Breast cancer - risk factors

The strongest risk factor for breast cancer (after gender) is age: the older the woman, the higher her risk. Risk by age is shown in Table 4.13.

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Women in developed countries are at increased risk of breast cancer compared with women from less developed countries. A large part of this variation can be explained by the fact that women in developed countries have fewer children on average and a limited duration of breastfeeding.

Calculations based on breast cancer incidence rates during the 1990s suggest that the cumulative incidence of breast cancer in developed countries would be reduced by more than half, from 6.3 to 2.7 per 100, if woman had the average number of births(6.5 instead of 2.5 births) and lifetime duration of breastfeeding (breastfeed each child, on average, for 24 months instead of 8 months) typical in developing countries around that time4 ( Figure 4.1).

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Reproductive factors that influence breast cancer risk

• Age at menarche

  Early age at menarche has been consistently associated with an increased risk of breast cancer. The estimated decrease in risk per five year delay in menarche is 22%.5 Average age of menarche in developed countries fell from around 16-17 years in the mid 19th century to 12-13 today 6. Good nutrition in early life reduces the age of menarche.7

• Age at first birth

  The younger the woman is when she begins childbearing, the lower her risk of breast cancer. The relative risk of developing breast cancer is estimated to increase by 3% for each year of delay 4. There is evidence that the reduction in risk of breast cancer with childbirth, and higher risk with later age at first full-time birth, may be limited to oestrogen-receptor-positive tumours.8

• Parity

  Childbearing reduces the risk of breast cancer and the higher the number of full-term pregnancies, the greater the protection. Risk of breast cancer reduces by 7% with each full-term pregnancy, and overall women who have had children have a 30% lower risk than nulliparous women 4, 8,9. A 15% risk reduction has ben shown for womenwith a twin birth, compared to women giving birth to a singleton 11.

• Breastfeeding

  Women who breastfeed reduce their risk compared with women who do not breastfeed. The longer a woman breastfeeds, the greater the protection: risk is reduced by 4% for every 12 months of breastfeeding 4.

• Age at menopause

  Late menopause increases the risk of breast cancer. Women who have undergone the menopause have a lower risk of breast cancer than pre-menopausal women of the same age and childbearing pattern.12 Risk increases by almost 3% for each year older at menopause (natural or induced by surgery), so that a women who has the menopause at 55 rather than 45, has approximately 30% higher risk 12.

The evidence does not support a link between abortion and breast cancer risk. 13-16

Higher levels of endogenous hormones have long been hypothesized to increase breast cancer risk. Studies show that post-menopausal women with the highest levels of oestrogen and testosterone have 2-3 times the risk of women with the lowest levels.17 The link between these hormones and pre-menopausal breast cancer risk is less clear.18,19 Higher levels of the hormone, prolactin, have been associated with an increased risk of breast cancer, particularly oestrogen-receptor-positive tumours.20 Having higher levels of insulin has been associated with an increased risk of post-menopausal breast cancer in women not taking hormone replacement therapy.21. 

Oral Contraceptives (OC's)

The use of oral contraceptives (OCs) increases the risk of breast cancer in current and recent users, but there is no significant excess risk ten or more years after stopping use ( Table 4.222).

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Cancers diagnosed in women who have used OCs tend to be less clinically advanced than those detected in never-users. 22 OC users are generally younger women whose breast cancer risk is comparatively low, so the small excess risk in current users will result in a relatively small number of additional cases.

The formulation of OCs has changed considerably since use became widespread in the 1960s but current evidence suggests that this does not affect risk 22. The risk associated with oral contraceptive use in women is similar regardless of a woman’s family history, ethnic origin, years of education, age at menarche, height, menopausal status, weight, and alcohol consumption

Hormone Replacement Therapy (HRT)

Women currently taking HRT have a 66% increased risk of breast cancer compared to non-users (Table 4.3) 12 The risk increase is temporary, with risk returning to that of a never-user within five years. A woman's BMI modifies the effect of HRT, with a stronger effect in women with a lower BMI.12,23 The risk is larger for use of oestrogen-progestagen therapy compared to oestrogen-only.24-27

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In the Million Women Study, current users of oestrogen-progestagen therapy had twice the risk of never-users, while users of oestrogen-only or tibolone had similar risk increases. 23  It was estimated in 2003, that 20,000 extra breast cancer cases had occurred among women aged 50-64 in the UK over the previous decade as a result of HRT use and three-quarters (15,000) of these additional breast cancers are due to the use of oestrogen-progestagen HRT.23

Breast density is strongly and independently related to the risk of breast cancer.29,30  Breast tissue is composed of fat, connective tissue and epithelial tissue. Breasts with a high proportion of fatty tissue are described as less dense. Women with the most dense breasts have almost five times higher risk of breast cancer than women with the least dense breasts. 31   The effect of breast density is independent of endogenous hormones.30   Density is affected by menopausal status, weight and number of children, but there is some evidence that the most important determinant is inherited.32 

Benign breast disease is a generic term describing all non-malignant breast conditions, some of which carry an increased risk for breast cancer while others do not. Women with proliferative breast disease without atypia have a two-fold increased risk, whilst those with atypical hyperplasia have a more that four-fold increased risk. 33  

Women with a strong family history and nonproliferative breast lesions have a 60% increase in risk of breast cancer, but there is no risk increase for women without a family history.33 (In this study the criteria for a strong family history includes women with at least one first-degree relative with breast cancer before the age of 50 years or two or more relatives with breast cancer, with at least one being a first-degree relative). Women are more likely to develop breast cancer in the same breast as the benign breast lesion than in the opposite breast. 33,34

Ductal carcinoma insitu (DCIS) and lobular carcinoma insitu (LCIS) are non-invasive conditions of the breast, which can in some cases develop into invasive cancer. Although women with insitudisease are more likely to develop invasive disease, it is difficult to know which are going to, although it is more likely to occur with high grade than low grade DCIS lesions.35 

A previous diagnosis of breast cancer raises the risk of developing a second primary breast cancer. Risk estimates vary from 1.4-fold36,37 to 3.5-fold.38

A woman with one affected first-degree relative (mother or sister) has approximately double the risk of breast cancer of a woman with no family history of the disease; if two (or more) relatives are affected, her risk increases further 39,40. Risk is higher if the relative is diagnosed aged under 50.

However, over 85% of women who have a close relative with breast cancer will never develop the disease, and more than 85% of women with breast cancer have no family history of it 39. In developed countries it is estimated that hereditary factors contribute around a quarter of inter-individual differences in susceptibility to breast cancer, while environmental and lifestyle factors contribute the remaining three-quarters 2.

A small proportion of women have a particularly strong family history of breast cancer and are at very high risk. Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 account for the majority of families with four or more affected members and 2-5% of all breast cancers 41. Women carrying such a mutation have a 45-65% chance of developing the disease by the age of 70.43The estimated prevalence of BRCA1 and BRCA2 mutation carriers in the general population is 0.11% and 0.12% respectively, meaning that around 1 in 450 women carries a fault in one of these genes.42

Genetic testing for faulty BRCA genes is available on the NHS for women with a very strong family history. Increased susceptibility to breast cancer is also a feature of several rare, familial cancer syndromes ( Table 4.4).

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Since breast cancer affects one woman in nine there will be many women who have a mother or sister with the disease. But only if there are several family members with early onset breast cancer is there a likelihood of a significant inherited predisposition to the disease 44.

Bodyweight

Overweight and obesity, as measured by high body mass index (BMI), moderately increases the risk of post-menopausal breast cancer and is one of the few modifiable risk factors for breast cancer.(BMI is calculated by dividing weight in Kg by height in metres squared. A BMI under 18.5 is classified as underweight, 18.5-24.9 as healthy weight, 25-29.9 as overweight and 30 or over as obese) Compared to lean (BMI 22.5-24.9) women, overweight post-menopausal women have a 10-20% increased risk of breast cancer, and obese post-menopausal women a 30% increase in risk. Women with a BMI under 22.5 have a 15% reduction in risk compared to women with a BMI of 22.5-24.9 (Table 4.5). In contrast, obese pre-menopausal women have a 20% reduction in cancer risk. Based on the results of the Million Women Study, an estimated 7% of breast cancers in post-menopausal women in the UK are due to overweight and obesity.45

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The link between BMI and breast cancer risk is likely to be due to hormones. In post-menopausal women, the main endogenous source of oestrogen is the conversion of hormones in fatty tissue. This is likely to explain the higher risk in overweight post-menopausal women.46 The reduction in risk in obese pre-menopausal women may be due to the increased likelihood of anovulatory menstrual cycles in this group.47

Physical activity

Physical activity probably protects against breast cancer, with studies showing a 20-40% risk reduction for women in the highest category of physical activity.48-50 Women in this category were walking or hiking for 10 or more hours per week or running for 3.5 hours. These studies suggest that the protective effect applies to both pre-and post-menopausal women. The effect of physical activity on breast cancer risk may be due to how it affects hormone levels, with a recent European Prospective Investigation of Cancer (EPIC) study showing lower levels of oestrogen and testosterone in post-menopausal women who reported higher levels of physical activity.51

Alcohol consumption

Epidemiological studies have consistently shown a significant association between alcohol consumption and breast cancer and a recent IARC report concluded that this association is causal.52 Estimates of the relative risk associated with every additional drink (~ 10g of alcohol) consumed on a daily basis range from about 7-12%.53-55 Recent results from the largest of these studies55 suggest that each additional drink consumed on a daily basis causes around 11 extra breast cancers before the age of 75 per 1,000 women, and that 11% of all breast cancers in the UK (5,000 cases annually) are caused by alcohol. This is possibly due to the higher levels of some sex hormones in the bloodstream of alcohol consumers than non-consumers.56

Diet

There has been a lot of research into the effects of dietary factors on breast cancer risk, but findings are generally inconsistent and inconclusive. The strongest evidence seems to be for fat intake: a meta-analysis of 45 studies57 reported that higher total fat intake increased breast cancer risk by 13% while a recent cohort study showed a small but significant risk increase for higher intakes of saturated, monounsaturated and polyunsaturated fat.58

Shift work

There is some evidence that women who do night shift work have an increased risk of breast cancer59 and other studies show that sleeping longer reduces risk of breast cancer.60,61 One theory is that disrupted or shorter duration of sleep leads to reduced levels of the hormone melatonin which has been shown to have anti-carcinogenic properties. Melatonin also suppresses the production of other hormones that have been linked to an increased risk of breast cancer. A recent study showed a 38% reduction in risk of breast cancer in women with the highest levels of the major melatonin metabolite, 6-sulfatoxymelatonin.62

In-utero exposure

A meta-analysis showed that women with higher birth-weight or birth-length or older maternal age at conception had a small (30%) raised risk of breast cancer and this has been associated with higher levels of oestrogen in maternal blood.63 Conversely, some studies suggest that breast cancer risk among offspring of mothers with pre-eclampsia or eclampsia may be reduced by as much as half and this has been connected to lower levels of maternal oestrogen.63

Height

Tallness is associated with an increased risk of breast cancer in post-menopausal women, with an approximate 7% increase in relative risk for each additional 5 centimetres in height.64 The underlying mechanism for the association between height and breast cancer risk is unclear but it is likely that height is a marker for other exposures that influence breast cancer risk.

Medical radiation exposure

Ionising radiation is an established risk factor for breast cancer.65,66 The effect is strongly related to age at exposure, that is, the younger the woman is exposed, the greater the excess risk. Studies show 12- to 25-fold increases for secondary breast cancer for women treated with mantle radiation therapy to the chest for Hodgkin’s lymphoma before the age of 30.67-70 Women who received diagnostic x-rays to the chest for tuberculosis or pneumonia between the ages of 10 to 29 have a three-fold increased risk of breast cancer.66 It has been estimated that exposure to diagnostic x-rays (much lower in dose than radiotherapy) may be responsible for 29 female breast cancer cases before the age of 75 each year in the UK, an attributable risk of 0.1% .71

Medications

A risk reduction of up to 25% has been shown for women regularly using aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).72-75 One study has shown that post-menopausal NSAID users have lower levels of oestrogen than non-users.76 However, because of the potential adverse consequences of high intake of aspirin, such as gastrointestinal haemorrhage, it would not be recommended as a prophylactic measure.