Hormonal Replacement Therapy

Hormonal replacement therapy (HRT) has been reported to increase breast cancer risk. In a collaborative reanalysis of individual data from 51 epidemiological studies including more than 52.000 women with breast cancer and 108.000 without breast cancer, breast cancer risk increased by about 2.3% per year of use, but dropped after cessation of use. There is evidence that combined oestrogen–progestogen HRT may be associated with higher risk of breast cancer compared with unopposed oestrogens. In contrast, unopposed oestrogen use, but not combined oestrogen–progestogen treatment, has been strongly related to endometrial cancer risk in observational studies.

HRT has also been reported to be positively associated with ovarian cancer risk, and inversely to colorectal cancer risk.

Important information on cancer risk in users of combined estrogen and progestogen HRT comes from the Women’s Health Initiative (WHI), a randomised primary prevention trial including 8.506 women aged 50–70 years treated with combined HRT and 8.102 untreated women. The combined treatment group was closed in May 2002, whereas an additional oestrogen only group is still ongoing (as of November 2002). With respect to breast cancer, no difference in risk was evident for the first 4 years after starting treatment, but an excess risk was evident thereafter. At the 7 years follow-up, 166 breast cancer cases were registered in the treated group versus 124 in the placebo group, corresponding to a RR of 1.24 (95% CI 1.03–1.66). Data from two other smaller randomised studies are available, one Heart and Estrogen/progestin Replacement Study (HERS) with combined oestrogen–progestogen therapy, and one (WEST) with estrogen only. In a combined analysis of the three randomised trials, 205 cases of breast cancer were registered in the treated groups versus 154 in the placebo, corresponding to an overall RR of 1.27. Since, however, this estimate is heavily weighted by the WHI study, the quantitative role of estrogen only HRT on breast cancer risk cannot be conclusively documented.

Data on endometrial cancer are available from the WHI and the HERS study, both based on combined therapy. Overall, 24 cases were observed in the combined HRT groups versus 30 in the placebo groups, corresponding to a pooled RR of 0.76.

With reference to colorectal cancer, the combined analysis of the WHI and HERS studies included 56 cases in the HRT treated group and 83 cases in the placebo group (RR = 0.64).

Thus, with reference to HRT and cancer risk, the recent findings of randomised trials are in broad agreement with those of observational (cohort and case–control) studies, and therefore provide strong evidence that:

• Combined oestrogen–progestogen HRT is associated with a moderate excess risk of breast cancer, which becomes evident after a few years of use. Such an increased risk appears to be restricted to current users

• The pattern of risk in relation to HRT use appears similar for ovarian cancer, although data remain inadequate.

• Unopposed estrogens are strongly related, but combined HRT is not associated to, a material excess risk of endometrial cancer.

• HRT may have a favourable effect on colorectal cancer risk, although the relation with duration and other time-related factors remains unclear.

• Considering also the apparently adverse effects of HRT on cardiovascular diseases, HRT should not be recommended for disease prevention. HRT remains indicated for short-term symptoms relief, while other treatments should be considered for osteoporosis.