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 4.1. These estimates are based on incidence and mortality data for 20083.

Table 4.1: Estimated risk of developing breast cancer by age, females, UK, 2008

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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 today6. 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 delay4. 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 women4,8,9. A 15% risk reduction has ben shown for womenwith a twin birth, compared to women giving birth to a singleton11.

• 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 breastfeeding4.
• A study published in December 2011 estimated that, in 2010, around 3% of breast cancers in women in the UK were linked to women breastfeeding every child for fewer than six months.99.

• 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 risk12.

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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  A link between high insulin levels and breast cancer might explain the 20% increased risk of breast cancer for women with diabetes shown in a meta-analysis.87 Insulin-like growth factor 1 is positively associated with breast cancer risk.82. 

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Oral Contraceptives (OCs)

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 4.2).22

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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. A study published in December 2011 estimated that around 1% of breast cancers in women in the UK in 2010 were linked to OCs.100

Hormone Replacement Therapy (HRT)

Women currently taking HRT have a 66% increased risk of breast cancer compared to non-users (Table 4.3)23 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.23-27

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A study published in December 2011 estimated that just over 3% of breast cancers in women in the UK (around 1,530 cases) in 2010 were linked to HRT use.100 According to an earlier study, three-quarters of these additional breast cancers are linked to the use of oestrogen-progestagen HRT.23

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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

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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 in situ (DCIS) and lobular carcinoma in situ (LCIS) are non-invasive conditions of the breast, which can in some cases develop into invasive cancer. Although women with in situdisease 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  Overall, women with a previous in situ tumour have double the risk of invasive breast cancer compared to the general population, higher in the same breast as the carcinoma in situ than in the other breast.86

A previous diagnosis of breast cancer raises the risk of developing a second primary breast cancer. Risk ratios vary from a 40% risk increase36,37 to almost five-fold risk increase.38,79 A recent analysis suggests that a substantial proportion of contralateral breast cancers (CBC) diagnosed within two years of the first breast cancer may be in actual fact tumour spread from the primary breast cancer, and two years may be an appropriate cut-off for separating independent breast cancers from those that have spread from a previous breast cancer.79 Nonetheless, risk of CBC remains higher two or more years after a primary breast cancer, particularly where the first breast cancer was diagnosed before the age of 40.79 Risk of CBC is higher for women whose first tumour was hormone-receptor negative compared to those with a previous hormone-receptor-positive tumour, according to a recent study.80 A recent randomised trial has shown that taking tamoxifen for five years, rather than two, can reduce risk of CBC by 30%.93

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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 it39. 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-quarters2.

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.41 Women carrying such a mutation have a 45-65% chance of developing the disease by the age of 70.43  The 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 These mutations probably account for around 2% of all breast cancers,107 and up to 20% of the familial or inherited genetic component of disease risk.108

Mutations in the BRCA genes are known as high-penetrance, and confer a greater than 10-fold increase in breast cancer risk. TP53 (Li Fraumeni syndrome) also falls into this category, but is thought to account for a very low proprtion of familial breast cancer due to its rarity.109 Intermediate-penetrance gene variants that confer a 2-3-fold increase in risk have been found in genes such as CHEK2, ATM, BRIP1 and PALB2. Some low-penetrance gene variants have also been identified.109

Genetic testing for faulty BRCA genes is available on the NHS for women with a very strong family history.

Table 4.4 lists some of the cancer syndromes associated with breast and other cancers.

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Since the lifetime risk of breast cancer for women in the UK in 2008 is 1 in 8, 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 disease44.

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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 breast cancer risk.45 A study published in December 2011 estimated that around 9% of breast cancers in women in the UK in 2010 were linked to excess bodyweight.101

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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

About 50 studies have looked at the association between physical activity and breast cancer, showing a 15-20% risk reduction for the most active women, with the strongest association shown for post-menopausal women.83 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 A study published in December 2011 estimated that more than 3% of breast cancers in women in the UK in 2010 were linked to inadequate physical activity (less than 150 minutes moderate physical activity per week).102

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 This is possibly due to the higher levels of some sex hormones in the bloodstream of alcohol consumers than non-consumers.56 A study published in December 2011 estimated that more than 6% of breast cancers in women in the UK in 2010 were linked to alcohol consumption.103

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 The EPIC study showed that women who ate the most saturated fat had twice the risk of breast cancer, compared to those eating the least.90

Phyto-oestrogens, plant compounds that are structurally similar to oestrogen, have been extensively studied in relation to breast cancer risk. The main type of phyto-oestrogens consumed in the west are lignans, found in a range of foodstuffs. A meta-analysis showed a 15% reduction in breast cancer risk for post-menopausal women with the highest intakes.84 The other type of phyto-oestrogens are isoflavones, found in soybeans. Consumption of soy-based foods is highest in parts of Asia, and a recent meta-analysis found a reduced risk for women with the highest intakes in studies conducted in Asian populations, but not in western populations.85

A meta-analysis showed a slight reduction in breast cancer risk for a higher intake of dietary fibre, although risk reductions were not shown for the main subtypes of fibre, and were only seen when intake of fibre was at least 25g/day. On average, women in Britain consume around 16g/day of fibre.110 Higher intake of fruit is associated with a small decrease in breast cancer risk, a meta-analysis showed; both the fibre and the antioxidants contained in fruit may be responsible for this effect.112

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 2007, the International Agency for Research on Cancer (IARC) classified night-time shift work as "probably carcinogenic to humans".92 It has been estimated that more than 4% of breast cancers in women in the UK are linked to shift work.104,106

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 This result was recently confirmed by the Million Women Study, which showed a 17% increase in risk of breast cancer for every 10 centimetre increase in height, and similar risk increases for nine other types of cancer.98 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 A much lower, 9%, risk increase has been shown for contralateral breast cancer in women treated with radiotherapy for a previous breast cancer (compared to women treated with surgery alone).77 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 A study published in December 2011 estimated that around 1% of breast cancers in women in the UK in 2010 were linked to radiation exposure. About 46% of these attributable cases were linked to medical radiation and most of the remainder to natural (background) radiation.105 Breast screening mammograms (imaging of the breast using X-ray) are associated with a very small number of breast cancers: of 10,000 women who are screened every three years between ages 47 and 73, between three and six will develop cancer during their lifetime because of mammogram radiation.113

Medications and medical conditions

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 Two studies have shown that post-menopausal NSAID users have lower levels of oestradiol than non-users.76,78 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.

The largest study to date of breast cancer risk in relation to anti-hypertensive medications suggests that taking them for five years or longer increases risk by around 20%.81

Women who took the synthetic oestrogen, diethylstilboestrol, during pregnancy between the 1940s and 1960s have been shown to have a 27% increase in risk of breast cancer.88

A 12% higher risk of breast cancer has been shown for people treated for Graves' Disease (hyperthyroidism).91

People with the autoimmune condition, coeliac disease, have been shown to have a reduced risk of breast cancer, although mechanisms are unclear.89

Smoking and secondhand smoke

In 2004, IARC concluded on the basis of the existing evidence that smoking and secondhand smoke do not cause breast cancer.94 Since that evaluation, however, the largest studies have shown an increased risk of breast cancer in women who began smoking before the age of 20 or before first birth,95,96 and IARC now states that there is limited evidence that tobacco smoking causes breast cancer.111 The risk increase for women who smoke compared to never-smokers in these studies was around 10-20%.95,96 However, evidence remains inconsistent as to whether smoking causes breast cancer after as well as before the menopause.96

The latest meta-analysis found no association between secondhand smoke and breast cancer in studies that collected information on exposure prior to the development of breast cancer.97 However, this study did not examine the effect of secondhand smoke exposure in relation to menopausal status or level of exposure, and more research is needed.

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