HST - Hormonengebruik van vrouwen in de overgang leidt tot significant meer kans op het krijgen van borstkanker en meer kans hieraan te sterven

9 april 2012: bron: Medscape

Ook een meta analyse van de Nurses' Health Study bevestigt dat vrouwen die tijdens en na de overgang 10 jaar of langer extra oestrogeen plus progesteron gebruiken daarbij de kans op borstkanker behoorlijk verhogen. Vrouwen die alleen extra oestrogeen gebruiken en dit beperken tot een jaar of 5 hebben nog wel iets groter risico maar veel minder dan de vrouwen die er ook progesteron - progestin bij gebruiken en dit dus 10 jaar of langer gebruiken.

Hier een citaat uit een groter artikel uit medscape over deze studie en daaronder studierapporten uit The Lancet over de relatie tussen hormoongebruik en borstkanker tijdens en na de overgang.

The researchers found that the risk for breast cancer was 88% higher in women who had taken estrogen plus progesterone for 10 to 14.9 years compared with women who did not use estrogen plus progesterone (relative risk 1.88). This risk more the doubled for women who used estrogen plus progesterone therapy for 15 to 19.9 years (RR 2.35).

For women who used estrogen only, the researchers found a 22% increased risk for breast cancer if used for 10 to 14.9 years (RR 1.22) and a 43% increased risk for 15 to 19.9 years of use (RR 1.43), compared with women who did not use unopposed estrogen.

To further clarify long-term risks of estrogen-only therapy, Dr. Chen and her colleagues evaluated a subset of the women who also met the criteria for participation in the Women's Health Initiative randomized trial of postmenopausal women aged 50 years or older.

They found that the risk for breast cancer was reduced slightly for women who used estrogen alone for less than 10 years, (RR 0.93) compared with non-users. The risk increased 30% for women who took estrogen for 15 to 19.9 years (RR 1.30).

Although breast cancer incidence was increased among women who used estrogen-progesterone or estrogen alone, there was no increase in fatal breast cancer, Dr. Chen reported.

Hormonengebruik van vrouwen in de overgang leidt tot 66% meer kans op het krijgen van borstkanker en op 22% meer kans hieraan te sterven.

Zoals al eerder gemeld op onze site, zie ook pagina alcohol en hormonen veroorzaken borstkanker, maar nu ook bevestigd door een groot studierapport onder meer dan een miljoen vrouwen wereldwijd en gepubliceerd in The Lancet d.d. 8 augustus 2003 veroorzaakt extra hormoongebruik voor vrouwen in de overgang een verhoogd risico op het krijgen van borstkanker. Vrouwen die na de menopauze hormonen slikken blijken 66 procent meer kans op borstkanker te hebben. Het risico om ook aan borstkanker te sterven blijkt voor vrouwen die 10 jaar of langer hormonen slikken 22 procent hoger te liggen. Voor wie de statistieken van de originele studie in wil zien gaat naar de volgende websitepagina's van The Lancet , waar de volledige studie wordt beschreven met commentaar en discussie over de gevolgen enz. Ook een bijdrage van de bij het onderzoek betrokken artsen waaronder een Nederlandse arts* verbonden aan de Radboud in Nijmegen: Toine Lagro-Janssen, Walter W Rosser, *Chris van Weel staat hieronder vermeld.

Voor een Nederlands artikel over dit onderwerp ga naar de website van NRC-Handelsblad en daar staat ook een en ander te lezen:

MEER KANKER DOOR GEBRUIK HORMONEN

Vrouwen die na de menopauze hormonen slikken hebben daardoor 66 procent meer kans op borstkanker. Hun risico om aan borstkanker te sterven is 22 procent verhoogd.

Hieronder de belangrijkste passage's uit the Lancet:

Source The Lancet d.d. 08-08-2003:

Summary

Background Current use of hormone-replacement therapy (HRT) increases the incidence of breast cancer. The Million Women Study was set up to investigate the effects of specific types of HRT on incident and fatal breast cancer.

Methods 1 084 110 UK women aged 50-64 years were recruited into the Million Women Study between 1996 and 2001, provided information about their use of HRT and other personal details, and were followed up for cancer incidence and death.

Findings Half the women had used HRT; 9364 incident invasive breast cancers and 637 breast cancer deaths were registered after an average of 2·6 and 4·1 years of follow-up, respectively. Current users of HRT at recruitment were more likely than never users to develop breast cancer (adjusted relative risk 1·66 [95% CI 1·58-1·75], p<0·0001) and die from it (1·22 [1·00-1·48], p=0·05). Past users of HRT were, however, not at an increased risk of incident or fatal disease (1·01 [0·94-1·09] and 1·05 [0·82-1·34], respectively). Incidence was significantly increased for current users of preparations containing oestrogen only (1·30 [1·21-1·40], p<0·0001), oestrogen-progestagen (2·00 [1·88-2·12], p<0·0001), and tibolone (1·45 [1·25-1·68], p<0·0001), but the magnitude of the associated risk was substantially greater for oestrogen-progestagen than for other types of HRT (p<0·0001). Results varied little between specific oestrogens and progestagens or their doses; or between continuous and sequential regimens. The relative risks were significantly increased separately for oral, transdermal, and implanted oestrogen-only formulations (1·32 [1·21-1·45]; 1·24 [1·11-1·39]; and 1·65 [1·26-2·16], respectively; all p<0·0001). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. 10 years' use of HRT is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 users of oestrogen-only preparations and 19 (15-23) additional cancers per 1000 users of oestrogen-progestagen combinations. Use of HRT by women aged 50-64 years in the UK over the past decade has resulted in an estimated 20 000 extra breast cancers, 15 000 associated with oestrogen-progestagen; the extra deaths cannot yet be reliably estimated.

Interpretation Current use of HRT is associated with an increased risk of incident and fatal breast cancer; the effect is substantially greater for oestrogen-progestagen combinations than for other types of HRT.

Lancet 2003; 362: 419-27

Discussion

The results of this study confirm previous findings that current and recent use of HRT increases the risk of breast cancer,1-10 but also provides new and reliable information about the effects of various patterns of use. The Million Women Study was set up to examine the effect of HRT on breast cancer incidence and mortality. Study participants were recruited at the time of their triennial invitation for routine mammography by the NHSBSP. The programme provides a routine screening service only; women cannot be referred or self-refer for mammography at times outside the 3-year screening cycle. The NHSBSP does not provide a diagnostic mammographic service, and women with breast lumps and other symptoms have mammograms and other investigations done outside the programme. Around 75% of UK women invited by the NHSBSP attend for routine mammography, and 71% of the women screened at participating centres took part in the Million Women Study, amounting to 53% participation in the general population. Study participants were similar to all women screened, who themselves are slightly more likely to use HRT and to come from less-deprived areas than women who do not attend the NHSBSP for routine mammography.12 Although the study cohort contains a slightly greater proportion of HRT users than in the general population, this difference would not bias internal comparisons within the cohort of breast cancer risk according to use of HRT.

All study participants had routine mammography soon after they completed their baseline questionnaires. Thus any biases resulting from differential reporting of use of HRT according to the outcome of interest--ie, breast cancer--or differential screening for the exposure of interest--ie, use of HRT--were virtually eliminated. Few women who attend the NHSBSP have mammography done privately at other times, and most breast cancers diagnosed among study participants in the interval between their triennial routine NHSBSP screens are symptomatic interval cancers. Use of HRT reduces the sensitivity of mammography, thus increasing the probability that a breast cancer is diagnosed as an interval rather than a screen-detected cancer.24 Therefore, to investigate how HRT affects the underlying risk of breast cancer, the overall incidence of breast cancer (taking screen-detected and interval breast cancers together) must be studied, as we have done. All women were flagged on the NHS Central Registers, with details of each registered incident cancer and death being automatically coded and reported to study investigators. Therefore, the recording of incident and fatal breast cancer is unbiased for use of HRT and there should be little, if any, differential loss to follow-up.

Randomised trials have reported significantly increased risks of breast cancer in HRT users.2,3 In non-randomised studies, such as this one, the relation between breast cancer and HRT use can be confounded by women's menopausal status: for women of a given age, premenopausal and perimenopausal women are at greater risk of breast cancer and are less likley to use HRT than postmenopausal women,1 as was found here. To keep such confounding to a minimum we excluded premenopausal and perimenopausal women and women aged 50-52 years if they had had a hysterectomy or had begun using HRT before the menopause (since menopause can be masked by such interventions). Sensitivity analyses, done to assess the extent of such potential confounding, showed that when stricter exclusion criteria were applied, the point estimates for the relative risk of breast cancer in current and past users of HRT varied by less than 1%.

Analyses were routinely stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, body-mass index, region of residence, and deprivation index, thus keeping to a minimum confounding by these factors. Examination of potential confounding by alcohol consumption, previous use of oral contraceptives, age at menarche and past health, did not alter the relative risk estimates for current and past users compared with never users. The only factor that modified the relative risk estimates was body-mass index, with the relative risk estimates being larger among the thinner women--ie, those with a lower rather than a higher index.

Misclassification of women's use of HRT should not affect the main conclusions. Self-reported information on use of HRT at baseline was used to define current, past, and never users, and users were further classified according to the reported specific proprietary preparation used most recently. Validation studies within the study population showed 96% agreement between self-reported data at baseline and family-physician prescriptions for current use of HRT.14 Moreover, among current users, there was 97% agreement as to whether oestrogen-only, oestrogen-progestagen combination, or another type of HRT was being used, and 90% agreement for the specific proprietary preparation used and its dose.14 An estimated two-thirds of current users used one proprietary HRT preparation exclusively; and five-sixths of the current users had used their current HRT for at least half their total period of use of HRT. The incident breast cancers were diagnosed on average 1·2 years after recruitment, and some women would have changed their use of HRT during that period. Results from a survey of a random sample of 12 221 study participants, done an average of 2·8 years after the recording of baseline information, showed that 78% of the current users at baseline were still using HRT, that 81% of past users were still past users, and that 89% of the never users were still never users. Among current users at baseline, the total duration of use of HRT at the time of diagnosis of breast cancer would be slightly longer than that recorded at baseline. However, any resultant underestimation of total duration of use of HRT would be counteracted, to some extent, by the fact that during follow-up some current users would have become past users and that some never users would have become current users.

Overall, these results confirm previous findings that current and recent users of HRT are at an increased risk of invasive breast cancer, and that the relative risk of breast cancer in current users increases with increasing duration of use of HRT.1-4 The estimated absolute increases in the incidence of breast cancer among women using oestrogen-only preparations are remarkably similar to estimates derived from a collaborative reanalysis of most of the relevant worldwide data in 1997, 80% of whom used oestrogen-only HRT.1 (The respective estimates per 1000 cases are 1·5 [0-3] and two [1-3] for 5 years' use, and five [3-7] and six [3-9] for 10 years' use.) Few estimates of the absolute increase in breast cancer incidence are available for users of oestrogen-progestagen HRT. The Women's Health Initiative trial found an increased incidence of breast cancer in women who complied with treament,3 of about six per 1000 women after 5 years' use, and 18 per 1000 after 7 years' use of oestrogen-progestagen HRT, similar to results from the Million Women Study, based on substantially larger numbers, of an increase in the cumulative incidence of six (5-7) per 1000 for 5 years' use and 19 (18-20) per 1000 for 10 years' use of oestrogen-progestagen HRT. Hence, for these durations oestrogen-progestagen combinations leads to about a four-fold greater increase in breast cancer incidence than does use of oestrogen-only preparations.

Other than the substantial difference between the effects of oestrogen-only and oestrogen-progestagen combinations, these results suggest no large variations between the effects of specific oestrogens (equine oestrogen and oestradiol) or between specific progestagens (medroxyprogesterone acetate, norgestrel, and norethisterone). They also suggest that results on the risk of breast cancer for the specific constituents used in the Women's Health Initiative trial3 do not differ materially from the results for other oestrogen-progestagen combinations. Nor does the available evidence suggest large differences between the effects of progestagens given sequentially or continuously on breast cancer, although if many women have switched use, this would dilute any real differences.

A significant excess of breast cancer was found for current use of tibolone. This increase is not due to confounding by known risk factors for breast cancer, such as family history of breast cancer, obesity, or late childbearing. Implanted and transdermal preparations of oestrogen-only HRT also led to a significant excess of breast cancer. There was, however, no significant difference between the effects of oral, transdermal, or implanted formulations. The implications of these findings need further investigation.

Current users of HRT at baseline had significantly increased mortality from breast cancer, although the relative risk estimate was of borderline significance and was not as large as for incident disease. The results for fatal disease are based on 517 deaths in women who had no history of breast cancer at recruitment. Had we included women with a history of breast cancer at baseline (among whom a further 485 deaths from breast cancer were reported, but only 3% of whom were using HRT at recruitment) we would have concluded, falsely, that current users of HRT had a substantially lower death rate from breast cancer than never users. Studies purporting to show that current users of HRT have lower death rates from breast cancer than non-users have generally been unable to account adequately for this fundamental source of bias.4 Results from the Women's Health Initiative trial show that breast cancers diagnosed in women allocated to HRT had a significantly larger size than the cancers in non-users of HRT,3 further challenging the validity of claims that use of HRT decreases mortality from breast cancer. Longer follow-up of this and other cohorts and further information on the effects of different patterns of use of HRT on mortality from breast cancer are needed.

The results from the Million Women Study suggest little or no overall increase in the relative risk of breast cancer in past users of HRT. No residual increase in the risk of breast cancer was seen separately for past users of oestrogen only, oestrogen-progestagen combinations, or tibolone. These findings are broadly in line with results from previous studies that had suggested that the effects of current use of HRT on the risk of breast cancer wore off largely, if not wholly, within 5 years of ceasing use of HRT.1

Use of HRT by UK women aged 50-64 years in the past decade is estimated to have resulted in an extra 20 000 incident breast cancers, combined oestrogen-progestagen HRT accounting for 15 000 of these additional cancers. The main reason that women are prescribed combined rather than oestrogen-only, HRT is because of the increased risk of endometrial cancer associated with use of oestrogen-only preparations. However, if the additional breast and endometrial cancers associated with each type of HRT are added together, there seems to be little advantage to using oestrogen-progestagen in preference to oestrogen-only HRT for women who still have a uterus. Use of either type of HRT is estimated to result in five to six extra cancers per 1000 women with 5 years' use and 15-19 extra cancers per 1000 with 10 years' use of HRT. The extra cancers are predominantly of the endometrium for users of oestrogen-only preparations, whereas they are exclusively breast cancer for users of oestrogen-progestagen HRT. Reliable estimates of the extra deaths from breast cancer attributable to use of HRT cannot be made at present.

Hormone-replacement therapy (HRT) as a health issue for women has triggered heated discussions since promotion of the treatment in the mid-1970s.1 Projected benefits were symptom relief, enhanced self-esteem and quality of life, prevention of cardiovascular disease, and improved bone-mineral status. These projections positioned HRT as being beneficial for all women in their sixth and seventh decade. Arguments against HRT formed a mixed bag: ideological (should a normal phase of life be medicalised by defining menopause as a disease?); doubts about the cardiovascular protection; and concerns about risks (cancer, thrombotic events). The Million Women Study in today's Lancet fuels this discussion with new and convincing data. The findings are in line with two recent publications2,3 on oestrogen-progestogen replacement therapy, which reported increased incidences of advanced or invasive breast cancer.

In an unselected population, the Million Women Study finds that HRT increases the risk of breast cancer--not only the incidence (relative risk 1·66), but also breast cancer mortality (1·22). A general practitioner would need to give combined HRT to 166 women for 5 years--or 53 women for 10 years--to see one extra case of breast cancer. This estimate has important consequences for current HRT practice.

Because most women on HRT are in primary care, these findings from the Million Women Study have particular implications for general practice. But how has it been possible to reach this low point in the health care provided to middle-aged women? More than 50% of the postmenopausal women in the Million Women Study use, or had used, a preventive therapy whose safety must now be questioned. Despite stringent modern control of drugs, how has heavy promotion of HRT put millions of women at risk? Any preventive intervention in healthy people must be supported by the strongest evidence of benefit and virtually no evidence of risk--digressing from this principle could be considered unethical.4

When the therapy was introduced, the health benefits of HRT were highlighted, but the increased risks of breast and endometrial cancer, although known, were downplayed. And in reporting correlations of HRT with cancer, absence of increased mortality5 and prognostically favourable typology6 were emphasised, and reassurance was given of the risk being only related to (very) long-term use of HRT.7 For many experienced general practitioners, the HRT story must present an all-too-familiar pattern. First, physicians with a special interest in the product who claim special expertise introduce a new development. They place the new product in a positive light, overwhelming sceptical general practitioners with "evidence" of benefits. The great influence of the drug industry was used to promote HRT to physicians (funding menopausal clinics) and directly to patients (women's magazines, leaflets, websites), reinforcing the process of neglecting risks. Now that these risks are firmly demonstrated, however, it is left to general practitioners and other primary-care providers to solve the problem. The missing link in this scenario is the early involvement of an unbiased platform of professionals (including those in primary care) in analysing benefits, harms, and costs. Strongly expressed concerns from general practitioners about the medicalisation of common signs and symptoms were not an esoteric exercise, but were about the safety of medical care and the protection of patients. Many general practitioners did not embrace HRT, and its promoters often denigrated them for their intransigence.

In pursuing safe and effective medical practice, the rules of engagement in primary care are clear: that of unbiased studies in representative populations with a specific health problem and which might benefit from the intervention.8 Far from a lost cause,9 this setting makes primary care the vital ingredient of clinical research before the introduction of new interventions. For HRT, this caution would have allowed, in a large sample of unselected users, a sufficiently long observation time to assess the cancer risk. Without clear evidence for or against the intervention, use of the drug would have been cautious rather than overoptimistic.

Unfortunately, for HRT, opportunities for proactive engagement have been lost, and general practitioners can do little more than damage limitation. The new evidence of breast cancer mortality dictates an explicit position for general practitioners--HRT should be discouraged and, for women presenting with new postmenopause-related health problems, general practitioners should seek alternative solutions. For postmenopausal symptoms, such solutions include information giving and, in some cases, a well-informed decision to prescribe HRT for no longer than 3-6 months. For cardiovascular and osteoporosis risk, regular prevention programmes should serve the needs of middle-aged women. Guidelines for care of the postmenopausal woman need to be rewritten to discourage HRT. All that is the simple part.

The problem is in those women who are already, often for a long time, taking HRT--estimated at between 20% and 50% of all women 45-70 years of age in the western population. This group should discontinue HRT use as soon as possible. Discontinuing HRT should be suggested in as supportive a way as possible, because no one will benefit from panic or over-reaction: general practitioners need to use the opportunities arising from their regular contacts with patients taking HRT to discuss treatment-related risks, to give advice about stopping, and to offer alternative support. There is a great need for a public information campaign, led by the medical professions, stating the current evidence in clear but unsensational wording and encouraging HRT users to consult their general practitioner. The Dutch College of General Practitioners has positive experience with this approach, when they issued a public information statement10 in guidelines on the menopause11 after an earlier report about breast cancer risk with HRT.12

The story of HRT is again a lesson for medicine to exercise extreme caution in promoting hormonal therapy, and, in general, a lesson of how not to introduce new developments. Analysis of potential harms and benefits should precede introduction, followed by close surveillance. This process must be independent from the pharmaceutical industry and other stakeholders with an interest in financial profits. It should include the medical professions directly involved in implementation from the earliest beginnings of their development--more often than not, general practitioners. Concerns about medicalisation deserve attention in this process, particularly when involving healthy people in disease prevention. Lack of evidence of harms (or benefits) is different from evidence of no harm (or benefit),13 a rule of evidence-based medicine almost completely overlooked in HRT promotion. This concept is the essential reason for testing innovations under real-life conditions before giving the final green light for implementation. A strategy of extreme caution and wider input in new drug approval is no panacea for all future problems when introducing innovations, but provides a scenario of how medicine can do better to protect and promote the health status of the population.

We have no conflicts of interest to declare.
Toine Lagro-Janssen, Walter W Rosser, *Chris van Weel

References:
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Department of General Practice, University Medical Centre Nijmegen, 6500 HB, Netherlands (TL-J, CvW); and Department Family Medicine, Queens University, Kingston, Ontario, Canada (WWR) (e-mail: C.vanWeel@hag.umcn.nl )

1 Wilson RA Feminine forever. New York: M Evans and Company Inc, 1966.

2 Chlebowski RT, Hendrix SL, Langer RD, et al. Infludence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003; 289: 3243-52.

3 Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 2003; 289: 3254-63.

4 Sackett DL. The arrogance of preventive medicine. CMAJ 2002; 167: 363-66.

5 Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of of breast cancer with favourable histology: results of the Iowa Women's Health Study. JAMA 1999; 281: 2091-97.

6 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997; 350: 1047-59.

7 Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997; 336: 1769-75.

8 van Weel C, Rosser WW. Improving health globally: the necessity of family medicine research--a critical review of its implications and recommendations to build its capacity. Ann Family Med (in press).

9 Editorial. Is primary-care research a lost cause? Lancet 2003; 361: 977.

10 De Overgang. Aanpak van de overgang. March, 2002:

http://www. artsennet.nl/nhg/patbrieven/u11b.htm (accessed Aug 5, 2003).

11 The Dutch College of General Practitioners (NHG) Practice Guideline. NHG practice guideline 'The menopause'. September, 2001: http://www.artsennet.nl/nhg/guidelines/E73.htm (accessed Aug 5, 2003).

12 Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-33.

13 van Weel C, Knottnerus JA. Evidence-based interventions and comprehensive treatment. Lancet 1999; 353: 916-18.

HRT, borstkanker, overgang, hormoongebruik