Oncology 1992:49(suppl 2): 18-21
Medical Breast Unit, Royal Marsdcn Hospital, London, UK
KeyWords Breast cancer Endocrine therapy Aromatase inhibitor Antiestrogens
Current Controversies in the Endocrine Therapy of Advanced Breast Cancer
Abstract The response of breast cancer to endocrine therapy depends on depriving the tumor cells of estrogen stimulation of cell division. This may be achieved by blocking estrogen synthesis in the body, using inhibitors of aromatase or by using drugs like tamoxifen, which interfere with the direct effects of estrogen on tumor cells. Current controversies relate to the mechanism for achieving more effective inhibition of estrogen synthesis and for the use of more specific antiestrogenic drugs.
For the most part, response to endocrine therapy seems to depend on reducing cell proliferation by remov ing estrogen stimulation of endocrine-sensitive breast cancer cells. Response may be achieved by (1) reducing endogenous estrogen synthesis by ovarian ablation in pre menopausal women or by use of aromatase inhibitors of estrogen synthesis in postmenopausal women or (2) the use of supposed antiestrogen drugs. The main controver sies in endocrine therapy of advanced breast cancer cur rently center on (1) the actions of aromatase inhibitors and (2) the use of antiestrogens. Inhibition of estrogen synthesis is usually evaluated by measuring circulating estradiol levels. However, total potential estrogen stimu lation depends on the estrogenic sum of estradiol, estrone, and estriol levels, as well as a large reserve of estrone sul fate. Furthermore, cellular stimulation may depend not only on ovarian and peripheral (by such tissues as fat) estrogen synthesis, but also on the ability of tumor cells and stromal cells within the tumor to produce estrogen. This could have a profound effect on intracellular estro
gen levels, effecting an autocrine stimulation mechanism, which has encouraged us to examine the possibility of increasing the degree of inhibition of estrogen stimulation by using either new agents or different mechanisms to lower estrogen levels.
Aromatase Inhibitors A pure aromatase inhibitor, such as 4-hydroxyandrostanedione (4-HAD), will produce objective response rates ranging from 20 to 26% in patients with advanced breast cancer [1], The mechanism of action of 4-HAD seems to depend entirely on blocking the aromatase enzyme sys tem. Inhibition of this system in vivo appears to be about 92%, which results in a reduction of estradiol levels of about 50% [2]. In phase II testing, aminoglutéthimide has produced objective response rates between 30 and 35%. These rates may be marginally higher than the response rates to 4-HAD, although this has never been tested in a
Trevor J. Powles. BSc, PhD. FRCP The Royal Marsdcn Hospital Medical Breast Unit Downs Road Sutton. Surrey 5M2 5PT(UK)
© 1992 S. Karger AG. Basel 0030-2414/92/0498-0018 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/28/2018 1:21:13 PM
Trevor J. Powles
low estrogen levels, perhaps < 1 pmol/1. Clinical mea surement of estrogens seems to indicate that relapse is not related to recovery of estrogen synthesis despite contin ued treatment, but rather depends on an adaptation of the tumor cells, allowing them to proliferate in the presence of a lower estrogen signal. This raises the possibility that achieving very low estrogen levels in the initial phase of treatment may be sufficient to prolong the endocrine response. We are thus focusing our research on mechanisms to achieve these very low levels of estrogen. Clinical trials of a combination of a competitive inhibitor and an aromatase inhibitor that works by a different mechanism and has the added advantage of accelerating the metabolism of estrone sulfate should indicate whether this approach will be of therapeutic benefit. Accurate measurement of very low levels of estrogen combined with the measure ment of estrogen-dependent markers within tumor cells such as the progesterone receptor, as well as measurement of other estrogen-dependent proteins, including growth factors and oncogenes, may help us sort out the mecha nism of response and relapse with endocrine therapy.
Antiestrogens It could be argued that the best mechanism for com pletely blocking estrogen-dependent growth of breast tu mors is to use a supposed ‘antiestrogen’ like tamoxifen. A pure antiestrogen could be defined as an agent that inhib its estrogen-stimulated proliferation of endocrine-sensi tive breast cancer cells by competitively blocking estrogen receptors. Considerable doubt now exists that tamoxifen works totally or even in part by this mechanism. Tamox ifen was known to have agonistic estrogenic activity, espe cially in the rat. Nonetheless, it was assumed that since tamoxifen could block the effects of estrogen in various in vitro systems, its main function was antiestrogenic. In many of these systems, however, excessive estrogen levels cause inhibition of effect, producing a bell-shaped curve. The possibility that tamoxifen could be acting as an impeded ‘super’ estrogen, thereby removing sensitivity to low levels of stimulating estrogen, has generally not been tested. For example, in the absence of estrogen, tamoxifen has been shown to have antiproliferative effects in vitro on breast cancer cells. This would seem to indicate a mechanism other than estrogen deprivation. In our tamoxifen prevention program in healthy wom en, we were concerned that tamoxifen could exert adverse antiestrogenic actions on normal tissues. We have now
19
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randomized clinical trial. Aminoglutéthimide will inhibit in vivo aromatase activity by about 91%, which is similar to the inhibition seen with 4-HAD. The mechanism of action, however, appears to depend on a cytochrome P450 enzyme system, which is essential for aromatase activity. Aminoglutéthimide also appears to lower estro gen levels by another mechanism - stimulating micro somal hepatic metabolism of estrone sulfate and its clear ance into the urine. In equilibrium with free estrone, estrone sulfate is the main constituent estrogen of the pool that can be metabolized within the body - and within cells - to estradiol. Patients already receiving 4-HAD show a significant added reduction in estrone sulfate levels when aminoglutéthimide 1 g/day plus hydrocortisone is added to their treatment [3], These observations seem to indi cate that aminoglutéthimide may have an advantage over 4-HAD in lowering the total estrogen pool. Moreover, the possibility exists that inhibition of aro matase activity by a competitive inhibitor like 4-HAD might be enhanced by the addition of an agent like amino glutéthimide, which depends on inhibition of cytochrome P-450 to inhibit estrogen synthesis. Preliminary results indicate that in vivo aromatase inhibition in humans by aminoglutéthimide and 4-HAD is only 91 and 92%, respectively. A combination of these two agents, working by different mechanisms, may increase this blockade. These preliminary results are being evaluated in a series of patients using a double isotope prelabeling technique to measure urinary excretion of labeled androstanedione and estrone [4], The essential question is whether high levels of estro gen blockade might increase the response rate or duration of response. Measurements of estrogen during response and relapse in patients taking endocrine therapy seem to support the hypothesis that very low estrogen levels might in fact enhance the therapeutic benefit of such treatment. For example, tumor progression in a premenopausal woman seems to depend on estrogen levels up to 1,000 pmol/1. Ovarian ablation, which may reduce estrogen syn thesis and consequent estradiol levels to about 100 pmol/1, is sufficient to achieve a maximum endocrine response in about 30% of patients. Responding patients will eventually relapse in spite of estradiol levels that remain at the postoophorectomy level. Introducing an aromatase inhibitor at this stage, which will reduce estradiol levels to below 50 pmol/1, is probably sufficient to achieve maximum second-line endocrine response similar to the responses and estrogen levels seen in postmenopausal women taking aromatase inhibitors. Subsequent response seems to depend on achieving very
Patients, %
Amenorrhea Period changes Libido Hot flushes Vaginal atrophy Vaginal discharge Bone density Clotting Liver SHBG Lipids Endometrial proliferation Vaginal cytology
tamoxifen
placebo
6 7 NC 33 0 6 NC Estrogenic
6 6 NC 17* 0 0* NC NC
Estrogenic Estrogenic Estrogenic Estrogenic
NC* NC* -
-
* p < 0.05. NC = No change.
Table 2. Response to estrogen therapy Agent
CR + PR
Patients n
Response1 %
Ethinyl estradiol Conjugated estrogens, 15 mg/day
12
30
40
14
31
45
1 Response was accompanied by flare and withdrawal response in 10 and 5 % of patients, respectively.
given tamoxifen 20 mg/day to more than 1,200 healthy women for up to 5 years. If this agent can inhibit the estro genic effects on normal tissues within the body, we would anticipate complete amenorrhea, loss of libido, vaginal atrophy, reduction in bone density, increased clotting tendency, reduction in sex hormone-binding globulin (SHBG), adverse changes in cholesterol and other lipid levels, and endometrial atrophy. Results of monitoring the healthy women in our prevention program have not shown any antiestrogen effects on these parameters. In fact, we have been able to show a clear estrogenic effect on fibrinogen, SHBG, and cholesterol and other lipids (ta ble 1). Endometrial proliferation and vaginal cytology indicate an estrogenic effect of tamoxifen and we have
20
Powles
seen no reduction in bone density with tamoxifen. In deed, experimental and early clinical data using such sophisticated technology as dual-energy photon absorp tion seem to indicate that tamoxifen may provide estro genic protection against loss of bone mass in postmeno pausal women. These observations in a variety of tissues seem to indi cate that tamoxifen is estrogenic rather than antiestrogen ic. To maintain the hypothesis that its antitumor effect is antiestrogenic, alternative mechanisms such as different receptors are required. The lack of evidence for this raises the possibility that the antiproliferative effect of tamox ifen may in fact arise because it is a super estrogen, not an antiestrogen, and works by down-regulating an essential intracellular mechanism such as receptor synthesis. The occasional tumor flare with hypercalcemia reported with tamoxifen treatment is probably an estrogenic event that occurs prior to down-regulation and block. Similarly, the occasional withdrawal response that has been seen on ces sation of treatment after response and subsequent relapse would seem unlikely to occur with an antiestrogen. Final ly, when 4-HAD (or aminoglutéthimide), an inhibitor of estrogen synthesis, is used in patients who have relapsed with tamoxifen, remission is achieved within a few weeks. This would seem unlikely to occur if tamoxifen acted as an antiestrogen rather than as an antiproliferative estro gen. These events are similar to those observed with treat ment using relatively high doses of estrogens like ethinyl estradiol or conjugated estrogens. Response rates of 3040% have been achieved with such treatments, accompa nied by flare in about 10% of patients and a withdrawal response after subsequent relapse in about 5% of patients (table 2). Those who responded to estrogen therapy were more likely to respond to subsequent ablative therapy within a few weeks. If this hypothesis is correct, use of hormone replacement therapy combined with tamoxifen will not be contraindicated. We have now treated more than 100 patients with such a combination and have seen no obvious interaction. An alternative approach is to achieve an antiestrogenic inhibition of proliferation by use of a pure antiestrogen that truly deprives all receptors of estrogen stimulation. This method has implications in terms of drug develop ment. The advantages of such pure antiestrogenic drugs would be the complete blockade of estrogen with the potential for high response rates and long duration of response. On the other hand, it is likely that such drugs would exert profound and detrimental antiestrogenic ef fects on other tissues such as bone, sex organs, and the cardiovascular system.
Endocrine Therapy of Advanced Breast Cancer
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/28/2018 1:21:13 PM
Table 1. Toxicity profile of tamoxifen
Current controversies in endocrine treatment of breast cancer center around the inhibition of estrogen stimula tion of tumor growth either by blocking estrogen synthesis in the body with aromatase inhibitors or by interfering with estrogen’s effects on cancer cells with antiestrogenic drugs. Use of new aromatase inhibitors or combinations of drugs working by different mechanisms may achieve increased estrogenic blockade, thereby improving the re
References
1
2
sponse rate or duration of response. In contrast, tamox ifen acts directly on the tumor cells, probably by causing a down-regulation of an essential part of the estrogen-stim ulated proliferative mechanism. Tamoxifen has the ad vantage of not being antiestrogenic in other tissues. Pure antiestrogens may be more effective at inhibiting tumor growth, but at the risk of causing detrimental antiestro genic effects in normal tissues. These controversies need to be sorted out because of the clear implications they have for new drug development.
Possinger K, Langcckcr P: Role of aromatase inhibitors in the treatment of metastatic breast cancer; in Jonat W, Sansten RJ (eds): Aroma tase Inhibition. Present and Future. New York, Pantheon Books. 1991. Jones AL, MacNeill F. Jacobs S. Lonning PE, Dowsett M. Powles TJ: The influence for intra muscular 4-hydroxyandrostenedione on pe ripheral aromatisation in breast cancer pa tients. EurJ Cancer 1992;28A(suppl 10): 1712— 1716.
3
4
Lonning PE, Dowsett M, Jones AL, Ekse D, Jacobs S. MacNeill F, Johannsen DO, Powles TJ: Influence of aminoglutéthimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione. Breast Cancer Res Treat, in press. MacNeill F, Dowsett M, Jacobs S, Lonning PE, Powles TJ; Combination of the aromatase in hibitors 4-hydroxyandrostcnedione (40HA) and aminoglutéthimide (AG): An approach to maximization of aromatase inhibition and E2 suppression? 2nd Nottingham International Breast Cancer Meeting, Nottingham, Septem ber 1992.
21
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Conclusion
Medical Breast Unit, Royal Marsdcn Hospital, London, UK
KeyWords Breast cancer Endocrine therapy Aromatase inhibitor Antiestrogens
Current Controversies in the Endocrine Therapy of Advanced Breast Cancer
Abstract The response of breast cancer to endocrine therapy depends on depriving the tumor cells of estrogen stimulation of cell division. This may be achieved by blocking estrogen synthesis in the body, using inhibitors of aromatase or by using drugs like tamoxifen, which interfere with the direct effects of estrogen on tumor cells. Current controversies relate to the mechanism for achieving more effective inhibition of estrogen synthesis and for the use of more specific antiestrogenic drugs.
For the most part, response to endocrine therapy seems to depend on reducing cell proliferation by remov ing estrogen stimulation of endocrine-sensitive breast cancer cells. Response may be achieved by (1) reducing endogenous estrogen synthesis by ovarian ablation in pre menopausal women or by use of aromatase inhibitors of estrogen synthesis in postmenopausal women or (2) the use of supposed antiestrogen drugs. The main controver sies in endocrine therapy of advanced breast cancer cur rently center on (1) the actions of aromatase inhibitors and (2) the use of antiestrogens. Inhibition of estrogen synthesis is usually evaluated by measuring circulating estradiol levels. However, total potential estrogen stimu lation depends on the estrogenic sum of estradiol, estrone, and estriol levels, as well as a large reserve of estrone sul fate. Furthermore, cellular stimulation may depend not only on ovarian and peripheral (by such tissues as fat) estrogen synthesis, but also on the ability of tumor cells and stromal cells within the tumor to produce estrogen. This could have a profound effect on intracellular estro
gen levels, effecting an autocrine stimulation mechanism, which has encouraged us to examine the possibility of increasing the degree of inhibition of estrogen stimulation by using either new agents or different mechanisms to lower estrogen levels.
Aromatase Inhibitors A pure aromatase inhibitor, such as 4-hydroxyandrostanedione (4-HAD), will produce objective response rates ranging from 20 to 26% in patients with advanced breast cancer [1], The mechanism of action of 4-HAD seems to depend entirely on blocking the aromatase enzyme sys tem. Inhibition of this system in vivo appears to be about 92%, which results in a reduction of estradiol levels of about 50% [2]. In phase II testing, aminoglutéthimide has produced objective response rates between 30 and 35%. These rates may be marginally higher than the response rates to 4-HAD, although this has never been tested in a
Trevor J. Powles. BSc, PhD. FRCP The Royal Marsdcn Hospital Medical Breast Unit Downs Road Sutton. Surrey 5M2 5PT(UK)
© 1992 S. Karger AG. Basel 0030-2414/92/0498-0018 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/28/2018 1:21:13 PM
Trevor J. Powles
low estrogen levels, perhaps < 1 pmol/1. Clinical mea surement of estrogens seems to indicate that relapse is not related to recovery of estrogen synthesis despite contin ued treatment, but rather depends on an adaptation of the tumor cells, allowing them to proliferate in the presence of a lower estrogen signal. This raises the possibility that achieving very low estrogen levels in the initial phase of treatment may be sufficient to prolong the endocrine response. We are thus focusing our research on mechanisms to achieve these very low levels of estrogen. Clinical trials of a combination of a competitive inhibitor and an aromatase inhibitor that works by a different mechanism and has the added advantage of accelerating the metabolism of estrone sulfate should indicate whether this approach will be of therapeutic benefit. Accurate measurement of very low levels of estrogen combined with the measure ment of estrogen-dependent markers within tumor cells such as the progesterone receptor, as well as measurement of other estrogen-dependent proteins, including growth factors and oncogenes, may help us sort out the mecha nism of response and relapse with endocrine therapy.
Antiestrogens It could be argued that the best mechanism for com pletely blocking estrogen-dependent growth of breast tu mors is to use a supposed ‘antiestrogen’ like tamoxifen. A pure antiestrogen could be defined as an agent that inhib its estrogen-stimulated proliferation of endocrine-sensi tive breast cancer cells by competitively blocking estrogen receptors. Considerable doubt now exists that tamoxifen works totally or even in part by this mechanism. Tamox ifen was known to have agonistic estrogenic activity, espe cially in the rat. Nonetheless, it was assumed that since tamoxifen could block the effects of estrogen in various in vitro systems, its main function was antiestrogenic. In many of these systems, however, excessive estrogen levels cause inhibition of effect, producing a bell-shaped curve. The possibility that tamoxifen could be acting as an impeded ‘super’ estrogen, thereby removing sensitivity to low levels of stimulating estrogen, has generally not been tested. For example, in the absence of estrogen, tamoxifen has been shown to have antiproliferative effects in vitro on breast cancer cells. This would seem to indicate a mechanism other than estrogen deprivation. In our tamoxifen prevention program in healthy wom en, we were concerned that tamoxifen could exert adverse antiestrogenic actions on normal tissues. We have now
19
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/28/2018 1:21:13 PM
randomized clinical trial. Aminoglutéthimide will inhibit in vivo aromatase activity by about 91%, which is similar to the inhibition seen with 4-HAD. The mechanism of action, however, appears to depend on a cytochrome P450 enzyme system, which is essential for aromatase activity. Aminoglutéthimide also appears to lower estro gen levels by another mechanism - stimulating micro somal hepatic metabolism of estrone sulfate and its clear ance into the urine. In equilibrium with free estrone, estrone sulfate is the main constituent estrogen of the pool that can be metabolized within the body - and within cells - to estradiol. Patients already receiving 4-HAD show a significant added reduction in estrone sulfate levels when aminoglutéthimide 1 g/day plus hydrocortisone is added to their treatment [3], These observations seem to indi cate that aminoglutéthimide may have an advantage over 4-HAD in lowering the total estrogen pool. Moreover, the possibility exists that inhibition of aro matase activity by a competitive inhibitor like 4-HAD might be enhanced by the addition of an agent like amino glutéthimide, which depends on inhibition of cytochrome P-450 to inhibit estrogen synthesis. Preliminary results indicate that in vivo aromatase inhibition in humans by aminoglutéthimide and 4-HAD is only 91 and 92%, respectively. A combination of these two agents, working by different mechanisms, may increase this blockade. These preliminary results are being evaluated in a series of patients using a double isotope prelabeling technique to measure urinary excretion of labeled androstanedione and estrone [4], The essential question is whether high levels of estro gen blockade might increase the response rate or duration of response. Measurements of estrogen during response and relapse in patients taking endocrine therapy seem to support the hypothesis that very low estrogen levels might in fact enhance the therapeutic benefit of such treatment. For example, tumor progression in a premenopausal woman seems to depend on estrogen levels up to 1,000 pmol/1. Ovarian ablation, which may reduce estrogen syn thesis and consequent estradiol levels to about 100 pmol/1, is sufficient to achieve a maximum endocrine response in about 30% of patients. Responding patients will eventually relapse in spite of estradiol levels that remain at the postoophorectomy level. Introducing an aromatase inhibitor at this stage, which will reduce estradiol levels to below 50 pmol/1, is probably sufficient to achieve maximum second-line endocrine response similar to the responses and estrogen levels seen in postmenopausal women taking aromatase inhibitors. Subsequent response seems to depend on achieving very
Patients, %
Amenorrhea Period changes Libido Hot flushes Vaginal atrophy Vaginal discharge Bone density Clotting Liver SHBG Lipids Endometrial proliferation Vaginal cytology
tamoxifen
placebo
6 7 NC 33 0 6 NC Estrogenic
6 6 NC 17* 0 0* NC NC
Estrogenic Estrogenic Estrogenic Estrogenic
NC* NC* -
-
* p < 0.05. NC = No change.
Table 2. Response to estrogen therapy Agent
CR + PR
Patients n
Response1 %
Ethinyl estradiol Conjugated estrogens, 15 mg/day
12
30
40
14
31
45
1 Response was accompanied by flare and withdrawal response in 10 and 5 % of patients, respectively.
given tamoxifen 20 mg/day to more than 1,200 healthy women for up to 5 years. If this agent can inhibit the estro genic effects on normal tissues within the body, we would anticipate complete amenorrhea, loss of libido, vaginal atrophy, reduction in bone density, increased clotting tendency, reduction in sex hormone-binding globulin (SHBG), adverse changes in cholesterol and other lipid levels, and endometrial atrophy. Results of monitoring the healthy women in our prevention program have not shown any antiestrogen effects on these parameters. In fact, we have been able to show a clear estrogenic effect on fibrinogen, SHBG, and cholesterol and other lipids (ta ble 1). Endometrial proliferation and vaginal cytology indicate an estrogenic effect of tamoxifen and we have
20
Powles
seen no reduction in bone density with tamoxifen. In deed, experimental and early clinical data using such sophisticated technology as dual-energy photon absorp tion seem to indicate that tamoxifen may provide estro genic protection against loss of bone mass in postmeno pausal women. These observations in a variety of tissues seem to indi cate that tamoxifen is estrogenic rather than antiestrogen ic. To maintain the hypothesis that its antitumor effect is antiestrogenic, alternative mechanisms such as different receptors are required. The lack of evidence for this raises the possibility that the antiproliferative effect of tamox ifen may in fact arise because it is a super estrogen, not an antiestrogen, and works by down-regulating an essential intracellular mechanism such as receptor synthesis. The occasional tumor flare with hypercalcemia reported with tamoxifen treatment is probably an estrogenic event that occurs prior to down-regulation and block. Similarly, the occasional withdrawal response that has been seen on ces sation of treatment after response and subsequent relapse would seem unlikely to occur with an antiestrogen. Final ly, when 4-HAD (or aminoglutéthimide), an inhibitor of estrogen synthesis, is used in patients who have relapsed with tamoxifen, remission is achieved within a few weeks. This would seem unlikely to occur if tamoxifen acted as an antiestrogen rather than as an antiproliferative estro gen. These events are similar to those observed with treat ment using relatively high doses of estrogens like ethinyl estradiol or conjugated estrogens. Response rates of 3040% have been achieved with such treatments, accompa nied by flare in about 10% of patients and a withdrawal response after subsequent relapse in about 5% of patients (table 2). Those who responded to estrogen therapy were more likely to respond to subsequent ablative therapy within a few weeks. If this hypothesis is correct, use of hormone replacement therapy combined with tamoxifen will not be contraindicated. We have now treated more than 100 patients with such a combination and have seen no obvious interaction. An alternative approach is to achieve an antiestrogenic inhibition of proliferation by use of a pure antiestrogen that truly deprives all receptors of estrogen stimulation. This method has implications in terms of drug develop ment. The advantages of such pure antiestrogenic drugs would be the complete blockade of estrogen with the potential for high response rates and long duration of response. On the other hand, it is likely that such drugs would exert profound and detrimental antiestrogenic ef fects on other tissues such as bone, sex organs, and the cardiovascular system.
Endocrine Therapy of Advanced Breast Cancer
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/28/2018 1:21:13 PM
Table 1. Toxicity profile of tamoxifen
Current controversies in endocrine treatment of breast cancer center around the inhibition of estrogen stimula tion of tumor growth either by blocking estrogen synthesis in the body with aromatase inhibitors or by interfering with estrogen’s effects on cancer cells with antiestrogenic drugs. Use of new aromatase inhibitors or combinations of drugs working by different mechanisms may achieve increased estrogenic blockade, thereby improving the re
References
1
2
sponse rate or duration of response. In contrast, tamox ifen acts directly on the tumor cells, probably by causing a down-regulation of an essential part of the estrogen-stim ulated proliferative mechanism. Tamoxifen has the ad vantage of not being antiestrogenic in other tissues. Pure antiestrogens may be more effective at inhibiting tumor growth, but at the risk of causing detrimental antiestro genic effects in normal tissues. These controversies need to be sorted out because of the clear implications they have for new drug development.
Possinger K, Langcckcr P: Role of aromatase inhibitors in the treatment of metastatic breast cancer; in Jonat W, Sansten RJ (eds): Aroma tase Inhibition. Present and Future. New York, Pantheon Books. 1991. Jones AL, MacNeill F. Jacobs S. Lonning PE, Dowsett M. Powles TJ: The influence for intra muscular 4-hydroxyandrostenedione on pe ripheral aromatisation in breast cancer pa tients. EurJ Cancer 1992;28A(suppl 10): 1712— 1716.
3
4
Lonning PE, Dowsett M, Jones AL, Ekse D, Jacobs S. MacNeill F, Johannsen DO, Powles TJ: Influence of aminoglutéthimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione. Breast Cancer Res Treat, in press. MacNeill F, Dowsett M, Jacobs S, Lonning PE, Powles TJ; Combination of the aromatase in hibitors 4-hydroxyandrostcnedione (40HA) and aminoglutéthimide (AG): An approach to maximization of aromatase inhibition and E2 suppression? 2nd Nottingham International Breast Cancer Meeting, Nottingham, Septem ber 1992.
21
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/28/2018 1:21:13 PM
Conclusion
