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Does hormone replacement therapy cause breast cancer

 Feb 15, 2012 Viewed: 592

Based principally on findings in three studies, the collaborative reanalysis (CR), the Women’s Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P.

Publication of the Million Women study in 2003 raised concerns about risks of HRT, in particular increased risk of breast cancer. This concerning news followed closely in the wake of the WHI trial, first published in 2002, which also emphasised risks of HRT. Not surprisingly, there followed a sudden loss of confidence in the use of HRT and a decline in prescriptions. Subsequently, attempts have been made to make sense of the study results. The most recent report from the Journal of Family Planning and Reproductive Healthcare, available now online, has examined in detail the data used in the Million Women study (MWS) and concludes that the evidence in the MWS was unreliable and that HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.

With reanalysis of the WHI trial also now showing that, when used appropriately, and especially in women under the age of 60 HRT is safe, surely the time has come for women and healthcare professionals to worry less about risks of HRT and return to considering the benefits and see HRT as a very useful option for women experiencing menopausal symptoms, or suffering from osteoporosis or premature ovarian failure.

What are the risks of HRT?

Although HRT can offer many benefits, for some women it can carry unacceptable potential risks. When deciding whether or not HRT is right for you, you must consider the balance between risks and benefits.

The main potential risks that have been identified are:

• breast cancer

• blood clots in the veins (venous thrombosis)

• blood clots in the arteries (heart attacks and strokes)

• cancer of the lining of the uterus (endometrium), though this can be prevented by the addition of progestogen.

It is important to understand these risks and put them into perspective – most women taking HRT do not experience any of these problems as a direct result of taking the hormones. Furthermore, other risk factors are often more important than HRT – particularly smoking or being very overweight – in creating these problems.

Evidence suggests that women with a family history of breast cancer have the same relative increase in risk of breast cancer from hormone replacement therapy (HRT) as the general population. Limited evidence suggests HRT does not increase the risk of breast cancer in women who carry the BRCA1 mutation.

- A review of 51 epidemiological studies carried out in 21 countries (mainly North America and Europe) analysed data from 52,705 women with breast cancer and 108,411 women without breast cancer [Collaborative Group on Hormonal Factors in Breast Cancer, 1997].

  • An increased risk of breast cancer was associated with:     Current use of HRT: the relative risk (RR) of breast cancer increased by a factor of 1.023 for each year of use (95% CI 1.011 to 1.036). In other words, there is a 2.3% increase in RR for each year that HRT is used.     Duration of use: the RR for women who had used HRT for 5 years or more was 1.35 (95% CI 1.20 to 1.49).
  • After cessation of HRT use for 5 years or more there was no significant increase in RR.
  • For women with a family history of breast cancer, the RR increase for HRT use was consistent with that for the general population.

- A prospective cohort study, the Million Women Study, looked at the effects of HRT on the incidence of, and mortality from, breast cancer [Million Women Study Collaborators, 2003]. The study enrolled 1,084,110 women 50–64 years of age:

  • After an average of 2.6 years, 9364 invasive breast cancers were registered.
  • After an average of 4.1 years, 637 breast cancer deaths were registered.
  • Current users of HRT were more likely than women who had never used HRT to develop breast cancer (RR 1.66, 95% CI 1.58 to 1.75, p < 0.0001) and die of it (RR 1.22, 95% CI 1.00 to 1.48, p = 0.05).
  • Past users of HRT were, however, not at an increased risk of breast cancer (RR 1.01, 95% CI 0.9 to 1.09).
  • There were significant differences in risk depending on which preparation of HRT was used:       Oestrogen alone (RR 1.30, 95% CI 1.20 to 1.40, p < 0.0001). Oestrogen-progestogen (RR 2.00, 95% CI 1.88 to 2.1, p < 0.0001). Tibolone (RR 1.45, 95% CI 1.2 to 1.68, p < 0.0001).
  • After 10 years’ use of HRT, this translated into an estimate of additional breast cancers per 1000 users of:     Oestrogen only: 5 (95% CI 3 to 7).     Oestrogen-progestogen combinations: 19 (95% CI 15 to 23).
  • Family history appeared to have no impact on the relative risks.
- A recent case-control study of 472 postmenopausal women with a BRCA1 mutation looked at whether the use of HRT was associated with an increased risk of breast cancer [Eisen et al, 2008]. Women with a BRCA1 mutation and breast cancer were matched with women with a BRCA1 mutation but no cancer. There were 236 pairs, and women were matched with respect to age, age at menopause, and type of menopause (surgical or natural):
  • Women who had ever used HRT: odds ratio (OR) 0.58 (95% CI 0.35 to 0.96, p = 0.93).
  • Women who had used oestrogen-only HRT: OR 0.51 (95% CI 0.27 to 0.98, p = 0.27).
  • Women who had used combined oestrogen and progestogen HRT: OR 0.66 (95% CI 0.34 to 1.27, p = 0.21).
  • The authors concluded that HRT was not associated with an increased risk of breast cancer.
### National Institute for Health and Clinical Excellence
The name ‘Million Women Study’ implies an authority beyond criticism or refutation. Many commentators, and the investigators, have repeatedly stressed that it was the largest study of HRT and breast cancer ever conducted. Yet the validity of any study is dependent on the quality of its design, execution, analysis and interpretation. Size alone does not guarantee that the findings are reliable. The MWS was an observational study, and it had the attendant problems and uncertainties intrinsic to such studies. If the evidence was unreliable, the only effect of its massive size would have been to confer spurious statistical authority to doubtful findings. Here we conclude that the evidence in the MWS was indeed unreliable. There were defects in the study design, and the findings did not adequately satisfy the principles of causation. In terms of time order, information bias, detection bias, confounding, statistical stability and strength of association, dose/durationresponse, internal consistency, external consistency and biological plausibility the study was defective. HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does. ### Source

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