Risk factors and epidemiology of breast cancer

BREAST CANCER

Risk factors and epidemiology of breast cancer Elinor Washbrook

Breast cancer is the most common malignancy in women; one in four new cancers diagnosed worldwide each year is a cancer of the female breast. It is also the principal cause of death from cancer among women globally, responsible for about 410,000 deaths in 2002 (14% of the total).1 Several factors are known to affect the risk of breast cancer in the population (Figure 1). The strongest risk factors for breast cancer include age, familial and reproductive factors. Lifestyle and hormonal factors have also been linked to breast cancer risk, but the data is inconsistent and inconclusive.

Age Ageing is one of the single greatest risk factors for the development of new breast cancer. Breast cancer incidence has a distinctive age-specific curve (Figure 2), with an estimated 64% of women over the age of 55 at the time of breast cancer diagnosis.1 In the USA, the estimated risk of new breast cancer is 1 in 13 for women aged 60 to 79, compared with 1 in 24 women aged 40 to 59 and 1 in 229 women aged 39 and younger.2

Reproductive factors Breast cancer risk increases with decreasing age at menarche, increasing age at first pregnancy, and low parity.3 Menopause: although risk for breast cancer increases with age, there is a marked decline in the rate of increased risk with age following menopause. Each 1-year delay in the onset of menopause is associated with a 3% increase in risk.4 Age at menarche: a 1-year delay in the onset of menarche is associated with a 5% reduction in risk for developing breast cancer in later life.5 Starting menarche at age 11 or earlier is considered an established breast cancer risk factor, and starting menarche at age 15 or older is considered an established protective factor.6 Parity: after a transient increase in risk for breast cancer, peaking at about 5 years after giving birth,7 having at least one child is associated with a decrease in the long-term risk of developing breast cancer. This protective effect increases with number of Elinor Washbrook PhD is a scientific consultant for Edelman in London, UK. She received a PhD in pharmacology from Southampton University, and conducted postdoctoral research on breast cancer at Imperial College School of Medicine, Hammersmith Hospital, London. Conflict of interests: Edelman has been commissioned by Unilever to provide counsel on communications activity surrounding antiperspirant safety.

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Established and probable risk factors for breast cancer Risk factor

Relative risk

High-risk group

Age

> 10

Elderly

Age at menarche

3

Menarche before age 11

Age at menopause

2

Menopause after age 54

Age at first pregnancy

3

Nulliparous or first child in early 40s

Diet

1.5

High intake of saturated fat

Body weight (postmenopausal)

2

Body mass index > 35

Alcohol

1.3

Excessive intake

Oral contraceptives

1.24

Current use

Hormone replacement therapy

1.35

Use for ≥ 10 years

Radiation

3

Abnormal exposure after age 10

Family history

≥2

Breast cancer in first-degree relative when young

Reproductive factors

Lifestyle factors

Hormonal status

Adapted from McPherson K, Steel C M, Dixon J M. ABC of breast diseases. Breast cancer – epidemiology, risk factors and genetics. BMJ 2000; 321(7261): 624–8.

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beyond that associated with multiple pregnancies (4% decrease in risk for every 12 months of breastfeeding).8

children. Each birth reduces the relative risk of breast cancer by an average of 7%.8 The reduction in risk per birth is greater for births at young ages than older ages, so that women who have their first birth before the age of 20 have a 30% lower risk than women with a first birth after the age of 35.9

Lifestyle factors A number of lifestyle factors have been linked to breast cancer, including diet, obesity, alcohol consumption and tobacco use.

Breastfeeding: the role of breastfeeding in reducing risk for breast cancer has been suspected for almost a century. The results of a review of the epidemiological evidence remain inconclusive, indicating either no association or a weak protective effect against breast cancer.10 However, a large collaborative study reported a modest increase in risk for breast cancer in women who breastfed,

Alcohol Alcohol is the best-established dietary risk factor for breast cancer and has been suggested as a risk factor in most studies (Figure 3),11,12 and some cohort studies have shown about a 30% increased risk of breast cancer among drinkers.13,14 For each additional 10 g of alcohol per day, the risk increases by approximately 7%.12 In several large prospective studies, high intake of folic acid appeared to mitigate completely the excess risk for breast cancer due to alcohol,15–17 and data from the Nurses Health Study has confirmed an inverse association between plasma folate and breast cancer risk.18

Age-specific incidence and mortality for breast cancer, Europe, 2002* 160 140

No. (000s)

120

Incidence

100 80

Type of diet The role of specific dietary factors in breast cancer causation is not completely resolved. Links have been suggested between the consumption of meat, dairy, dietary fat and fibre and breast cancer.

60 40

Mortality

20 0 0–14

15–44

45–54

55–64

Meat and dairy: more than 20 studies have investigated the relation between meat and dairy food consumption and breast cancer risk, with conflicting results. Some studies have indicated an increase in breast cancer risk and the consumption of meat (especially red, well-cooked meat).19 However, in a pooled analysis of large cohort studies (7379 cases), no association was observed with consumption of red meat, white meat or dairy products.20 The prospective Nurses Health Study also found no evidence of

65+

Age (years) *estimates. Source: Ferlay J, Bray F, Pisani P, Parkin D M. GLOBOCAN 2002. Cancer incidence, mortality and prevalence worldwide. IARC CancerBase No. 5, version 2.0. Lyon: IARCPress, 2002.

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increased with increasing BMI, but the elevated risk was substantially attenuated by adjustment for serum oestrogen concentration (serum oestrogen levels tend to be higher in obese women due to increased conversion of androgens to oestrogen by aromatase, an enzyme present in body fat. This may be responsible for the risk associated with increasing BMI, rather than the high BMI per se).34 Moreover, studies indicate a non-significant or decreased risk in women with a high BMI who are under the age of 50 and/or premenopausal.30, 35–37

Relative risk (95% FCI)

Relative risk* of breast cancer in relation to reported intake of alcohol 1.6 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0 (0)

10 (1)

20 (2)

30 (3)

40 (4)

50 (5)

Physical activity appears to be protective for breast cancer risk, even if activity begins after menopause.38 There is a 20–40% decrease in breast cancer risk among the most physically active women, regardless of menopausal status, type or intensity of activity.39

60 (6)

Self-reported alcohol consumption, g per day (~ number of drinks daily) *Relative risks are calculated as floating absolute risk (FAR) and stratified by study, age, parity, age at first birth and smoking. Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco and breast cancer collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002; 87: 1234–45.

Adult height is known to be associated with breast cancer risk. The mechanism underlying this association is complex, as adult height is positively correlated with age at menarche, which is negatively associated with breast cancer risk. However, a study using prospective data from a British cohort found that adult height was positively associated with age at menarche and breast cancer, particularly in women with early menarche (age < 12.5 years).40

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an association between intake of meat and fish and breast cancer risk.21 Dietary fat: a link between dietary fat and breast cancer has also been reported,22 but prospective studies have not supported this association. For specific types of fat, the evidence is more complex. A pooled analysis of prospective studies found no association between breast cancer risk and intake of total fat or specific types of fat, with the exception of a weakly positive association with saturated fat.23 Moreover, prospective studies on fat intake and breast cancer risk have included relatively few premenopausal women with breast cancer. This relationship was examined in the Nurses Health Study, and intake of animal fat during premenopausal years was found to be associated with an increased risk of breast cancer. Relative to women in the lowest quintile of fat intake, women in the highest quintile of intake had a slightly increased risk of breast cancer (RR = 1.25, 95% CI = 0.98 to 1.59; P for trend = 0.06).24

Size at birth: emerging evidence suggests that body size at birth is also positively correlated with breast cancer risk in adulthood. There is some evidence that birth weight and length is associated with breast cancer, but whether this association differs between premenopausal and postmenopausal ages is still unclear.41–44 The evidence is also conflicting as to whether this effect is independent of postnatal growth.40 Smoking Despite considerable research, the relationship of tobacco to breast cancer remains controversial. A major problem has been that alcohol and tobacco consumption are closely correlated. In a collaborative reanalysis of individual data from 53 epidemiological studies, smoking had little or no effect on the risk of developing breast cancer.12 In a recent prospective study among active smokers, breast cancer risks were significantly increased compared with nonsmokers, among women who started smoking at a younger age, who began smoking at least 5 years before their first full-term pregnancy, or who had longer duration or greater intensity of smoking.45 Further research is required to evaluate these results, given the widely inconsistent results published to date.

Dietary fibre may be protective against breast cancer. In a Swedish cohort including 342 cases, a lower risk for postmenopausal breast cancer (RR = 0.58, 95% CI = 0.40–0.84) for the highest, compared with the lowest quintile of fibre intake, was identified.25 However, other prospective studies have not supported a link between fibre intake and breast cancer.26–29 Weight and anthropometric measures Many studies have examined breast cancer in relation to body weight, height, and overall body size (as measured by body mass index (BMI)). More recent research has focused on body size at birth and breast cancer risk.

Hormonal status An increase in risk of breast cancer has been suggested in women with exposure to exogenous hormones, such as oral contraceptives and hormone replacement therapy (HRT).46,47 Oral contraceptive use Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of 54 published studies, current users of the combined contraceptive pill (containing an oestrogen and a

Obesity is associated with an increased risk of breast cancer in postmenopausal women30,31 – in particular, the effect of large weight gains after the age of 1832 – with risk increasing by 2% per unit BMI.33 However, a recent pooled analysis of eight prospective studies of postmenopausal women found that breast cancer risk

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progestogen) had a relative risk of 1.24. No difference in risk was observed 10 or more years after stopping use of the combined contraceptive pill (relative risk of 1.01).46 More recent results are broadly compatible with these findings, but inconsistencies remain.

acknowledged, if somewhat rare, risk factor for breast cancer.6,51,52 However, other environmental factors, such as exposure to electromagnetic radiation, occupational exposures and organochlorine pesticides, have not been conclusively linked to an increased risk.53 Recently, there have been claims, which are not supported by experimental or epidemiological evidence, that antiperspirant use is related to breast cancer (Figure 5). Such inaccurate messages can have a negative impact, and their effects on public perceptions are discussed below.

HRT use HRT has been a controversial area in the breast cancer literature. • Before publication of the randomized controlled Women’s Health Initiative (WHI) study in 2002, large pooled analyses of observational studies found that current users of HRT, or those who ceased use 1–4 years previously, had a 2.3% excess risk of being diagnosed with breast cancer for each year of use; an increase in risk that is comparable with the effect of delaying menopause for a year.4 • The WHI study confirmed an increase in breast cancer risk of about 26% over 5.2 years with combined oestrogen/progestogen HRT.48 The results of the WHI study did not vary significantly by type of HRT, although the study had relatively little power to assess relationships with combined oestrogen/progestogen therapy. • More recent studies have reported that the long-term use of preparations containing progestogen is more detrimental than the use of oestrogen alone.49,50 • The Million Women Study has confirmed previous findings that current and recent use of HRT increases the risk of breast cancer and that the relative risk of breast cancer in current users increases with increasing substantial differences between the effects of oestrogen only (1.30, P < 0.0001) and oestrogen/progestogen (2.00, P < 0.0001) preparations (Figure 4).47

Genetics Women with a family history of breast cancer are at increased risk of the disease. The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results. It has been estimated, based on 53 epidemiological studies, that having one first-degree relative with breast cancer increases risk by about 80%, two first-degree relatives increases risk approximately threefold, and in those with three or more first-degree relatives the risk is elevated fourfold.57 Breast cancer susceptibility is generally inherited as an autosomal dominant with limited penetrance; the number of breast cancer genes is not yet known. Two common mutations in breast cancer genes, BRCA1 and BRCA2, which are located on chromosomes 17 and 13 respectively, have been identified and account for a substantial proportion of very high risk families; that is, those with four or more breast cancers among close relatives. The lifetime risk of developing breast cancer for BRCA 1 and BRCA2 mutation carriers is 80–85%.58 BRCA1 and BRCA2 are believed to have a combined population frequency of about 1.2 per 1000 women.59 According to a combined analysis of 22 studies, the average cumulative risks in BRCA1-mutation carried by age 70 was 65%, and 45% in BRCA2-mutation carriers.60

Radiation and environmental chemicals Exposure to industrial environmental factors such as moderateto-high-dose ionizing radiation, especially at a young age, is an

Relative risk of breast cancer relating to HRT use HRT use at baseline Never users Current users Last use < 5 years previously Last use 5–9 years previously Last use > 10 years previously

Cases/population 2894/392,757 3202/285,987 579/81,875 207/29,395 79/12,568

Relative risk (95% FCI)* 1.00 (0.97–1.04) 1.66 (1.60–1.72) 1.04 (0.95–1.12) 1.01 (0.88–1.16) 0.90 (0.72–1.12) 0.5

χ2 for heterogeneity between users = 161.5, p < 0.0001 HRT use at baseline All never users All past users Current users of: oestrogen only oestrogen/progestogen tibolone other/unknown types

Cases/population

1.0

1.5

2.0

Relative risk (95% FCI)*

2894/392,757 1044/150,179

1.00 (0.96–1.04) 1.01 (0.95–1.08)

991/115,383 1934/142,870 184/18,186 93/9548

1.30 (1.22–1.38) 2.00 (1.91–2.09) 1.45 (1.25–1.67) 1.44 (1.17–1.76) 0.5

FCI = floated CI.

1.0

1.5

2.0

2.5

*Relative to never users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, body mass index, region, and deprivation index. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419–27.

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important risk factors, yet studies in the USA, Australia and the UK have found that women incorrectly believe that their risk of breast cancer decreases with age.68–71 Awareness of familial risk is also poor.66,72 For example, about one-quarter to one-third of women do not appear to be aware of the added risk a family history of breast cancer poses, and many women with a family history overestimate their risk.72 Other risk factors are also poorly understood. Only 37.1% of women perceived oral contraceptives and 35.9% HRT as risk factors for breast cancer in a recent study,66 and knowledge of obesity as a breast cancer risk factor was poor among six ethnic groups.67 This lack of understanding is perpetuated by inaccuracies reported in the media regarding risk factors. Indeed, the media have a central role in communicating information about the risk of breast cancer, and women derive much of their health information from the media.73 Studies have reported that the popular and general-interest media often misrepresent decreased age as a risk factor, frequently reporting breast cancer among young women.71,74 Moreover, only 14% of articles about breast cancer presented the factual information about age as a risk factor.75 The negative influence on risk perceptions created by inconsistent and inaccurate messages in the media about breast cancer risk factors may ultimately increase psychological distress and prevent women from making informed decisions.76,77 Knowledge of risk factors and perception of personal risk are important for motivating people to prevent, detect and manage disease. Therefore it is vital that accurate information is communicated by physicians and the media. 

Antiperspirants and breast cancer • It has been claimed that antiperspirants are a leading cause of breast cancer, that they prevent the body from purging toxins that deposit in the lymph nodes and produce cancer-causing mutations, and that antiperspirants contain harmful substances which can be absorbed through the skin or enter the body through cuts caused by shaving (www.truthorfiction.com/rumors/ b/breastcancer.htm; but also see www.antiperspirantsinfo.com). • A case-control study of 813 women with breast cancer and 793 women with no history of breast cancer failed to find any evidence to support an association between antiperspirant use and increased risk for breast cancer. The data also showed no increased breast cancer risk for women who reported using a blade (non-electric) razor and antiperspirant/deodorant, or for women who reported using an antiperspirant/deodorant within 1 hour of shaving with a blade razor. The author concludes that the absence of any observed associations may help alleviate concerns that use of underarm antiperspirant/deodorants could affect their risk for breast cancer.54 • In vitro and in vivo research has focused on certain preservatives (parabens) that are used in antiperspirants/ deodorants, as well as many cosmetic, food and pharmaceutical products. Parabens have been shown to mimic the activity of oestrogen in the cells of the body.55 Because oestrogen promotes the growth of breast cancer cells, some scientists have suggested that the use of antiperspirants/deodorants could cause the accumulation of parabens in breast tissues, which may contribute to the development of breast cancer. This was supported by a 2004 study that found parabens within 18 of 20 samples of tissue from human breast tumours.56 However, an editorial noted that this study did not analyse healthy breast tissue or tissues from other areas of the body, and did not demonstrate that parabens are found only in cancerous breast tissue.55 Furthermore, the Scientific Committee on Consumer Products (SCCP), advisor to the European Commission, has stated that the oestrogenic potency of parabens is extremely low (1000 to 1,000,000 times below the potency of 17-estradiol) and the majority of underarm cosmetics do not contain parabens as preservatives (> 98%), and concludes that there is no evidence of risk of breast cancer caused by the use of parabens-containing underarm cosmetics (www.europa.eu.int/ comm/health/ph_risk/committees/04_sccp/docs/sccp_o_00d. pdf).

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