National Breast and Ovarian Cancer Centre

NBOCC position statements

Hormone Replacement Therapy and Risk of Breast Cancer

This position statement applies only to Hormone Replacement Therapy (HRT) and breast cancer risk in women – it does not address other risks or benefits to women from HRT usage.

For more information see the NBOCC - Recommendations – HRT & Breast cancer risk

July 2008

For the purposes of this position statement, the National Breast and Ovarian Cancer Centre (NBOCC) defines HRT as the use of exogenous hormones (eg oestrogens, progestogen, testosterone) to manage menopausal symptoms. 

There are various forms and combinations of HRT. This position statement refers to the following types of HRT: oestrogen-alone (unopposed oestrogen), combined HRT (oestrogen and progestogen, either sequential or continuous combined), combined oestrogen and testosterone, tibolone and natural therapies.

The 2004-2005 National Health Survey (Australian Bureau of Statistics) indicates that 11% of Australian women aged 45 years and over were currently using HRT prescribed by a doctor, and that of these women the majority (65%) had been using HRT for 5 years or more.1

The National Health and Medical Research Council (NHMRC) has undertaken an extensive review of research evidence about HRT and published several documents for women and health professionals based on this evidence (2005). For further information about the risks and benefits of HRT refer to the following NHMRC documents:

  • Hormone Replacement Therapy: A Summary of the Evidence for General Practitioners and other Health Professionals2
  • Hormone Replacement Therapy: Exploring the Options for Women3
  • Making Decisions: Should I use hormone replacement therapy? (HRT)4

This position statement has two sections – a synopsis of evidence to date about the use of

HRT and breast cancer risk, and recommendations based on this evidence. The information in this NBOCC position statement is based on the NHMRC evidence review and relevant quality research evidence subsequently published.

The evidence considered in this statement relates to populations of women. Women continuing or initiating the use of HRT should discuss the benefits and risks of HRT with their doctor, in the context of their own personal history, family history and individual circumstances, so that they can make informed decisions about usage.

Further information and updates about HRT are available through the Therapeutic Goods Administration (TGA) website (www.tga.gov.au/alerts/hrt.htm).

Breast Cancer

Risk of invasive breast cancer

Combined (oestrogen and progestogen) HRT

There is high quality evidence from systematic reviews and clinical trials that indicates an association between the use of combined HRT and an increased risk of breast cancer that increases with duration of use.5 In a randomised controlled trial published in 2002 and conducted by the Women’s Health Initiative (WHI), women who had used combined HRT for 5.6 years had an increased risk of breast cancer compared with women who had not used HRT (RR: 1.24; 95%CI: 1.02, 1.50; p=0.003).6

In women aged 50-79yrs, the absolute risk* of breast cancer is 38 cases per 10,000 women per year in users of combined HRT (averaged over 5yrs) compared with 30 cases per 10,000 women per year in women who have never used combined HRT (ie 8 additional cases per 10,000 women over 5 years (*where absolute risk estimate was determined from WHI population).

It is not possible to precisely determine the duration of therapy after which risk is increased, however greater than 3 years usage appeared to be associated with increased risk (WHI, 2002).6 A more recent analysis of the Women’s Health Initiative trial data (2006) found that the significant increase in breast cancer risk in the trial overall after 6 years was concentrated in the women who had had prior exposure to HRT (RR: 1.96; 95%CI: 1.17, 3.27; p=0.03).7 While no overall increase in breast cancer risk was detected in women without prior HRT exposure (RR: 1.02; 95%CI: 0.77, 1.36), it was not possible to determine a safe interval for combined HRT usage.7

Cohort studies have also indicated an increase in breast cancer risk associated with the use of combined HRT. The Women’s Health Study (2002) reported a relative risk of breast cancer of 1.37 (95%CI: 1.05, 1.78) for women who had used combined HRT for 5.6 years compared to women who had never used HRT.8 The Million Women Study (2006) reported a relative risk of breast cancer of 2.14 (95%CI: 2.04, 2.24) for women who had used combined HRT compared to women who had never used HRT.9

It is important to note that both the randomised controlled trials and observational studies rely heavily on data from women who are older and/or who have taken HRT for a longer duration than may be current practice.5 

Regarding regimens for combined HRT, there is conflicting evidence about whether risk differs between sequential or continuous-combined HRT. The inconsistent data are thought to be due to the different regimes prescribed in different countries. A significantly higher risk has been associated with continuous-combined HRT in the Scandinavian studies, however, the total doses of progestin used in these studies were much higher for continuous-combined than for sequential HRT.10 

Evidence suggests that the risk of breast cancer diminishes with increasing time since HRT usage has ceased,5 returning to a risk level comparable with ‘never-users’ within 5 years of ceasing use.11

There does not appear to be a significant difference in the risk of breast cancer for the different routes of combined HRT administration (eg oral, transdermal, or implants).

Oestrogen-only HRT

High quality evidence indicates that the short-term use of oestrogen-only HRT in women with a prior hysterectomy has little or no effect on risk of breast cancer.5-7 In a randomised controlled trial conducted by the Women’s Health Initiative, women who had used oestrogen-only HRT for 7.1yrs had no increased risk of breast cancer compared with women who had not used HRT.12 However, there is evidence from observational studies to indicate that usage for more than 8 years is associated with increased breast cancer risk.13 The Nurses’ Health Study indicated a significant increase in risk of breast cancer after 20 years or more of oestrogen-only HRT usage.14

Combined oestrogen and testosterone HRT

Limited evidence is available from one prospective cohort study - the Nurses’ Health Study - indicating that the use of oestrogen and testosterone HRT is associated with a 17% increase in risk of breast cancer per year of use.15

Tibolone

Tibolone is a steroid with oestrogen-, progesterone- and androgen-like effects. There is evidence from an observational study that tibolone increases the risk of breast cancer more than oestrogen-only therapy, but less than combined HRT.9

Women with a personal history of breast cancer

There are inconsistent findings about the impact of HRT on breast cancer recurrence from two Scandinavian randomised clinical trials. From one trial of 434 women there is evidence that HRT use for about 2 years is associated with an increase in risk of recurrence of breast cancer.16 Another trial of 378 women, however, indicates that menopausal use of HRT for about 4 years was not associated with the increased risk of recurrence of breast cancer.17 The difference in risk levels may be due to the types of HRT used, with the increase in recurrence being associated more with combined HRT use than oestrogen alone. A pooled analysis of both trials indicated a significant increase in overall risk and both trials were terminated prior to completion.

A randomised clinical trial (LIBERATE) investigating the impact of tibolone on breast cancer recurrence in women with a personal history of breast cancer was stopped in May 2007 prior to completion. A trend for an excess of breast cancer recurrences was found in the group of women randomised to receive tibolone.

Women with a family history of breast cancer

There is limited evidence about HRT and risk of breast cancer for women with a family history of breast cancer. Available evidence suggests that family history has no additive impact on risk of breast cancer with HRT usage.18,19 Short-term, oestrogen-only HRT usage in women with a family history with a prior hysterectomy may be preferable to combined HRT as it does not appear to be associated with increased breast cancer risk. There are no data to support using lower dosages for any particular type of HRT as being more ‘breast safe’.18

‘Natural’ therapies

Hormone preparations referred to as ‘natural’ or ‘bio-identical’ HRT are typically prepared by compounding chemists and sold in pharmacies as troches (lozenges) or creams. These preparations are neither tested nor approved by the Therapeutic Goods Administration. There are no large, good quality studies on these ‘natural’ hormone preparations to show whether they are effective in treating menopausal symptoms, and whether they carry health risks.5

 Recommendations – HRT & Breast cancer risk:

These recommendations are from National Breast and Ovarian Cancer Centre’s Position Statement Hormone Replacement Therapy and Risk of Breast Cancer (see above).

Women continuing or initiating the use of HRT should discuss the benefits and risks of HRT with their doctor, in the context of their own personal history, family history and individual circumstances, so that they can make informed decisions about usage.

Women with no personal or family history of breast cancer

  • Women who are considering using combined HRT should be advised that the use of combined HRT (oestrogen and progestogen) is associated with an increased risk of breast cancer which increases with duration of use. Although this risk appears to be associated with more than 3 years usage, it is not possible to determine a safe interval for use of combined HRT. For this reason, combined HRT should only be considered as a short-term option for the control of severe menopausal symptoms.
  • Women who are already using combined HRT should be aware that there are both benefits and risks associated with the use of HRT. Women should review their needs every six to 12 months in consultation with their general practitioner, as their menopausal symptoms and underlying risk of breast cancer will have changed over time.
  • Women using combined HRT should be advised that the risk of breast cancer decreases with increasing time since ceasing HRT usage, returning to the level of ‘never-users’ within 5 years of ceasing use.
  • Women with a prior hysterectomy should be advised that the use of oestrogen-alone HRT for up to 8 years appears to have little or no effect on risk of breast cancer.
  • Women should be advised that there is limited evidence indicating that combined oestrogen and testosterone HRT is associated with an increased risk of breast cancer which increases with each year of use.
  • Women should be advised that there is limited evidence indicating that tibolone is associated with an increased risk of breast cancer.

Women with a personal or family history of breast cancer

  • Women with a personal history of breast cancer should be advised that there is limited evidence indicating that the use of HRT is associated with an increased risk of breast cancer recurrence.
  • Women with a family history of breast cancer should be advised that family history has no additive impact on risk of breast cancer with HRT usage.
  • Women with a family history of breast cancer with a prior hysterectomy should be advised that short-term, oestrogen-only HRT would appear preferable to combined HRT.

'Natural' therapies

  • Women should be advised that the risks of ‘natural’ HRT in relation to breast cancer are unknown.

References:

  1. Australian Bureau of Statistics (2006). National Health Survey, Australia (2004-2005). Canberra, Australian Bureau of Statistics.
  2. National Health and Medical Research Council (2005). Hormone Replacement Therapy: A Summary of the Evidence for General Practitioners and other Health Professionals. Canberra, National Health and Medical Research Council.
  3. National Health and Medical Research Council (2005). Hormone Replacement Therapy: Exploring the Options for Women. Canberra, National Health and Medical Research Council.
  4. National Health and Medical Research Council (2005). Making Decisions: Should I use hormone replacement therapy (HRT)? Canberra, National Health and Medical Research Council.
  5. National Health and Medical Research Council (2004). Hormone replacement therapy for women at or after the menopause: A comprehensive literature review.  Canberra, National Health and Medical Research Council.
  6. Writing Group for the Women’s Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002;288:321-333.
  7. Anderson GL, Chlebowski RT, Rossouw JE, Rodabough RJ, McTiernan A, Margolis KL, Aggerwal A, Curb JD, Hendrix SL, Hubbell FA, Khandekar J, Lane DS, Lasser N, Lopez AM, Potter J, Ritenbaugh C. Prior Hormone Therapy and Breast Cancer Risk in the Women's Health Initiative Randomized Trial of Estrogen Plus Progestin. Maturitas 2006;55:103-115.
  8. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin replacement therapy and breast cancer risk: the Women's Health Study (United States). Cancer Causes and Control 2002 13:847-854.
  9. Reeves GK, Beral V, Green J, Gathani T, Bull D for Million Women Study Collaborators. Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol. 2006;7(11):910-8
  10. Lee SA, Ross RK, Pike MC. An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Brit. J. Cancer. 2005;92:2049-2058.
  11. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003; 362:419-27.
  12. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chlebowski RT. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA 2006;295(14):1647-1657.
  13. Zhang SM, Manson JAE, Rexrode KM, Cook NR, Buring JE, Lee IM. Use of oral conjugated estrogeon alone and risk of breast cancer. Am. J. Epidemiol. 2007;165:524-529.
  14. Chen WY, Manson JAE, Hankinson SE, Rosner B, Homes MD, Walter CW, Colditz GA. Unopposed Estrogen Therapy and the Risk of Invasive Breast Cancer. Archives of Internal Medicine 2006;166:1027-1032.
  15. Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA. Combined Estrogen and Testosterone Use and Risk of Breast Cancer in Postmenopausal Women Archives of Internal Medicine 2006:166;1483-1489.
  16. Holmberg L, Anderson H for the HABITS Steering and Data Monitoring Committee. HABITS (hormonal replacement therapy after breast cancer – is it safe?) a randomised comparison: trial stopped. Lancet 2004;363:453-455.
  17.  Schoulz EV, Rutqvist LE on behalf of the Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: The Stockholm Randomized Trial. J Natl. Cancer Inst. 2005;97:533-535.
  18. Rippy L, Marsden J. Is HRT justified for symptom management in women at higher risk of developing breast cancer. Climacteric 2006;9:404-415.
  19. Ursin G, Tseng CC, Paganini-Hill A, Enger S, Wan PC, Formenti S, Pike MC, Ross RK.Does Menopausal Hormone Replacement Therapy Interact With Known Factors to Increase Risk of Breast Cancer? J. Clin. Oncology 2002;20:699-706.

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