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Hormone replacement therapy and the breast cancer issue
325
Phatwlacological Research, Vol. 32, No. 6, 1995
H O R M O N E R E P L A C E M E N T T H E R A P Y AND THE BREAST C A N C E R ISSUE GORAN SAMSIOE D e p a r t m e n t o f Obstetrics and Gynecology, University Hospital, S-221 85 Lund, Sweden A c c e p t e d 12 October 1995
selection bias could not be ruled out completely. Meta-analysis of all studies of oestrogen use and breast cancer may minimize the selection potential but it can not be ruled out due to our current prescribing routines. It is important that one study, even if it is a large and well conducted cohort study, does not stand on its own but it is put in perspective with other studies on HRT and breast cancer. Several authors have performed meta-analyses of the published data. These meta analyses are inclusive of the Nurse Health Cohort study but only of its previous reports. Table I summarizes the results by the published meta-analysis. As can be seen the overall risk for the development of breast cancer during HRT seems to be 1.0 indicating no change in risk. This is not to say that certain subgroups may not have an increased risk e.g. current users and long-term users. If this is the case then a subgroup of women may well be at a decreased risk for breast cancer. Even if the study by Stampfer and Colditz is an important step in our jigsaw puzzle about oestrogens and breast cancer it is not the final answer. As was mentioned above the present study from Stampfer and Colditz also reported an increase in breast cancer mortality. Recently an Australian study [4] indicated a much lower risk in breast cancer survivors having oestrogen than in breast cancer survivors with no oestrogen (Table I). Unfortunately, mass media report scientific data in an uncritical way. In particular data that seemingly increase the risk of cancer has a large impact. Fear of cancer is a good sales argument for the media and therefore, scientific data of indications of a statistical association are translated into 'final proof--oestrogens increase breast cancer'. Hence, the paper by Stampfer and Colditz obtained great attention in mass media when it was published in
Despite the ostensible benefits with oestrogen as well as hormone replacement therapy regarding cardiovascular disease, osteoporotic fractures and possibly Alzheimer's disease, concerns have been expressed about a possibility of an increased risk of breast cancer. Recently a number of papers have been published that highlight this issue further. In the New England Journal of Medicine the Nurse Health Cohort Study reported its findings after an observation time of 14 years [1]. This publication is a follow-up to the previous publication on the same issue [2]. In comparison with those data the longer follow-up period has generated new interesting information. It would seem that in the age group over 60 there is a moderate increase of breast cancer. This seems to be true not only for the diagnosis of breast cancer but also for the number of breast cancer deaths. The last part is a new piece of information as several other studies have indicated a higher survival rate, i.e. a better prognosis in women who developed breast cancer during the use of HRT [3]. As always it should be remembered that this is observational data from a cohort study. It means that the observer does not control exposure. It is conceivable that oestrogens were given due to oestrogen deficiency symptoms such as sweats and hot flushes. It is also possible that oestrogens were only prescribed taking into account a number of precautions and warnings which go along with the labelling of oestrogen packages. Hence, it is conceivable that oestrogens were given to a cohort of women with fewer risk factors for breast cancer and with more marked oestrogen deficiency than controls. The first of these notions could tentatively explain why the increased risk of breast cancer is not seen until a period of time after the use of oestrogens. As observational data do not control exposure
Table I Relative risk of breast cancer associated with oestrogen therapy: five meta-analyses showing no or slight increase in ever users but increased risk with long duration of oestrogen therapy First attthor (year)
Dupont (1991) Steinberg (1991) Sillero Arenas (1992) Grady (!992) Colditz (1993)
Oestrogen ever ttsers RR
1.07 1.00 1.06 1.01 1.02
Oestrogen use for >--8years RR
Oestrogen use for >-10 years RR
Oestrogen use for >>.15years RR
1.30 1.25 1.23
326
Phalwlacological Research, Vol. 32, No. 6. 1995
M a y this year. The p a p e r by Steingold e t al. published in July 1995 [5] which showed that oestrogen use did not increase breast cancer. It was not even mentioned by mass media. Hence, the general public is given an unbalanced view o f oestrogen use in breast cancer by media. The scientific c o m m u n i t y has a great responsibility in giving a more balanced view on this interesting topic. The relative risk o f 1.5 should also be considered in relation to the incidence o f prevalence o f a given disease. As c a r d i o v a s c u l a r disease and osteoporotic fractures are much more c o m m o n in elderly
Table II Demographics for oestrogen users and their controls Variable
Oestrogen users
Controls
n= 180
n=90 Age at diagnosis (years) 47 (24-71) Max. tumour diameter (cm) 1.8 (0.40-7.0) Nodes involved 0 (0-18) Tamoxifen usage 12 (13%) ER measured 22 (24%) Total follow-up (years) 7 (0.3-30) Deaths 0
48 (27-96) 1.5 (0.20-10.0) 0 (0-18) 39 (22%) 42 (23%) 6 (0.3-29) 11 (6%)
Despite matching, oestrogen users tended to be younger, to use tamoxifen less often, and to have larger primary tumours than the controls, although the magnitude of these differences was small. Oestrogen users also had significantly longer follow-up than controls (despite matching for year of diagnosis), but this difference was explained by the observation that there were no deaths among oestrogen users and 11 deaths among controls.
w o m e n the n u m b e r o f deaths prevented by oestrogen r e p l a c e m e n t therapy far exceeds those induced should oestrogens really increase breast cancer deaths by a factor of 1.5. It should also be r e m e m b e r e d that a 50% increase is not the same as a 50% decrease. W h e n looking at the figures a doubling corresponds to the halving. In percentages, however, this yields a 50% decrease equal to 100% increase. H o w e v e r , the m e d i a often use percentages thereby giving a false impression o f the risks and underestimating the benefits o f any given measure.
REFERENCES 1. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer M J, llennekens C, Rosner B, Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J M e d 1995; 332: 1589-93. 2. Colditz GA, Stampfer MJ, Willett WC et al. Type of postmenopausal hormone use and risk of breast cancer. 12-year follow-up from the Nurses' Health Study, Cancer Causes Control 1992; 3: 433-9. 3. Bergkvist L, Adami HO, Persson I, BergstrOm R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1992; 130: 221-8. 4. Eden JA, Bush T, Nand S, Wren BG. A case-control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause: North A m Menopause Soc 1995; 2: 67-72. 5. Stanford JL, Weiss NS, Voigt LF et al. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 1995; 274: 137--42.
Phatwlacological Research, Vol. 32, No. 6, 1995
H O R M O N E R E P L A C E M E N T T H E R A P Y AND THE BREAST C A N C E R ISSUE GORAN SAMSIOE D e p a r t m e n t o f Obstetrics and Gynecology, University Hospital, S-221 85 Lund, Sweden A c c e p t e d 12 October 1995
selection bias could not be ruled out completely. Meta-analysis of all studies of oestrogen use and breast cancer may minimize the selection potential but it can not be ruled out due to our current prescribing routines. It is important that one study, even if it is a large and well conducted cohort study, does not stand on its own but it is put in perspective with other studies on HRT and breast cancer. Several authors have performed meta-analyses of the published data. These meta analyses are inclusive of the Nurse Health Cohort study but only of its previous reports. Table I summarizes the results by the published meta-analysis. As can be seen the overall risk for the development of breast cancer during HRT seems to be 1.0 indicating no change in risk. This is not to say that certain subgroups may not have an increased risk e.g. current users and long-term users. If this is the case then a subgroup of women may well be at a decreased risk for breast cancer. Even if the study by Stampfer and Colditz is an important step in our jigsaw puzzle about oestrogens and breast cancer it is not the final answer. As was mentioned above the present study from Stampfer and Colditz also reported an increase in breast cancer mortality. Recently an Australian study [4] indicated a much lower risk in breast cancer survivors having oestrogen than in breast cancer survivors with no oestrogen (Table I). Unfortunately, mass media report scientific data in an uncritical way. In particular data that seemingly increase the risk of cancer has a large impact. Fear of cancer is a good sales argument for the media and therefore, scientific data of indications of a statistical association are translated into 'final proof--oestrogens increase breast cancer'. Hence, the paper by Stampfer and Colditz obtained great attention in mass media when it was published in
Despite the ostensible benefits with oestrogen as well as hormone replacement therapy regarding cardiovascular disease, osteoporotic fractures and possibly Alzheimer's disease, concerns have been expressed about a possibility of an increased risk of breast cancer. Recently a number of papers have been published that highlight this issue further. In the New England Journal of Medicine the Nurse Health Cohort Study reported its findings after an observation time of 14 years [1]. This publication is a follow-up to the previous publication on the same issue [2]. In comparison with those data the longer follow-up period has generated new interesting information. It would seem that in the age group over 60 there is a moderate increase of breast cancer. This seems to be true not only for the diagnosis of breast cancer but also for the number of breast cancer deaths. The last part is a new piece of information as several other studies have indicated a higher survival rate, i.e. a better prognosis in women who developed breast cancer during the use of HRT [3]. As always it should be remembered that this is observational data from a cohort study. It means that the observer does not control exposure. It is conceivable that oestrogens were given due to oestrogen deficiency symptoms such as sweats and hot flushes. It is also possible that oestrogens were only prescribed taking into account a number of precautions and warnings which go along with the labelling of oestrogen packages. Hence, it is conceivable that oestrogens were given to a cohort of women with fewer risk factors for breast cancer and with more marked oestrogen deficiency than controls. The first of these notions could tentatively explain why the increased risk of breast cancer is not seen until a period of time after the use of oestrogens. As observational data do not control exposure
Table I Relative risk of breast cancer associated with oestrogen therapy: five meta-analyses showing no or slight increase in ever users but increased risk with long duration of oestrogen therapy First attthor (year)
Dupont (1991) Steinberg (1991) Sillero Arenas (1992) Grady (!992) Colditz (1993)
Oestrogen ever ttsers RR
1.07 1.00 1.06 1.01 1.02
Oestrogen use for >--8years RR
Oestrogen use for >-10 years RR
Oestrogen use for >>.15years RR
1.30 1.25 1.23
326
Phalwlacological Research, Vol. 32, No. 6. 1995
M a y this year. The p a p e r by Steingold e t al. published in July 1995 [5] which showed that oestrogen use did not increase breast cancer. It was not even mentioned by mass media. Hence, the general public is given an unbalanced view o f oestrogen use in breast cancer by media. The scientific c o m m u n i t y has a great responsibility in giving a more balanced view on this interesting topic. The relative risk o f 1.5 should also be considered in relation to the incidence o f prevalence o f a given disease. As c a r d i o v a s c u l a r disease and osteoporotic fractures are much more c o m m o n in elderly
Table II Demographics for oestrogen users and their controls Variable
Oestrogen users
Controls
n= 180
n=90 Age at diagnosis (years) 47 (24-71) Max. tumour diameter (cm) 1.8 (0.40-7.0) Nodes involved 0 (0-18) Tamoxifen usage 12 (13%) ER measured 22 (24%) Total follow-up (years) 7 (0.3-30) Deaths 0
48 (27-96) 1.5 (0.20-10.0) 0 (0-18) 39 (22%) 42 (23%) 6 (0.3-29) 11 (6%)
Despite matching, oestrogen users tended to be younger, to use tamoxifen less often, and to have larger primary tumours than the controls, although the magnitude of these differences was small. Oestrogen users also had significantly longer follow-up than controls (despite matching for year of diagnosis), but this difference was explained by the observation that there were no deaths among oestrogen users and 11 deaths among controls.
w o m e n the n u m b e r o f deaths prevented by oestrogen r e p l a c e m e n t therapy far exceeds those induced should oestrogens really increase breast cancer deaths by a factor of 1.5. It should also be r e m e m b e r e d that a 50% increase is not the same as a 50% decrease. W h e n looking at the figures a doubling corresponds to the halving. In percentages, however, this yields a 50% decrease equal to 100% increase. H o w e v e r , the m e d i a often use percentages thereby giving a false impression o f the risks and underestimating the benefits o f any given measure.
REFERENCES 1. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer M J, llennekens C, Rosner B, Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J M e d 1995; 332: 1589-93. 2. Colditz GA, Stampfer MJ, Willett WC et al. Type of postmenopausal hormone use and risk of breast cancer. 12-year follow-up from the Nurses' Health Study, Cancer Causes Control 1992; 3: 433-9. 3. Bergkvist L, Adami HO, Persson I, BergstrOm R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1992; 130: 221-8. 4. Eden JA, Bush T, Nand S, Wren BG. A case-control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause: North A m Menopause Soc 1995; 2: 67-72. 5. Stanford JL, Weiss NS, Voigt LF et al. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 1995; 274: 137--42.