British Menopause Society comment

Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence

Collaborative Group on Hormonal Factors in Breast Cancer

August 2019

A meta-analysis published in the Lancet this week by the Collaborative Group on Hormonal Factors in Breast Cancer reported on the risk of breast cancer with HRT in relation to the type and timing of hormonal intake.

The review covered the period January 1992 to January 2018 and included information from 58 studies of which 24 were prospective. Prospective follow-up identified 108,647 postmenopausal women who developed breast cancer of which 55,575 (51%) had used HRT.

The report showed an increase in the risk of breast cancer with HRT intake. The meta-analysis sought information on breast cancer incidence but did not collect information on breast cancer mortality.

The risk of breast cancer was noted to be higher with combined estrogen / progestogen intake, but was also increased, although to a lesser extent, with estrogen only systemic HRT. The risk was reported to be higher with combined HRT regimens where progestogen was taken daily (non-bleed preparations) compared to cyclical (bleed preparations). The risk appeared to vary in relation to the type of progestogen used, with Dydrogesterone appearing to have a lower risk compared to other synthetic preparations. The review only included a small number of women on micronised progesterone and as a result it would be difficult to draw meaningful conclusions from this report on the risk of breast cancer with micronised progesterone.

The meta-analysis reported that the risk of breast cancer remained elevated for more than 10 years after discontinuing HRT and this appeared dependant on the duration of HRT use.

The meta-analysis also suggested that starting HRT between the age of 40 and 50 was also associated with an increased risk of breast cancer compared with postmenopausal women younger than 50 years not using HRT. This, however, was not compared to age-matched premenopausal women which would have provided a clinically more meaningful comparator. In addition, the number of women in this sub-group was relatively small and it is not possible to determine from the presented data what proportion of women in this group discontinued HRT before the age of 50. These findings need to be further evaluated in an adequately powered prospective study. Furthermore, this also needs to be taken in the context of the significant bone protective effects and cardiovascular benefits that HRT offers to younger postmenopausal women.

There are a number of limitations that need to be taken into consideration when interpreting the findings from this meta-analysis including the heterogeneity of the data and the differences in study protocols given the various observational studies included.

In addition, this meta-analysis did not assess mortality associated with breast cancer and only reported on the incidence of breast cancer. It is important to highlight that previous large long-term follow (up to 13 years) data from the Women’s Health Initiative (WHI) randomised controlled trials showed no significant difference in cancer deaths in the HRT arms of the study compared to placebo. In addition, no difference was noted in all-cause mortality in the HRT arms of the study compared to placebo.

Findings from this meta-analysis, including the risk of breast cancer in relation to the type of progestogen used, the type of progestogen regimen (continuous or cyclical) and the risk of breast cancer in women starting HRT before the age of 50 require further evaluation in adequately powered prospective studies.

We welcome this further data on the incidence of breast cancer which will help us counsel our patients and women in general better. This paper provides further data on the impact of estrogen and progestogen combined and estrogen that adds more detail to that we have already gathered from overall assessment of the literature and some new information which includes some on different types of progestogen that surprisingly were found not to vary as much as had been thought. Of particular interest though is the impact of estrogen and different regimens of combined HRT on obese women where the former is found to have little effect but the increase with the latter is greatest with continuous combined HRT. However, in practice this must be weighed against the rapidly rising incidence of endometrial cancer which is significantly decreased by the continuous combined preparations.

Observational data such as these emphasise the importance of funding properly designed future randomised trials with adequate power to assess the impact of different types of HRT in different groups of women taking into account ethnicity as well as background risk factors including obesity.

The overall findings from this study are in keeping with the NICE Menopause guideline recommendations which show a small increase in risk of breast cancer with HRT. Women must be informed of the data on breast cancer risk with HRT to help them make an informed decision. This should also be considered in comparison to the risk of breast cancer with other lifestyle factors such as alcohol intake and obesity which have been shown to be associated with a higher risk compared to that with HRT. This should also be taken in the context of the overall benefits obtained from using HRT including symptom control and improving quality of life as well as considering the bone and cardiovascular benefits associated with HRT use.