Update on hormone replacement therapy and breast cancer

A recent meta-analysis has shown that an increased risk of breast cancer was associated with the use of all types of hormone replacement therapy (HRT), except vaginal oestrogens. The analysis also found that the excess risk of breast cancer with systemic HRT persisted after stopping HRT for longer than previously reported. In view of the above, HSA would like to update healthcare professionals on these findings and the recommendations on the use of HRT. 

About the meta-analysis1

The meta-analysis, published in The Lancet in August 2019, was conducted by the Collaborative Group on Hormonal Factors in Breast Cancer to assess the association between the type and timing of HRT use and the risk of incident invasive breast cancer in post-menopausal women. The main analysis used a nested case-control design, where 108,647 cases of breast cancer from prospective epidemiological studies were each matched with up to four randomly selected controls (i.e. women without breast cancer) by age, year of birth, and broad geographical region, as appropriate. The studies conducted mostly in early 2000s included long-term follow-up of women who were current users, past users, or never users of HRT. Among women who developed breast cancer, the mean HRT duration was 10 years in current users and seven years in past users. The mean age at HRT initiation and at menopause was the same, both at 50 years.

Key findings from the meta-analysis1

1) Effect on risk by type of HRT

All forms of HRT, except vaginal oestrogens, were associated with an increased breast cancer risk, regardless of the type (combined oestrogen-progesterone or oestrogen-only) and route of delivery (oral or transdermal). Low doses of oestrogen applied directly via the vagina to treat local symptoms were not found to have an effect on breast cancer risk.

The relative risk of breast cancer in women taking HRT was greater for combined HRT than oestrogen-only preparations, when compared to never users of HRT. Among current users of combined HRT, the risk of breast cancer during years 5 –14 was greater with continuous HRT (i.e. daily progesterone use) than with sequential HRT (i.e. intermittent progestogen use) (Relative risk (RR) 2·30, 95% CI 2·21, 2·40 vs RR 1·93, 95% CI 1·84, 2·01; heterogeneity p<0·0001).

2) Effect on risk by duration of use

The risk of breast cancer increased with longer duration of use. There appeared to be little or no excess risk of breast cancer with current or previous use of HRT for duration of less than one year. However, during years 1 – 4 of current use, an excess risk was found with both combined HRT (RR 1·60, 95% CI 1·52, 1·69) and oestrogen-only systemic HRT (RR 1·17, 95% CI 1·10, 1·26). This risk approximately doubled during years 5 – 14 of use (combined HRT: RR 2·08, 95% CI 2·02, 2·15; oestrogen-only systemic HRT: RR 1·33, 95% CI 1·28, 1·37). The relative risks for past users were lower than in current users, but some excess risk persisted for more than 10 years after stopping, and its magnitude depended on the duration of previous use. However, there was little information about breast cancer risk associated with past use that had ceased more than 15 years.

Similar findings from earlier studies

The risk of breast cancer associated with the use of HRT had been previously highlighted by large research studies such as the Women’s Health Initiative (WHI)2,3 in the US and the UK Million Women Study (MWS)4 published in 2002 and 2003. Both studies found an increased risk of breast cancer associated with combined HRT use. In addition, the MWS also noted an excess breast cancer risk with oestrogen-only HRT use and increasing total duration of use in current users, regardless of HRT type. This recent meta-analysis adds to this body of evidence by confirming the earlier findings. However, contrary to the MWS which observed a decline in breast cancer risk after stopping HRT that reached the same level as never users of HRT by five years, the meta-analysis noted this risk to persist for more than 10 years when compared to never users.

Local situation

There are 16 HRT products registered in Singapore. These products are contraindicated for use in patients with known, past or suspected breast cancer. In response to the earlier studies, HSA had published a series of bulletin articles in 20025, 20046 and 20117 to update healthcare professionals on the benefits and risks of HRT. An advisory was also issued in 2002 by HSA, in consultation with medical experts in the management of HRT, to advise physicians not to use HRT for the prevention of coronary heart disease.8

HSA’s advisory

Healthcare professionals are advised to use the lowest effective dose and the shortest duration of HRT for the treatment of menopausal symptoms in their patients wherever possible and to review their patients regularly. As the potential harm may outweigh the potential benefits for women who are using HRTs solely for the long-term prevention of osteoporosis, it may be beneficial for patients to be also made aware of other non-HRT therapies for the treatment and prevention of osteoporosis. In addition, HRT does not protect postmenopausal women against cardiovascular events and hence these products are not to be initiated or continued for the purpose of reducing cardiovascular risk or preventing coronary heart disease.

References

  1. http://dx.doi.org/10.1016/S0140-6736(19)31709-X
  2. JAMA 2002; 288: 321-33
  3. JAMA 2010; 304: 1684-92
  4. Lancet 2003; 362: 419-27
  5. HSA ADR News Bulletin 2002 Aug; 4: 1,4
  6. HSA ADR News Bulletin 2004 July; 6: 2
  7. HSA ADR News Bulletin 2011 April; 13: 8
  8. https://www.hsa.gov.sg/announcements?contenttype=dear%20healthcare%20professional%20letters
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