Reduced use of hormones and the drop in breast cancerBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b2116 (Published 03 June 2009) Cite this as: BMJ 2009;338:b2116
- Helen Roberts, senior lecturer women’s health
Recent studies have shown falls in the incidence of breast cancer in Australia and the United Kingdom.1 2 This decline in hormone receptor positive tumours was found in post-menopausal women but not in pre-menopausal women, and has also been noted across much of Europe and the United States.1 3 Most of these reports have linked this declining diagnosis of breast cancer to a decrease in use of hormone replacement therapy (HRT) following publication of the women’s health initiative study. The oestrogen plus progestogen arm of this study was halted in May 2002 because of an excess risk of breast cancer.4
A subsequent US study that examined trends of breast cancer incidence and HRT use within a screened population likewise found a fall in the incidence of breast cancer corresponding to a decrease in the use of HRT.5 The rapid decrease in breast cancer incidence reported in these studies suggests that withdrawal of hormone therapy leads to a regression of preclinical cancers.6
In the first 2 years of the oestrogen plus progestogen versus placebo arm of the women’s health initiative study, fewer breast cancers were diagnosed in the women taking combined HRT than in those taking placebo. This finding is thought to be the result of increases in breast density induced by the hormones, making the mammograms harder to interpret and causing delay in diagnosis. Thereafter, the number of cases of breast cancer increased for the women on HRT (hazard ratio 1.26, 95% CI 1.02 to 1.55), and the cancers being diagnosed were larger and more advanced than those in women not on HRT.4 After discontinuation, follow-up of the women who had stopped HRT showed that the raised risk of breast cancer in this group had decreased rapidly: the risk was 28% less in the first post-intervention year despite a similar frequency of mammography.6
The increased risk was mainly in women who had used oestrogen and progestogen before joining the study (1.96, 1.17 to 3.27), as the risk was considerably lower in those who had not used these hormones (1.02, 0.77 to 1.35). There was, however, a significant and increasing trend in the risk of breast cancer with follow-up time among women with no previous hormone use. Ongoing use for durations only slightly longer than 5 years does seem to be associated with an increased risk of breast cancer in women who have not previously used hormones.4 The combined analysis of the clinical and observational women’s health initiative studies also suggests that women who initiate oestrogen plus progestogen soon after menopause and continue for many years seem to be at particularly high risk of breast cancer.7
The combined analysis of the clinical and observational results also looked at the effect of “gap time”; that is, the time from menopause to first use of hormones. This analysis showed that the decreased risk of breast cancer associated with oestrogen therapy only occurred if the hormone was used later in the post-menopausal period and not around the time of menopause.8 Breast cancers make adaptive changes during periods of oestrogen deprivation such as menopause, and this response subsequently decreases the likelihood that the cancer will respond to stimulation with oestrogen later in the post-menopausal period.8
The oestrogen only arm of the women’s health initiative found a reduced but not significant difference in the incidence of invasive breast cancer in the hormone group compared with the placebo group (0.80, 0.62 to 1.04). Much of this possible decrease in risk is owing to the inclusion of women who had not used oestrogen before study entry.8
Other reasons for the decrease in breast cancer diagnoses have been discussed; for example, a change in the number of women undergoing mammographic screening or alterations in modifiable risk factors such as BMI. Neither of these appear to be the explanation, however, as on the whole the number of women undergoing mammography has remained constant, and modifiable risk factors have not changed appreciably.1 2 3
Given the association between breast cancer and HRT use, can women at high risk of breast cancer use hormones? Women with mutations in the BRCA1 or BRAC2 gene have an increased risk of breast and ovarian cancer and are advised to have prophylactic oophorectomy after having children. This measure reduces the risk of ovarian cancer by 90% and breast cancer by 50%. Short term observational studies suggest that hormone use following bilateral oophorectomy does not alter the reduction in the risk of breast cancer associated with the surgery.9 This result may be a false negative finding, however, similar to the initial low incidence of breast cancer in the combined arm of the women’s health initiative owing to delay in detection.9
Only 10% of all breast cancers are hereditary and only half of these cases are owing to known mutations in the BRCA1 and BRAC2 genes. Predictive models—such as the Gail model, part of the breast cancer risk assessment tool of the National Cancer Institute—can be used to estimate the risk of breast cancer. An analysis of the oestrogen only arm of the women’s health initiative suggested a higher incidence of breast cancer with hormone use for those women at high risk of breast cancer according to the Gail model.8 Caution is therefore advised in prescribing hormone therapy to women who are already at high risk of breast cancer.
For women diagnosed with breast cancer chemotherapy, ovarian ablation, and adjuvant therapy can all contribute to the occurrence of severe flushes. Clinical trials comparing hormone replacement therapy and tibolone with placebo in women with previous breast cancer found increased breast cancer recurrence for those women using hormones. Hormone use following breast cancer treatment should thus be avoided.10 11
Placebo controlled randomised trials have found that clonidine, gabapentin, selective serotonin reuptake inhibitors, and selective noradrenaline reuptake inhibitors can reduce hot flushes. The antidepressant drug venlaflaxine seems to interfere less than other antidepressants with the efficacy of tamoxifen. Vitamin E can be tried in women wishing to avoid taking pharmaceutical agents.12
These recent reports of a reduction in the incidence of breast cancer following a drop in hormone use, along with the results from ongoing analyses of the women’s health initiative studies, support the use of the lowest dose of hormones for the shortest period of time for the relief of menopausal flushes. This approach will not only decrease the risk of hormone related breast cancers in the individual, but also the risk for entire populations.
Cite this as: BMJ 2009;338:b2116
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.