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Risk factors

There are different types of risk factors, some of which can be changed or modified, and some which cannot.

A risk factor is any factor that is associated with an increased chance of developing a certain condition, such as breast cancer. There are different types of risk factors, some of which can be changed or modified, and some which cannot.

Risk factors for breast cancer can include personal factors, family history and genetic factors, reproductive, lifestyle and environmental factors and medical history and medications.

Having one or more risk factors does not mean that you will develop cancer. Many people have at least one risk factor but will never develop cancer, while others with cancer may have had no known risk factors. Even if a person with cancer has a risk factor, it is usually hard to know how much that risk factor contributed to the development of their disease.

Read more below to find out more about factors that are associated with an increased risk of breast cancer.

Personal factors

Personal factors are general and physical factors about a woman that can influence her risk for breast cancer. These factors can include her age, place of residence, socioeconomic status, height, weight at birth and breast density. 

Age

Getting older is associated with an increased risk of breast cancer.

Increasing age is one of the strongest risk factor for breast cancer, other than being female. Based on incidence rates in Australia, women who are 50 years old are approximately 10 times more likely to develop breast cancer compared to women who are 30 years old.

In Australia, the average age of women diagnosed with breast cancer is 61 years. More than 75% of breast cancers in Australia are diagnosed in women aged 50 years or older. Approximately 0.5% of all breast cancers in Australia are diagnosed in women under 30 years, 4% in women aged 30-39 years, and 16% diagnosed in women aged 40-49 years.1

The longer a woman lives, the more mutations occur in the body’s cells, and the more likely it is that these mutated cells will progress to cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that increasing age is associated with an increased risk of breast cancer.

Age is the most significant factor for developing breast cancer (other than being female).

Mechanisms

Changes or aberrations in the genome, such as DNA mutations, can contribute to the development of cancer. There are different genetic changes or ‘drivers’ of cancer, such as changes in oncogenes (cancer-causing genes), tumour suppressor genes (genes that usually protect cells from abnormal proliferation), or DNA repair genes. These changes can be inherited or can arise during a person’s lifetime due to errors as cells divide or damage to DNA caused by certain environmental exposures.2

The longer a person lives, the more mutations occur in cells and the more likely it is that cells may progress to cancer.

Evidence

In Australia, the risk of breast cancer increases rapidly from the age of 30–34 years (25.6 per 100 000 in 2014) to 50–54 years (255.9 per 100 000 in 2014).1 It increases more slowly to a peak around 70–74 years of age (412.4 per 100 000 in 2014), and then decreases (317.6 per 100 000 for women aged 85+ years in 2014).1 This equates to a risk of diagnosis of 1 in 10 before the age of 75 and 1 in 8 before the age of 85. Based on incidence rates in Australia1, women aged 50 years are at approximately 10 times higher risk of breast cancer compared to women aged 30 years.

The average age of women diagnosed with breast cancer in Australia is 61 years.1 Approximately 0.5% of all breast cancers in Australia are diagnosed in women under 30 years, 4% in women aged 30-39 years, and 16% diagnosed in women aged 40-49 years.1 Approximately 79% of all breast cancers in Australia are diagnosed in women aged 50 years or more.1

Data from the United States indicate that, if women less than 65 years of age are compared with women aged 65 years or older, the relative risk of breast cancer associated with age is 5.8.3

Read the full Review of the Evidence

References
  1. Australian Institute of Health and Welfare (2017). Australian cancer incidence and mortality (ACIM) books, AIHW, Canberra.
  2. PDQ Screening and Prevention Editorial Board. Breast Cancer Prevention. Bethesda MD: National Cancer Institute. Updated 2018. [Available from: https://www.cancer.gov/types/breast/hp/breast-prevention-pdq.]
  3. Singletary SE (2003). Rating the risk factors for breast cancer. Annals of Surgery 237(4):474–482.

Place of residence

Living in certain countries is associated with an increased risk of breast cancer.

Different countries have different rates of breast cancer. Australia has lower rates than some European countries, but higher rates than Asian and South American countries.

Differences in breast cancer risk between countries may be due to a range of factors. Lifestyle factors that are associated with breast cancer risk, such as body weight and physical activity, might vary between different countries.

Reproductive factors might also differ between countries. For example, in some countries, women might tend to have their first child at a later age, have fewer children or breastfeed for less time in total. These factors are all related to the risk of breast cancer.

Even within countries, breast cancer risk may vary between different ethnic groups due to a range of factors such as reproductive, lifestyle and genetic factors. For example, in Australia, breast cancer incidence differs between Indigenous and non-Indigenous women.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that living in certain countries is associated with increased risk of breast cancer.

The incidence of breast cancer differs substantially in different countries. Australia has lower rates than some European countries, but higher rates than Asian and South American countries.

Mechanisms

Differences in breast cancer incidence between countries may reflect different lifestyle and reproductive factors.

Lifestyle differences might include differences in diet and obesity, which are associated with risk of breast cancer.

Differences in reproductive patterns might include differences in a woman’s likely age at birth of the first child, in the number of children a woman is likely to have and duration of breastfeeding – all of these are associated with breast cancer risk.4

Evidence 

The highest breast cancer rates are reported from countries in northern and western Europe (eg 105.9 per 100,000 in the Netherlands), Australia (94.5 per 100,000), New Zealand (92.6 per 100,000) and North America (84.9 per 100,000 in the United States).1,2 The lowest rates are reported from countries in Africa (eg 27.9 per 100 000 in middle Africa), eastern Asia (eg 57.6 per 100,000 in Japan) and South America (eg 40.9 per 100,000 in Chile).1

Breast cancer incidence rates are increasing in developing countries.2

There are also differences between countries in the median age at diagnosis of breast cancer. The age at diagnosis is higher in developed countries than in Asia and Africa.2

Even within countries, breast cancer risk may vary between different ethnic groups due to a range of factors such as reproductive, lifestyle and genetic factors. For example, in Australia, breast cancer incidence differs between Indigenous and non-Indigenous women.3 The age-standardised breast cancer incidence rate is lower for Aboriginal and Torres Strait Islander women at 98.8 per 100,000 (2009–2013) compared with 111.7 per 100,000 in 2009–2013 for non-Indigenous women.1 Internationally, there are lower breast cancer incidence rates for Indigenous compared with non-Indigenous populations, except for Indigenous women in Alaska and New Zealand who have higher rates than their non-Indigenous counterparts.3,5

Differences in breast cancer incidence associated with a woman’s country of birth have been reported in a New South Wales (NSW) study.4 The highest rates of breast cancer in NSW were in women born in the Western world, typically English speaking areas.4 The breast cancer incidence rates averaged for 2004–2008 were: women born in Australia (81.9 per 100,000), New Zealand (91.4 per 100,000) and Western Europe (84.4 per 100,000), compared with women born in southeast Asia (62.7 per 100,000), East Asia (57.2 per 100,000), and high-income Asia Pacific countries (49.8 per 100,000).4 Over time, migrants tend to experience the breast cancer incidence rates of their adoptive countries. For example, changes in lifestyle, including adoption of a western diet, less physical activity and more overweight and obesity associated with acculturation among Asian women is suggested to have contributed to the increased incidence of breast cancer observed in this population group in the United States.6,7

Read the full Review of the Evidence

References
  1. Cancer Australia (2018). National cancer control indicators: cancer incidence, https://ncci.canceraustralia.gov.au/diagnosis/cancer-incidence/cancer-incidence
  2. Ginsburg O, Bray F, Coleman MP, et al. (2017). The global burden of women’s cancers: a grand challenge in global health. Lancet 389(10071):847–860.
  3. Moore SP, Antoni S, Colquhoun A, et al. (2015). Cancer incidence in indigenous people in Australia, New Zealand, Canada, and the USA: a comparative population-based study. Lancet Oncology16(15):1483–92.
  4. Feletto E, Sitas F (2015). Quantifying disparities in cancer incidence and mortality of Australian residents of New South Wales (NSW) by place of birth: an ecological study. BMC Public Health15:823.
  5. Teng AM, Atkinson J, Disney G, et al. (2016). Ethnic inequalities in cancer incidence and mortality: census-linked cohort studies with 87 million years of person-time follow-up. BMC Cancer 16(1):755.
  6. Institute of Medicine (IOM). Breast cancer and the environment: A life course approach. Washington, DC: The National Academies Press; 2012 [Available from: http://www.nationalacademies.org/hmd/Reports/2011/Breast-Cancer-and-the-Environment-A-Life-Course-Approach.aspx.]
  7. Liu L, Zhang J, Wu AH, et al. (2012) Invasive breast cancer incidence trends by detailed race/ethnicity and age. International Journal of Cancer130(2):395–404.

Remoteness of residence

Living in urban areas compared with living in rural and remote areas is associated with increased risk of breast cancer. This is the case in both Australia and other developed countries.

These differences may be because of a range of lifestyle and reproductive factors which affect risk of breast cancer. Differences in reproductive patterns might include a woman’s age at the birth of her first child and the number of children she has. In addition, women living in urban areas might be more likely to access screening and diagnostic services for early detection of breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that living in an urban area rather than a more remote area is associated with increased risk of breast cancer.

Mechanisms

Remoteness or urbanisation is related to socioeconomic status. Living in an area of higher socioeconomic status is associated with increased risk of breast cancer.

Differences in breast cancer incidence between urban and remote areas may reflect different lifestyle factors, such as levels of physical activity.

In addition, women living in urban areas might have better access to screening and diagnostic services for early detection of breast cancer.1

Evidence 

In Australia in 2009–13, the age-standardised breast cancer incidence was 121.1 per 100,000 for women living in major cities and 106.4 per 100,000 for women living in very remote areas.2

A systematic review and meta-analysis of studies conducted in the United States, Canada, the United Kingdom, Australia, Italy and Switzerland indicated that living in urban versus rural areas was associated with a 9% higher breast cancer incidence (pooled relative rate for urban vs rural 1.09; 95% confidence interval 1.01–1.19).3

Read the full Review of the Evidence

References
  1. Dasgupta P, Baade PD, Youlden DR, et al. (2018). Variations in outcomes by residential location for women with breast cancer: a systematic review BMJ Open 8:e019050.
  2. Cancer Australia (2018). National cancer control indicators: cancer incidence, https://ncci.canceraustralia.gov.au/diagnosis/cancer-incidence/cancer-incidence.
  3. Akinyemiju TF, Genkinger JM, Farhat M, et al. (2015). Residential environment and breast cancer incidence and mortality: a systematic review and meta-analysis. BMC Cancer 15:191.

Socioeconomic status

Living in an area of greater affluence is associated with increased risk of breast cancer.

In both Australia and other developed countries, women who live in areas of higher socioeconomic status have a higher incidence of breast cancer than women who live in more disadvantaged areas.

There might be a number of factors that explain this difference including reproductive factors, lifestyle factors and remoteness of residence. In addition, women living in more affluent areas might be more likely to access screening and diagnostic services for early detection of breast cancer. 

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that living in an area of higher socioeconomic status is associated with increased risk of breast cancer.

This relationship has been found in Australia and other developed countries.

Mechanisms

Differences in breast cancer incidence between areas of different socioeconomic status may reflect different reproductive and lifestyle factors.

Differences in reproductive patterns might include differences in a woman’s likely age at birth of the first child and in the number of children a woman is likely to have – both of these are associated with breast cancer risk.

In addition, women living in more advantaged areas might be more likely to access screening and diagnostic services for early detection of breast cancer.

In Australia, socioeconomic status is also related to Indigenous status and remoteness of residence, which are both associated with breast cancer risk.

Evidence 

In Australia in 2009-13, age-standardised breast cancer incidence was 110.9 per 100 000 for women in the most socioeconomically disadvantaged quintile, compared with 133.0 per 100 000 in the least disadvantaged quintile.1

A systematic review and meta-analysis of studies conducted in the United States, Canada, the United Kingdom, Australia, Italy and Switzerland indicated that living in socioeconomic areas characterised by higher income was associated with higher breast cancer incidence.2

In the United States, an analysis of breast cancers diagnosed in 2010 noted that the higher breast cancer incidence for women living in areas of high socioeconomic status was observed across all ethnic groups.3

Read the full Review of the Evidence

References
  1. Cancer Australia (2018). National cancer control indicators: cancer incidence, https://ncci.canceraustralia.gov.au/diagnosis/cancer-incidence/cancer-incidence.
  2. Akinyemiju TF, Genkinger JM, Farhat M, et al. (2015). Residential environment and breast cancer incidence and mortality: a systematic review and meta-analysis. BMC Cancer 15:191.
  3. Akinyemiju TF, Pisu M, Waterbor JW et al. (2015). Socioeconomic status and incidence of breast cancer by hormone receptor subtype. Springerplus 4:508.

Birthweight

Premenopausal women

Having a higher birthweight is probably associated with an increased risk of breast cancer in premenopausal women.

The risk of premenopausal breast cancer increases by about 5% for each 500 g increase in birthweight.

It is likely that this is due to other factors that lead to higher birthweight, such as genetic and hormonal factors which both affect birthweight. Some of these factors could also affect breast cancer risk.

Postmenopausal women

There is no conclusive evidence that having a higher birthweight is associated with increased risk of postmenopausal breast cancer. The studies that have looked for a link between birthweight and risk of breast cancer in postmenopausal women have been inconsistent in their findings.

Summary of the evidence

Evidence classifications: Probable (premenopausal breast cancer)
Evidence classifications: Inconclusive (postmenopausal breast cancer)

Higher birthweight is probably associated with an increased risk of breast cancer in premenopausal women. The increase in risk is estimated as 5% for each 500 g increase in birthweight (RR 1.05, 95% CI 1.02–1.09).1

The evidence for any association between birthweight and risk of postmenopausal breast cancer is inconclusive. Findings across cohort studies are inconsistent.

Mechanisms

Any association between birthweight and risk of breast cancer is unlikely to be causal. Rather, it is likely that factors that lead to higher birthweight are associated with an increased risk of breast cancer. Birthweight, which reflects prenatal growth, is determined by both genetic and environmental influences, which may include hormonal factors and foetal nutrition. Birthweight also predicts later growth and maturation (e.g. age at menarche), which affect breast cancer risk.1

Evidence 

The World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) has judged the evidence as ‘strong–probable’ for an association between higher birthweight and increased risk of premenopausal breast cancer.1 A dose-response analysis of 16 studies estimated the relative risk per 500g increase in birthweight as 1.05 (95% confidence interval 1.02–1.09). Some of the studies contributing to the dose-response analysis had not adjusted for age, alcohol intake, reproductive factors and/or adult body mass index.

For postmenopausal breast cancer risk, the WCRF/AICR considered that the evidence for an association with birthweight was limited, and no conclusion was possible.1

Findings from two recent large prospective cohort studies are consistent with the findings of the WCRF/AICR – that is, an increased risk of premenopausal but not postmenopausal breast cancer with higher birthweight.2,3 However, another cohort study found no association between birthweight and either premenopausal or postmenopausal breast cancer.4

Read the full Review of the Evidence

References
  1. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  2. Dartois L, Fagherazzi G, Baglietto L, et al. (2016). Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: estimates from the E3N‐EPIC cohort. International Journal of Cancer 138(10):2415–2427.
  3. Xue F, Rosner B, Eliassen H et al. (2016). Body fatness throughout the life course and the incidence of premenopausal breast cancer. International Journal of Epidemiology 45(4):1103–1112.
  4. Sandvei MS, Lagiou P, Romundstad PR, et al. (2015). Size at birth and risk of breast cancer: update from a prospective population-based study. European Journal of Epidemiology 30(6):485–492.

Height

Being taller as an adult is associated with an increased risk of breast cancer.

The risk of breast cancer increases by about 17% for each extra 10 cm in a woman’s adult height.

It is unlikely that height as an adult directly affects breast cancer risk. Rather, being taller and having an increased risk of breast cancer probably have mechanisms in common. For example, growth processes might affect both adult height and breast cancer risk. These are affected by both genetics and the environment, including nutrition.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that being taller as an adult is associated with an increased risk of breast cancer compared to being shorter.

The increased risk of breast cancer per 10 cm increase in height has been estimated as 17% (RR 1.17, 95% CI 1.15–1.19).1 It has been estimated as 6% for premenopausal breast cancer 1.06 (95% CI 1.02–1.11) and 9% (RR 1.09, 95% CI 1.07–1.11) for postmenopausal breast cancer.2

Mechanisms

It is unlikely that height as an adult directly affects breast cancer risk. Rather, shared mechanisms – for example, growth processes – may determine both height and cancer risk. Growth processes are affected by genetic and environmental, e.g. nutritional, factors.3

Evidence 

The World Cancer Research Fund International/American Institute for Cancer Research concluded that the ‘developmental factors leading to greater linear growth (marked by adult attained height)’ are a convincing cause of premenopausal and postmenopausal breast cancer.2 This was based on evidence from 29 studies reporting on premenopausal breast cancer and 41 studies reporting on postmenopausal breast cancer. The increased risk of breast cancer per 5 cm increase in adult height was 1.06 (95% confidence interval [CI] 1.02–1.11) for premenopausal breast cancer and 1.09 (95% CI 1.07–1.11) for postmenopausal breast cancer.

A meta-analysis of a large number of prospective studies estimated that the increased risk of breast cancer per 10 cm increase in adult height was 1.17 (95% CI 1.15–1.19).1 The estimate was similar for premenopausal and postmenopausal breast cancer. The increase was not seen for oestrogen receptor-negative (ER-) disease.

A significant association between greater height and risk of premenopausal and postmenopausal ER+ breast cancer was found in another large cohort study.4 However, a cohort study of Japanese women did not find an association between adult height and breast cancer risk.5

Read the full Review of the Evidence

References
  1. Zhang B, Shu XO, Delahanty RJ, et al. (2015). Height and breast cancer risk: evidence from prospective studies and Mendelian randomization. Journal of the National Cancer Institute 107(11).
  2. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  3. Elands RJ, Simons CC, Riemenschneider M, et al. (2017). A systematic SNP selection approach to identify mechanisms underlying disease aetiology: linking height to post-menopausal breast and colorectal cancer risk. Scientific Reports 24(7):410.
  4. Horn-Ross PL, Canchola AJ, Bernstein L, et al. (2016). Lifetime body size and estrogen-receptor-positive breast cancer risk in the California Teachers Study cohort. Breast Cancer Research 18(1):132.
  5. Nitta J, Nojima M, Ohnishi H, et al. (2016). Weight gain and alcohol drinking associations with breast cancer risk in Japanese postmenopausal women: results from the Japan Collaborative Cohort (JACC) Study. Asian Pacific Journal of Cancer Prevention 17(3):1437–1443.

Breast density

Higher than average mammographic breast density is associated with an increased risk of breast cancer.

Breast density is something that can only be seen on a mammogram. Breast density is not related to how breasts look or feel and is not based on size or firmness. Breast density reflects the relative amounts of dense glandular breast tissue, which appears white on a mammogram, compared with non-dense fatty tissue, which appears dark on a mammogram.

The mechanism linking breast density with breast cancer risk is not well understood. Breast density is associated with genetic and several other established risk factors for breast cancer, including body mass index (BMI) and whether a woman has had children.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that higher than average mammographic breast density is associated with an increased risk of breast cancer. Conversely, lower than average mammographic breast density is associated with a decreased risk of breast cancer.

The increased risk of breast cancer associated with higher percent breast density has been estimated as 1.53 per standard deviation from the mean (95% CI 1.44–1.64).1 Approximately 70% of women will have an increased or decreased risk of breast cancer, associated with breast density, between 1.53 (moderately dense breasts) and 0.65 (moderately non-dense breasts).

Women with extremely dense breasts (BI-RADS 4) and women with heterogeneously dense breasts (BI-RADS 3) have approximately 2.14 times and 1.28 times increased risk of breast cancer compared to women with average breast density, respectively. Conversely, women with scattered fibroglandular densities (BI-RADS 2) and almost entirely fatty breasts (BI-RADS 1) have approximately 0.80 times and 0.48 times decreased risk of breast cancer compared to average breast density, respectively.

Mechanisms

Breast density refers to the appearance of the breast on a mammogram. It reflects the relative amounts of stromal and epithelial tissues (‘glandular tissue’, white in appearance) and fat (dark in appearance) in the breast.2 Glandular tissue is denser.

The main tool used to classify mammographic breast density is the Breast Imaging Reporting and Data System (BI-RADS) which uses four categories:

  • BI-RADS 1: Almost entirely fat—less than 25% glandular tissue
  • BI-RADS 2: Scattered fibroglandular densities—approximately 25–50% glandular tissue
  • BI-RADS 3: Heterogeneously dense—approximately 51–75% glandular tissue
  • BI-RADS 4: Extremely dense—greater than 75% glandular tissue.

International research3-7 suggests that the distribution of breast density into BI-RADS categories 1–4 is approximately 10%, 40%, 40%, and 10% of women, respectively.

The mechanism linking breast density with breast cancer risk is not well understood. A higher breast density means a higher proportion of glandular tissue in the breast and a greater number of stromal and epithelial cells that are at risk of becoming cancer cells.8

A range of other factors contribute to breast density including genetics, age, body mass index (BMI) and hormones.9 Breasts tend to become less dense as women get older, especially after menopause, as the glandular tissue degenerates and the breasts become more fatty. Breast density is also lower in women who have had children than in women who have not,10 decreases with increasing BMI11,12 and is higher in women who use combined menopausal hormone therapy (MHT).13 In addition, since cancers appear as white areas on a mammogram, there is potential for breast cancer to be missed as a result of the masking effect associated with breast density.14

Evidence 

A collaborative analysis of 13 case-control studies examining the association between mammographic density and breast cancer risk showed an increased risk of premenopausal and postmenopausal breast cancer with higher breast density.1 The odds ratio per standard deviation (SD) was 1.53 (95% confidence interval [CI] 1.44–1.64) for per cent dense area (PDA) for postmenopausal breast cancer, with very similar odds for premenopausal breast cancer. These estimates were adjusted for age, BMI, and whether the woman had had children.

The odds ratio per SD of 1.53 relates to the 85th percentile of density, and conversely an odds ratio of 0.65 (the inverse of 1.53) relates to the 15th percentile of density. This can be interpreted as women with moderately dense breasts on mammography having 1.53 times increased risk of breast cancer and women with moderately non-dense breasts having 0.65 times decreased risk of breast cancer, compared to women with average breast density. Approximately 70% of women will have a risk of breast cancer associated with breast density in between these two values.

An odds ratio per SD of 1.53 for PDA can also be interpreted as a relative risk for each BI-RADS category. Assuming a distribution of women in BI-RADS categories 1-4 of 10%:40%:40%:10%5, respectively, women with extremely dense breasts (BI-RADS 4) have around 2.14 times increased risk of breast cancer than women with average breast density and women with heterogeneously dense breasts (BI-RADS 3) have around 1.28 times increased risk of breast cancer than women with average breast density. Conversely women with scattered fibroglandular densities (BI-RADS 2) have around 0.80 times decreased risk of breast cancer than women with average breast density; and women with the least dense breasts (BI-RADS 1) have around 0.48 times decreased risk of breast cancer than women with average breast density.1

An increased risk of breast cancer in women with higher breast density compared with women with the least dense breasts has also been found in two additional meta-analyses12,13, prospective data from a randomised controlled trial of mammographic screening15 and a recent retrospective study.7

Read the full Review of the Evidence

References
  1. Pettersson A, Graff RE, Ursin G, et al. (2014). Mammographic density phenotypes and risk of breast cancer: a meta-analysis. Journal of the National Cancer Institute 106(5): dju078.
  2. Yaghjyan L, Mahoney MC, Succop P, et al. (2012). Relationship between breast cancer risk factors and mammographic breast density in the Fernald Community Cohort. British Journal of Cancer 106(5):996–1003.
  3. BreastScreen Australia (2016). Breast Density and Screening: Position Statement http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/br-policy-breast-density
  4. Kerlikowske K, Ichikawa L, Miglioretti DL, et al. (2007). Longitudinal measurement of clinical mammographic breast density to improve estimation of breast cancer risk. Journal of the National Cancer Institute 99:386‒395.
  5. Sprague BL, Gangnon RE, Burt V, et al. (2014) Prevalence of mammographically dense breasts in the United States. Journal of the National Cancer Institute 106(10): dju.255
  6. Sickles E, D’Orsi C, Bassett L, et al. (2013). ACR BI-RADS Atlas: Breast imaging reporting and data system. Reston, VA: American College of Radiology 123–6
  7. Moshina N, Sebuødegård S, Lee CI, et al. (2018). Automated volumetric analysis of mammographic density in a screening setting: worse outcomes for women with dense breasts. Radiology 288 (2):343–352.
  8. Boyd NF, Dite GS, Stone J, et al. (2002). Heritability of mammographic density, a risk factor for breast cancer. New England Journal of Medicine 347:886–894.
  9. Baglietto L, Krishnan K, Stone J, et al. (2013). Associations of mammographic dense and nondense areas and body mass index with risk of breast cancer. American Journal of Epidemiology. 179(4):475‒483.
  10. Wang AT, Vachon CM, Brandt KR, et al. (2014). Breast density and breast cancer risk: a practical review. Mayo Clinic Proceedings 89(4):548–557.
  11. Zhu W, Huang P, Macura KJ et al. (2016). Association between breast cancer, breast density, and body adiposity evaluated by MRI. European Radiology 26(7):2308–2316.
  12. Boyd NF, Martin LJ, Sun L, et al. (2006). Body size, mammographic density, and breast cancer risk. Cancer Epidemiology, Biomarkers & Prevention 15(11):2086–2092.
  13. McTiernan A, Martin CF, Peck JD, et al. (2005). Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women’s Health Initiative randomized trial. Journal of the National Cancer Institute 97(18):1366–1376.
  14. Boyd NF, Guo H, Martin LJ, et al. (2007). Mammographic density and the risk and detection of breast cancer. New England Journal of Medicine 356 (3):227–236
  15. Chiu Y, Duffy S, Yen AM, et al. (2010). Effect of baseline breast density on breast cancer incidence, stage, mortality, and screening parameters: 25-year follow-up of a Swedish mammographic screening. Cancer Epidemiology, Biomarkers & Prevention 19(5):1219–1228.

Family history and genetic factors

A family history of breast cancer means having one or more blood relatives who have, or have had, breast cancer. These relatives could be on either the father’s or mother’s side of the family.

As breast cancer is common, many women will have a family history by chance.  However, some women with a family history may have inherited a faulty gene which increases the risk of cancer. We all inherit a set of genes from each of our parents. Sometimes there is a fault, or mutation, in one copy of a gene which stops that gene working properly and this can lead to an increased risk of breast cancer.

Around 5% of breast cancers can be explained by an inherited gene fault. Genetic changes can also occur during our lifetime. On this page you will find information about family history of breast cancer and other cancers and genetic mutations which are associated with risk of breast cancer.

There are several genes in which mutations may be involved in the development of breast cancer, including rare to very rare high-risk gene mutations such as those in BRCA1 and BRCA2, TP53, PTEN, CDH1 and STK11 and some rare moderate-risk gene mutations such as PALB2, ATM and CHEK2.

It may be appropriate for some women who have a strong family history to be referred to a family cancer clinic. Family cancer clinics can provide a more precise risk assessment, advice about genetic testing and an individualised management plan.

Family history of breast cancer

Having a family history of breast cancer is associated with an increased risk of breast cancer.

However, most women who develop breast cancer do not have a family history of the disease. Because breast cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Only about 5% of breast cancer can be explained by an inherited gene fault. However, a family history on either the mother’s side or the father’s side increases a woman’s risk of breast cancer.

The significance of a family history of breast cancer increases with the number of family members affected and the younger their ages at diagnosis.

Women with one first-degree relative (parent, sibling or child) who has had breast cancer have about 2 times the risk of breast cancer compared to women with no family history. Women with two first-degree relatives who have had breast cancer have about 3 times the risk. Women with three or more relatives who have had breast cancer have nearly 4 times the risk.

Women with one or more second-degree relative who has had breast cancer have about 1.5 times the risk of breast cancer as women with no family history. A second-degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew or half-sibling.


It is important to note that a family history on the father’s side is just as important as on the mother’s side of the family.

The risk is higher if two or more relatives have other characteristics associated with increased risk, such as being diagnosed before age 50 or being of Ashkenazi Jewish descent.

Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.Family members have genetic factors in common and this might explain the association between family history of breast cancer and increased breast cancer risk. These genetic factors could include mutations in genes such as BRCA1 or BRCA2.

In addition, family members often have similar environments and lifestyles as each other. These shared backgrounds could also contribute to the increased breast cancer risk in women with a family history of breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a family history of breast cancer is associated with an increased risk of breast cancer.

Women with one first-degree relative (parent, sibling or child) who has had breast cancer are estimated to have 1.80 (95% CI 1.69–1.91) times the risk of breast cancer as women with no family history.1

Women with two first-degree relatives who have had breast cancer are estimated to have 2.93 (95% CI 2.36–3.64) times the risk of breast cancer as women with no family history.1

Women with three or more first-degree relatives who have had breast cancer have about 3.9 (95% CI 2.03–7.49) times the risk of breast cancer as women with no family history.1

Women with one or more second-degree relatives who have had breast cancer are estimated to have 1.5 times (95% CI 1.4–1.6) the risk of breast cancer as women with no family history.2 (A second-degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew or half-sibling.)

Mechanisms

Family members share both genetic factors and environmental factors, both of which could contribute to an association between family history of breast cancer and increased risk of breast cancer. Genetic factors could include mutations in genes such as BRCA1 or BRCA2. Environmental factors include exposures, lifestyles and diets.2,3

Evidence 

For women who have one affected first-degree relative (compared with women who have no affected relatives), meta-analyses have estimated a relative risk for breast cancer of 1.80 (95% confidence interval [CI] 1.69–1.91)1 and 2.1 (95% CI 2.0–2.2).2 Two more recent large cohort studies and a case–control study reported a similarly increased risk of breast cancer for women with 1 affected first-degree relative.3-5

For women with two affected first-degree relatives, a relative risk for breast cancer of 2.93 (95% CI 2.36–3.64) has been estimated in a meta-analysis.1 For women with three or more affected first-degree relatives, a relative risk for breast cancer of 3.90 (95% CI 2.03–7.49) has been estimated in the same meta-analysis. Other studies have provided similar estimates of increased risk.2,4,5

For women with one or more affected second-degree relatives, the relative risk of breast cancer (compared with women who have no affected relatives) has been estimated in a meta-analysis as 1.5 (95% CI 1.4–1.6).2

The increased breast cancer risk associated with having a first-degree relative with breast cancer was found to be higher for younger compared with older women in a large meta-analysis1 and in a cohort study.3 One meta-analysis reported inconsistent findings on breast cancer risk according to the age of the person with a family history of breast cancer.2

The increased breast cancer risk associated with having a first-degree relative with breast cancer has also been found to be higher for women whose relative was diagnosed with breast cancer at a younger compared with an older age.1-3,6

Read the full Review of the Evidence

References
  1. Collaborative Group on Hormonal Factors in Breast Cancer (2001). Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease. Lancet 358(9291):1389–1399.
  2. Pharoah PDP, Day NE, Duffy S, et al. (1997). Family history and the risk of breast cancer: a systematic review and meta-analysis. International Journal of Cancer 71:800–809.
  3. Kharazmi E, Chen T, Narod S, et al. (2014). Effect of multiplicity, laterality, and age at onset of breast cancer on familial risk of breast cancer: a nationwide prospective cohort study. Breast Cancer Research and Treatment 144:185–192.
  4. Beebe-Dimmer JL, Yee C, Cote ML, et al. (2015). Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121(8):1265–1272.
  5. Bevier M, Sundquist K, Hemminki K (2012). Risk of breast cancer in families of multiple affected women and men. Breast Cancer Research and Treatment 132:723–728.
  6. Colditz GA, Kaphingst KA, Hankinson SE et al. (2012). Family history and risk of breast cancer: nurses’ health study. Breast Cancer Research and Treatment 133(3):1097–1104.

Family history of other cancers

Having a family history of some cancers other than breast cancer is associated with an increased risk of breast cancer.

The majority of evidence for increased risk of breast cancer for women with a family history of cancers other than breast cancer, exists for family history of ovarian cancer and/or prostate cancer and/or pancreas cancer.

Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.

Family members have genetic factors in common and this might explain the association between family history of cancers and increased breast cancer risk. For example, mutations or faults in the BRCA1 and BRCA2 genes increase the risk of ovarian cancer and prostate cancer as well as breast cancer. Faulty BRCA2 genes are also associated with pancreatic cancer. Since relatives share many genes, they also share the risk of cancers associated with the faulty genes.

In addition, family members often have similar environments and lifestyles, such as diet and levels of physical activity. These shared backgrounds could also contribute to the increased breast cancer risk in women with a family history of breast cancers.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that a family history of ovarian cancer and prostate cancer and probably some other cancers, including pancreatic cancer, is associated with an increased risk of breast cancer. The more relatives affected, the higher the risk. The risk is also higher if a woman also has a family history of breast cancer.

Mechanisms

Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.

Mutations in genes associated with increased risk of breast cancer are also associated with increased risk of some other cancers. For example, mutations in the BRCA1 and BRCA2 genes also increase the risk of ovarian cancer, and are associated with male breast cancer and prostate cancer. BRCA2 gene mutations are also associated with pancreatic cancer.1

Other gene mutations that increase the risk of both breast cancer and other cancers include PALB2 (pancreatic cancer), TP53 (associated with Li–Fraumeni syndrome and childhood sarcomas), CDH1 (associated with diffuse gastric cancer), PTEN (associated with Cowden syndrome, and thyroid and endometrial cancers) and STK11 (associated with Peutz–Jeghers syndrome, and gastrointestinal, pancreatic and gynaecological cancers). Similar biological mechanisms are likely to increase the risk of breast cancer and these other cancers.

In addition, family members tend to share environments and lifestyles, such as diet and levels of physical activity. Some of these factors are associated with the risk of breast cancer.

Evidence 

Family history of ovarian cancer

The risk of breast cancer in women from families with two or more first‐degree relatives with ovarian cancer has been estimated as 3.74 (95% confidence interval [CI] 2.04–6.28) for women under 50 years of age and 1.79 (95% CI 1.02–2.90) for women 50 years of age and older.2 

From a large, population-based case-control study, the lifetime risks of developing breast cancer for a woman with one or two first-degree relatives with ovarian cancer were estimated to be 14% and 31%, respectively.3

Family history of prostate cancer

A large cohort study and a pooled analysis of case-control studies found that a family history of prostate cancer in a first-degree relative was associated with an increase in breast cancer risk (hazard ratio [HR] 1.14, 95% CI 1.02–1.26 and odds ratio [OR] 1.6, 95% CI 1.1–2.4, respectively).4,5 A family history of both breast and prostate cancer in first-degree relatives was associated with a higher risk of breast cancer (HR 1.78, 95% CI 1.45–2.19).

An increased risk of breast cancer in women with a family history of prostate cancer was also found in a consecutive series study of prostate cancer families.5  Breast cancer risk was higher for women who had more than one relative with prostate cancer, and relatives who were diagnosed with prostate cancer at younger ages.

Family history of pancreatic cancer

About 5% of patients with pancreatic cancer carry germline mutations in BRCA2. PALB2 gene mutations are also associated with increased risk of pancreatic cancer.

Family history of colorectal cancer

A large cohort study did not find a significant association between a family history of colorectal cancer and risk of breast cancer after adjustments for a family history of breast and prostate cancer (HR 1.08, 95% CI 0.99–1.19).4 However, a family history of both breast and colorectal cancer in first-degree relatives was associated with an increased risk of breast cancer (HR 1.47, 95% CI 1.34–1.61).4

A pooled analysis of case–control studies found that a family history of colorectal cancer in first-degree relatives was associated with an increased risk of breast cancer (OR 1.5, 95% CI 1.1–1.9).5 An increased risk of breast cancer has also been found in women with either a first-degree (OR 1.26, 95% CI 1.08–1.45) or a second-degree relative (OR 1.21, 95% CI 1.07–1.36) with colon cancer in a population-based case–control study.7

Family history of other cancers

An association has been found between family history of haemolymphopoietic cancers and increased breast cancer risk in a network of case–control studies from Italy and Switzerland (OR 1.7, 95% CI 1.2–2.4).8

Read the full Review of the Evidence

References
  1. EviQ. 2018 Facts for people and families with a faulty BRCA2 gene https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3427-facts-for-people-and-families-with-a-faulty-b##what-is-the-risk-of-cancer-for-people-with-a-fault
  2. Sutcliffe S, Pharoah PD, Easton DF, et al. (2000) Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer. International Journal of Cancer 87(1): 110-117
  3. Claus EB, Risch N, Douglas Thompson W (1993). The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Research and Treatment 28(2):115–120.
  4. Beebe-Dimmer JL, Yee C, Cote ML, et al. (2015). Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121(8):1265–1272.
  5. Turati F, Edefonti V, Bosetti C, et al. (2013). Family history of cancer and the risk of cancer: a network of case-control studies. Annals of Oncology 24:2651–2656.
  6. Valeri A, Fournier G, Morin V, et al. (2000). Early onset and familial predisposition to prostate cancer significantly enhance the probability for breast cancer in first degree relatives. International Journal of Cancer 86:883–887.
  7. Slattery ML, Kerber RA (1993). A comprehensive evaluation of family history and breast cancer risk. JAMA: The Journal of the American Medical Association 270(13):1563–1568.
  8. Turati F, Negri E, La Vecchia C (2014). Family history and the risk of cancer: genetic factors influencing multiple cancer sites. Expert Review of Anticancer Therapy 14(1):1–4.

Single nucleotide polymorphisms

Having certain patterns of single nucleotide polymorphisms (SNPs) or variants in a woman’s DNA may be associated with an increased risk of breast cancer.

Information on a large number of individual SNPs associated with breast cancer risk can be combined into a ‘polygenic risk score’. Women who have the highest ‘score’ using this approach (in a study including 77 SNPs) have about 3 times the risk of breast cancer compared to women who have a score near the middle of the range of scores.

SNPs are normal variations in the genetic material (DNA) in our cells at many single locations (nucleotides) in the DNA. SNPs are a common and normal type of genetic variation between people: about 10 million SNPs are thought to occur in human DNA. Most SNPs have no effect on health. They often act as ‘markers’ of genes that may be associated with a disease, such as breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a high polygenic risk score (PRS), based on certain patterns of a large number of individual single nucleotide polymorphisms (SNPs) or variants across the whole genome, is associated with an increased risk of breast cancer.

Women who have a PRS (based on 77 SNPs) in the highest 1% of the PRS distribution are estimated to have 3.36 times the risk of breast cancer as women in the middle quintile of the distribution (OR 3.36, 95% CI 2.95–3.83).1 Women with a PRS in the lowest 1% of the PRS distribution are estimated to have 0.31 times the risk of breast cancer as women in the middle quintile of the distribution (OR 0.31, 95% CI 0.24–0.39).1

These data may be used in the future to provide more accurate risk prediction than family history alone. They may also be used to influence decisions on cancer risk management for women at high risk of breast cancer.2,3

Mechanisms

SNPs are normal variations in the DNA sequence at many single locations (nucleotides). SNPs are a common and normal type of genetic variation between people: about 10 million SNPs are thought to occur in the human genome. Most SNPs have no effect on health or development. They can act as biological markers of genes that may be associated with a disease such as breast cancer.4

SNPs associated with an increased risk of breast cancer are identified using genome-wide association studies (GWASs), which compare large numbers of SNPs between cases and controls. PRSs for breast cancer risk can then be developed based on combined scores for large numbers of SNPs.1,5

Evidence 

A large GWAS and meta-analysis used an array of more than 500,000 SNPs for genotyping cases and controls.4 It was estimated that 172 common susceptibility variants explain 18% of familial relative risk of breast cancer.4 Another large GWAS estimated that 125 variants explain approximately 14% of the familial risk of oestrogen receptor-negative (ER-) breast cancer.5

A large collaborative case-control study found that the risk of breast cancer was increased for women in the highest 1% of a PRS based on 77 SNPs compared with women in the middle quintile, with an odds ratio (OR) of 3.36 (95% confidence interval [CI] 2.95–3.83).1 Women in the lowest 1% of the PRS distribution had an estimated OR compared with women in the middle quintile of 0.31 (95% CI 0.24–0.39).1 For women in the highest quintile of the PRS, the lifetime risk of breast cancer was 16.6% for women without a family history of breast cancer and 24.4% for women with a first-degree family history.1 For the lowest PRS quintile, women without a family history had a lifetime risk of breast cancer of 5.2%, and women with a family history had a lifetime risk of 8.6%.1

An association between PRS for breast cancer and breast cancer risk has also been found in other studies.2,6,7 For example, a PRS based on 24 SNPs among women from two breast cancer familial cohorts in Australia, Canada, the US and NZ, was associated with increased breast cancer risk, with a hazard ratio [HR] for upper versus lower quintile PRS 3.18 (95% CI 1.84–5.23), and HR for continuous PRS (per standard deviation [SD]) 1.38 (95% CI 1.22–1.56).7

Incorporation of PRSs into models for predicting breast cancer risk has improved the performance of the models.2,7

Read the full Review of the Evidence

References
  1. Mavaddat N, Pharoah PD, Michailidou K, et al. (2015). Prediction of breast cancer risk based on profiling with common genetic variants. Journal of the National Cancer Institute 107(5):1–15.
  2. Li H, Feng B, Miron A, et al. (2016) Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab. Genetics & Medicine 19(1):30–35.
  3. Kuchenbaecker K, McGuffog L, Barrowdale D, et al. (2017) Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers. JNCI: Journal of the National Cancer Institute 109(7).
  4. United States National Library of Medicine (2018). Genetics Home Reference: What are genome-wide association studies?, https://ghr.nlm.nih.gov/primer/genomicresearch/gwastudies.
  5. Milne RL, Kuchenbaecker KB, Michailidou K, et al. (2017). Identification of ten variants associated with risk of estrogen receptor-negative breast cancer. Nature Genetics 49(12):1767–1778.
  6. Dite GS, MacInnis RJ, Bickerstaffe A, et al. (2016). Breast cancer risk prediction using clinical models and 77 independent risk-associated SNPs for women aged under 50 years: Australian Breast Cancer Family Registry. Cancer Epidemiology, Biomarkers & Prevention 25(2):359–365.
  7. Shieh Y, Hu D, Ma L, et al. (2016). Breast cancer risk prediction using a clinical risk model and polygenic risk score. Breast Cancer Research and Treatment 159(3):513–525.

Rare to very rare, high-risk genes

BRCA1 Gene mutation

Having a mutation or fault in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer.

BRCA1 gene faults are considered to be rare, high-risk gene mutations.

Over the course of her lifetime (up to 80 years of age), a woman who has a faulty BRCA1 gene has about a 70% chance of developing breast cancer and about a 44% chance of developing ovarian/fallopian tube/primary peritoneal cancer.

Not everyone who has a faulty BRCA1 gene will develop cancer. Only 5% of female breast cancers and 15% of invasive epithelial ovarian cancers can be explained by an inherited gene fault.

About 1 in 400 to 1 in 800 people have a BRCA1 gene fault.

Everyone has two BRCA1 genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty BRCA1 gene, or having a BRCA1 mutation. A BRCA1 gene fault can be inherited from either parent.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the BRCA1 (BReast CAncer susceptibility 1) gene is associated with an increased risk of breast cancer.

Women who have a BRCA1 mutation are estimated to have 5.91 (95% CI 5.25–6.67) times the risk of breast cancer compared to women who do not have a BRCA1 mutation.1 The relative risk is estimated to be higher among women with a family history of breast and/or ovarian cancer and among younger women compared with older women.

Women with a BRCA1 mutation have about a 72% chance of developing breast cancer and about a 44% chance of developing ovarian cancer over their lifetime. Men with a BRCA1 mutation have about a 9% chance of developing prostate cancer and about a 1% chance of developing breast cancer over their lifetime.2

Mechanisms

The BRCA1 gene is one of the two most well-known genes associated with risk of breast cancer, the other being BRCA2 (BReast Cancer gene 2). Approximately 1 in 400 to 1 in 800 of the population are estimated to carry a BRCA1 mutation.3 The frequency of BRCA1 and BRCA2 mutations is higher among some ethnic groups, for example Ashkenazi Jewish people.4 These gene mutations occur in 2.5 per cent of Ashkenazi Jews compared to 0.2 per cent of the general population.4

The increased cancer risk associated with a BRCA1 gene mutation is inherited in an autosomal dominant manner, i.e. the mutation can be inherited from either parent, and both women and men can be carriers.5

The BRCA1 gene codes for a protein that is involved in repairing damaged DNA. Mutations in the gene can allow DNA damage to accumulate.6

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that having a BRCA1 gene mutation was associated with increased odds of breast cancer of 5.91 (95% confidence interval [CI] 5.25–6.67).1 The analyses in this study were adjusted for age, ethnicity and family history of cancer.

A study of three prospective cohorts of BRCA1 mutation carriers identified through clinical genetics centresa, and that included Australian families, estimated the lifetime cumulative risk of breast cancer (to age 80 years) among BCRA1-mutation carriers as 72% (95% CI 65%–79%).7 Similar cumulative risk estimates have been provided by other studies. The cumulative risk of ovarian cancer (to age 80 years) was 44% (95% CI 36%–53%) for BRCA1 mutation carriers.7 

The incidence of breast cancer for BRCA1 mutation carriers increased rapidly in early adulthood until age 40 years, and then remained at a constant incidence until age 80 years.7

The standardised incidence ratio (SIR) was 16.6 (95% CI 14.7–18.7) for BRCA1 mutation carriers, overall.7 (SIR is the ratio of the observed number of cases to the expected number of cases in the population.) SIRs decreased with increasing age. For example, women aged 21–30 years, the SIR was estimated as 73.7 (95% CI 42.9–126.8) and for women aged 71-80 years, the SIR was estimated as 4.8 (95% CI 1.8–12.8).7

The risk of breast cancer in BRCA1 mutation carriers increases with the number of first- and second-degree relatives diagnosed with breast cancer.7,8

  1. Mutation carriers identified through clinical genetics centres have a stronger family history of cancer compared with mutation carriers identified through population-based sampling of cases

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. EviQ.2018. Facts for people and families with a faulty BRCA1 gene. https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3426-facts-for-people-and-families-with-a-faulty-b#what-is-the-risk-of-cancer-for-people-with-a-fault
  3. Hall MJ, Reid JE, Burbidge LA, et al. (2009). BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115(10): 2222–33.
  4. Bahar AY, Taylor PJ, Andrews L, et al. (2001). The frequency of founder mutations in the BRCA1, BRAC2 and APC genes in Australian Ashkenazi Jews: implications for the generality of US population data. Cancer 92(2): 440–445
  5. National Institutes of Health, National Library of Medicine (2018). BRCA1 gene, https://ghr.nlm.nih.gov/gene/BRCA1.
  6. National Cancer Institute (2018). Genetics of breast and gynecologic cancers (PDQ) – health professional version, www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq.
  7. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. (2017). Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA: The Journal of the American Medical Association 317(23):2402–2416.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.

BRCA2 Gene mutation

Having a mutation or fault in the BRCA2 gene is associated with an increased risk of breast and ovarian cancer.

BRCA2 gene faults are considered to be rare, high-risk gene mutations.

Over the course of her lifetime (up to 80 years of age), a woman who has a faulty BRCA2 gene has about a 69% chance of developing breast cancer and about a 17% chance of developing ovarian/fallopian tube/primary peritoneal cancer.

Not everyone who has a faulty BRCA2 gene will develop cancer. Only 5% of female breast cancers and 15% of invasive epithelial ovarian cancers can be explained by an inherited gene fault.

About 1 in 400 to 1 in 800 people have a BRCA2 gene fault.

Everyone has two BRCA2 genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty BRCA2 gene, or having a BRCA2 mutation. A BRCA2 gene fault can be inherited from either parent.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the BRCA2 (BReast CAncer susceptibility 2) gene is associated with an increased risk of breast cancer.

Women who have a BRCA2 gene mutation are estimated to have 3.31 (95% CI 2.95–3.71) times the risk of breast cancer compared to women who do not have a BRCA2 mutation.1 The relative risk is estimated to be higher among women with a family history of breast and/or ovarian cancer and among younger women compared with older women.

Women with a BRCA2 mutation have about a 69% chance of developing breast cancer and about a 17% chance of developing ovarian/ fallopian tube cancer/ primary peritoneal cancer over their lifetime. Men with a BRCA2 mutation have about a 15% chance of developing prostate cancer and about a 7% chance of developing breast cancer over their lifetime. Both men and women with a BRCA2 mutation have a less than 5% chance of developing pancreatic cancer over their lifetime.2,3

Mechanisms

The BRCA2 gene is one of the two most well-known genes associated with risk of breast cancer, the other being BRCA1 (BReast Cancer gene 1). Approximately 1 in 400 to 1 in 800 of the population are estimated to carry a BRCA2 gene fault.4 The frequency of BRCA1 and BRCA2 mutations is higher among some ethnic groups, for example Ashkenazi Jewish people.5 These gene mutations occur in 2.5 per cent of Ashkenazi Jews compared to 0.2 per cent of the general population.5

The increased cancer risk associated with a BRCA2 gene mutation is inherited in an autosomal dominant manner, i.e. the mutation can be inherited from either parent, and both women and men can be carriers.6

The BRCA2 gene codes for a protein that is involved in repairing damaged DNA. Mutations in the gene can allow DNA damage to accumulate.6

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that having a BRCA2 gene mutation was associated with increased odds of breast cancer of 3.31 (95% confidence interval [CI] 2.95–3.71).1 The analyses in this study were adjusted for age, ethnicity and family history of cancer.

A study of three prospective cohorts of BRCA2 mutation carriers identified through clinical genetics centresa, and that included Australian families, estimated the lifetime cumulative risk of breast cancer (to age 80 years) as 69% (95% CI 61–77%) for BRCA2 mutation carriers.7 Similar, although generally slightly lower, estimates have been provided by other studies.

The cumulative risk of ovarian cancer (to age 80 years) was 17% (95% CI 11%–25%) for BRCA2 mutation carriers.7

The incidence of breast cancer for BRCA2 mutation carriers increased rapidly in early adulthood until age 50 years, and then remained at a constant incidence until age 80 years.7

The standardised incidence ratio (SIR) was 12.9 (95% CI 11.1–15.1) for BRCA2 mutation carriers, overall.7 (SIR is the ratio of the observed number of cases to the expected number of cases in the population.) SIR decreased with increasing age. For example, for women aged 21–30 years, the SIR was estimated as 60.8 (95% CI 25.5–144.9) and for women aged 71–80 years, the SIR was estimated as 6.6 (95% CI 3.1–14.7).7

The risk of breast cancer in BRCA2 mutation carriers increases with the number of first- and second-degree relatives diagnosed with breast cancer.7,8

  1. Mutation carriers identified through clinical genetics centres have a stronger family history of cancer compared with mutation carriers identified through population-based sampling of cases.

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. eviQ.2018. Facts for people and families with a faulty BRCA1 gene. https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3426-facts-for-people-and-families-with-a-faulty-b#what-is-the-risk-of-cancer-for-people-with-a-fault
  3. eviQ. 2018. Risk management for a female BRCA2 mutation carrier. https://www.eviq.org.au/cancer-genetics/adult/risk-management/3814-brca1-or-brca2-risk-management-female
  4. Hall MJ, Reid JE, Burbidge LA, et al. (2009). BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115(10): 2222–33.
  5. Bahar AY, Taylor PJ, Andrews L, et al. (2001) The frequency of founder mutations in the BRCA1, BRAC2 and APC genes in Australian Ashkenazi Jews: implications for the generality of US population data. Cancer 92(2): 440–445
  6. National Institutes of Health, National Library of Medicine (2018). BRCA2 gene, https://ghr.nlm.nih.gov/gene/BRCA2.
  7. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. (2017). Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA: The Journal of the American Medical Association 317(23):2402–2416.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.

CDH1 Gene mutation

Having a mutation or fault in the CDH1 gene is associated with an increased risk of invasive lobular breast cancer. This is cancer that develops in the milk-producing glands of the breast.

CDH1 is considered to be a very rare, high-risk gene, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer.

Over the course of her lifetime (up to 80 years of age), a woman who has a CDH1 gene fault has about a 42% chance of developing lobular breast cancer. Men and women with a CDH1 gene mutation are also at very high risk of diffuse gastric cancer.

Summary of the evidence

Evidence classification: Convincing (lobular breast cancer)

There is convincing evidence that having a mutation or fault in the CDH1 gene is associated with an increased risk of lobular breast cancer.

Women who have a CDH1 gene mutation are estimated to have 17.7 times (95% CI 7.68–40.1) the risk of lobular breast cancer compared to women who do not have a CDH1 mutation.1

Mechanism

The CDH1 gene codes for the protein epithelial cadherin (E-cadherin), which is found in the membrane that surrounds epithelial cells. E-cadherin is a tumour suppressor protein that prevents cells from growing and dividing too rapidly or in an uncontrolled way.2 When the CDH1 gene is faulty, the protein stops working, which can lead to cancer.

Inherited (germline) mutations in the CDH1 gene are also associated with hereditary diffuse gastric cancer (HDGC).

Evidence

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the CDH1 gene were strongly associated with increased risk of lobular breast cancer, with an odds ratio (OR) of 17.7 (95% confidence interval [CI] 7.68–40.10). However, CDH1 mutations were not associated with risk of ductal breast cancer (OR 1.34, 95% CI 0.66–2.68).1

All other studies were not population-based but were based on gene panel tests in, families with hereditary breast cancer disposition, and predominantly among families with known HDGC. 

A case-control study, using results of germline multigene panel tests, found that CDH1 mutations were associated with increased risk of breast cancer (OR 5.34; 95% CI 1.60–20.94).3 In a large case series analysis among women with familial CDH1 mutation-positive HDGC, CDH1 germline mutations were associated with increased risk of breast cancer, with relative risks of 7.7 for age 10–49 years and 7.4 for age ≥50 years.4 The cumulative risk of breast cancer to age 80 years for women with a CDH1 mutation and familial CDH1 mutation-positive HDGC was 42% (95% CI 23%–68%).4

A similarly increased risk of breast cancer associated with mutations in the CDH1 gene in women with familial HDGC is supported by two smaller studies.5,6

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. United States National Library of Medicine (2018). Genetics Home Reference: CDH1 gene, https://ghr.nlm.nih.gov/gene/CDH1.
  3. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  4. Hansford S, Kaurah P, Li-Chang H, et al. (2015). Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncology 1(1):23–32.
  5. Kaurah P, MacMillan A, Boyd N, et al. (2007). Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA: The Journal of the American Medical Association 297(21):2360–2372.
  6. Pharoah PD, Guilford P, Caldas C et al. (2001). Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121:1348–1353.

PTEN Gene mutation

Having a mutation or fault in the PTEN gene is associated with an increased risk of breast cancer.

PTEN is considered to be a very rare, high-risk gene, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer.

Women who have a PTEN gene fault may have about 6 times the risk of breast cancer compared to women who do not have a PTEN gene fault.

Everyone has two PTEN genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty PTEN gene, or having a PTEN mutation. People with a faulty PTEN gene are known to have Cowden syndrome. Cowden syndrome is part of the PTEN Hamartoma syndrome. PTEN mutations are extremely rare.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the PTEN gene is associated with an increased risk of breast cancer.

Women who have a PTEN gene mutation are estimated to have 5.83 (95% CI 2.43–14.0) times the risk of breast cancer compared to women who do not have a mutation in this gene.1 The large confidence intervals reflect the rarity of PTEN mutations, hence the magnitude of breast cancer risk associated with a PTEN mutation is uncertain.1,2

Lifetime risks have been estimated to be 67% to 60 years of age, 77% to 70 years of age, and 85% over a lifetime.

Mechanism

The PTEN gene codes for a ‘phosphatase and tensin homolog’. This protein acts as a tumour suppressor protein, which helps to prevent cells from growing and dividing too rapidly, or in an uncontrolled way.3,4

Pathogenic mutations in PTEN are extremely rare, estimated to occur in approximately one in 200,000 individuals.5

Cowden syndrome (part of the PTEN hamartoma syndromes) is a rare autosomal dominant condition caused by heritable mutations in the PTEN gene. It is characterised by multiple non-cancerous growths (hamartomas) and an increased risk of developing certain cancers.6

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the PTEN gene were associated with increased odds of breast cancer of 5.83 (95% confidence interval [CI] 2.43–14.0).1 The analyses in this study were adjusted for age, ethnicity and family history of cancer.

Another case-control study, using results of germline multigene panel tests of women with histories suggestive of hereditary breast cancer predisposition, also found that PTEN mutations were associated with increased risk of breast cancer (odds ratio [OR] 12.66, 95% 2.01–258.89).2

Several studies have estimated the absolute lifetime risk of breast cancer associated with PTEN gene mutations by comparing breast cancer incidence among women with PTEN Hamartoma Tumour Syndrome (PHTS) and/or an identified PTEN mutation compared to breast cancer incidence in the general population. Risk estimates for absolute lifetime risk of breast cancer were 67% (by 60 years of age),4 77% (by 70 years of age),7 and 85% (over a lifetime).8

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
  2. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  3. United States National Library of Medicine (2018). Genetics Home Reference: PTEN gene, https://ghr.nlm.nih.gov/gene/PTEN.
  4. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. (2014). Cancer risk and genotype–phenotype correlations in PTEN hamartoma tumor syndrome. Familial Cancer 13:57–63.
  5. Ngeow J, Sesock K, Eng C (2017). Breast cancer risk and clinical implications for germline PTEN mutation carriers. Journal of Breast Cancer Research and Treatment 165: 1–8.
  6. eviQ 2018. Risk management for PTEN hamartoma syndrome. https://www.eviq.org.au/cancer-genetics/risk-management/546-risk-management-for-pten-hamartoma-syndrome##lifetime-risk-of-cancer
  7. Bubien V, Bonnet F, Brouste V, et al. (2013). High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. Journal of Medical Genetics 50:255–263.
  8. Tan MH, Mester JL, Ngeow J, et al. (2012). Lifetime cancer risks in individuals with germline PTEN mutations. Clinical Cancer Research 18(2):400–407.

STK11 Gene mutation

A mutation or fault in the STK11 gene causes a rare genetic disorder known as Peutz–Jeghers Syndrome (PJS). Women with PJS have an increased risk of breast cancer.

STK11 is considered to be a very rare, high-risk gene, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer, including breast cancer.

Women with PJS have about 6 times the risk of breast cancer compared to women in the general population.

Everyone has two STK11 genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty STK11 gene, or having an STK11 mutation. People with a faulty STK11 gene have Peutz-Jeghers syndrome. PJS is a rare genetic disease that occurs in 1 in 200,000 to 1 in 8300 people.

For women who have a mutation in the STK11 gene in but no clinical signs or symptoms of PJS, the evidence is inconclusive regarding any association with increased risk of breast cancer.

Summary of the evidence

Evidence classifications:

  • Convincing (women with Peutz-Jeghers Syndrome)
  • Inconclusive (women with STK11 gene mutation but not PJS)

There is convincing evidence that having Peutz–Jeghers Syndrome (PJS) is associated with an increased risk of breast cancer. The majority of women with PJS have a mutation in the STK11 gene.

Women who have PJS are estimated to have about 6 times the risk of breast cancer as the general population.1-4,5

Both men and women with PJS have about a 40% chance of developing bowel cancer and about a 25% chance of developing pancreatic cancer over their lifetime. Women with PJS have about a 45% chance of developing breast cancer and about a 20% chance of developing cervical cancer or ovarian cancer over their lifetime. Not everyone with PJS will develop cancer.5

The evidence for any association between mutations in the STK11 gene in women with no clinical symptoms of PJS and risk of breast cancer is inconclusive. Only one large gene panel sequencing study was identified.1 No association with breast cancer was found, however only very small numbers of STK11 gene mutations were detected.

Mechanisms

PJS is a rare autosomal dominant genetic disease that occurs in 1 in 200,000 to 1 in 8,300 people. It is associated with noncancerous growths in the gastrointestinal tract and by mucocutaneous pigmentation. It is also associated with increased risk of some types of cancer, especially colorectal cancer. In most people with PJS, the disease is caused by an inherited mutation in the STK11 gene.

The STK11 gene codes for the protein serine threonine kinase 11. This enzyme acts as a tumour suppressor protein – it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the gene can interfere with this function.5

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found no association between mutations in the STK11 gene and invasive breast cancer risk (odds ratio [OR] 4.41, 95% confidence interval [CI] 0.66–29.6).1 Only very small numbers of STK11 gene mutations were detected in the panel (5 in all women, and 2 in women with breast cancer).

A systematic review of cancer risk in PJS patients reported increased breast cancer risk (from three studies) associated with PJS.6  The cumulative risk of breast cancer wsa 45% at 70 years of age. One of the included case studies estimated an approximate 6-fold increased risk of breast cancer among 419 women with PJS.4 

Higher risk estimates but with wide confidence intervals have been observed in other studies. A meta-analysis found an increased risk of breast cancer in 104 women with PJS.2 The relative risk (RR) of breast cancer in women with PJS was 15.2 (95% CI 7.6–27.0) compared with the general population. A retrospective cohort study also found an increased risk of breast cancer in 119 women with PJS (RR 12.5, 95% CI 5.1–26.0).3

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
  2. Giardiello FM, Brensinger JD, Tersmette AC, et al. (2000). Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119:1447–1453.
  3. Resta N, Pierannunzio D, Lenato GM, et al. (2013). Cancer risk associated with STK11/LKB1 germline mutations in Peutz–Jeghers syndrome patients: results of an Italian multicentre study. Digestive and Liver Disease 45:606–611.
  4. Hearle N, Schumacher V, Menko FH, et al. (2006). Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. Clinical Cancer Research 12(1):3209–3215.
  5. eviQ. 2018. Facts for people and families with Peutz-Jeghers syndrome. https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3431-facts-for-people-and-families-with-peutz-jegh#what-is-the-risk-of-cancer-and-other-features-of-p
  6. United States National Library of Medicine (2018). Genetics Home Reference: STK11 gene, https://ghr.nlm.nih.gov/gene/STK11#.

TP53 Gene mutation

Having a mutation or fault in the TP53 gene is associated with an increased risk of breast cancer.

TP53 is considered to be a very rare, high-risk gene mutation, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer, including breast cancer.

Women with a mutation in the TP53 gene have about 5 times the risk of breast cancer as women without the TP53 gene mutation. The increase in risk is higher among women with a mutation in the TP53 gene who are younger than 40 years.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the TP53 gene is associated with an increased the risk of breast cancer.

Women who have a TP53 mutation are estimated to have 5.37 times the risk of breast cancer compared to women in the general population (OR 5.37, 95% CI 2.78-10.4).1 The increased risk of breast cancer associated with a TP53 mutation is higher for women at a younger age (≤40 years) than at an older age.2

Mechanisms

TP53 is a tumour suppressor gene that codes for tumour protein p53. The protein has a critical role in the cell in repairing DNA damage and preventing cells from growing in an uncontrolled way.3,4

The frequency of TP53 gene mutations in the general population is uncertain, with estimates varying from 1 in 20,000 to 1 in 5000.3

Inherited mutations in the TP53 gene are associated with Li–Fraumeni syndrome (LFS). LFS is a rare condition inherited in an autosomal dominant pattern. It is characterised by a high lifetime risk of malignancy;5 the commonest cancers are soft tissue sarcomas, particularly in children and young adults, and early-onset breast cancer in women.3

Germline TP53 mutations have been found in approximately 4–8% of women with early-onset breast cancer without a family history of LFS.6,7

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the TP53 gene were associated with an odds ratio (OR) for invasive ductal breast cancer of 5.37 (95% confidence interval [CI] 2.78–10.4).1

Another case-control study, using results of germline multigene panel tests, also found that TP53 mutations were associated with increased risk of breast cancer.2 The OR was 2.58 (95% CI 1.39–4.90) overall and 8.25 (95% CI 4.27–15.84) for women aged ≤40 years at diagnosis of breast cancer.2

Increased risk of breast cancer has also been found in a pooled analysis8 and a prospective cohort study8 among women with a family history of LFS. The cohort study found a cumulative incidence of breast cancer for women with a TP53 gene mutation of approximately 85% by age 60 years.6 In a case series study of French women with a history suggestive of LFS, breast cancer was observed in 79% of women with a TP53 gene mutation, and 31% of these women also developed breast cancer in the other breast.9

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  3. Schon K, Tischkowitz M (2017). Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Research and Treatment 167(2): 417–423.
  4. United States National Library of Medicine (2018). Genetics Home Reference: TP53 gene, https://ghr.nlm.nih.gov/gene/TP53.
  5. eviQ. 2018. Risk management for adults with a TP53 mutation. https://www.eviq.org.au/cancer-genetics/risk-management/749-risk-management-for-adults-with-a-tp53-mutatio##cancer-risk-management-guidelines
  6. Mai PL, Best AF, Peters JA, et al. (2016). Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni Syndrome cohort. Cancer 122(23):3673–3681.
  7. Mouchawar J, Korch C, Byers T, et al. (2010). Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Research 70(12): 4795–4800.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
  9. Bougeard G, Renaux-Petel M, Flaman JM, et al. (2015). Revisiting Li–Fraumeni syndrome from TP53 mutation carriers. Journal of Clinical Oncology 33(21):2345–2352.

Rare, moderate-risk genes

ATM Gene mutation

Having a mutation or fault in the ataxia-telangiectasia mutated (ATM) gene is associated with an increased risk of breast cancer.

ATM is considered to be a rare, moderate-risk gene mutation, meaning that there is a moderately increased risk of breast cancer. About 1% of men and women carry a fault in ATM*.

Women who have an ATM gene fault have about 1.7 times higher risk of breast cancer compared to women in the general population. There is one specific gene fault associated with a somewhat higher risk of breast cancer. Most women who carry an ATM gene fault will not develop breast cancer.

* If two mutation carriers have a child, there is a 1 in 4 chance that the child will have a very rare, serious condition known as ataxia-telangiectasia (AT). AT is a rare genetic disorder that affects the nervous system and other body systems. It is caused by having two ATM gene faults, one from each parent. Most children with AT are diagnosed between the ages of 1 to 4 years. Carriers of a single mutation in the ATM gene do not get ataxia-telangiectasia.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the ATM gene is associated with an increased the risk of breast cancer.

Women who are heterozygous carriers of an ATM mutation are estimated to have 1.74 (95% CI 1.46–2.07) times the risk of breast cancer compared to women without an ATM mutation.1 The risk of breast cancer is higher if a woman carrying the ATM gene mutation has relatives with ataxia-telangiectasia (RR 3.0, 95% CI 2.1–4.5) and the risk is also higher among younger women than older women.2

Mechanisms

The ATM gene codes for a protein that has a key role in DNA repair. Mutations in the gene can allow DNA damage to accumulate, which can lead to formation of cancerous tumours. Approximately 1% of the population are heterozygous carriers of an ATM gene mutation.

Homozygous ATM gene mutations are associated with ataxia-telangiectasia (A-T), a rare autosomal recessive genetic disease occurring in 1 in 40,000 to 1 in 100,000 people, which begins in childhood and affects the nervous system. A-T increases the risk of several cancers, including leukaemia and lymphoma.

Evidence 

Recent studies include a large case-control study using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk. This study found that heterozygous carriers of an ATM gene mutation had a risk of breast cancer that was 1.74 times (95% confidence interval [CI] 1.46–2.07) higher than in women without the mutation.1 Several other case-control studies and meta-analyses of cohort studies among A-T family members have also found that breast cancer risk is increased in women who are heterozygous carriers of an ATM mutation.

Two meta-analyses of cohort studies2,3 have shown that the increased risk of breast cancer is higher among women with familial A-T who are heterozygous carriers of an ATM mutation (relative risk [RR] 3.0, 95% CI 2.1–4.5 and RR 2.8, 95% CI 2.2–3.7; respectively). The increased breast cancer risk was shown to be substantially higher for heterozygous younger women (aged less than 45–55 years) in A-T families than for women aged older than 55 years in A-T families (RR 7.0, 95% CI 4.1–11.9 versus RR 2.1, 95% CI 1.2–3.6).2

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
  2. van Os NJ, Roeleveld N, Weemaes CM, et al. (2016). Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clinical Genetics 90:105–117.
  3. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.

 

CHEK2 Gene mutation

Having a mutation or fault in the CHEK2 gene is associated with an increased risk of breast cancer.

CHEK2 is considered to be a rare, moderate-risk gene, meaning that a fault in this gene is associated with a moderately increased risk of breast cancer.

Women who have a CHEK2 gene fault have about 2 times the risk of breast cancer compared to women in the general population.

Few women are carriers of a CHEK2 gene fault and most women who carry a CHEK2 gene fault will not develop breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the CHEK2 gene is associated with an increased risk of breast cancer.

Women who are carriers of a CHEK2 mutation are estimated to have 1.99 (95% CI 1.70–2.33) times the risk of breast cancer compared to women without a CHEK2 mutation.1

The estimated risk associated with a CHEK2 gene mutation depends on the specific type of mutation, with the increased risk for the most studied variant, CHEK 1100delC mutation, estimated to be between 2.31 (95% CI 1.88–2.85)2 and 3.10 (95% CI 2.59–3.71)3 times the risk of women without this mutation.

Mechanisms

The CHEK2 gene codes for the checkpoint kinase 2 (CHK2) protein. This protein is a tumour suppressor protein, which prevents cells from growing and dividing too rapidly or in an uncontrolled way.4 Mutations in the CHEK2 gene can allow cells with damaged DNA to continue dividing, leading to the development of cancer.

The CHEK 1100delC mutation, which has been most extensively studied, occurs mainly in individuals of northern and eastern European descent, and has a frequency of approximately 1% in these populations.5

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the CHEK2 gene were associated with increased breast cancer risk.1 The odds ratio (OR) was 1.99 (95% confidence interval [CI] 1.70–2.33), adjusted for family history of breast cancer.

Another large case-control study, using results of germline multigene panel tests found that CHEK2 mutations were associated with an increased risk of breast cancer in women of European ancestry (OR 2.26, 95% CI 1.89–2.72).2

A meta-analysis found an approximately three times increased risk of breast cancer associated with CHEK2 mutations among high-risk women.6 A similarly increased risk associated with CHEK2 mutations was also found in a UK population-based case-control study, with a stronger association found for oestrogen-receptor-positive (ER+) breast cancer than for oestrogen-receptor-negative (ER–) breast cancer.7

Four meta-analyses3,8-10 and a large case-control study2 have indicated that the CHEK 1100delC mutation is associated with increased breast cancer risk, with risk estimates ranging from 2.31 (95% CI 1.88–2.85)2 to 3.10 (95% CI 2.59–3.71)3.

An increased risk of breast cancer has also been found with several other, but not all, specific CHEK2 gene mutations.3,11,12

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  3. Zhang B, Beeghly-Fadiel A, Long J, et al. (2011). Genetic variants associated with breast cancer risk: comprehensive field synopsis, meta-analysis, and epidemiologic evidence. Lancet Oncology 21(5):477–488.
  4. United States National Library of Medicine (2018). Genetics Home Reference: CHEK2 gene, https://ghr.nlm.nih.gov/gene/CHEK2.
  5. Meijers-Heijboer, van den Ouweland A, Klijn J, et al. (2002). Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genetics 31(1):55–59.
  6. Aloraifi F, McCartan D, McDevitt T, et al. (2015). Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. Cancer Genetics 208:455–463.
  7. Decker B, Allen J, Luccarini C, et al. (2017). Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of Medical Genetics 54:732–741.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
  9. Yang Y, Zhang F, Wang Y et al. (2012). CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls. Asian Pacific Journal of Cancer Prevention 13:3501–3505.
  10. Weischer M, Bojesen SE, Ellervik C, et al. (2008). CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. Journal of Clinical Oncology 26(4):542–548.
  11. Southey MC, Goldgar DE, Wingvist R, et al. (2016). PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of Medical Genetics 53:800–811.
  12. Liu C, Wang Y, Wang QS et al. (2012). The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention 13:1355–1360.

PALB2 Gene mutation

Having a mutation or fault in the PALB2 gene is associated with an increased risk of breast cancer.

PALB2 is considered to be a rare, moderate-risk gene mutation, meaning that there is a moderately increased risk of breast cancer.

Women who have a PALB2 gene fault have at least 3 times the risk of breast cancer compared to women in the general population. PALB2 gene mutations may also be linked to an increased risk of pancreatic cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the PALB2 gene is associated with an increased risk of breast cancer.

Women who have a PALB2 mutation are estimated to have 3.39 (95% CI 2.79–4.12)1 times the risk of breast cancer compared to women without a PALB2 mutation.1 Higher risks of breast cancer associated with a PALB2 mutation have been estimated in other studies conducted among women with histories suggestive of hereditary breast cancer predisposition.

Mechanisms

The PALB2 gene codes for the ‘Partner and localizer of BRCA2’ (PALB2) protein. The PALB2 protein interacts with the BRCA1 and BRCA2 proteins. This complex plays a key role in DNA repair. Mutations in the PALB2 gene disrupt this repair pathway, and can thereby increase the risk of cancer.2

Approximately 0.2% of the population are estimated to carry a mutation in the PALB2 gene.3

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the PALB2 gene were associated with an increased risk of breast cancer, with an odds ratio [OR] of 3.39 (95% confidence interval [CI] 2.79–4.12), adjusted for family history of cancer.1

A population-based case-control study of 18,575 women in the United Kingdom indicated an odds ratio of 4.69 (95% CI 2.27–9.68) between women with PALB2 mutations and increased breast cancer risk.4

Risk estimates are higher among studies which have included women at higher risk of breast cancer due to a family history of cancer. For example, a large case-control study using results of multigene panel tests among women with clinical histories suggestive of hereditary breast cancer predisposition, found that PALB2 mutations were associated with 6.25 times increased risk of breast cancer (95% CI 4.82–8.14).5

In a meta-analysis6 of three studies, including a study among women with a family history of breast cancer and a germline PALB2 mutation,7 the estimated relative risk of breast cancer associated with PALB2 gene mutations was 5.3 (90% CI 3.0–9.4). A similarly higher estimate of breast cancer risk associated with mutations in the PALB2 gene has also been found in another meta-analysis of case-control studies among high-risk groups of women.8

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. Cybulski C, Kluźniak W, Huzarshki T, et al. (2015). Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncology 16:638–644.
  3. United States National Library of Medicine (2018). Genetics Home Reference: PALB2 gene, https://ghr.nlm.nih.gov/gene/PALB2.
  4. Decker B, Allen J, Luccarini C, et al. (2017). Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of Medical Genetics 54:732–741.
  5. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  6. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
  7. Antoniou AC, Casadei S, Heikkinen T, et al. (2014). Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine 371(6):497–506.
  8. Aloraifi F, McCartan D, McDevitt T, et al. (2015). Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. Cancer Genetics 208(9):455–463.

Reproductive factors

Reproductive factors can have an important effect on a woman’s risk for breast cancer by influencing her hormone levels, which, over a woman’s lifetime, can be associated with increased or decreased risk of breast cancer. 

Factors associated with an increased risk of breast cancer risk include age at first period, whether or not a woman has had children, her age when she had her first child, her reproductive hormone levels and her age at menopause.

Age when periods started

Starting menstrual periods at a younger age is associated with an increased risk of breast cancer. Women who had their first period when younger than 12 years have a slightly higher risk of breast cancer than women who had their first period at 12 years or older.

The risk of breast cancer increases by about 5% for each year younger a woman is when she starts having periods. For example, someone whose periods start when she is 10 years old has about a 19% increased risk of breast cancer than someone who starts having periods when she is 13 years old.

The way in which age when periods start is associated with the risk of breast cancer probably relates to hormonal factors. Women who start having periods at a younger age have a higher lifetime exposure to the hormones oestrogen and progesterone. This can increase the risk of breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that earlier age when menstrual periods start (menarche) is associated with an increased risk of breast cancer.

The risk of breast cancer is estimated to increase by 5% (RR 1.05, 95% CI 1.04–1.06) for each year younger a woman is at menarche.1

Mechanisms

Early age at menarche increases a woman’s lifetime exposure to oestrogen and progesterone, which drive mitotic activity in the breast. A greater total extent of breast mitotic activity is thought to increase the risk of breast cancer.

Early age at menarche also increases the time between menarche and a woman’s first pregnancy, when breast cells undergo differentiation. Since undifferentiated breast cells are more likely to undergo malignant transformation, a longer period before cells differentiate is thought to increase the risk of breast cancer.

Evidence 

The World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) lists early menarche as an established cause of breast cancer and states that ‘early menarche [before the age of 12] increases lifetime exposure to oestrogen and progesterone and the risk of breast cancer’ and that ‘late menarche decreases the risk of breast cancer’.2

A large pooled analysis conducted by the Collaborative Group on Hormonal Factors in Breast Cancer used data from 117 international studies. Risk of breast cancer increased by a factor of 1.05 (95% confidence interval [CI] 1.044–1.057) for each year younger a woman was at menarche.1 The mean age of menarche was 13.1 years in the combined dataset. Compared with women aged 13 years at menarche, the relative risk (RR) for women aged 12, 11 and less than 11 years were 1.07 (95% CI 1.05–1.09), 1.09 (95% CI 1.06–1.12) and 1.19 (95% CI 1.13–1.25), respectively; and women aged 14, 15 and 16 years or older 0.98 (95% CI 0.96–1.00), 0.92 (95% CI 0.89–0.95) and 0.82 (95% CI 0.79–0.85), respectively.1 The association was stronger for lobular than for ductal tumours, but there were no significant differences by oestrogen receptor status of the cancer.

Data from two more recent cohort studies3,4 generally support these findings.

Read the full Review of the Evidence

References
  1. Collaborative Group on Hormonal Factors in Breast Cancer (2012). Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncology 13(11):1141–1151.
  2. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  3. Dartois L, Fagherazzi G, Baglietto L, et al. (2016). Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: estimates from the E3N‐EPIC cohort. International Journal of Cancer 138(10):2415–2427.
  4. Bodicoat DH, Schoemaker MJ, Jones ME, et al. (2014). Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study. Breast Cancer Research 16(1):R18.

Age when first child was born

Being older at the birth of a woman's first child is associated with an increased risk of breast cancer.

For each extra year older a woman is when she has her first child, the risk of breast cancer increases by about 3%. For example, women who have their first child when they are aged 30 years old have about a 20% higher risk of breast cancer than women who have their first child when they are 25–29 years old.

When a woman becomes pregnant for the first time, changes occur in cells in the breast which mean that these cells are less likely to become cancer cells. The younger a woman is when she becomes pregnant for the first time, the less chance there is for the cells in her breasts to become cancer cells. This may be one way that having a first child at a later age is associated with an increased risk of breast cancer.

In addition, full-term pregnancies reduce the levels of certain hormones in the body. This could also explain some of the association between age at birth of the first child and the risk of breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that older age at first birth is associated with an increased risk of breast cancer.

A woman’s risk of breast cancer is estimated to increase by about 3% for each year older she is at the birth of her first child (RR 1.03, 95% CI 1.02–1.05).1

Mechanisms

Before a woman’s first full-term pregnancy, the breast has a high proportion of undifferentiated epithelial cells.2 These undifferentiated cells are more likely to undergo malignant transformation than terminally differentiated cells. The shorter the time between menarche (onset of menstruation) and first birth, the less time these undifferentiated breast cells are at risk of carcinogenesis.2

Full-term pregnancies also cause long-term reductions in levels of circulating sex hormones. This may contribute to the association between age at birth of the first child and the risk of breast cancer.2

Evidence 

The World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) states that ‘a first pregnancy/birth over the age of 30 increases the risk of breast cancer’. The WCRF/AICR also noted that ‘pregnancy before the age of 30 decreases the risk of breast cancer’, overall indicating age at first birth as an established risk factor for breast cancer.3

A meta-analysis of five studies reported a relative risk (RR) for breast cancer overall of 1.20 (95% confidence interval [CI] 1.02–1.42) for women aged 30 years or older at first birth compared with women aged 25–29 years at first birth.4

A more recent meta-analysis of 3 cohort studies and 9 case–control studies did not report on a risk of breast cancer overall. It found that women aged >24 years compared with women aged ≤24 years at first birth had an increased risk of breast cancer of the luminal subtypes (RR 1.15, 95% CI 1.00–1.32).5 No association was seen for HER2 or triple-negative subtypes of breast cancer.

Two large cohort studies have also found an increased risk of breast cancer in women who are older at birth of their first child. One found that women aged ≥35 years at first birth had an increased risk of oestrogen receptor-positive, progesterone receptor-positive (ER+PR+) breast cancer compared with women aged ≤19 years at first birth, but not of ER-PR- breast cancer.3 In the Nurses Health Studies a dose–response relationship was observed between age at first birth and risk of breast cancer (RR per 1 year increase in age at first birth 1.03; 95% CI 1.02–1.03).1 The association was seen for luminal A breast cancer but not for HER2+ breast cancer.

Read the full Review of the Evidence

References
  1. Sisti JS, Collins LC, Beck AH, et al. (2016). Reproductive factors in relation to molecular subtypes of breast cancer: results from the nurses’ health studies. International Journal of Cancer 138:2346–2356. doi:10.1002/ijc.29968
  2. Ritte R, Tikk K, Lukanova A, et al. (2013). Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study. BMC Cancer 13(1):584.
  3. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  4. Nelson HD, Zakher B, Cantor A, et al. (2012). Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Annals of Internal Medicine 156(9):635–648.
  5. Lambertini M, Santoro L, Del Mastro L, et al. (2016). Reproductive behaviors and risk of developing breast cancer according to tumor subtype: a systematic review and meta-analysis of epidemiological studies. Cancer Treatment Reviews 49:65–76.

Reproductive hormone levels

Higher levels of the naturally-occurring (endogenous) hormone oestrogen are associated with an increased risk of postmenopausal breast cancer.

Naturally-occurring hormones testosterone and insulin-like growth factor 1 (IGF-1) are also associated with an increased risk of breast cancer.

There is no conclusive evidence that naturally-occurring oestrogen is associated with an increased risk of premenopausal breast cancer. There is no conclusive evidence that the hormones progesterone, sex hormone binding globulin [SHBG] and prolactin are associated with an increased risk of breast cancer. Studies that have looked at these factors are limited and inconsistent.

Sex hormones (also known as steroid hormones) are produced naturally by women’s bodies and include oestrogens, progesterone and androgens (such as testosterone). These hormones affect sexual development during puberty, the menstrual cycle and reproduction. Levels of these hormones naturally decline when a woman goes through menopause.

The more a woman is exposed to oestrogen during her lifetime, the higher her risk of breast cancer. Longer exposure to oestrogen promotes the growth of breast cancer cells.

Summary of the evidence

Evidence classification

  • Convincing:
    • oestrogen (postmenopausal breast cancer),
    • testosterone,
    • insulin-like growth factor 1 [IGF-1]
  • Inconclusive:
    • oestrogen (premenopausal breast cancer),
    • sex hormone binding globulin [SHBG]
    • progesterone,
    • prolactin

There is convincing evidence from large pooled analyses that higher circulating levels of oestrogen, testosterone, and IGF-1 are associated with an increased risk of postmenopausal breast cancer (OR 2.15, 95% CI 1.87–2.461; OR 2.04, 95% CI 1.76–2.371, and OR 1.28, 95% CI 1.14–1.442; for highest versus lowest levels, respectively). 

The evidence for an association between circulating levels of oestrogen and risk of premenopausal breast cancer, progesterone and SHBG and risk of breast cancer, is inconclusive. Findings are inconsistent. For prolactin the evidence is limited in amount. 

Mechanisms

Sex hormones or steroid hormones that occur naturally in women’s bodies (endogenous) include oestrogens, progesterone, and androgens such as testosterone. Levels of these hormones decline when a woman goes through menopause. Sex hormone binding globulin (SHBG) is a protein that binds oestrogen and testosterone, transports them in the bloodstream and influences their bioavailability to cells.  Insulin-like growth factor 1 [IGF-1] is a hormone which plays an important role in childhood growth and development and is involved in adult metabolism. 

A woman’s lifetime exposure to circulating oestrogen and progesterone appears to play a role in the development of breast cancer. Oestrogen, progesterone and growth factors such as IGF-1 promote proliferation of breast cells, decreased cell death (apoptosis) and possibly DNA damage.3 In addition, research suggests that in breast cancer, the hormone progesterone can have a negative effect on cell growth.7 Androgens have more complex actions, with both inhibitory and proliferative effects on breast cells.4 Levels of SHBG are inversely related to BMI, and any effect of SHBG on breast cancer risk may be mediated through the level of body fat.5 Prolactin might affect breast cancer risk by increasing cell proliferation and reducing apoptosis, as well as through synergistic effects with oestrogen and progesterone in the breast.6,7

Evidence 

Endogenous steroid hormones and sex hormone binding globulin

The Endogenous Hormones and Breast Cancer Collaborative Group (EHBCCG) conducted a pooled analysis of individual participant data from 7 prospective studies among premenopausal women.8 It found increased risk of breast cancer for circulating oestradiol (odds ratio [OR] for doubling of levels 1.19; 95% confidence interval [CI] 1.06–1.35), free oestradiol (OR 1.17; 95% CI 1.03–1.33), oestrone (OR 1.27, 95% CI 1.05–1.54) and testosterone (OR 1.18; 95% CI 1.03–1.35).  However, there were inconsistent findings across the studies regarding oestrogens and an earlier pooled analysis of many of the same studies did not show an association between levels of oestrogens and risk of premenopausal breast cancer. Luteal phase progesterone and SHBG were not associated with breast cancer risk.1

The EHBCCG also analysed data from 18 prospective studies and found a positive association between levels of circulating oestradiol, oestrone and testosterone and risk of postmenopausal breast cancer, with approximately twice the odds of breast cancer for highest versus lowest levels of oestradiol, oestrone and testosterone.9 An earlier analysis showed that SHBG was associated with a borderline decreased risk of postmenopausal breast cancer for the highest versus lowest levels.2 Significant dose–response relationships were seen for all hormones.

Associations of breast cancer with endogenous oestrogens and androgens are strongest for oestrogen-receptor-positive (ER+) breast cancers, although associations have been reported with ER- breast cancers.

Prolactin

A prospective study has shown an increased breast cancer risk for higher prolactin measured within 10 years of breast cancer diagnosis (relative risk [RR] 1.20, 95% CI 1.03–1.40 for highest vs lowest quartiles).6 The association was stronger for ER+ breast cancer and for postmenopausal women. Another cohort study also found a positive association between prolactin levels and risk of postmenopausal breast cancer (OR 1.29; 95% CI 1.05–1.58 for highest vs lowest quartile).7 The risk was significant only in women who used postmenopausal hormone therapy.7

Insulin-like growth factor 1

In a pooled analysis of prospective cohort studies by the EHBCCG, plasma IGF-1 concentrations were associated with increased breast cancer risk for women in the highest versus the lowest quintile of IGF-1 concentration (OR 1.28; 95% CI 1.14–1.44).10 The association was only significant for ER+ breast cancer.

More recent data from a cohort study have also shown an association only for ER+ breast cancer, and for ER+ postmenopausal but not premenopausal breast cancer.11

Read the full Review of the Evidence

References
  1. Walker K, Bratton DJ, Frost C (2011). Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis. British Journal of Cancer 105(9):1451–7.
  2. Endogenous Hormones and Breast Cancer Collaborative Group (2002). Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. Journal of the National Cancer Institute 94(8):606–616.
  3. Fortner RT, Eliassen AH, Spiegelman D, et al. (2013) Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses’ Health Study II. Breast Cancer Research 15: R19.
  4. Carroll JS, Hickey TE, Tarulli GA, et al. (2017). Deciphering the divergent roles of progestogens in breast cancer. Nature Reviews Cancer 17 (1):54–64
  5. Interagency Breast Cancer and Environmental Research Coordinating Committee (2013). Breast cancer and the environment: prioritizing prevention, report of the Interagency Breast Cancer and Environmental Research Coordinating Committee, National Institutes of Health, Bethesda, Maryland, https://www.niehs.nih.gov/about/assets/docs/ibcercc_full_508.pdf.
  6. Tworoger SS, Eliassen AH, Zhang X, et al. (2013). A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Research 73(15):4810–4819.
  7. Tikk K, Sookthai D, Johnson T, et al. (2014). Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort. Annals of Oncology 25(7):1422–1428.
  8. Endogenous Hormones and Breast Cancer Collaborative Group (2013). Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncology 14(10):1009–1019.
  9. Endogenous Hormones and Breast Cancer Collaborative Group (2015). Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: reanalysis of eighteen prospective studies. Steroids 99:49–55.
  10. Endogenous Hormones and Breast Cancer Collaborative Group (2010). Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncology 11(6):530–542.
  11. Kaaks R, Johnson T, Tikk K, et al. (2014). Insulin-like growth factor 1 and risk of breast cancer by age and hormone receptor status: a prospective study within the EPIC cohort. International Journal of Cancer 134(11):2683–2690.

Not having had children

Not having had children is associated with an increased risk of breast cancer.

Women who have not had any children have about a 16% greater risk of breast cancer than women who have had at least one child.

When a woman has a full-term pregnancy, changes occur in cells in the breast in preparation for breastfeeding. These changes are thought to make the cells less likely to become cancer cells. This might explain why women who have not had children have a higher risk of breast cancer than women who have had children.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that not having had children is associated with an increased risk of breast cancer.

Women who have not had any children have about a 16% greater risk of breast cancer than women who have had at least one child.1

Mechanisms

Having children might decrease the risk of breast cancer through changes that occur in breast epithelial cells in preparation for lactation. These changes involve differentiation of epithelial cells, which is thought to make the cells less vulnerable to DNA damage.2 This differentiation does not occur in women who have not had children, resulting in an increased risk of breast cancer compared with women who have had children.

Evidence 

The World Cancer Research Fund International/American Institute for Cancer Research concluded that ‘not bearing children increases lifetime exposure to oestrogen and progesterone and the risk of breast cancer’ and listed ‘not bearing children’ as an established cause of breast cancer.3

Two meta-analyses have examined the association between number of children and breast cancer risk. The most recent, which reported on the association according to tumour subtype, found a significant protective effect of having had children for luminal breast cancer but not HER2+ or triple-negative breast cancer.4 The other meta-analysis found that the relative risk of breast cancer in woman who had not had children compared with women who had had children was 1.16 (95% confidence interval [CI] 1.04–1.26), and that women with 3 or more births had a lower risk of breast cancer than women with none.1

A pooled analysis of data from 47 epidemiological studies in 30 countries reported that women with breast cancer had, on average, fewer births than did controls (2.2 vs. 2.6).1 The relative risk of breast cancer decreased by 7% (95% CI 5–9%) for each birth.1

A cohort study found that women who had not had children had a greater risk of postmenopausal breast cancer than women who had had more than 1 child with the first birth before the age of 30 years.5 In another cohort study, having had a full-term birth was associated with risk of oestrogen receptor-positive, progesterone receptor-positive (ER+PR+) breast cancer, with evidence of a dose–response relationship, but not with risk of ER-PR- breast cancer.6

Read the full Review of the Evidence

References
  1. Nelson HD, Zakher B, Cantor A, et al. (2012). Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Annals of Internal Medicine 156(9):635–648.
  2. Russo J, Moral R, Balogh GA, et al. (2005). The protective role of pregnancy in breast cancer. Breast Cancer Research 7(3):131–142.
  3. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  4. Lambertini M, Santoro L, Del Mastro L, et al. (2016). Reproductive behaviors and risk of developing breast cancer according to tumor subtype: a systematic review and meta-analysis of epidemiological studies. Cancer Treatment Reviews 49:65–76.
  5. Dartois L, Fagherazzi G, Baglietto L, et al. (2016). Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: estimates from the E3N–EPIC cohort. International Journal of Cancer 138(10):2415–2427.
  6. Ritte R, Tikk K, Lukanova A, et al. (2013). Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study. BMC Cancer 13(1):584.

Age at menopause

Later age at menopause is associated with increased risk of breast cancer. Menopause occurs when a woman stops having periods. The average age of menopause in Australia is 51 years.

A woman’s risk of breast cancer increases by about 3% for each year older she is at menopause. For example, a woman who goes through menopause at the age of 55 years or older has about a 12% higher risk of breast cancer than a woman who is aged 50–54 years.

After menopause, the body produces less of the hormone oestrogen. If a woman goes through menopause later, her breast tissue is exposed to more oestrogen than if menopause occurs earlier. Longer exposure to oestrogen promotes the growth of breast cancer cells.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that older age at menopause is associated with increased risk of breast cancer. A woman’s risk of breast cancer is estimated to increase by about 3% for each year older she is at menopause (RR 1.029, 95% CI 1.025‒1.034).1

Mechanisms

The median age of menopause in Australian women is 51 years.1 During natural menopause, the body’s production of oestrogen and progesterone decreases. The later a woman goes through menopause, the longer her breast tissue is exposed to oestrogens released by the ovaries during her menstrual periods and the greater her lifetime exposure to oestrogen. The increased risk of breast cancer with later age at menopause is consistent with other evidence that factors that increase exposure to endogenous oestrogen increase the risk of breast cancer.

Evidence

A large pooled analysis was undertaken of 117 international studies that included 118,964 women with invasive breast cancer and 306,091 without the disease.2 Among 35 cohort studies, risk of postmenopausal breast cancer increased by approximately 3% for every 1-year increase in age at menopause (relative risk [RR] 1.029; 95% confidence interval [CI] 1.025–1.034), with a dose-response relationship.

Women aged 55 years or older at menopause had a 12% higher risk of breast cancer than women aged 50–54 years at menopause (RR 1.12; 95% CI 1.07–1.17). The risk of breast cancer was correspondingly lower for women who experienced menopause at age less than 50 years. Women aged 45–49 years at menopause had a 14% lower risk of breast cancer than women aged 50 years or older at menopause (RR 0.86; 95% CI 0.84–0.89).2

This association was observed both for women with natural menopause and for women who had an induced menopause – for example, as a result of surgical removal of their ovaries.

Read the full Review of the Evidence

References
  1. Do KA, Treloar SA, Pandeya N, Purdie D, Green AC, Heath AC & Martin NG (1998). Predictive factors of age at menopause in a large Australian twin study. Human Biology 70(6):1073–1091.
  2. Collaborative Group on Hormonal Factors in Breast Cancer (2012). Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet 13:1141–1151.

Lifestyle factors

Lifestyle factors are behaviours that are part of everyday life that are associated with increased or decreased risk of breast cancer. 

Lifestyle factors associated with an increased risk of breast cancer include bodyweight and weight gain, and alcohol consumption, and may include processed meat consumption and smoking.

Overweight and obesity

After menopause

Being overweight or obese is associated with an increased risk of breast cancer for women who have experienced menopause (postmenopausal women).

Body fatness can be measured in several ways including:

  1. body mass index (BMI);
  2. waist circumference.

Both measures are associated with increased risk of breast cancer among women after menopause.

For each 5-unit increase in BMI after menopause, the risk of breast cancer increases by about 12%.

For each 10 cm increase in waist circumference, the risk of postmenopausal breast cancer increases by about 6%.

It is estimated that 8% of postmenopausal breast cancers each year in Australia are attributable to overweight or obesity.

The way in which body fat increases or decreases the risk of breast cancer is not fully understood. The most likely explanation is that higher body fatness after menopause influences the levels of circulating hormones in the body, including oestrogen, which can affect the risk of breast cancer.

Before menopause

In contrast to the effect of higher BMI in women after menopause, having a higher BMI before menopause is associated with a decreased risk of premenopausal breast cancer.

For each 5-unit increase in BMI the risk of premenopausal breast cancer is decreased by about 7%.

The link between body fatness and premenopausal breast cancer is complex and not well understood.

* Body mass index (BMI) is a measure of body fat based on your weight in relation to your height, and applies to most adult men and women aged 20 and over. 

Commonly accepted BMI ranges are underweight: under 18.5 kg/m2, normal weight: 18.5 to 25 kg/m2, overweight: 25 to 30 kg/m2, obese: over 30 kg/m2.

Summary of the evidence

Evidence classifications:

  • Convincing (adult body fatness - marked by BMI, waist circumference and waist‒hip ratio - and increased risk of postmenopausal breast cancer)1
  • Probable (body fatness before the menopause and decreased risk of premenopausal breast cancer)1

There is convincing evidence that being overweight or obese is associated with an increased risk of breast cancer in postmenopausal women. Being overweight or obese before the menopause is probably associated with a decreased risk of premenopausal breast cancer.

Body fatness can be measured in several ways including:

  1. Body mass index (BMI);

The increased risk of postmenopausal breast cancer associated with BMI in adulthood is estimated as RR 1.12 (95% CI 1.09–1.15) (per 5 kg/m2).

The decreased risk of premenopausal breast cancer is estimated as RR 0.93 (95% CI 0.90–0.97) per 5 kg/m2 during the premenopausal period. 1

  1. Waist circumference.

Waist circumference was associated with an increased risk for postmenopausal breast cancer (RR per 10 cm increase = 1.06, 95% CI 1.01–1.12; based on studies adjusted for BMI).1

Despite BMI being associated with a decreased risk of premenopausal breast cancer, waist circumference was associated with an increased risk of premenopausal breast cancer (RR per 10 cm increase = 1.14, 95% CI 1.04–1.26; based on studies adjusted for BMI).1

Mechanisms

The mechanisms by which differences in body fat and fat distribution affect breast cancer are complex, particularly during early life and young adulthood, but are likely to involve the effects of adipose tissue on circulating sex hormone levels.2 Obesity in premenopausal women probably reduces ovarian progesterone production.1 Obesity in postmenopausal women increases the production of oestradiol.1 Both hormones are associated with breast cancer.  In addition, studies are increasingly implicating obesity as associated with a low-grade chronic inflammatory state and the activation of inflammatory cascades is one process that may predispose to carcinogenesis.1

Evidence 

WCRF/AICR (2018) summarised a vast literature in relation to measures of body fatness across the life-course and risk of premenopausal and postmenopausal breast cancer (see above).1  The International Agency for Research on Cancer (IARC) concluded in 2016 that ‘the absence of excess body fatness decreases the risk of cancer of the breast in postmenopausal women’, citing an approximately increased risk of 1.1 per 5 kg/m2  BMI.2,3

The conclusions of IARC (2016) and WCRF/AIRC (2018) are supported by more recently published analyses.  For example, a recent meta-analysis of data from seven prospective cohort studies also found a significantly increased risk of postmenopausal breast cancer associated with higher BMI (hazard ratio [HR] per 1 standard deviation (SD) increase = 1.15, 95% confidence intreval [CI] 1.03–1.27).4 A pooled analysis of Australian cohort studies reported an increased risk of postmenopausal breast cancer associated with increasing waist circumference (relative risk [RR] per 1 SD increase = 1.06, 95% CI 1.01–1.12).5 

Several cohort studies have shown that the association between body fatness and postmenopausal breast cancer risk may only occur, or may be greater, in women who do not use menopausal hormone therapy (MHT).1,4,6,7However, another cohort study did not find an effect of MHT use on the relationship between BMI and postmenopausal breast cancer risk.8

In a large, multicentre pooled analysis of premenopausal women aged 18–54 years, BMI at all ages during the premenopausal period was negatively associated with risk of breast cancer, with a dose–response relationship (RR per 5 kg/m2 0.77, 95% CI 0.73–0.80).9 The effect was greater for younger age groups.

It is estimated that 8% of postmenopausal breast cancers each year in Australia are attributable to overweight or obesity.10

Read the full Review of the Evidence

References
  1. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  2. Lauby-Secretan B, Scoccianti C, Loomis D, et al. (2016). Body Fatness and Cancer – Viewpoint of the IARC Working Group. New England Journal of Medicine 375(8);794–8
  3. International Agency for Research on Cancer (2016). IARC handbooks volume 16: questions and answers, IARC, Lyon, https://www.iarc.who.int/wp-content/uploads/2018/11/QAHandbook16.pdf.
  4. Freisling HM, Arnold M, Soerjomataram I, et al. (2017). Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe. British Journal of Cancer 116(11):1486–1497.
  5. Harding JL, Shaw JE, Anstey KJ, et al. (2015) Comparison of anthropometric measures as predictors of cancer incidence: A pooled collaborative analysis of 11 Australian cohorts. International Journal of Cancer 137 (7):1699–708
  6. Horn-Ross PL, Canchola AJ, Bernstein L, et al.  (2016). Lifetime body size and estrogen-receptor-positive breast cancer risk in the California Teachers Study cohort. Breast Cancer Research 18(1):132.
  7. Collaborative Group on Hormonal Factors in breast cancer (1996). Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 347(9017):1713–1727
  8. Neuhouser ML, Aragaki AK, Prentice RL, et al. (2015). Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncology 1(5):611–621.
  9. Premenopausal Breast Cancer Collaborative Group (2018). Association of body mass index and age with subsequent breast cancer risk in premenopausal women. JAMA Oncology e181771.
  10. Kendall BJ, Wilson LF, Olsen CM, et al. (2015) Cancers in Australia in 2010 attributable to overweight and obesity. Australian and New Zealand Journal of Public Health 39 (5):452–457.

Weight gain

Postmenopausal women

Gaining weight as an adult is associated with an increased risk of postmenopausal breast cancer.

The risk of postmenopausal breast cancer increases by about 6% for each 5 kg increase in a woman’s weight. This corresponds to approximately a 12% and 26% increased risk for 10 kg and 20 kg weight gain, respectively.

The way that weight gain affects breast cancer risk is likely to involve hormones. Weight gain means that the body is storing more fat, which can affect levels of circulating hormones.

In postmenopausal women, weight gain increases the levels of circulating oestrogen. This can affect the risk of some types of breast cancer.

Premenopausal women

There is no conclusive evidence that weight gain in premenopausal women is associated with increased risk of breast cancer. Only a small number of studies have been done and the evidence was inconclusive.

Summary of the evidence

Evidence classifications:

  • Convincing (postmenopausal breast cancer)
  • Inconclusive (premenopausal breast cancer)

There is convincing evidence that adult weight gain is associated with an increased risk of postmenopausal breast cancer. The increase in risk is estimated as 6% for each 5 kg increase in weight (RR 1.06, 95% CI 1.05–1.08).1

The evidence for an association between adult weight gain and risk of premenopausal breast cancer is inconclusive. There are only a small number of studies examining this association.

Mechanisms

Long-term weight gain in adults is associated with increased storage of body fat. This may increase the risk of breast cancer in postmenopausal women by reducing levels of serum hormone binding protein, which results in higher levels of circulating oestrogen.2 

Evidence 

The International Agency for Research on Cancer (IARC) concluded that there was sufficient evidence for a cancer-preventive effect of avoidance of weight gain for postmenopausal breast cancer;3 and the World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) concluded that there was convincing evidence that greater weight gain in adulthood is a cause of postmenopausal breast cancer.1 A dose-response analysis provided a relative risk per 5 kg increase in weight of 1.06 (95% confidence interval [CI] 1.05–1.08).1

WCRF/AICR reported that the increased risk associated with weight gain was significant only for oestrogen receptor positive, progesterone-receptor positive (ER+PR+) breast cancer, and not ER+PR- or ER-PR- disease. Contrary to the IARC review, risk was not affected by use of menopausal hormone therapy (MHT).1

For premenopausal breast cancer, IARC concluded that the available evidence suggested a lack of a cancer-preventive effect of avoidance of weight gain.3 WCRF/AICR considered the evidence for an association between adult weight gain and premenopausal breast cancer to be limited, and no conclusion was made.1

Findings from two more recent cohort studies are consistent with the findings of the WCRF/AICR.4,5

Read the full Review of the Evidence

References

  1. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  2. Endogenous Hormones Breast Cancer Collaborative Group (2003). Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. Journal of the National Cancer Institute 95(6):1218–1226.
  3. International Agency for Research on Cancer (2002). Weight control and physical activity, IARC Handbooks of Cancer Prevention, vol 6, IARC, Lyon.
  4. Neuhouser ML, Aragaki AK, Prentice RL, et al. (2015). Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncology 1(5):611–621.
  5. Nitta J, Nojima M, Ohnishi H, et al. (2016). Weight gain and alcohol drinking associations with breast cancer risk in Japanese postmenopausal women: results from the Japan Collaborative Cohort (JACC) Study. Asian Pacific Journal of Cancer Prevention 17(3):1437–1443.

Alcohol

Drinking alcohol on a daily basis is associated with an increased risk of breast cancer in postmenopausal women. Drinking alcohol is probably associated with an increased risk of breast cancer in premenopausal women also.

Women who drink one standard glass of alcohol each day have a 7% higher risk of breast cancer than women who never drink alcohol. The risk of breast cancer increases as the number of drinks regularly consumed increases.

It is estimated that nearly 6% of breast cancer cases each year in Australia are due to alcohol consumption.

There does not appear to be a ‘safe’ level of regular alcohol consumption for risk of breast cancer, according to the evidence.

Alcohol may increase risk for breast cancer in a number of ways, including helping cancer-causing molecules to enter cells or damaging cell DNA. Alcohol is also thought to increase levels of the hormone oestrogen, which can influence breast cancer risk.

Summary of the evidence

Evidence classification: Convincing (postmenopausal breast cancer)1
Evidence classification: Probable (premenopausal breast cancer)1

There is convincing evidence that alcohol consumption is associated with an increased risk of breast cancer, particularly in postmenopausal women. The risk of breast cancer among women who regularly drink alcohol compared to women who never drink alcohol is estimated by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR 2018) to increase by 7% for every 10 grams increase in daily alcohol consumption (RR 1.07, 95% CI 1.05–1.09).1 This corresponds to an increase in risk of breast cancer by 15% for 2 drinks per day and 31% for 4 drinks per day. (One ‘standard’ drink contains approximately 10 grams of alcohol).

Mechanisms

Several mechanisms have been proposed for how alcohol may increase breast cancer risk. Alcohol is a lipid solvent and can help carcinogens to enter cells. Alcohol can also increase the level of free-radical oxygen species, which can lead to DNA damage in cells. Genetic differences in ethanol metabolism can affect breast cancer risk. Alcohol consumption has also been associated with higher circulating oestrogen concentrations which can influence risk of breast cancer.1

Evidence 

The International Agency for Research on Cancer (2012) concluded that there is ‘sufficient evidence’ that ‘alcohol consumption causes cancer of the breast’.2 

The findings of World Cancer Research Fund International/American Institute for Cancer Research (2018)1 were based on evidence from 62 studies, 23 of which were included in dose–response meta-analyses. A relative risk (RR) for every 10 g/day increase in alcohol consumption of 1.05 (95% confidence interval [CI] 1.02–1.08) was reported for premenopausal breast cancer and of 1.09 (95% CI 1.07–1.12) for postmenopausal breast cancer.1 There is no threshold for consumption with an increased risk of breast cancer observed even at low levels of daily alcohol consumption.1,3,4  A pooled analysis of prospective cohort studies has indicated a positive association between oestrogen receptor-positive (ER+) and alcohol consumption, but not oestrogen receptor-negative (ER-) breast cancers,5 as observed in analyses by WCRF/AICR (2018).

It is estimated that about 5.8% of breast cancer cases each year in Australia are due to alcohol consumption.6

Read the full Review of the Evidence

References
  1. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  2. International Agency for Research on Cancer (2012). Personal habits and indoor combustions, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100E, IARC Working Group on the Evaluation of Carcinogenic Risk to Humans, Lyon, http://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E.pdf.
  3. Bagnardi V, Rota M, Botteri E, et al (2013). Light alcohol drinking and cancer: a meta-analysis. Annals Oncology 24: 301–308.
  4. Seitz HK, Pelucchi C, Bagnardi V, et al. (2012). Epidemiology and pathophysiology of alcohol and breast cancer: Update 2012. Alcohol and Alcoholism  47(3): 204–212
  5. Jayasekara H, MacInnis RJ, Room R, et al. (2016). Long-term alcohol consumption and breast, upper aero-digestive tract and colorectal cancer risk: a systematic review and meta-analysis. Alcohol and Alcoholism  51(3): 315–330.
  6. Pandeva N. Wilson LF. Webb PM et al (2015) Cancers in Australia in 2010 attributable to the consumption of alcohol. Australian and New Zealand Journal of Public Health 39 (5): 408–13

Smoking

There are many studies showing that tobacco smoking may be associated with a increased risk of breast cancer. While there are some limitations to the evidence, studies have been generally consistent in supporting a link between tobacco smoking and increased risk of breast cancer.

Tobacco smoking may be associated with an increased risk of breast cancer particularly in women who start smoking when they are younger or who start smoking many years before having their first child.

Tobacco smoke contains more than 5,300 chemicals, including more than 70 chemicals that are known to cause cancer.

Tobacco smoking is the major known and preventable cause of cancer worldwide. Smoking causes lung cancer and cancers of many other organs including the nasal cavity, throat, stomach, liver, kidney, bowel, and bladder.

Summary of the evidence

Evidence classification: Suggestive

The evidence is suggestive of an association between tobacco smoking and risk of breast cancer. The evidence from a large number of cohort studies is generally consistent in showing a positive association between current or former tobacco smoking versus never smoking and risk of breast cancer. The associations are stronger among women who started smoking at a young age or many years before their first birth. However the evidence for a dose-response effect is inconsistent.

Mechanisms

Tobacco smoke contains more than 5300 chemical compounds, including more than 70 that are known to be carcinogenic.1 Tobacco smoking has been classified by the International Agency for Research on Cancer (IARC) as a Class 1 carcinogen and has been identified to cause cancer of the lung and many other organs, including the nasal cavity, oral cavity and organs of the digestive and urinary tract.1 Some of the compounds in tobacco smoke, including polycyclic aromatic hydrocarbons and aromatic amines, can induce mammary tumours in rodents,1 and some have been found in human breast milk.2

Evidence 

IARC3 concluded that there was limited evidence to show a causal link between tobacco smoking and risk of breast cancer, although a positive association was acknowledged.

More recently published data, including a large pooled analysis of data from 14 international prospective cohort studies,4 and a large meta-analysis of 31 cohort studies and 44 case–control studies,5 show a small increase in risk of breast cancer with current or former tobacco smoking. Risk estimates from prospective studies are in the range of 1.07 (95% confidence interval [CI] 1.04–1.10)4 and 1.13 (95% CI 1.09–1.17)5 among current smokers compared to never smokers. No dose-response relationship was observed in the pooled analysis.

Higher risks of breast cancer compared with never smokers have been reported among women who start smoking 10 years before their first birth in the pooled analysis4 and more generally when starting smoking before first birth in a previous meta-analysis of cohort studies.7 A more recent large cohort study has also reported an increased risk of breast cancer for ever smoking versus never smoking, particularly for starting smoking at a young age.6  In this study there was also a dose-response relationship for number of pack-years and number of cigarettes per day after 10 or more years of smoking, although there was no association with duration of smoking.

Read the full Review of the Evidence

References
  1. Phillips DH, Martin FL, Grover PL et al. (2001). Toxicological basis for a possible association of breast cancer with smoking and other sources of environmental carcinogens. Journal of Women's Cancer 3:9–16.
  2. Thompson PA, DeMarini DM, Kadlubar FF, et al. (2002). Evidence for the presence of mutagenic arylamines in human breast milk and DNA adducts in exfoliated breast ductal epithelial cells. Environmental and Molecular Mutagenesis 39:134–142.
  3. International Agency for Research on Cancer (2012). Personal habits and indoor combustions, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100E, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon, http://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E.pdf.
  4. Gaudet MM, Carter BD, Brinton LA, et al. (2017). Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies. International Journal of Epidemiology 46(3):881–893.
  5. Macacu A, Autier P, Boniol M et al. (2015). Active and passive smoking and risk of breast cancer: a meta-analysis. Breast Cancer Research and Treatment 154(2):213–224.
  6. Jones ME, Schoemaler MJ, Wright LB, et al. (2017). Smoking and risk of breast cancer in the Generations Study cohort. Breast Cancer Research 19:118.
  7. Gaudet MM, Gapstur SM, Sun J, et al. (2013). Active smoking and breast cancer risk: original cohort data and meta-analysis. Journal of the National Cancer Institute 105(8):515–525.

Processed meats

Eating processed meat may be associated with an increased risk of breast cancer. Studies have given inconsistent results, with recent studies suggesting that processed meat in the diet does increase the risk of postmenopausal breast cancer, but possibly not premenopausal breast cancer.

Processed meat is meat that has been salted, cured, fermented or smoked to improve its flavour or to preserve it. Most processed meat is pork or beef – for example, ham, sausages and corned beef.

The way in which processed meat might increase the risk of breast cancer is not known. Processing can produce some cancer-causing chemicals. Cooking of processed meat can also produce cancer-causing chemicals.

Summary of the evidence

Evidence classification: Suggestive

There is suggestive evidence that consumption of processed meat may be associated with an increased risk of breast cancer, but there are some limitations to the evidence.

Although earlier evidence of a possible association between processed meat in the diet and breast cancer risk was inconsistent, recent meta-analyses have reported a positive association between high levels of processed meat consumption and risk of breast cancer. This association is observed for breast cancer overall, and postmenopausal breast cancer, but possibly not premenopausal breast cancer.

Mechanisms

Processed meat is meat that has been salted, cured, fermented, smoked or treated in some other way to improve its flavour or to preserve it. Processed meats are mainly pork or beef – for example, ham, sausages and corned beef – but can include other red meats, poultry, offal or meat by-products.

The International Agency for Research on Cancer (IARC) concluded that processed meat is carcinogenic to humans (Group 1 carcinogen), noting sufficient evidence that consumption of processed meat causes colorectal cancer.1,2

The mechanism by which consumption of processed meat might increase the risk of breast cancer is not known. Processing of meat can produce some carcinogenic chemicals, including N-nitroso-compounds and polycyclic aromatic hydrocarbons.1 Cooking processed meat, especially at high temperatures, can also produce known or suspected carcinogens.1

Evidence 

IARC reviewed 10 cohort and nested case–control studies and 16 case-control studies reporting on an association between consumption of processed meat and breast cancer risk.2 Four of the 10 cohort studies reported a statistically significant positive association with breast cancer risk for the consumption of red and processed meat combined. However, the case–control studies provided inconsistent evidence. IARC concluded that there was insufficient data to evaluate the association separately for premenopausal and postmenopausal breast cancer, or by hormone receptor status.2

The World Cancer Research Fund/American Institute for Cancer Research concluded that there was limited evidence for an association between consumption of processed meat and breast cancer risk, and did not make a formal conclusion.3

A recent meta-analysis of prospective cohort, nested case-control and clinical trial studies showed that high, compared with low, intake of processed meat was associated with overall breast cancer risk (relative risk [RR] 1.05, 95% confidence interval [CI] 1.03‒1.16) and postmenopausal breast cancer risk (RR 1.10, 95% CI 1.03‒1.17), but not with premenopausal breast cancer risk (RR 1.09, 95% CI 0.95‒1.25).4 Another recent meta-analysis of data from the United Kingdom Biobank cohort study, combined with data from 10 previous cohort studies, had similar findings.5

An earlier meta-analysis reported an increased breast cancer risk for the highest category compared with the lowest category of processed meat consumption, and a statistically significant dose-response relationship (RR per 50 g/day increment 1.09, 95% CI 1.02‒1.17).6

A French cohort study reported no association between processed meat consumption and risk of breast cancer.7 However, the level of consumption of processed meat was low in this study, which reduced the ability to detect any association.

Read the full Review of the Evidence

References
  1. Bouvard V, Loomis D, Guyton KZ, et al. (2015). Carcinogenicity of consumption of red and processed meat. Lancet Oncology 16(16):1599–1600.
  2. International Agency for Research on Cancer (2018). Red meat and processed meat, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 114, IARC Working Group on the Evaluation of Carcinogenic Risk to Humans, Lyon, https://monographs.iarc.fr/wp-content/uploads/2018/06/mono114.pdf.
  3. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  4. Farvid MS, Stern MC, Norat T, et al. (2018). Consumption of red and processed meat and breast cancer incidence: a systematic review and meta-analysis of prospective studies. International Journal of Cancer 2018 Sep 5 (Epub ahead of print).
  5. Anderson JJ, Darwis NDM, Mackay DF, et al. (2018) Red and processed meat consumption and breast cancer: UK Biobank cohort study and meta-analysis.  European Journal of Cancer 90:73–82.
  6. Wu J, Zeng R, Huang J, et al. (2016). Dietary protein sources and incidence of breast cancer: a dose–response meta-analysis of prospective studies. Nutrients 8(11):E730.
  7. Diallo A, Deschasaux M, Latino-Martel P, et al.  (2018). Red and processed meat intake and cancer risk: results from the prospective NutriNet-Santé cohort study. International Journal of Cancer 142(2):230–237.

Medical history and medications

Factors in a woman’s medical history can be associated with an increased or decreased risk of breast cancer.

Factors in a woman's medical history associated with an increased risk of breast cancer include previous breast disease and breast conditions, use of medicines, radiation therapy to treat cancer and having been diagnosed with other types of cancer.

Menopausal hormone therapy (MHT)/Hormone replacement therapy (HRT) - (combined oestrogen-progestogen)

Using menopausal hormone therapy (MHT) that contains both oestrogen and progestogen is associated with an increased risk of breast cancer.

Women who are currently using combined oestrogen-progestogen MHT, also referred to as combined hormone replacement therapy or combined HRT, have about 1.7 times the risk of breast cancer as women who have never used it. The risk of breast cancer increases the longer a woman uses combined MHT, and decreases after treatment is stopped.

It is estimated that 3.2% of breast cancers each year in Australia are attributable to the use of MHT that contains the hormones oestrogen and progestogen.

Some women take MHT around the time of menopause to help manage the symptoms of menopause, such as hot flushes. The use of MHT may also have other benefits including reduction in osteoporosis and fracture risk and colorectal cancer.

The way in which combined oestrogen-progestogen MHT increases the risk of breast cancer is likely to be through hormonal pathways. It increases a woman’s lifetime exposure to oestrogen and progestogen. Longer exposure to oestrogen and progestogen promote the growth of breast cancer cells.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that menopausal hormone therapy (MHT) that contains combined oestrogen-progestogen is associated with an increased risk of breast cancer.

Current users of combined oestrogen-progestogen MHT are estimated to be at 1.72 (95% CI 1.55–1.92) times the risk of breast cancer compared to women who have never used combined MHT.1 The risk in current users increases with increasing duration of use. Cohort studies have consistently shown that risk decreases after stopping use of combined MHT. 

Mechanisms

Combined MHT, also referred to as hormone replacement therapy or HRT, involves the co-administration of an oestrogen and a progestogen to perimenopausal or menopausal women to mitigate the effects of diminishing oestrogen and progesterone at menopause.

Use of combined MHT may influence breast cancer risk through hormonal-mediated pathways. It increases a woman’s lifetime exposure to oestrogen and progestogen.2

Evidence 

The International Agency for Research on Cancer (IARC) concluded that there is sufficient evidence that combined MHT causes cancer of the breast.1,3 It noted evidence for an increasing risk with increasing duration of use among current users.

The World Cancer Research Fund International/American Institute for Cancer Research lists combined MHT as an established cause of breast cancer, and stated that ‘hormone therapy (also known as hormone replacement therapy) containing oestrogen with or without progesterone increases the risk of breast cancer, and the risk is greater with combined oestrogen plus progesterone preparations.4

Two large meta-analyses published since the evaluation by IARC have reported an approximately 1.3 times increased risk of breast cancer for 'ever-use' versus 'never-use' of combined MHT.1,5 For current users compared with never users the relative risk (RR) was 1.72 (95% confidence interval [CI] 1.55–1.92).1 This association was seen only for oestrogen-receptor-positive, progesterone-receptor-positive (ER+PR+) breast cancer, and not for ER-PR- breast cancer.1

Some recent cohort studies have reported higher relative risks for current users versus never users of combined MHT.6,7

Long-term follow-up of the Women’s Health Initiative (WHI) randomised controlled trial has shown an increased risk of breast cancer in current users of combined MHT.8,9 The risk remained elevated after use of MHT stopped, up to a median of 13.2 years.8 However, numerous cohort studies have found that the increased risk did not persist after stopping use.

The increased risk of breast cancer among current users of combined MHT is greater with longer duration of use – this was noted in meta-analyses cited by the IARC and in several cohort studies.

With regard to formulations of MHT, one cohort study7 reported similarly elevated risks for both continuous (every day) and sequential (cyclic) MHT use, whereas two other cohort studies10,11 suggested that the risk associated with continuous regimes was higher.

It is estimated that 3.2% of breast cancers each year in Australia are attributable to the use of MHT that contains the hormones oestrogen and progestogen. 12

Read the full Review of the Evidence

References
  1. Munsell MF, Sprague BL, Berry DA, et al. (2014). Body mass index and breast cancer risk according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiologic Reviews 36:114–136.
  2. International Agency for Research on Cancer (2012). Pharmaceuticals, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100A, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
  3. International Agency for Research on Cancer (2007). Combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 92, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
  4. World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
  5. Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, et al.  (2013). Risk factors of breast cancer: a systematic review and meta-analysis. Asia Pacific Journal of Public Health 25(5):368–387.
  6. Jones ME, Schoemaker MJ, Wright L, et al. (2016). Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? British Journal of Cancer 115:607–615.
  7. Román M, Sakshaug S, Graff-Iversen S, et al. (2015). Postmenopausal hormone therapy and the risk of breast cancer in Norway. International Journal of Cancer 138:584–593.
  8. Manson JE, Chlebowski RT, Stefanick ML, et al. (2013). Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA: The Journal of the American Medical Association 310(13):1353–1368.
  9. Chlebowski RT, Rohan TE, Manson JE, et al. (2015). Breast cancer after use of estrogen plus progestin and estrogen alone analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncology 1:296–305.
  10. Bakken K, Fournier A, Lund E, et al. (2011). Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer 128(1):144–156.
  11. Porch JV, Lee IM, Cook NR, et al.  (2002). Estrogen–progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes & Control 13(9):847–854.
  12. Whiteman DC, Webb PM, Green AC, et al. (2015). Cancers in Australia in 2010 attributable to modifiable factors: summary and conclusions. Australian and New Zealand Journal of Public Health 39 (5):477–84

Oral contraceptive pill (combined oestrogen-progestogen)

Taking ‘combined’ oral contraceptives (that contain both oestrogen and progestogen) is associated with a small increased risk of breast cancer while a woman is currently using it. Oral contraceptives are also known as birth-control pills or ‘the Pill’.

The risk of breast cancer in women who are currently using the ‘combined’ oral contraceptive pill increases by about 7% for every 5 years of use. The risk goes down again when a woman stops using it.

It is estimated that 0.7% of breast cancers each year in Australia are attributable to the use of oral contraception that contains the hormones oestrogen and progestogen.

However, combined oral contraceptives are associated with a decreased risk of endometrial and ovarian cancer, which may persist for decades after stopping use.1,2

The way in which combined oral contraceptives increase the risk of breast cancer is likely to be through hormonal pathways. Oestrogen and progestogen affect the growth of some types of breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that current use of the combined oestrogen-progestogen oral contraceptive pill is associated with an increased risk of breast cancer.

The risk of breast cancer among current users of combined oral contraceptives is estimated to increase by 7% for every 5 years of use (RR 1.07, 95% CI 1.03–1.11).3 The increased risk decreases when use of the oral contraceptive ceases.

Mechanisms

Combined hormonal oral contraceptives contain an oestrogen and a progestogen. Their main contraceptive action is through preventing ovulation. Combined oral contraceptives are available in many combinations of the oestrogen and progestogen components, dosages and modes of delivery.

Oestrogens and progestogens may influence breast cancer risk through hormone-receptor-mediated pathways or through hormone-induced DNA damage.4,5

Evidence 

The International Agency for Research on Cancer (IARC) concluded that there is sufficient evidence in humans for the carcinogenicity of combined oestrogen–progestogen oral contraceptives for cancer of the breast.5 Evidence considered by IARC included a large pooled analysis of data from more than 150,000 women who participated in 54 epidemiologic studies.6 The relative risk (RR) of breast cancer among women who were currently using the oral contraceptive pill compared with women who had never used oral contraceptives  was 1.24 (95% confidence interval [CI] 1.15–1.33); and for recent users, 1–4 years after stopping it, the relative risk was 1.16 (95% CI 1.08–1.23).6 There was no increased  risk 10 years after use of the combined oral contraceptive had stopped.6

A recent meta-analysis7 and cohort study8 support IARC findings that the incidence of breast cancer is higher in recent users of combined oral contraceptives (less than 5 years since use stopped) than in the general population, and this risk declines with time after stopping use.

In addition, a dose-response meta-analysis suggested an increased risk for every 5 years of use of 7% (RR 1.07, 95% CI 1.03–1.11).3

Several other cohort studies have reported an increased risk of breast cancer associated with use of oral contraceptives. One found that current use of triphasic preparations containing levonorgestrel as the progestin was associated with a higher risk than use of other formulations.9

It is estimated that 0.7% of breast cancers each year in Australia are attributable to the use of oral contraception that contains the hormones oestrogen and progestogen.10

Read the full Review of the Evidence

References
  1. Collaborative group on Epidemiological Studies on Endometrial Cancer (2015). Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. Lancet Oncology 16 (9):1061–1070
  2. Havrilesky LJ, Moorman PG, Lowery WJ, et al. (2013). Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis. Obstetrics and Gynecology 122 (1):139–47
  3. Zhu H, Lei X, Feng J & Wang Y (2012). Oral contraceptive use and risk of breast cancer: a meta-analysis of prospective cohort studies. European Journal of Contraception & Reproductive Health Care 17(6):402–414.
  4. Pike MC, Spicer DV, Dahmoush L et al. (1993). Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiologic Reviews 15(1):17–35.
  5. International Agency for Research on Cancer (2012). Pharmaceuticals, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100A, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
  6. Collaborative Group on Hormonal Factors in Breast Cancer (1996). Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 347:1713–1727.
  7. Iversen L, Sivasubramaniam S, Lee AJ, et al. (2017). Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study. American Journal of Obstetrics & Gynecology 216(6):580.
  8. Gierisch JM, Coeytaux RR, Urrutia RP, et al. (2013). Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiology, Biomarkers & Prevention 22(11):1931–1943.
  9. Hunter DJ , Colditz GA, Hankinson SE, et al. (2010). Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiology, Biomarkers & Prevention 19:2496–2502.
  10. Whiteman DC, Webb PM, Green AC, et al. (2015) Cancers in Australia in 2010 attributable to modifiable factors: summary and conclusions. Australian and New Zealand Journal of Public Health 39 (5):477–84

Cardiac glycosides (digoxin)

Taking digoxin may be associated with an increased risk of breast cancer.

Digoxin is a medicine that is taken to treat congestive heart failure and irregular heart beats.

The chemical structure of digoxin is similar to the hormone oestrogen that occurs naturally in women’s bodies. Oestrogen levels influence the risk of breast cancer and it is proposed that digoxin might influence the risk of breast cancer in much the same way as oestrogen.

Summary of the evidence

Evidence classification: Suggestive.

The evidence is suggestive of an association between use of the cardiac glycoside digoxin and increased risk of breast cancer. However there are limitations to the evidence.

Mechanisms

Digoxin is an extract from the foxglove plant (Digitalis lanata) and is the main cardiac glycoside in current use. Its chemical structure is similar to that of oestradiol.  It has been suggested that digoxin may promote the development of breast cancer through an oestrogen-receptor-mediated mechanism.1

Older people are more likely to use digoxin than younger people, and so any increased risk of breast cancer is probably more relevant to postmenopausal women.

Evidence 

The International Agency for Research on Cancer (IARC) has classified digoxin as possibly carcinogenic to humans (Group 2B). The IARC noted the compelling nature of human epidemiological evidence from 3 cohort studies and 4 case–control studies associating use of digoxin with increased risk of breast cancer, but also noted a lack of other supportive evidence.2

Several recent meta-analyses have indicated an increased risk of breast cancer of approximately 1.3 times among users of digoxin and other similar cardiac glycosides (from plants of the genus Digitalis) compared to non-users.3-5 There was no evidence of significant heterogeneity among the included studies. The association was stronger among cohort than among case–control studies. However the findings were limited by lack of adjustment for potential confounders such as body mass index in several of the included studies. A more recent cohort study also found a similarly increased risk of breast cancer among digoxin users.6

Two cohort studies have reported an association between digoxin use and risk of oestrogen-receptor-positive (ER+) but not oestrogen-receptor negative (ER-) breast cancer.4

Read the full Review of the Evidence

References
  1. Masood S (2015). Is digoxin a breast cancer risk factor? Acute Cardiac Care 17(2):29–31.
  2. International Agency for Research on Cancer (2016). Some herbal products, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 108, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon, https://monographs.iarc.fr/ENG/Monographs/vol108/mono108-13.pdf.
  3. Karasneh RA, Murray LJ & Cardwell CR (2017). Cardiac glycosides and breast cancer risk: a systematic review and meta‐analysis of observational studies. International Journal of Cancer 140(5):1035–1041.
  4. Osman MH, Farrag E, Selim M, et al. (2017). Cardiac glycosides use and the risk and mortality of cancer: systematic review and meta-analysis of observational studies. PloS ONE 12(6):e0178611.
  5. Zhang C, Xie SH, Xu B, et al. (2017). Digitalis use and the risk of breast cancer: a systematic review and meta-analysis. Drug Safety 40(4):285–292.
  6. Chung MH, Wang YW, Chang YL, et al. (2017). Risk of cancer in patients with heart failure who use digoxin: a 10-year follow-up study and cell-based verification. Oncotarget 8(27):44203–44216.

Previous cancer other than breast cancer

Hodgkin lymphoma and thyroid cancer

Having a previous history of Hodgkin lymphoma or thyroid cancer may be associated with  an increased risk of breast cancer.

Hodgkin lymphoma occurs when certain types of white blood cells called lymphocytes grow in an uncontrolled way. Lymphocytes are part of the immune system that help fight infection. A number of studies have suggested that having been treated for Hodgkin lymphoma with radiation therapy (with or without chemotherapy) may be the reason for the increased risk of breast cancer but other studies show an increased risk regardless of radiation treatment.

A small number of studies have found an association between a history of thyroid cancer and increased risk of breast cancer. The thyroid is a gland that is located at the base of the throat which produces hormones that help control the body’s heart rate, temperature and metabolism, and the amount of calcium in the blood.

The risks of both ovarian cancer and breast cancer are increased if a woman carries a faulty BRCA1 or BRCA2 gene.

Other cancers

There is no conclusive evidence that having a previous history of other types of cancer is associated with increased risk of breast cancer.

Other cancers that have been investigated for a possible link with breast cancer risk include colorectal cancer, gastric cancer, non-Hodgkin lymphoma, lymphohaematopoietic cancers such as leukaemia, oesophageal cancer and skin cancer. Results from these studies have been inconsistent or have shown no association with breast cancer risk.

Women who have previously had another type of cancer might have a higher risk of breast cancer as a result of genetic susceptibility, shared risk factors or cancer treatment–related effects.

Summary of the evidence

Evidence classifications:

  • Suggestive (Hodgkin lymphoma, thyroid cancer)
  • Inconclusive (other types of cancer)

The evidence is suggestive of an association between having had a previous cancer, other than breast cancer, and risk of breast cancer.

The cancers that have been most studied in relation to previous diagnosis and subsequent risk of breast cancer are Hodgkin lymphoma, non-Hodgkin lymphoma and thyroid cancer. There is some evidence that a personal history of Hodgkin lymphoma and thyroid cancer may be associated with an increased risk of breast cancer independent of radiation treatment effects. The risks of both ovarian cancer and breast cancer are increased if a woman carries a BRCA1 or BRCA2 mutation.

There have been too few studies to make a classification regarding an association between previous history of other cancers and risk of breast cancer, although the evidence is indicative of an association across a range of cancers.

Mechanisms

Women with a previous history of another cancer might have an increased risk of breast cancer as a result of genetic susceptibility, shared risk factors or cancer treatment–related effects.

Evidence 

Any cancer diagnosis

A retrospective cohort study conducted in Queensland reported that women with a personal history of cancer other than breast cancer had a significantly elevated risk of developing breast cancer compared with the general population.1

Hodgkin lymphoma

A consistent positive association between a history of Hodgkin lymphoma and breast cancer risk has been seen. A large meta-analysis reported a pooled relative risk (RR) of 8.23 (95% confidence interval [CI] 5.43–12.47).2 The level of risk varied according to the type of treatment therapy for Hodgkin lymphoma: an elevated risk was seen only for women treated with radiation therapy (with or without chemotherapy), suggesting that radiation therapy for Hodgkin lymphoma accounts for the increased risk of breast cancer.2 However, two more recent individual studies have given inconsistent results on risk of breast cancer in women with Hodgkin lymphoma who did not receive radiation therapy.

Five additional cohort studies have also reported an increased risk of breast cancer associated with a history of Hodgkin lymphoma.3-7

A meta-analysis found that breast cancer risk was inversely related to age at diagnosis of Hodgkin lymphoma, with the highest rate observed in young patients (≤15 years old).2

Thyroid cancer

Five cohort studies have found an association between a history of thyroid cancer and increased risk of breast cancer.8-12 The association did not appear to vary by age at diagnosis of thyroid cancer.11

Other cancers

Other cancers that have been investigated for a possible link with breast cancer risk include colorectal cancer, gastric cancer, non-Hodgkin lymphoma, lymphohaematopoietic neoplasm, oesophageal cancer, and skin cancer. Results from these studies have been inconsistent or have shown no association with breast cancer risk.

Read the full Review of the Evidence

References
  1. Youlden DR, Baade PD (2011). The relative risk of second primary cancers in Queensland, Australia: a retrospective cohort study. BMC Cancer 11(1):83.
  2. Ibrahim EM, Abouelkhair KM, Kazkaz GA, et al. (2012). Risk of second breast cancer in female Hodgkin’s lymphoma survivors: a meta-analysis. BMC Cancer 12(1):197.
  3. Baras N, Dahm S, Haberland J, et al. (2017). Subsequent malignancies among long‐term survivors of Hodgkin lymphoma and non‐Hodgkin lymphoma: a pooled analysis of German cancer registry data (1990–2012). British Journal of Haematology 177(2):226–242.
  4. Schaapveld M, Aleman BM, van Eggermond AM, et al. (2015). Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. New England Journal of Medicine 373:2499–2511.
  5. Dörffel W, Riepenhausen M, Lüders H, et al. (2015). Secondary malignancies following treatment for Hodgkin’s lymphoma in childhood and adolescence: a cohort study with more than 30 years’ follow-up. Deutsches Ärzteblatt International 112(18):320.
  6. Veit-Rubin N, Rapiti E, Usel M, et al.(2012). Risk, characteristics, and prognosis of breast cancer after Hodgkin’s lymphoma. Oncologist 17(6):783–791.
  7. Royle JS, Baade P, Joske D et al. (2011). Risk of second cancer after lymphohematopoietic neoplasm. International Journal of Cancer 129(4):910–919.
  8. Lin C-Y, Lin C-L, Huang W-S, et al. (2016). Risk of breast cancer in patients with thyroid cancer receiving or not receiving 131I treatment: a nationwide population-based cohort study. Journal of Nuclear Medicine 57:685-690.
  9. Cho YY, Lim J, Oh CM, et al. (2015). Elevated risks of subsequent primary malignancies in patients with thyroid cancer: a nationwide, population‐based study in Korea. Cancer 121(2):259–268.
  10. Kim C, Bi X, Pan D, et al.(2013). The risk of second cancers after diagnosis of primary thyroid cancer is elevated in thyroid microcarcinomas. Thyroid 23(5):575–582.
  11. Lu CH, Lee KD, Chen PT, et al. (2013). Second primary malignancies following thyroid cancer: a population-based study in Taiwan. European Journal of Endocrinology 169(5):577–585.
  12. Tabuchi T, Ito Y, Ioka A, et al. (2012). Incidence of metachronous second primary cancers in Osaka, Japan: update of analyses using population‐based cancer registry data. Cancer Science 103(6):1111–1120.

Exposure to diethylstilboestrol (DES) while pregnant

Taking diethylstilboestrol (DES) during pregnancy is associated with an increased risk of breast cancer.

Women who took DES during pregnancy are estimated to have a 27% increased risk of breast cancer than women who did not take DES during pregnancy. 

DES is a synthetic form of the hormone oestrogen. From the 1940s to the 1970s, DES was taken by some women to prevent complications of pregnancy. It was also used as an emergency contraceptive (‘morning-after pill’). Use of DES declined when it was found to be ineffective, and following concerns about a possible link with a rare vaginal cancer among daughters of women who took DES during pregnancy, it is no longer registered for use in Australia.

The way in which DES increases the risk of breast cancer probably involves damage to DNA in the cells of breast tissue during pregnancy.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that exposure to the synthetic oestrogen diethylstilboestrol  (DES) during pregnancy is associated with an increased risk of breast cancer.

Women who took DES during pregnancy are estimated to have a 27% increased risk of breast cancer than women who did not take DES during pregnancy (RR 1.27, 95% CI 1.07–1.52).1

Mechanisms

From the 1940s to the 1970s, DES was commonly prescribed to prevent some complications of pregnancy. It was also used as an emergency contraceptive (‘morning-after pill’). Use of DES declined when it was found to be ineffective, and following concerns about a possible link with a rare vaginal cancer among daughters of women who took DES during pregnancy. DES is no longer registered for use in Australia.

DES probably causes chromosomal breaks and other chromosomal aberrations in breast tissue cells during pregnancy, in a process mediated largely by oestrogen receptors.2

Evidence 

The International Agency for Research on Cancer (IARC) concluded that DES causes cancer of the breast in women who were exposed while pregnant.2 The IARC’s evaluation included data from the Dieckmann clinical trial cohort,3 the Women’s Health Study4,5 and several other small cohort studies.

The most recent and largest study1 was included in the IARC evaluation. It included extended follow-up from the Dieckmann clinical trial cohort and the Women’s Health Study. A relative risk of breast cancer of 1.27 (95% confidence interval [CI] 1.07–1.52) was observed in exposed women compared with unexposed women. The association was not modified by reproductive history, menopausal status, or use of oral contraceptives or menopausal hormone replacement therapy. The data did not support a dose-response relationship; however, as exposure to DES is brief, even among women with multiple exposed pregnancies.1

Read the full Review of the Evidence

References
  1. Titus-Ernstoff L, Hatch EE, Hoover RN, et al. Long-term cancer risk in women given diethylstilboestrol  (DES) during pregnancy. British Journal of Cancer 2001; 84(1):126–133.
  2. International Agency for Research on Cancer (2012). Pharmaceuticals, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100A, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
  3. Bibbo M, Haenszel WM, Wied GL, et al. (1978). A twenty-five-year follow-up study of women exposed to diethylstilboestrol  during pregnancy. New England Journal of Medicine 298(14):763–767.
  4. Greenberg ER, Barnes AB, Resseguie L, et al. (1984). Breast cancer in mothers given diethylstilboestrol  in pregnancy. New England Journal of Medicine 311(22):1393–1398.
  5. Colton T, Greenberg ER, Noller K, et al. (1993). Breast cancer in mothers prescribed diethylstilboestrol  in pregnancy: further follow-up. JAMA: The Journal of the American Medical Association 269(16):2096–2100.

Radiation therapy to treat cancer

Receiving radiation therapy (or radiotherapy) in the chest region as a treatment for Hodgkin lymphoma and childhood cancers is associated with an increased risk of breast cancer.

The increased risk depends on how much radiation the woman received. Women who were treated for Hodgkin lymphoma using radiation alone have about 5 times the risk of breast cancer as women who did not receive this treatment. The risk is higher for those treated at a younger age, particularly close to the age when periods started.

Ionising radiation can lead to DNA damage in cells by ionising molecules in cells in the breasts, which can increase risk of breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that use of therapeutic ionising radiation (radiotherapy) in the chest region for Hodgkin lymphoma and childhood cancers is associated with an increased risk of breast cancer.

The increased risk depends on the dose of radiation received. An increased risk has been estimated as 1.31 (95% CI 1.16‒1.59) per Gy, for radiation treatment of childhood cancers.1 The relative risk for radiation (only) treatment of Hodgkin lymphoma has been estimated as 4.70 (95% CI 3.28–6.75).2 The risk is higher among those treated when younger, particularly close to menarche.

Mechanisms

Hodgkin lymphoma was treated in the past using mantle field irradiation, which delivered radiation to a large area of the neck, chest and armpits. Other types of radiation treatment of the chest to treat childhood cancers include mediastinal irradiation (irradiation of the area of the chest that separates the lungs), whole lung irradiation and total body irradiation.

Ionising radiation causes cancer by ionising molecules in cells, which can lead to DNA damage. Nonlethal damage to DNA can eventually lead to malignant disease.3  Risks are likely to be higher for exposure during childhood when tissues and organs are developing and more radiation-sensitive, and there is a longer time post-exposure for developing radiation-induced malignancies.

Due to the increased risk of cancers, current radiotherapy techniques have become much more targeted delivering lower doses of radiation to precise body sites.4

Evidence 

The International Agency for Research on Cancer (IARC) concluded that there is ‘sufficient’ evidence that X-radiation and γ (gamma)-radiation are associated with increased risk of breast cancer.3 

One meta-analysis of four studies and a single cohort study has estimated a linear increased risk per Gy radiation received for the treatment of childhood cancers, indicating increased risks of 1.31 (95% confidence interval [CI]1.16‒1.59) and 1.27 (95% CI 1.10‒1.67), respectively.1,2

A meta-analysis found that female survivors of Hodgkin lymphoma who were treated with radiation only had increased risk of breast cancer of 4.70 (95% CI 3.28–6.75).5 The risk was higher among those treated when less than 30 years of age (relative risk [RR] 14.08; 95% CI 9.93–19.98). This meta-analysis noted a dose-response effect only in some studies.

Treatment at a younger age and particularly closest to menarche is associated with the highest risk.6,7

Higher risks have been reported for whole lung irradiation, followed by mantle irradiation and then mediastinal irradiation.8,9 Treatment with total body irradiation for childhood cancers was associated with an increased risk of breast cancer of 10.6 (95% CI 3.7–30.2) compared with no radiation.10

An increased risk of breast cancer was found for women treated with spinal irradiation for childhood leukaemia.11

Read the full Review of the Evidence

References
  1. Ibrahim EM, Abouelkhair KM, Kazkaz GA, et al. (2012). Risk of second breast cancer in female Hodgkin’s lymphoma survivors: a meta-analysis. BMC Cancer 12(1):197.
  2. International Agency for Research on Cancer (2009). Radiation, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100D, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon, http://monographs.iarc.fr/ENG/Monographs/vol100D/mono100D.pdf.
  3. Inskip PD, Robison LL, Stovall M, et al. (2009) Radiation dose and breast cancer risk in the childhood cancer survivor study. Journal of Clinical Oncology 27(24):3901‒3907.
  4. Radiation Oncology Targeting Cancer (2017). Radiation Therapy. Faculty of Radiation Oncology, The Royal Australian and New Zealand College of Radiologists https://www.targetingcancer.com.au/
  5. Shaapveld M, Aleman BM, van Eggermond AM, et al. (2015) Second cancer risk up to 40 years after treatment for Hodgkin’s Lymphoma. The New England Journal of Medicine 373(26):2499‒2511.
  6. Moskowitz CS, Chou JF, Sklar CA, et al. (2017). Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study. British Journal of Cancer 117(2):290–299.
  7. Cooke R, Jones ME, Cunningham D, et al. (2013). Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors. British Journal of Cancer 108(11):2399–2406.
  8. Moskowitz CS, Chou JF, Wolden SL, et al. (2014). Breast cancer after chest radiation therapy for childhood cancer. Journal of Clinical Oncology 32(21):2217–2223.
  9. De Bruin ML, Sparidans J, van’t Veer MB, et al. (2009). Breast cancer risk in female survivors of Hodgkin’s lymphoma: lower risk after smaller radiation volumes. Journal of Clinical Oncology 27(26):4239–4246.
  10. Teepen JC, van Leeuwen FE, Tissing WJ, et al. (2017). Long-term risk of subsequent malignant neoplasms after treatment of childhood cancer in the DCOG LATER study cohort: role of chemotherapy. Journal of Clinical Oncology 35(20):2288–2298.
  11. Moskowitz CS, Malhotra J, Chou JF, et al. (2015). Breast cancer following spinal irradiation for a childhood cancer: a report from the Childhood Cancer Survivor Study. Radiotherapy and Oncology 117(2):213–216.

Benign breast disease

Having had some types of benign breast disease is associated with an increased risk of breast cancer.

Women who have had a type of benign breast disease called “atypical hyperplasia” have risk of breast cancer about four-fold higher than other women.

Women who have had a type of benign breast disease called “proliferative disease without atypia” have risk of breast cancer about 1.5 to 2-fold higher than other women.

Current evidence shows no association of non-proliferative benign breast disease with risk of breast cancer.

Benign breast disease involves benign (noncancerous) changes in breast tissue. One type of benign breast disease is caused by an increase in the number of cells. This is called proliferative benign breast disease (atypical hyperplasia or proliferative disease without atypia). Another type of benign breast disease is non-proliferative benign breast disease.

The way that some types of benign breast disease increase a woman’s risk of breast cancer is not known. Benign breast disease and breast cancer have some risk factors in common – for example, genetic factors. These common risk factors might explain the association between benign breast disease and increased risk of breast cancer. Another possibility is that benign breast disease might change to become breast cancer.

Summary of the evidence

Evidence classifications:

  • Convincing (history of proliferative benign breast disease)
  • Evidence of no association (history of non-proliferative benign breast disease)

There is convincing evidence that proliferative benign breast disease (BBD) (atypical hyperplasia or proliferative disease without atypia) is associated with an increased risk of breast cancer.

However, good-quality, consistent evidence does not support an association between non-proliferative BBD and risk of breast cancer.

For proliferative BBD, women who have had atypical hyperplasia are estimated to have 3.93 (95% CI 3.24‒4.76) times the risk of breast cancer as other women.1 Women who have had proliferative disease without atypia are estimated to have 1.76 (95% CI 1.58‒1.95) times the risk of breast cancer as other women.1

Mechanisms

BBD is term used to describe a broad group of benign (noncancerous) changes in breast tissue. There are two main types of BBD: proliferative and non-proliferative. Proliferative BBD involves an increase in the number of cells. Proliferative BBD is classified as either atypical hyperplasia or proliferative disease without atypia.

The mechanism for the association between BBD and breast cancer is not known. The two conditions have some risk factors in common – for example, genetic susceptibility – which may contribute to the association. BBD is regarded as a marker for breast cancer susceptibility. It is also possible that precursors to breast cancer in BBD may progress to breast cancer.1,2

Evidence 

A meta-analysis of 32 studies found that BBD in general was associated with an increased breast cancer risk, but no association was found between non-proliferative disease and breast cancer risk.1 Further analyses have examined risks according to the type of proliferative disease (i.e. with or without atypia). The meta-analysis estimated that atypical hyperplasia had a relative risk (RR) of 3.93 (95% confidence interval [CI] 3.24–4.76) and proliferative disease without atypia had an RR of 1.76 (95% CI 1.58–1.95).1

Studies from the prospective Mayo Clinic BBD cohort of approximately 13,400 women in the United States who had a benign breast biopsy between 1967 and 2001 had similar findings.3-6

Breast cancer risk varies with the degree of atypia of BBD. A greater number of atypical foci in the breast is associated with increased breast cancer risk.6,7

Read the full Review of the Evidence

References
  1. Dyrstad SW, Yan Y, Fowler AM et al. (2015). Breast cancer risk associated with benign breast disease: systematic review and meta-analysis. Breast Cancer Research and Treatment 149(3):569–575.
  2. Hartmann LC, Sellers TA, Frost MH, et al. (2005). Benign breast disease and the risk of breast cancer. New England Journal of Medicine 353(3):229–237.
  3. Visscher DW, Frank RD, Carter JM, et al. (2017). Breast cancer risk and progressive histology in serial benign biopsies. Journal of the National Cancer Institute 109(10):djx035.
  4. Radisky DC, Visscher DW, Frank RD, et al. (2016). Natural history of age-related lobular involution and impact on breast cancer risk. Breast Cancer Research and Treatment 155:423–430.
  5. Said SM, Visscher DW, Nassar A, et al. (2015). Flat epithelial atypia and risk of breast cancer: a Mayo cohort study. Cancer 121(10):1548–1555.
  6. Hartmann LC, Radisky DC, Frost MH, et al. (2014). Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prevention Research (Philadelphia) 7(2):211–217.
  7. Degnim AC, Dupont WD, Radisky DC, et al. (2016). Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer 122(19):2971–2978.

LCIS (lobular carcinoma in situ)

Being previously diagnosed with lobular carcinoma in situ (LCIS) is associated with an increased risk of breast cancer.

LCIS is an abnormality of cells in the milk-producing glands (lobules) of the breast. The abnormal cells have not spread from the lobules into the surrounding tissue. LCIS cannot usually be felt as a breast lump or other breast change. Changes due to LCIS only sometimes show up on a mammogram or are detected incidentally in breast biopsies performed for another reason.

LCIS and breast cancer have some risk factors in common. These common risk factors might explain the association between LCIS and increased risk of breast cancer. Another possibility is that the abnormal cells in LCIS might become invasive and lead to breast cancer.

It is important that a woman diagnosed with LCIS receives adequate information. This should include an explanation of her risk of subsequent invasive breast cancer and options regarding surgery, risk-reducing strategies and regular check-ups.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that lobular carcinoma in situ (LCIS) is associated with an increased risk of breast cancer.

The evidence is consistent across studies, however differences in study methods combined with a low incidence of LCIS, have resulted in substantially different risk estimates across studies. The body of evidence suggests that the risk of breast cancer after a diagnosis of LCIS may not be as high as reported in earlier studies; although a best estimate of risk remains unclear.

Mechanisms

LCIS is a non-invasive abnormality of the breast, characterised by changes in the cells in the lobules and terminal ducts of the breast. The abnormal cells have not spread into surrounding tissue. LCIS is often found incidentally in breast biopsies performed for another reason. Even then it is an infrequent finding, with an estimated prevalence of 0.4–3.8% in women with otherwise benign breast biopsies.1

The association between LCIS and risk of breast cancer may reflect common risk factors that predispose women to both LCIS and invasive breast cancer. In this way LCIS can be considered a breast cancer marker. It has been suggested that LCIS can also be a precursor lesion that can progress to invasive breast cancer.2

Evidence 

Although there is consistent evidence from a large number of studies that LCIS is associated with an increased risk of breast cancer, the estimated risk magnitude has varied widely across studies, and confidence intervals for the point estimates are also wide in most studies.

Some studies have indicated that the risk of subsequent breast cancer after LCIS is higher than after ductal carcinoma in situ (DCIS), whereas other studies have indicated the opposite. None of the studies comparing both LCIS and DCIS has shown a significantly different risk of subsequent breast cancer.

A cohort study of 4853 women diagnosed with LCIS estimated the standardised incidence ratio for invasive breast cancer for women with LCIS compared with the general population as 2.4 (95% confidence interval [CI] 2.1–2.6).3 There was no difference between risks of breast cancer in either breast. Another cohort study, including about 630 women with LCIS, found a relative risk for invasive breast cancer associated with LCIS of 4.74 (95% CI 2.46–9.11) for cancer in the same breast (ipsilateral) and a relative risk of 3.16 (95% CI 1.42–7.03) for cancer in the other breast (contralateral).4 The higher risk of ipsilateral compared to contralateral breast cancer after a diagnosis of LCIS was also observed in a more recent large cohort study.5

Many earlier studies have reported much higher risks in the range of 5.46 to 127 in studies including smaller sample sizes, but generally longer follow-up periods, conducted in the 1970s and 1990s.

The risk of breast cancer following LCIS varies depending on the treatment for LCIS. Lower risks have been found for surgical treatment and radiotherapy for LCIS (compared with not receiving this treatment)8 and risk-reducing medication (e.g. tamoxifen).4

A higher risk of subsequent invasive breast cancer has been found in women with hormone-receptor-negative LCIS compared with hormone-receptor-positive LCIS8; and subsequent cancer is more likely to be lobular than ductal.3,9,10

Read the full Review of the Evidence

References

  1. Cancer Australia. Clinical guidance for the management of lobular carcinoma in situ https://canceraustralia.gov.au/publications-and-resources/clinical-practice-guidelines/clinical-guidance-management-lobular-carcinoma-situ
  2. Ginter PS, D’Alfonso TM (2017) Current concepts in diagnosis, molecular features, and management of Lobular carcinoma in situ of the breast with a discussion of morphologic variants. Archives of Pathology & Laboratory Medicine 141(12): 1668‒1678
  3. Chuba PJ, Hamre MR, Yap J, et al. (2005). Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data. Journal of Clinical Oncology 23(24):5534–5541.
  4. Rawal R, Bermejo JL , Hemminki K (2005). Risk of subsequent invasive breast carcinoma after in situ breast carcinoma in a population covered by national mammographic screening. British Journal of Cancer 92(1):162.
  5. King TA, Pilewskie M, Muhsen S, et al. (2015). Lobular carcinoma in situ: a 29-year longitudinal experience evaluating clinicopathologic features and breast cancer risk. Journal of Clinical Oncology 33(33):3945–3952.
  6. Bodian CA, Perzin KH, Lattes R (1996) Lobular neoplasia. Long term risk of breast cancer and relation to other factors. Cancer 78(5):1024‒1034.
  7. Andersen JA (1977). Lobular carcinoma in situ of the breast. Cancer 39:2597‒2602.
  8. Mao K, Yang Y, Wu W, et al. (2017). Risk of second breast cancers after lobular carcinoma in situ according to hormone receptor status. PloS ONE 12(5):e0176417.
  9. Levi F, Randimbison L, Te VC, et al. (2005). Invasive breast cancer following ductal and lobular carcinoma in situ of the breast. International Journal of Cancer. 116(5):820–823.
  10. Li CI, Malone KE, Saltzman BS, et al. (2006) Risk of invasive breast carcinoma among women diagnosed with ductal carcinoma in situ and lobular carcinoma in situ, 1988‐2001. Cancer. 106(10):2104–2112.

DCIS (ductal carcinoma in situ)

Having had ductal carcinoma in situ (DCIS) is associated with an increased risk of breast cancer.

Women who have been diagnosed with DCIS have 3.9 times the risk of breast cancer compared to other women.

DCIS is an abnormality of cells in the milk ducts of the breast. The abnormal cells have not spread from the milk ducts into the surrounding tissue. DCIS is often detected during screening for breast cancer using a mammogram.

For some women, these abnormal cells in DCIS may develop into invasive breast cancer which can spread outside the ducts into the breast tissue.

DCIS and breast cancer also have some factors in common, for example, breast density and family history, which may increase a woman’s risk for breast cancer.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having ductal carcinoma in situ (DCIS) is associated with an increased risk of breast cancer.

Australian women who have been diagnosed with DCIS are estimated to have 3.9 times the risk of breast cancer compared to other women (RR 3.9, 95% CI 3.6–4.2).1

Mechanisms

DCIS is a heterogeneous, non-invasive abnormality of the breast, characterised by changes in the cells in the milk ducts. The abnormal cells are contained within the milk ducts and have not spread into surrounding tissue. DCIS is often diagnosed during mammography screening.

DCIS and breast cancer have some risk factors in common – for example, breast density and family history.2,3 These common risk factors might independently lead to DCIS and invasive breast cancer in either the same breast or the other breast.

Another possibility is that DCIS might progress to invasive breast cancer.2 Research is in progress to examine the malignant potential of DCIS lesions and factors that predict progression to invasive breast cancer.

Evidence 

An Australian cohort study of 13,749 women diagnosed with DCIS between 1995 and 2005 found that the relative risk of invasive breast cancer compared with all Australian women was 3.9 (95% confidence interval [CI] 3.6–4.2).1 Cohort studies in other countries have also shown an association between DCIS and increased breast cancer risk.

Several of these studies have shown that the increased risk of invasive breast cancer is higher among women who were younger when they were diagnosed with DCIS. For example, for Australian women aged less than 40 years at DCIS diagnosis, the relative risk was 19.8 (95% CI 14.2–25.4).1 In addition, the increased risk was lower in the period up to 5 years from DCIS diagnosis than in the period 5–11 years from DCIS diagnosis in Australian women.1

A recent meta-analysis found a higher risk of invasive breast cancer after DCIS that had positive (rather than negative) margins, and for DCIS detected by methods other than screening (rather than by screening).4

A number of cohort studies have reported differences in risk of invasive breast cancer for different treatment regimens for DCIS.

Read the full Review of the Evidence

References
  1. Australian Institute of Health and Welfare & National Breast and Ovarian Cancer Centre (2010). Risk of invasive breast cancer in women diagnosed with ductal carcinoma in situ in Australia between 1995 and 2005, Cancer Series 51, cat. no. CAN 47, AIHW, Canberra, www.aihw.gov.au/publication-detail/?id=6442468334.
  2. Gorringe KL & Fox SB (2017). Ductal carcinoma in situ biology, biomarkers, and diagnosis. Frontiers in Oncology 7:248.
  3. Virnig BA, Wang SY, Shamilyan T, et al. (2010). Ductal carcinoma in situ: risk factors and impact of screening. Journal of the National Cancer Institute. Monographs 2010(41):113–116.
  4. Zhang X, Dai H, Liu B, et al. (2016). Predictors for local invasive recurrence of ductal carcinoma in situ of the breast: a meta-analysis. European Journal of Cancer Prevention 25 (1):19–28.

Environmental factors

Environmental factors are factors that can occur in our surroundings that are associated with increased or decreased risk of breast cancer.

An environmental factor that may be associated with an increased risk of breast cancer include exposure to light at night through shift work. 

Shift work

Some studies have suggested that shift work that disrupts the normal sleeping cycle may be associated with an increased risk of breast cancer. The evidence is stronger for an increased risk of breast cancer after 20 years or more of shift work.

Shiftwork is work during hours other than standard daylight hours. It can be permanent (regular work on one shift only), continuous (all days of the week) or discontinuous (interruption on weekends).

Working at night, in light, might reduce the production of the hormone ‘melatonin’ which is normally produced during the night under dark conditions. Melatonin might play a role in reducing DNA damage so reducing its production might increase the risk of breast cancer. 

Summary of the evidence

Evidence classification: Suggestive

The evidence is suggestive of an association between shift work that disrupts the circadian rhythm and an increased risk of breast cancer. However, there are some limitations to the evidence. The supportive evidence is mostly from case-control studies rather than the more robust cohort studies.  There is some evidence of a dose-response relationship. The evidence is stronger for an increased risk of breast cancer either after over 20 years of night shift work or after shorter periods with many consecutive shifts.1

Mechanisms

Shift work can disrupt the circadian system, with hormonal effects, including on melatonin. Melatonin is produced with a regular circadian rhythm, and disruption to its levels indicates circadian disruption. Melatonin has anti-proliferative effects on cultured human cancer cells, and there is some evidence of an anti-oestrogenic effect.2 There is also evidence from animal models that melatonin inhibits or reduces DNA damage by free radicals.2 However, data from clinical trials on the role of melatonin in lowering the risk of breast cancer are lacking.

Evidence 

The International Agency for Research on Cancer (IARC) has indicated that ‘shiftwork involving circadian disruption’ is ‘probably carcinogenic to humans’ (Group 2A).3 It concluded that there was limited epidemiological evidence in humans for a link between night shift work and cancer; most of the human epidemiological evidence was for breast cancer.

Some, but not all, recent meta-analyses support an association between night shift work and breast cancer risk. This association is seen mostly in case–control studies rather than the more robust cohort studies. There is some evidence of a dose-response relationship. The evidence is stronger for an increased risk of breast cancer after more than 20 years of night shiftwork.4

The Nurses’ Health Study (NHS) found an association between 20 or more years of rotating shiftwork and increased risk of breast cancer among women who were younger at recruitment.5 A second report from the NHS II reported a dose-response relationship with increased risk of breast cancer among premenopausal but not postmenopausal women who had increasing exposure to outdoor light at night and worked night shifts.6

Read the full Review of the Evidence

References
  1. Hansen J (2017). Night shift work and risk of breast cancer. Current Environmental Health Reports 4 (3):325–339
  2. International Agency for Research on Cancer (2010). Painting, firefighting, and shiftwork, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 98, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
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Last updated 6 March 2025
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