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Medical history and medications

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

Modifiable medical factors associated with risk of breast cancer include menopausal hormonal therapy and the oral contraceptive pill. 

Read more below to find out changes you can make to reduce your risk of breast cancer, and what you can do

 

Menopausal hormonal therapy (combined oestrogen-progestogen)

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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 1.72 (95% CI 1.55–1.92) times the risk in 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 forever versus never use of combined MHT.1,5 For current users compared with never users the relative risk 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)

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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



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