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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.

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 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 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-analysisAsia 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
Cardiac glycosides (digoxin)

Suggestive

The evidence is indicative of an association between the factor and increased or decreased risk of breast cancer, but there is not sufficiently strong evidence to be more certain.

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.

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

Suggestive

The evidence is indicative of an association between the factor and increased or decreased risk of breast cancer, but there is not sufficiently strong evidence to be more certain.

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.

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

Convincing

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

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 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.

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

Convincing

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

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

Convincing

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

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.

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 studyCancer 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)

Convincing

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

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.

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)

Convincing

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

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.

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.

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