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Medical history and medications

Factors in a woman's medical history on this page have been the subject of research to investigate whether they are associated with risk of breast cancer.

Study results have shown these factors, including  use of some medications, some medical conditions, pregnancy termination, breast implants, injury to the breast and stress to be unproven or unlikely to influence risk of breast cancer. 

 

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

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that oestrogen-only menopausal hormone therapy (MHT) is associated with an increased risk of breast cancer.

Oestrogen-only MHT, also referred to as oestrogen-only hormone-replacement therapy (HRT), is medication that contains the hormone oestrogen without a progestogen. It is mainly prescribed to women who have had a hysterectomy to reduce symptoms of menopause. Women with an intact uterus are usually prescribed combined oestrogen-progestogen MHT.

Evidence classification: Inconclusive

The evidence for any association between menopausal hormone therapy (MHT) containing oestrogen only (without progestogen) and risk of breast cancer is inconclusive.

There are inconsistent findings across studies. Although an increased risk of breast cancer was found with 'ever use' versus 'never use' of oestrogen-only MHT in a meta-analysis of cohort and case-control studies, and among current users in some but not all more recently published cohort studies, there is no evidence of a dose-response relationship. Evidence from a randomised controlled trial does not support an association with breast cancer.

Proposed mechanisms

Oestrogen-only MHT refers to use of oestrogen without a progestogen to reduce the symptoms of menopause associated with diminished circulating oestrogens. It is mainly prescribed to women who have had a hysterectomy; women with an intact uterus are usually prescribed combined oestrogen-progestogen MHT.

Proposed pathways for an association with breast cancer relate to the generally longer duration of exposure to oestrogen over a lifetime among oestrogen-only MHT users compared to non-users.

Evidence

IARC reviewed evidence from one systematic review, one randomised controlled trial, and more than 20 cohort and case–control studies.1 It concluded that ‘a positive association has been observed between exposure to oestrogen-only MHT and cancer of the breast’. However, inconsistencies between studies or within studies meant that a causal relationship could not be determined.

A randomised controlled trial (Women’s Health Initiative) of women aged 50–79 years who had had a hysterectomy suggested a decreased risk of breast cancer among women who received conjugated equine oestrogens alone compared with women who received a placebo.2

Other recent studies, including a meta-analysis and several cohort studies, have provided inconsistent results. An increased risk of breast cancer was found with ‘ever’ use versus ‘never’ use of oestrogen-only MHT in a meta-analysis of cohort and case-control studies.3 Some, but not all, more recently published cohort studies have found an increased risk of breast cancer among current users of oestrogen-only MHT.4,5,6 However, there is no evidence of a dose-response relationship.4,5

Read the full Review of the Evidence

References
  1. 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 Risk to Humans, Lyon.

  2. 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.

  3. 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.

  4. 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.

  5. Bakken K, Fournier A, Lund E, Waaseth M, 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.

  6. Fournier A, Mesrine S, Dossus L et al.(2014). Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Research and Treatment145: 535–543

Hormonal contraception (progestogen only)

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that using progestogen-only contraceptives is associated with an increased risk of breast cancer. Only a small number of poor-quality studies have looked at a possible link between progestogen-only contraceptives and breast cancer, and most of these studies have shown no association.

Progestogen-only contraceptives contain progesterone or its synthetic alternative without oestrogen (see combined oral contraception). They are available in different forms: as a pill, an injection, an implant or a hormone-releasing intrauterine device.

Evidence classification: Inconclusive

The evidence for any association between the use of progestogen-only contraceptives and risk of breast cancer is inconclusive.

Only a small number of poor-quality studies have looked at a possible association between progestogen-only contraception and risk of breast cancer. Studies have been limited in sample size and by poor measurement of exposure. Most studies have shown no association with risk of breast cancer.

Evidence 

The International Agency for Research on Cancer (IARC) concluded that there was inadequate evidence for carcinogenicity of progestogen-only oral contraceptives in humans and no evidence of an increased risk of breast cancer.1

There is only a limited amount of more recent evidence. A case-control study found an increased risk of breast cancer in women who had ever used progestogen -only oral contraceptives compared with those who had never used it.2 The risk was highest for current or recent users. However, another cohort study3 and a case-control study4 found no association between current or ever use of progestogen-only oral contraceptives and breast cancer risk.

For injectable and implantable forms of progestogen-only contraceptives, a case-control study in South Africa found an increased risk of breast cancer associated with current use of an injectable formulation.5 However, a larger case-control study in the United States found no association between ever use of injectable or implantable progestogen-only contraceptives and risk of breast cancer.6

A cohort study found no association between use of the levonorgestrel-releasing intrauterine system and risk of breast cancer.7

Read the full Review of the Evidence

References
  1. International Agency for Research on Cancer (1999). Hormonal contraception and post-menopausal hormonal therapy, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 72, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
  2. Kumle M, Weiderpass E, Braaten T, et al. (2002). Use of oral contraceptives and breast cancer risk: the Norwegian–Swedish Women’s Lifestyle and Health Cohort Study. Cancer Epidemiology, Biomarkers & Prevention 11(11):1375–1381.
  3. Fabre A, Fournier A, Mesrine S, et al. (2007). Oral progestagens before menopause and breast cancer risk. British Journal of Cancer 96(5):841–844.
  4. Marchbanks PA, McDonald JA, Wilson HG, et al. (2002). Oral contraceptives and the risk of breast cancer. New England Journal of Medicine 346(26):2025–2032.
  5. Shapiro S, Rosenberg L, Hoffman M, et al. (2000). Risk of breast cancer in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen contraceptives. American Journal of Epidemiology 151(4):396–403.
  6. Strom BL, Berlin JA, Weber AL, et al. (2004). Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contraception 69(5):353–360.
  7. Backman T, Rauramo I, Jaakkola K, et al. (2005). Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstetrics and Gynecology 106(4):813–817.
Aspirin

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that the use of aspirin is associated with a reduced risk of breast cancer

Studies that have looked for an association between use of aspirin and risk of breast cancer have varied in methodology and been inconsistent in their findings. 

Aspirin is an anti-inflammatory medicine that is used to treat pain, fever and inflammation. It can also be used in the prevention of heart attacks in some people.

Aspirin affects the activity of some enzymes that play a role in development of cancer. This led to the suggestion that taking aspirin might reduce the risk of breast cancer.

Evidence classification: Inconclusive

The evidence for any association between use of aspirin and risk of breast cancer is inconclusive.

Studies have varied widely in the doses, frequencies and durations of aspirin use. The evidence is inconsistent, with data from a large randomised controlled trial and the most recent meta-analysis of 13 cohort studies providing evidence of no association but meta-analysis of case-control studies showing a small protective effect. A limited amount of data is available to enable dose-response analyses.

Proposed mechanisms

Aspirin, or acetylsalicylic acid, is one of a group of anti-inflammatory medications called non-steroidal anti-inflammatory drugs (NSAIDs) that are used to treat pain, fever and inflammation. Aspirin has a similar mode of action to other NSAIDs, but additionally inhibits platelet aggregation and is therefore also used in the prevention of cardiovascular disease. 1

Evidence 

A large randomised controlled trial examined regular use of low-dose aspirin (100 mg every other day for 10 years) in almost 40,000 women aged 45 years or older.2 After 18 years of follow-up, aspirin use was not associated with risk of breast cancer.

Nine meta-analyses have examined the association between aspirin use and breast cancer risk. The studies varied markedly in the doses, frequencies and durations of aspirin use. Limited data are available on dose-response relationships, including duration of aspirin use.

Some meta-analyses have found a small protective effect of aspirin use on risk of breast cancer. However, this was mainly seen in case-control studies, which are particularly subject to bias, and not in cohort studies.

The most recently published meta-analysis, which included only large prospective cohort studies (13 studies), did not find an association between overall use of aspirin and risk of breast cancer.3

A cohort study that reported a marginally protective effect against breast cancer of 3 or more tablets per week of low-dose aspirin found that this effect was seen only for hormone-receptor positive/HER2-negative subtype of breast cancer.4 Another cohort study found that aspirin use was associated with a lower incidence of breast cancer for postmenopausal women aged 55–69 years with a family history of the disease and a personal history of benign breast disease.5

Potential dose-response relationships, with respect to duration and frequency of aspirin use, have been reported in some studies,3,6 but were not established due to data limitations such as publication bias and heterogeneity between studies.

Read the full Review of the Evidence

References
  1. Coccheri S (2017). Use and misuse of aspirin in primary cardiovascular prevention. Clinical Medicine Insights: Cardiology 11:1179546817702149.
  2. Cook NR, Lee IM, Zhang SM et al.(2013). Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Annals of Internal Medicine 159(2):77–85.
  3. Lu L, Shi L, Zeng J et al. (2017). Aspirin as a potential modality for the chemoprevention of breast cancer: a dose–response meta-analysis of cohort studies from 857,831 participants. Oncotarget 8(25):40389.
  4. Clarke CA, Canchola AJ, Moy LM, et al. (2017). Regular and low-dose aspirin, other non-steroidal anti-inflammatory medications and prospective risk of HER2-defined breast cancer: the California Teachers Study. Breast Cancer Research 19(1):52.
  5. Bardia A, Keenan TE, Ebbert JO, et al. (2016). Personalizing aspirin use for targeted breast cancer chemoprevention in postmenopausal women. Mayo Clinic Proceedings 91(1):71–80.
  6. Zhong S, Chen L, Zhang X, et al. (2015) Aspirin use and risk of breast cancer: systematic review and meta-analysis of observational studies. Cancer Epidemiology, Biomarkers & Prevention 24(11): 1645–55
Pregnancy termination

Evidence of no association

There is consistent evidence from good quality studies to show that this factor neither increases nor decreases the risk of breast cancer.

Pregnancy termination or spontaneous miscarriage is not associated with an increased risk of breast cancer.

This finding is supported by a large number of high-quality studies.

Pregnancy termination is a medical procedure to end a pregnancy. A spontaneous miscarriage is the loss of a baby before 20 weeks gestation.

These events interrupt the normal cycle of changes in hormones that occurs during a full-term pregnancy. Some of the hormonal changes that occur late in pregnancy are thought to decrease the risk of breast cancer. These changes do not occur in women who have a pregnancy termination or a miscarriage, and this has led to a concern that pregnancy termination or miscarriage might increase the risk of breast cancer.

Evidence classification: Evidence of no association

There is evidence of no association between having had a pregnancy termination or spontaneous miscarriage and risk of breast cancer.

Good-quality, consistent evidence from a large number of cohort and record linkage studies indicates that pregnancy termination (or induced abortion) and spontaneous miscarriage (loss of a baby before 20 weeks gestation; or spontaneous abortion) are not associated with risk of breast cancer.

Evidence 

A meta-analysis of 15 prospective cohort studies involving 31,816 cases found no increase in the risk of breast cancer associated with pregnancy termination or spontaneous miscarriage.1 Further, no association was found when the studies were analysed by subgroups: women with no children; women who had a termination or miscarriage before or after a first full-term pregnancy; number of terminations or miscarriages; and women who had a first termination or miscarriage after 30 years of age.

A pooled analysis of 53 studies undertaken in 16 countries involving 83,000 women with breast cancer did not find an association between having one or more pregnancy terminations or miscarriages and risk of breast cancer.2

Read the full Review of the Evidence

References
  1. Guo J, Huang Y, Yang L, et al. (2015). Association between abortion and breast cancer: an updated systematic review and meta-analysis based on prospective studies. Cancer Causes & Control 26(6):811–819.
  2. Collaborative Group on Hormonal Factors in Breast Cancer (2004). Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83 000 women with breast cancer from 16 countries. Lancet 363:1007–1016.
Injury to the breast

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that injury to the breast is associated with increased risk of breast cancer.

Only a very small number of poor quality studies have looked at any association between injury to the breast and risk of breast cancer.

Concerns have been raised that an injury or a bump or knock to the breast could increase the spread of breast cancer cells. There is no evidence to support this or any of the mechanisms that have been suggested for an association.

However, a bump or knock can draw attention to an existing lump in the breast.

Evidence classification: Inconclusive

The evidence for any association between trauma to the breast and risk of breast cancer is inconclusive.

Only a very small number of poor-quality studies are available. The most reliable of the available studies indicates no association between trauma to the breast and risk of breast cancer. There is no plausible biological mechanism.

Proposed mechanisms

A proposed mechanism is that tissue injury to areas containing undiagnosed in situ disease might promote the dissemination of malignant cells. There is no evidence to support this or any other theories.1  Trauma to the breast might lead to detection of pre-existing disease.

Evidence 

Three very low quality studies have looked at a potential association between physical trauma to the breast and breast cancer risk.1-3

In a retrospective cohort study of women presenting for breast examinations, women were asked about previous trauma to the breast. No association was found between reported breast trauma and risk of breast cancer.2

A small case-control study reported that women with breast cancer were more likely to report physical trauma to the breast in the preceding five years than women without breast cancer.3 However this type of study is prone to recall bias, making the results unreliable.

A systematic review of case reports of women who had breast injury from wearing a seatbelt reported that breast cancer had developed in 5 of the 43 women in the 3 weeks to 4 years after the injury.1 However, case reports cannot show causality.

Read the full Review of the Evidence

References
  1. Song CT, Teo I, Song C (2015). Systematic review of seat-belt trauma to the female breast: a new diagnosis and management classification. Journal of Plastic, Reconstructive & Aesthetic Surgery 68:382–389.
  2. Gatta G, Di Grezia G, Lieto R, et al (2012). No evidence of an association between trauma and breast carcinoma: a retrospective cohort study. Global Advanced Research Journal of Medicine and Medical Sciences 1(7):172–180.
  3. Rigby JE, Morris JA, Lavelle J, et al. (2002). Can physical trauma cause breast cancer? European Journal of Cancer Prevention 11:307–311.
Silicone breast implants

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that silicone-filled breast implants are associated with risk of breast cancer. A number of studies have been done, and while these have had limitations, none has shown any link between silicone breast implants and increased risk of breast cancer.

Women may have breast implants inserted for cosmetic reasons, or for breast reconstruction after surgery. There are different types of breast implants, with different fillings, surfaces and shapes.

Use of breast implants with a textured surface are associated with an increased risk of a rare cancer, anaplastic large cell lymphoma. This can develop, very rarely, near breast implants, but it is not breast cancer.

Evidence classification: Inconclusive

The evidence for any association between silicone breast implants and risk of breast cancer is inconclusive.

Studies have had methodological problems, including lack of adjustment for possible confounding factors. Two meta-analyses of poor quality studies have found that breast implants are associated with a decreased risk of breast cancer compared to women without breast implants. 

Textured breast implants are associated with an increased risk of anaplastic large cell lymphoma, but this is not breast cancer.

Background

Breast implants may be used for cosmetic reasons, or for breast reconstruction after surgery that has removed one or both breasts. There are different types of breast implants, with different fillings (including silicone gel), surfaces (textured or smooth) and shapes.

Evidence 

Breast cancer

Evaluation of the evidence by the International Agency for Research on Cancer (IARC) indicated that there is a lack of evidence for carcinogenicity of silicone breast implants for breast cancer. The overall evaluation was that silicone breast implants are ‘not classifiable as to their carcinogenicity in humans’ (Group 3).1 

Two meta-analyses have examined the association between breast implants used for cosmetic reasons and breast cancer, with considerable overlap in included studies.2,3 Both meta-analyses found that breast implants were associated with a decreased risk of breast cancer.

The included studies were limited by inadequate adjustment for possible confounders, such as body mass index, reproductive factors, alcohol consumption, family history and other possible underlying differences in women who undergo breast implantation. There were also limited descriptions of the types of implants used.2

Anaplastic large-cell lymphoma

There is convincing evidence that breast implants (containing silicone or saline) that have a textured, rather than smooth, surface are associated with an increased risk of anaplastic large-cell lymphoma (ALCL).4 ALCL is rare type of lymphoma that usually affects the lymph nodes, skin, lungs or liver. It can develop near breast implants but it is not breast cancer.4

The risk of breast implant-associated ALCL for women with textured breast implants is very small and has been estimated at between 1 in 1,000 and 1 in 10,000 women with textured implants.5 The Australian Breast Device Registry is prospectively monitoring women with breast implants5 and experts do not recommend removal of breast implants for women who have no problems with the implant.4

Read the full Review of the Evidence

References
  1. International Agency for Research on Cancer (1999)Surgical implants and other foreign bodies, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 74, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon.
  2. Balk EM, Earley A, Avendano EA et al. (2016). Long-term health outcomes in women with silicone gel breast implants: a systematic reviewAnnals of Internal Medicine 164(3):164–175.
  3. Noels EC, Lapid O, Lindeman JH et al. (2015). Breast implants and the risk of breast cancer: a meta-analysis of cohort studies. Aesthetic Surgery Journal 35(1):55–62.
  4. Therapeutic Goods Administration (TGA). Breast implants and anaplastic large cell lymphoma 2018 [Available from: https://www.tga.gov.au/node/733565.]
  5. Hopper I, Ahern S, McNeil JJ, et al. (2017) Improving the safety of breast implants: implant-associated lymphoma. Medical Journal of Australia 207(5):185‒186.
Stress

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that stress is associated with an increased risk of breast cancer. While some studies have indicated a link between various psychological factors and an increased risk of developing cancer, most studies have not.

Stress is the mental or emotional strain that results from difficult circumstances. Life changes such as illness, bereavement, breakdown in a relationship or loss of a job can cause stress.

Stress might affect processes in the body, such as the immune system. It can also lead to lifestyle changes, such as drinking alcohol. These factors could increase the risk of breast cancer.

Evidence classification: Inconclusive

The evidence for any association between stress and risk of breast cancer is inconclusive.

Studies have provided inconsistent results, but the majority of studies, particularly those that have adjusted for confounders, have not found an association. It is difficult to quantify exposure to psychological stress, and the defined exposure has differed across studies.

Proposed mechanisms

Stress is a state of mental or emotional strain resulting from adverse or demanding circumstances. It can result from life changes such as illness, bereavement, breakdown in a relationship or loss of a job. 

Several biological pathways have been proposed, including an effect on oestrogen synthesis1 and alterations in immune function2. Stress could influence breast cancer risk indirectly through associations with unhealthy lifestyle behaviours that are known risk factors for breast cancer, including alcohol consumption.

Evidence 

Several meta-analyses have reported on perceived stress or stressful life events and risk of breast cancer.3-5 They included mainly case-control studies, and provided inconsistent findings, with large differences between studies and poor adjustment for confounders. Three additional large cohort studies did not find any association between perceived stress and breast cancer risk, after adjustment for known risk factors.6-8

One of the meta-analyses reported no association between ‘widowhood’ and breast cancer risk.4 Another found significantly increased risks of breast cancer associated with death of a spouse and death of a relative or friend.5 Two cohort studies did not find an association between loss events and breast cancer risk.6,8

No association between divorce or separation and breast cancer risk was found in two meta-analyses4,5 and one cohort study.6

Another meta-analysis found no association between work stress and breast cancer risk after adjustment for potential confounding factors.9 No association between job loss and breast cancer incidence was found in a cohort study.6

Read the full Review of the Evidence

References
  1. Schliep KC, Mumford SL, Vladutiu CJ, et al. (2015) Perceived stress, reproductive hormones, and ovulatory function: a prospective cohort study. Epidemiology 26(2):177.
  2. Dhabhar FS, Saul AN, Daugherty C, et al. (2010) Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma. Brain, Behavior, and Immunity 24(1):127–137.
  3. Lin Y, Wang C, Zhong Y, et al. (2013). Striking life events associated with primary breast cancer susceptibility in women: a meta-analysis study. Journal of Experimental & Clinical Cancer Research 32(1):53.
  4. Santos MC, Horta BL, Amaral JJ, et al. (2009). Association between stress and breast cancer in women: a meta-analysis. Cadernos de Saúde Pública 25:S453–63.
  5. Duijts SF, Zeegers MP, Borne BV (2003). The association between stressful life events and breast cancer risk: a meta-analysis. International Journal of Cancer 107(6):1023–1029.
  6. Schoemaker MJ, Jones ME, Wright LB, et al. (2016). Psychological stress, adverse life events and breast cancer incidence: a cohort investigation in 106,000 women in the United Kingdom. Breast Cancer Research 18(1):72.
  7. Sawada T, Nishiyama T, Kikuchi N, et al. (2016). The influence of personality and perceived stress on the development of breast cancer: 20-year follow-up of 29,098 Japanese women. Scientific Reports 6:32559.
  8. stressSurtees PG, Wainwright NW, Luben RN, et al. (2010). No evidence that social stress is associated with breast cancer incidence. Breast Cancer Research and Treatment 120(1):169–174.
  9. Heikkilä K, Nyberg ST, Theorell T, et al. (2013). Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women. British Medical Journal 346:f165.
Diabetes

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that type 2 diabetes is associated with an increased risk of breast cancer.

Study results have been inconsistent. While a few studies have suggested that women with type 2 diabetes have slightly higher risks of breast cancer (especially in postmenopausal women), these studies had a number of weaknesses.

Type 2 diabetes is a metabolic disorder. People with type 2 diabetes have high blood sugar, and their bodies have trouble controlling the level of blood sugar. Obesity and lack of physical activity can lead to type 2 diabetes. A family history of type 2 diabetes can also play a role.

Some of the metabolic changes that occur in people with type 2 diabetes could potentially be associated with an increased risk of cancer.

Evidence classification: Inconclusive

The evidence for any association between type 2 diabetes and risk of breast cancer is inconclusive.

The evidence is limited because studies did not differentiate between type 1 and type 2 diabetes, the findings were very inconsistent across studies, and studies failed to adjust for other factors associated with both diabetes and breast cancer, such as body mass index (BMI).

Evidence

Four meta-analyses have shown a small positive association between type 2 diabetes and breast cancer risk, particularly in postmenopausal women.1-4 However, two of these did not differentiate between type 1 and type 2 diabetes.

Analysis of 21 studies of women with diabetes that adjusted for family history, age and BMI resulted in a smaller effect size, although the association with breast cancer risk was still significant.3

More recent data from two population-based cohort studies5,6 reported increased risks of breast cancer in women with type 2 diabetes compared with the general population. Neither of these studies was able to take account of the potentially confounding influence of BMI or other breast cancer risk factors.

Read the full Review of the Evidence

References
  1. Boyle P, Boniol M, Koechlin A, et al. (2012). Diabetes and breast cancer risk: a meta-analysis British Journal of Cancer 107(9):1608–1617.
  2. De Bruijn KM, Arends LR, Hansen BE, et al. (2013). Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. British Journal of Surgery 100:1421–1429.
  3. Hardefeldt PJ, Edirimanne S & Eslick GD (2012). Diabetes increases the risk of breast cancer: a meta-analysis. Endocrine-related Cancer 19:793–803.
  4. Liao S, Li J, Wei W, Wang L, et al. (2011). Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature. Asian Pacific Journal of Cancer Prevention 12(4):1061–1065.
  5. Gini A, Bidoli E, Zanier L, et al. (2016). Cancer among patients with type 2 diabetes mellitus: a population-based cohort study in northeastern Italy. Cancer Epidemiology 41:80–87.
  6. Xu HL, Fang H, Xu WH, et al. (2015). Cancer incidence in patients with type 2 diabetes mellitus: a population-based cohort study in Shanghai. BMC Cancer 15:852.
Polycystic ovarian syndrome (PCOS)

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that polycystic ovarian syndrome (PCOS) is associated with an increased risk for breast cancer.

Only a small number of low-quality studies have looked at a possible link between PCOS and increased risk for breast cancer, and these have not shown any association.

PCOS is a hormonal disorder that affects around 1 in 10 women of child-bearing age. Women with this condition have irregular or absent periods, skin and hair changes and cysts on the ovaries. Some of the factors associated with PCOS, such as overweight and later age at first pregnancy, can also influence a woman’s risk of breast cancer.

Evidence classification: Inconclusive

The evidence for any association between polycystic ovarian syndrome (PCOS) and risk of breast cancer is inconclusive.

The limited moderate and low quality evidence available indicates no association between PCOS and risk of breast cancer.

Proposed mechanisms

Polycystic ovarian syndrome (PCOS) is an endocrine disorder that affects around 8-13% of women of reproductive age in Australia.1 Women with PCOS have irregular or absent menstrual periods, skin and hair changes (such as hirsutism) related to high levels of androgens, and cysts on the ovaries. High blood pressure and obesity, and metabolic abnormalities (such as insulin resistance, diabetes and high cholesterol levels) can also be associated with PCOS.2 Some of the factors associated with PCOS such as obesity, later age at first pregnancy or menarche and anovulatory cycles can influence the risk of breast cancer.3

Evidence 

Only a small number of studies have looked at whether PCOS is associated with breast cancer risk. These studies have been of low to moderate quality. For example, studies have not taken into account potential confounders such as body mass index and other risk factors for breast cancer; they have used patient recall for diagnosis of PCOS; and they have used different diagnostic criteria for PCOS.2-4

A meta-analysis that included 5 cohort studies (no heterogeneity) and 3 case-control studies (low heterogeneity) found no association between PCOS and risk of breast cancer.3 Another meta-analysis that included an additional case-control study also found no association.4

Read the full Review of the Evidence

References
  1. Teede HJ, Misso ML, Boyle JA, et al. (2018). Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Medical Journal of Australia 209 (7 Suppl): S3-S8
  2. Harris HR & Terry KL (2016). Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertility Research and Practice 2:14.
  3. Shobeiri F & Jenabi E (2016). The association between polycystic ovary syndrome and breast cancer: a meta-analysis. Obstetrics & Gynecology Science 59(5):367.
  4. Chittenden BG, Fullerton G, Maheshwari A et al. (2009). Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reproductive BioMedicine Online 19(3):398–405.
Hormonal treatment for infertility

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that hormonal treatment for infertility is associated with an increased risk of breast cancer.

The majority of studies have found no association between hormonal infertility treatment and risk of breast cancer.

Women who have hormonal treatment for infertility take hormones to stimulate ovulation to try to become pregnant. Some of these treatments also involve in-vitro fertilisation (IVF).

While long term exposure to high levels of oestrogen is associated with breast cancer risk, the evidence does not show an increased risk associated with hormonal infertility treatment.

Evidence classification: Inconclusive

The evidence for any association between hormonal treatment for infertility and risk of breast cancer is inconclusive. 

The evidence is limited by substantial methodological issues but the majority of evidence, from a large number of cohort studies, shows no association between hormonal infertility treatment, with or without in vitro fertilisation (IVF), and risk of breast cancer.

Proposed Mechanisms

During hormonal treatment for infertility, hormones and other agents are used to stimulate ovulation or egg maturation. These can include selective oestrogen receptor modulators (e.g. clomiphene citrate, tamoxifen), follicle-stimulating hormone, gonadotropins and gonadotropin-releasing hormone analogues. Hormonal treatment for infertility can include  IVF, which uses individualised protocols of hormonal treatment and fertilisation of the collected eggs outside the body.

Hormonal infertility treatments result in levels of oestrogens that are higher than those during natural menstrual cycles.1 Prolonged exposure to higher levels of circulating oestrogen are associated with risk of breast cancer, but little is known about the transient but significantly elevated levels of oestrogens associated with hormonal treatment for infertility.2

Evidence

The evidence from recent meta-analyses and cohort studies is limited by multiple methodological issues including differences in reference populations and categorisation of exposures, and varying control for important confounders such as age at menarche, age at hormonal treatment for infertility, body mass index, previous hormonal infertility treatment, pre-eclampsia and multiple births.

A recent meta-analysis of 20 cohort studies with a total of more than 200,000 participants found no association between hormonal treatment for infertility and breast cancer risk, with or without IVF.2 There was, however, evidence of an increased risk of breast cancer in studies with a follow-up period of at least 10 years. Of the 7 included studies, 3 showed an increased risk of breast cancer among women treated without IVF. 

Three large cohort studies did not find any association between assisted reproductive technologies (ART), with or without IVF, and risk of breast cancer.1,3,4  Another large cohort study showed a decreased risk of breast cancer in women treated with ART compared with the expected incidence in the general population.5

Read the full Review of the Evidence

References
  1. van den Belt-Dusebout AW, Spaan M, Lambalk CB, et al. (2016) Ovarian stimulation for in vitro fertilization and long-term risk of breast cancer. JAMA: The Journal of the American Medical Association. 316(3):300-12.
  2. Gennari A, Costa M, Puntoni M, et al. (2015). Breast cancer incidence after hormonal treatments for infertility: systematic review and meta-analysis of population-based studies. Breast Cancer Research and Treatment 150:405–413.
  3. Lundberg FE, Iliadou AN, Rodriguez-Wallberg K, et al. (2017). Ovarian stimulation and risk of breast cancer in Swedish women. Fertility and Sterility 1098(1):137–144.
  4. Reigstad MM, Storeng R, Myklebust TA, et al. (2017) Cancer risk in women treated with fertility drugs according to parity status - a registry-based cohort study. Cancer Epidemiology Biomarkers & Prevention 26(6):953–962.
  5. Luke B, Brown MB, Spector LG, et al. (2015). Cancer in women after assisted reproductive technology. Fertility and Sterility 104(5):1218–1226.
Exposure to diethylstilboestrol (DES) before birth (in utero)

Inconclusive

The evidence is too limited to determine the likelihood of an association with increased or decreased risk of breast cancer.

There is no conclusive evidence that exposure to diethylstilboestrol (DES) before birth is associated with an increased risk for breast cancer. Studies that have looked into this have been inconsistent in their results.

Diethylstilboestrol (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 it is no longer registered for use in Australia.

Because evidence has shown that exposure to diethylstilboestrol (DES) during pregnancy is associated with an increased risk of breast cancer, this led to concerns that women who were exposed to DES in the womb might also be at increased risk.

Evidence classification: Inconclusive

The evidence for any association between exposure to the synthetic oestrogen diethylstilboestrol (DES) before birth (in utero) and risk of breast cancer is inconclusive.

Findings from pooled analyses of cohort studies in the United States initially suggested an increased risk of breast cancer among women who were exposed to DES in utero and were older than 40 years at diagnosis. However longer-term follow-up of these cohorts and another cohort in the Netherlands has shown no significant increase in risk of breast cancer.

Background

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.1 DES is no longer registered for use in Australia.

Evidence 

The International Agency for Research on Cancer (IARC) found little evidence of an association between in utero exposure to DES and breast cancer.1 IARC reviewed 3 cohort studies. Only one of these reported an increased incidence of breast cancer among women aged over 40 years who had been exposed to DES in utero.2

Analyses of cohort studies in the United States initially indicated an increased risk of breast cancer among women exposed to DES in utero who were aged over 40 years at diagnosis.3,4 However longer-term follow-up of the same cohorts found no significant difference in risk of breast cancer between exposed and unexposed women or by age at diagnosis.5

Similarly, a large cohort study in the Netherlands found no significant increase in the risk of breast cancer overall or by age at diagnosis in women exposed to DES in utero.6

Read the full Review of the Evidence

References
  1. 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.
  2. Palmer JR, Wise LA, Hatch EE, et al. (2006). Prenatal diethylstilboestrol exposure and risk of breast cancer. Cancer Epidemiology, Biomarkers & Prevention 15(8):1509–1514.
  3. Hoover RN, Hyer M, Pfeiffer RM, et al. (2011). Adverse health outcomes in women exposed in utero to diethylstilboestrol . New England Journal of Medicine 365(14):1304–1314.
  4. Troisi R, Hatch EE, Titus‐Ernstoff L, et al. (2007). Cancer risk in women prenatally exposed to diethylstilboestrol . International Journal of Cancer 121(2):356–360.
  5. Troisi R, Hatch EE, Titus L, et al. (2017). Prenatal diethylstilboestrol exposure and cancer risk in women. Environmental and Molecular Mutagenesis doi: 10.1002/em.22155 (e-pub ahead of print).
  6. Verloop J, van Leeuwen FE, Helmerhorst TJ, et al. (2010). Cancer risk in DES daughters. Cancer Causes & Control 21(7):999–1007.



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