, the mixture of oestrogen and progesterone may also stimulate mitotic activity in the breast.⁴³ Initial epidemiological studies did not suggest an increase in breast cancer risk with OC use.⁴⁴

However, more recent studies have found an association, either overall or in specifc subgroups of women including current users of combined OCs, young long-term users and those who started OCs at an early age.^45-48 However, ten or more years after cessation of OCs, there was no evidence of increased risk.^49,50

Family history of breast cancer has not been shown to modify the effect of OCs use on risk.⁴⁹ However, a recent report has suggested that OC use in BRCA1/2 mutation carriers may increase the risk of breast cancer more than in noncarriers.⁵¹

Despite initial controversy about the link between post-menopausal  exogenous HRT and increased risk of breast cancer, most meta-analyses now indicate that a significant relationship exists between the duration of use of postmenopausal hormones and the risk of breast cancer. The increase in risk is seen among current and recent, but not past users.^52-54

A recent study has demonstrated that combined oestrogen-progestin increases breast cancer risk more than oestrogen alone.⁵⁵ However, despite the increase in breast cancer, overall mortality is reduced because of fewer deaths related to cardiovascular disease and osteoporosis.^56,57

This apparent favourable risk/benefit ratio may be reversed in women at a substantially increased breast cancer risk.⁵⁸ Although oestrogen is the prime hormonal influence in breast cancer, breast tissue is also known to interact with other compounds such as androgens, prolactin, insulin, insulin growth factors (IGFs) and epidermal growth factor ß1 (EGFß1). ^41,59 The  importance of androgens is supported by the observation that external beam irradiation of the climacteric ovary is associated with lower levels of circulating testosterone and a lower risk of breast cancer.⁶⁰ However, case control studies exploring the role of androgens in breast cancer risk have produced variable results.^15-17

Chest wall radiation
Radiation exposure has for many years been known to increase breast cancer risk.^61,62 Retrospective studies have linked mantle irradiation given for Hodgkin’s disease with increased breast risk.⁶³ These cancers tend to develop in or close to the irradiated region suggesting a cause-effect relationship.^64-67 The most signficant risk factor for breast cancer is treatment between puberty and age 30.^69-70 This is when breast tissue is most active and most susceptible to the carcinogenic effects of radiation.⁷¹ This relationship of age at the time of radiotherapy to breast cancer risk shows that this factor too may also have a hormonal basis.⁶³

GENETIC AND FAMILIAL FACTORS
The association of a family history of breast cancer with increased personal risk is well established (see Table 1). A pooled analysis of 36 studies has shown that the relative risk conferred by a first degree relative with breast cancer is 2:1.72 However, less than 10% of women in the general population have a family history of breast cancer.⁷³

Approximately 5% to 10% of breast cancer cases have been shown to be due to germline mutations in cancer susceptibility genes that are inherited in an autosomal dominant fashion. The expression of the mutated gene has incomplete penetrance, meaning that a carrier despite being at substantially increased risk will not inevitably develop cancer. In the last decade, two breast cancer susceptibility genes have been isolated and have been shown to be responsible for up to 80% of large breast cancer kindreds.^74,75

The BRCA-1 and BRCA-2 genes were cloned from chromosomes 17q and 13q, respectively.^76,77 They both encode large proteins involved in the control of cell cycle progression and maintaining genomic integrity. Recent research has shown that they interact with other proteins involved in DNA repair.⁷⁸ They are expressed in most tissue types constitutively and behave as classical tumour suppressor genes, i.e. the normal allele is inactivated in tumorigenesis.

Defects in BRCA-1 and BRCA-2 function also make cells deficient in the repair of radiation-induced DNA damage. Although it has been suggested that this could be the cause of the high cancer incidence in mutation carriers, this has not been proven and no sequelae have been seen in carriers treated by radiotherapy after breast conservation therapy.⁷⁹

As well as breast cancer, both BRCA-1 and BRCA-2 mutations are associated with ovarian cancer although this risk is greaterforBRCA-1(cumulativeriskatag 70, 60% compared with 15%). BRCA-2 mutations are also associated with male breast cancer, prostate and pancreatic cancers. Histologically, BRCA-1 positive breast cancers are often poorly differentiated and oestrogen-receptor negative.⁸⁰ Whether these adverse histological parameters result in a poorer prognosis is uncertain.⁸¹ The reasons for the tissue-restricted phenotype of breast and ovarian cancer with BRCA-1/-2 mutations is unclear. It is probable, however, that oestrogen-driven cell proliferation may have a significant role.⁸²

Estimates of the cumulative breast cancer risk in BRCA-1 and BRCA-2 mutation carriers are variable ranging up to 85% (see Pharoah and Mackay [2001] for summary).⁸³ Early estimates were derived from large cancer kindreds in which the mutation is highly penetrant. Later population-based studies of Ashkenazi Jews, in which three founder mutations are prevalent, derived an overall risk of 56% by age 70.⁸⁴ A figure of 37% has been obtained from a similar Icelandic study looking at the founder mutation 995del5 in BRCA-2.85 These are probably more accurate estimates and demonstrate that the type of mutation may play a role in determining the likelihood of a carrier developing cancer.

OTHER CANCER SUSCEPTIBILITY GENES
Heterozygosity for a mutated ataxia telangiectasia (ATM) gene has also been suggested as a risk factor for breast cancer. Initial epidemiological studies indicated that the 1% of the female population that carries a mutated ATM gene were at a signi.cantly increased risk of breast cancer (relative risk 3.9-6.4) suggesting that germline ATM mutations may account for up to 5% of all breast cancers.⁸⁶ Subsequent research directly typing for ATM mutations has, however, produced contradictory results.^87,88

At present three other autosomal dominantly inherited syndromes involving breast cancer have been identified and these are summarised in Table 2. They are much less common than BRCA-associated breast cancer but should be borne in mind when assessing patients with significant family histories.

COMPOSITE RISKS
While acknowledging that exposure to oestrogens and a positive family history are important risk factors for breast cancer, three out of four women who develop breast cancer do not clearly have any of these risk factors.^36,73,89 The predictive value of these factors in assessing the risk of breast cancer is increased by combining them. For example, the combination of current age, age at first delivery of a child and time since childbirth provides a more accurate assessment of risk than each factor provides individually.^90,91

TOOLS FOR RISK IDENTIFICATION
While accepting that breast cancer aetiology is complex, how can we actually assess the breast cancer risk of an individual patient? Gail et al (1989) developed a statistical model for estimating breast cancer risk in white women screened annually with mammography.⁹² This model computes an individualised absolute risk (i.e. the chance that a woman with specific risk factors at a given age will develop breast cancer in a specified future time period). The variables included in this model are current age, age at menarche, age at first live birth, number of breast biopsies, presence of atypical hyperplasia and number of first degree relatives with breast cancer.

In North America the Gail model is being used not only to predict individual breast cancer risk but also for guiding patient cohort selection for clinical breast cancer prevention trials. However, while it provides a good estimate of breast cancer risk in selected women, it has definite limitations. It over-predicts risk for younger women, women younger than age 20 at first birth and those who do not participate in annual screening and under-predicts risk in women older than 60 years. ^93-96 As it does not consider second degree relatives, it may overestimate risk for women whose mother or sisters developed breast cancer late and similarly underestimate risk in those with multiple affected second or third degree relatives. Therefore, modifications have been developed.⁹⁷ One of these is the basis for the breast cancer risk assessment tool that is available online at www.bcra.nci.nih.gov/brc. This will provide rapid five-year and lifetime risk estimates for women over the age of 35.

The Claus model was developed using data from the Cancer and Steroid Hormone Study and is useful for defining the probability of developing breast cancer in women with a family history.⁹⁸ The model assumes that the elevated risk is due to a rare autosomal dominant mutation with a high penetrance and provides a risk estimate based on the patient’s current age, the number of affected first or second degree relatives and the age at cancer diagnosis in these. The model can only accommodate two affected family members, so is not useful for very high risk pedigrees. It also, unlike the Gail model, does not take into account environmental, behavioural or reproductive factors that alter risk.

Although the Claus model is based on genetic modelling, it was not designed to predict the likelihood of a BRCA-1/BRCA-2 mutation. Several statistical models have been designed to do this although none have been prospectively validated. BRCAPRO is the most accessible and is available online at www.jhsph.edu/biostats/brcapro.⁹⁹

MANAGEMENT OF A POSITIVE FAMILY HISTORY IN PRIMARY CARE
Although BRCA-1 and BRCA-2 mutations may be responsible for a significant proportion of families with a large history of breast cancer, many women will have concerns about less significant family histories that may lead them to consult their general practitioners.¹⁰⁰ Although guidelines exist for referral for genetic counselling and screening mammography in the UK (see Table 3 for a summary), many primary care physicians admit they need further education in cancer genetics to be able to fully support their patients.¹⁰¹ As the lifetime risk of breast cancer is very high in the general population (1 in 10), it can be expected to frequently affect two members of a large family even in the absence of a deleterious mutation (a summary of relative risks for specific family histories is given in Table 1). Therefore, the ability to provide appropriate reassurance may relieve anxiety in many cases. The drawbacks of genetic testing, for instance, false negative tests and the detection of gene variants of uncertain significance, have often not been considered by the patient and the lack of evidence for prophylactic interventions in  patients carrying mutations also needs to be considered.¹⁰² Referring patients appropriately to cancer geneticists/breast cancer surgeons and tackling the patients’ concerns and expectations are keyroles of primary care physicians.

CONCLUSION
Assessment of an individual woman’s actual breast cancer risk remains difficult. Even when combining conventional markers of oestrogen exposure (such as age at menarche, age at first birth and age of menopause) with other risk factors such as family history to determine breast cancer risk, three out of four women who develop breast cancer do not have a significant predicted increase in risk.^{36,73,89,103-106}

The Gail model is being used to predict breast cancer risk in women as well as affecting patient cohort selection into clinical trials. The model, however, is less useful in postmenopausal women as the impact of family history decreases. In this article we have reviewed more sophisticated markers of lifetime oestrogen exposure; plasma oestradiol, BMD and mammographic breast density. The addition of these to existing models should allow the identification of women with a higher breast cancer event rate than currently possible. As these are often routinely measured, it should be simple to incorporate them into baseline assessments in current breast cancer prevention trials. If subsequent modelling allows the identification of high risk cohorts, this will enable the efficacy of novel chemoprevention strategies to be tested more rapidly. This is of particular importance as tamoxifen has taken over 30 years to go from initial testing in metastatic breast cancer to US licencing for the prevention of breast cancer in high risk women.⁹⁷ It is to be hoped, therefore, that in future we will not only be able to better identify women at an increased risk of breast cancer but be able to target prevention strategies at these women.

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Copyright: 27 July 2002

Edinburgh Surgical Masterclass
Upper GI, Hepatobiliary and Pancreatic Surgery

12th, 13th & 14th March 2003

Convenors:
Professor O James Garden
Professor S Michael Griffin

The masterclass will be held in the Symposium Hall of the College. Surgeons may register for the first two days, the last two days or all three days. Registrants for two days will receive a copy of 'A Companion to Specialist Surgical Practice - Upper GI Surgery or Hepatobiliary and Pancreatic Surgery', registrants for three days will receive both volumes.

£300 for two days and £400 for three days.
Trainees deduct 5%.

For a detailed programme, please apply to Mrs Maureen Lowrie, Education Section, Royal College of Surgeons of Edinburgh.
Telephone: +44 131 668 9209
Email: m.lowrie@rcsed.ac.uk

CPD = 6 credits per day