In our study, current users of hormone therapy had a 2 – 4 times higher risk of breast cancer than never-users. This corresponded with the earlier «Women and cancer» study. The risk was greatest with use of combination therapy for more than five years. The prevalence of use was halved from 2002 to 2008 and attributable risk declined correspondingly from 27 % to 16.6 %. Nonetheless, this means that 232 breast cancer cases annually in this age group could be attributed to hormone use. By way of comparison, the European Prospective Investigation into Cancer and Nutrition (EPIC) recruited a cohort of postmenopausal women from various European countries who were all monitored for breast cancer. It was found that current use of oestrogen and combination products gave increased relative risk: 1.42 and 1.77 respectively (13).
In our study the average time from responding to the questionnaire to diagnosis was less than two years. It is a weakness that the control group is not monitored over a longer period, because some may develop cancer later. Hormone therapy may stimulate the growth of cancer cells (14). This may be the reason why users receive an earlier diagnosis. Therefore our study does not in itself provide a basis for stating that the use of hormone products gives increased lifetime risk of breast cancer. However, hormone replacement therapy after the menopause is considered to be a known risk factor (15), and the combination oestrogen-progestogen is classified by the International Agency for Research on Cancer (IARC) as a carcinogen for breast cancer (16).
The study is a nested case-control study in which data on exposition have been collected prior to the cancer diagnosis. As a result, memory bias is of little relevance. We have not taken into account the fact that women may have changed to a different kind of product during the therapy. External validation of the «Women and cancer» cohort has shown that there are few sources of selection bias that prevent the generalisation of results to the female segment of the Norwegian population or preclude the calculation of attributable risk (17).
We chose to include patients who were diagnosed with carcinoma in situ. Invasive breast cancer and ductal carcinoma in situ appear to have the same risk factors and development mechanism (18) – (20). The analysis results only changed insignificantly when we excluded women with cancer in situ.
Studies from several countries show that the decline in the use of hormone therapy is followed by a decline in breast cancer incidence (21). Data from the US Surveillance, Epidemiology and End Results Program showed a decline in incidence from 1999 to 2003 for those over 45, corresponding to the saturation of mammography screening. A sharp drop was observed in the period 2002 – 03 for oestrogen receptor positive tumours in women aged 50 – 69, which may be due to the decline in the use of hormone therapy (22).
In Norway the incidence of breast cancer rose in the 1990s and then levelled off before falling slightly after 2002 (fig 1). The introduction of the Norwegian mammography programme led to the detection of a larger number of Stage 1 tumours, particularly in women aged 50 – 69 (23). Nevertheless, the increase in incidence cannot be explained merely as an effect of the screening itself (24). A recent Norwegian study has shown that the changes in incidence can be attributed almost equally to mammography screening and hormone therapy (25). Hormone therapy correlates with more mammographically dense breast tissue (26). Women who used hormone therapy or had used it recently had a significantly higher average density. Use of combination products and long-term use of these gave the highest density. Increased mammography density is an independent risk factor for breast cancer (27), and can also give false negative mammography findings (28). Mammography is therefore a poorer test for hormone users.
The average duration of use by the women in our study was almost ten years. It is a matter of concern that older women use hormone therapy and that they continue as users when we know that age is a key risk factor and that the risk of breast cancer increases for every year of hormone therapy.
According to a study with data from 2004 on Norwegian GPs’ attitudes to oestrogen therapy for women during and after the menopause, the majority of GPs were familiar with the effects and side-effects. Hot flushes were the most important indication and previous breast cancer and breast cancer in first-degree relatives were contraindications for therapy. The duration of therapy was longer than what is recommended. Moreover, the study indicated that Norwegian women doctors were more updated professionally, more often had a general rule for duration of treatment and administered treatment for a shorter period of time (29). The study also showed that Norwegian doctors have become more restrictive about prescribing hormone therapy but recommendations on use varied. A number of doctors would recommend hormone therapy in the case of minor, less troublesome hot flushes if the woman either had irregular bleeding or felt depressed, had skin ageing changes and was dissatisfied with intimate relationships. Most doctors would neither recommend nor advise against hormone therapy on the basis of the case reports presented. The older the doctor, the greater the tendency to recommend use (30).
Current guidelines state that hormone therapy is indicated when the woman’s afflictions are pronounced and lead to reduced life quality, alternative treatment has had no effect and additionally that the advantages of therapy are greater than the disadvantages (31, 32). Before hormone therapy is commenced, an individual assessment must be conducted with a thorough case history that focuses on the woman’s predisposition to hormone sensitive cancer forms and cardiovascular disease. The Norwegian Society for Gynaecology and Obstetrics has listed the contraindications for hormone therapy (33). In our view, other risk factors, such as high age, late menopause, overweight, late birth or nulliparity and high alcohol consumption should be included in the assessment. According to the Norwegian Medicines Agency the treatment should be reviewed annually. After 2 – 3 years the women must be fully informed of unwanted side-effects and together with the doctor in charge of the case balance the need for therapy against the risk. Hormone therapy must not be used in cases of menstrual irregularities (31).
Tibolone is a tissue-specific regulator with oestrogenic and androgenic properties, and is the latest of the hormone products that improve menopausal symptoms and prevent osteoporosis. Tibolone reduces the level of active oestrogen in breast tissue and breast cancer cells and has proved to have little effect on cell proliferation and breast tissue density (34). Hence use of tibolone might be expected to be more favourable. Some small studies have shown that tibolone reduces the risk of breast cancer (35), but large observational studies have shown the opposite. In both the Million Women and the EPIC studies an increased risk was found with the current use of tibolone, RR 1.45 (1.25 – 1.67) and RR 1.95 (1.43 – 2.65) (7). Until we have more extensive studies and more knowledge about long-term effects we cannot therefore recommend a switch to tibolone.