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Plasma hormones in patients with advanced breast cancer treated with tamoxifen
Europ. J. Cancer Vol. 12, pp. 719-723. Pergamon Press 1976. Printed in Great Britain
Plasma Hormones in Patients with Advanced Breast Cancer Treated with Tamoxlfen M E R I E L P. GOLDER~, M. ELIZABETH A. PHILLIPS,, D. R. FAHMY~-, P. E. PREECE$, V. JONES§, J. M. H E N K § and K. GRIFFITHS~ Tenovus Institute for Cancer Research, Welsh National School of Medicine, Heath, Cardiff, CF4 4XX, Waler Abstract--Plasma concentrations of prolactin, FSH, L H and oestradiol-17[3 were measured in patients with advanced breast cancer being treated with tamoxifen. Plasma FSH levels dropped during the first month of treatment in patients who subsequently responded to therapy and in those who did not. After prolonged therapy plasma FSH in the responders ret~rrned to pre-treatment levels whereas those in the non-responders remained lower that,, the pre-treatment value. L H levels were lowered during tamoxifen therapy but there was no significant difference between the two group of patients. Plasma prolactin and oestradiol-17 fl concentrations were unaffected by treatment.
INTRODUCTION
prolactin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and oestradiol-171~ have been studied in patients with advanced breast cancer treated with the anti-oestrogen tamoxifen, (I.C.I. 46474). This compound has been used extensively in the treatment of the disease in recent years by other groups [3, 4]. There are however no reports of studies of plasma hormone changes in treated patients.
ALTHOUGH it iS well recognized that a large proportion of patients with recurrent breast cancer require palliative treatment, only approximately one third of these respond to hormone therapy, whether additive or ablative. The selection c,f the type of treatment given is largely empirical and a more scientific basis is required. Little is known regarding the biochemical effects of the hormonal therapy regimes which are used although it is accepted that these may involve a suppression of pituitary hormone secretion, a direct action on the tumour cells or an enhancement of the immune competence of the patient. Although a number of studies have been undertaken in an attempt to provide a scientific basis for the selection of therapy [1,2] little is known about the endocrine changes that occur during the treatment of patients with various hormone regimes or of the plasma hormone concentrations of those who respond 1:o therapy compared to those who do not. In this study, plasma concentrations of
MATERIAL AND M E T H O D S Patients Studies were carried out on patients attending the Combined Breast Clinic of the Departments of Surgery and Radiotherapy. All patients included in the study had either local or general carcinoma of the breast. They were either post-menopausal (in all cases more than two years since the last menstrual period) or had undergone oophorectomy. Thirty patients were treated with tamoxifen and of these 24 had sufficient blood samples taken for analysis. None had previously received any hormone treatment nor had undergone ablative endocrine surgery which would require maintenance therapy. None had received cytotoxic drugs. Blood samples were taken from the patient on the morning before the commencement of treatment. Subsequent samples were taken at 7 and 14 days a n d at one, two and three months later.
Accepted 22 March 1976. *Supported by the Tenovus Organization. ++Departmentof Surgery, UniversityHospital of Wales. §Velindre Hospital, Whitchurch, Cardiff, United Kingdom. 719
720
Merid P. Golder et al.
Treatment Patients were given tamoxifen (tram- (p-fidimethylamino- ethoxyphenyl) - 1, 2 - diphenylbut-l-ene, Nolvadex, I.C.I. Ltd., Macclesfield, Cheshire) 20 mg twice a day for a minimum of one month. Hormone assays Blood was collected into lithium sequestrene tubes, centrifuged at 4°C, separated, and the plasma stored at - 2 0 ° C until assayed. Protein hormones Prolactin was assayed by a double antibody radioimmunoassay using the method described by Cole & Boyns [5]. Results are expressed in terms of M R C Standard 71/222 and 1 m U is equal to 50 ng in this assay system. LH and FSH were assayed using methods described previously [6], L H is expressed in terms of M R C Standard 68•40 and FSH in terms of 2nd 1 R P - H M G where 1 m I U is equivalent to 230 ng. Plasma oestradiol-17fl Oestradiol-17fl was determined by a R I A procedure, using an antiserum raised against an oestradiol-6-[O-carboxymethyl]-oxime bovine serum albumin conjugate. Steroids were extracted with diethyl ether (the recoveries ranged from 95-105~o) and no purification procedures were incorporated in the assay since results, with and without chromatography, showed no significant difference. Free and bound steroid were separated using dextran' coated charcoal and the free steroid in a 500 #1 aliquot dissolved in 5 m l Aquasol (NEN Chemicals) and counted in a liquid scintillation counter. Data analysis The clinical response to tamoxifen was assessed three months after beginning therapy according to the criteria described by Forrest [7], and patients were grouped as responders or non-responders. Their pretreatment plasma hormone values were compared and are presented as median and range because the distributions for prolactin and oestradiol-17fl were markedly skewed. Within subjects, however, hormone concentrations approximated to a Gaussian distribution so that transformation of the data was not warranted. In order to minimize between subject variation hormone concentrations were first normalized by expressing each concentration as a fraction of the average for an individual. For both groups of patients at each time interval mean + S.E.M.
was calculated and the figures then scaled to make the pretreatment value 100. RESULTS
Three months after the start of treatment all patients were assessed clinically and classified as responders, non-responders or those with an equivocal response. For the purpose of analysis the two patients assessed as equivocal responders were grouped with the non-responders. The distribution of sites of the disease with which the patient presented was similar between the two groups of patients (Table 1). There were no differences between the ages, years post-menopausal and cancer free intervals in all the patients studied (Table
2). Table 1. Distribution of disease type in patients treated with tamoxifen Number of patients Disease type Responders Local General Local and General Total
5 1 4 10 (42%)
Non-responders 5 2 7 14 (58%)
Patients were assessed 3 months after start of treatment and classed as responders or non-responders.
Table 3 shows the pre-treatment plasma hormone concentrations of the patients treated with tamoxifen. The results indicate that the nature of the response of the patients to the anti-oestrogen treatment is not determined by differences in the hormonal status of the patient before commencement of hormone therapy. Plasma prolactin levels in the patients were unaffected by tamoxifen treatment (Fig. la). Although there was a wide range of concentrations before the start of therapy in both responders and non-responders, some patients having high prolactin levels and others very low levels, the values in the individual patients did not alter significantly during the treatment time and there was no difference between the two groups of patients. Plasma oestradiol-17p concentrations were also unaffected by tamoxifen treatment in either group of patients (Fig. lb). Gonadotrophin levels during treatment are shown in Fig. 2. Plasma FSH decreased in the
Plasma Hormones in Patients with Advanced Breast Cancer Treated with Tamoxifen Table 2.
72l
Distribution of patients treated with tamoxifen
N
Age (yr)
Time since L.M.P. (yr)
Cancer free Interval (yr)
Responders
10
64.5 (56-80)
14 (2-40)
2-0 (0-12)
Non-responders
14
61.5 (54-82)
14 (3-29)
1-5 (0-6)
Patients were assessed 3 months after starting treatment and classed as responders or non-responders. Values are expressed as the median and range. N ----number of patients in each sub-group. There are no differences between responders or non-responders, L M P ----Last Menstrual period. 0 ----Patients who presented with advanced disease.
Table 3.
Plasma Hormone concentrations before starting treatment with tamoxifen Plasma hormones
N Responders
10
Non.-responders
14
Prolactin (mU/ml)
Oestradiol- 17fl LH (pg/ml) (mlU/ml)
0" 13 (0-04-0"98) 0"21 (0.04-0.41)
27 (16-52) 25 (16-52)
FSH (mIU/ml
25 (15-48) 36 (17-50)
72 (33-112 80 (28-124
Results are expressed as Median and range. There are no differences between responders and non-responders. {a)
(a) 15o-
Prola(-fin
150-
e
g $
FSH
ioo-
I00"I(.0 b_
......... ~.°°-'"
o
o
o
5o-
50-
o
o-
2;
-; ,~
5~
.~
~
(b)
Oestradiol
- 17/~
5'6
.'2
'
LH
g
~
100-
"r _I
100-
i
50--
._o "~ 50-
ft. O-
~
2~
150-
(b) 150-
÷,:~
Days after starting treatment
Days after starting treatment
~
,
'
0
,
~'4
2'8
~6
.'2 '
Days after starting treatment
' ~ 4
2'8
~6
~1'2 '
Days .after starting treatment
Fig. 1. Response of plasma prolaain and oestradiol-17fl to tamoxifen therapy in responding and non-responding breast cancer patients. Values are expre.~sedas mean ± S.E,M. of normalised data, (see text for details of analyris). • - - - • responders 0 - " - - • non-responder$
Fig. 2. Response of plasma FSH and L H to tamoxifen therapy in responding and non-responding breast cancer patients. Values are expressedas mean + S.E.M. of normalised data. (see text for details of analysis). • - - - • responders • • non-responders *VFSHpretreatment value P < 0.05 t Non-responders v. responders P < 0-05
722
Meriel P. Golder et al.
first week of tamoxifen therapy and at o n e month was significantly lower (P ~ 0-05) than the pretreatment level in both responders and non-responders. However, within 2 and 3 months of the start of treatment, plasma FSH concentration in patients responding to tamoxifen had returned to the value found before tamoxifen treatment started, whereas in the non-responders, hormone concentrations were significantly lower (P < 0.05) than the basal level throughout the course of therapy. There was a significant difference (P ~ 0.05) between the FSH levels in the responders and nonresponders in the second and third month of treatment. By contrast, there was no difference between LH concentrations in the two groups of patients (Fig. 2b). After 1 week of treatment, plasma LH had decreased in both groups and remained significantly lower than the pretreatment value over the three-month period. DISCUSSION
The remission rate of approximately 40~o which was induced by tamoxifen treatment in this series of patients is similar to that obtained by other groups who have also used this agent in the treatment of advanced breast cancer [3, 4]. This proportion of patients showing an objective response is comparable with the results of other studies from this group using other single hormone agents [8]. Using clomiphene, a compound closely related chemically to tamoxifen, a response rate of approximately 40 ~o has also been observed [9]. Evidence from animal studies suggests that the rat mammary tumour, induced by the administration of dimethylbenz-anthracene is dependent o n the pituitary hormone prolactin [10, 11]. Although Murray [12] demonstrated elevated plasma prolactin levels in postmenopausal women with advanced breast cancer, other studies from the Tenovus Institute have, however, failed to demonstrate such a difference or any relationship between plasma prolactin concentration and breast disease [13, 14]. In this study, neither prolactin concentrations nor oestradiol-17fl levels altered during the course of tamoxifen therapy. The plasma prolactin c o n c e n t r a t i o n before treatment
ranged from low normal through to high normal values but in each patient levels were not affected by treatment. This result appears to be in contrast to the action of tamoxifen in the pre-menopausal woman, when tamoxifen administration caused a decrease in plasma prolacfin with a subsequent increase in oestradiol- 17fl concentration [ 15]. Plasma FSH concentrations were lowered during the first week of treatment with tamoxifen in patients who subsequently responded to therapy and in those who did not. Significantly reduced levels were maintained during the first month of treatment but after prolonged therapy, plasma FSH in the responders returned to pre-treatment levels whereas those in the non-responders remained lower than the pretreatment value. At two and three months after the start of tamoxifen administration, FSH concentrations, in the group of non-responders remained significantly lower than in the responders. Plasma FSH levels are also affected in a similar way when patients with advanced breast cancer were treated with clomiphene [9]. Both these compounds are generally regarded to be anti-oestrogens although the mechanism of action of neither is fully understood. Although tamoxifen is known to affect the binding of oestradiol-17fl to the cytoplasmic receptor protein in both the rat DMBA-tumour [16] and in human breast carcinoma [17], it would also seem to have some action on the hypothalamic-pituitary axis. The response of the rat to antioestrogen treatment appears to be dependent on dose since a large amount of tamoxifen administered over a long period of time can be oestrogenic and cause an elevation of prolactin levels (R. Nicholson & M. P. Golder, unpublished observations) whereas lower doses are antioestrogenic [18, 19]. In view of the use of tamoxifen in pituitarygonodal function tests in the pre-menopausal woman it will be interesting to study in greater depth pituitary function in post-menopausal women. A c k n o w l e d g e m e n t s - - W e thank Miss K. Baker for expert technical assistance.
We arc grateful to Professgr L. E. Hughes, Mr. M. Baum, and Dr. T. Priestman for allowing us to study patients under their care.
REFERENCES
.
R. D. BULBROOKand J. L. HAYWARD,Abnormal urinary steroid excretion a n d subsequent breast cancer. Lancet i, 519 (1967).
Plasma Hormones in Patients with Advanced Breast Cancer Treated with Tamoxifen
2. 3. 4. 5. 6. 7.
E.R. DE SOMBRE,S. SMITH, G. E. BLOCK,D. J. FERGUSONand E. V. JENSEN, Prediction of breast cancer response to endocrine therapy. Cancer Chemother. Rep. p. 39, (1974). M . P . CozaL C. T. A. JONES and I. D. H. TODD, A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of I.C.I. 46474. Brit. J. Cancer 25, 270 (1971). H . W . C . WARD, Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Brit. med. J. 1, 13 (1973). E . N . COLE and A. R. BOYNS, Radioimmunoassay for human pituitary prolactin using antiserum against an extract of human amniotic fluid. Horm. Res. 4, 261 (1973). G . V . GROOM, M. A. GROOM, I. D. COOKE and A. R. BOYNS,The secretion of immunoreactive luteinizing hormone and follicle stimulating hormone by the human foetal pituitary in organ culture..1. Endocr. 49, 335 (1971). A . P . M . FORREST, In: The Clinical Management of Advanoed Breast Cancer, p. 88, (Edited by C. A. F. JOSLINand E. N. GLEAVE). Alpha Omega Alpha, Cardiff
(1970).
v . JoN~s, A prospective trial of oestrogens, androgens and progestogens for the treatment of advanced carcinoma of the breast. In: The Clinical Management of Advanced Breast Cancer, p. 24, (Edited by C. A. F. JosuN and E. N. CLEAVE). Alpha Omega Alpha, Cardiff (1970). 9. M.P. GOLDER, M. E. A. PHILLIPS, P. E. PREECE, V. JONES, C. A. F. JOSUN and K. GR*FFITHS, Submitted for publication. 10. 0. n. PEARSON, R. L. MURRAY, G. MOZAFFERIAN and J. PENSKY, Prolactin and experimental breast cancer. In: Prolactin and Carcinogenesis, p. 154, (Edited by A. R. BOYNSand K. GRIFFITHS).Alpha Omega Alpha, Cardiff (1972). 11. A . R . BOYNS,R. BUCHAN,E. N. COLE, A. P. M. FORRESTand K. GRn~FITHS, Basal prolactin blood levels in three strains of rats with differing incidence of 7,12,dimethylbenz(a)anthracene-induced mammary tumours. Europ. J. Cancer 9, 169 (1973). 12. R . M . L . MURRAY,G. MOZAFFERIANand O. H. PEARSON,Prolactin levels with L-Dopa treatment in metastatic breast carcinoma. In: Prolactin and Carcinogenesis, p. 158. (Edited by A. R. BOX,NS and K. GRr~VITHS). Alpha Omega Alpha, Cardiff (1972). 13. A . R . BOYNS,E. N. COLE, K. GRIFFITI-IS,M. M. ROBERTS,R. BUCHAN,R. G. WILSON and A. P. M. FOREST, Plasma prolactin in breast cancer. Europ. J. Cancer 9, 99 (1973). 14. R . G . WILSON, R. BUCHAN,M. M. ROBERTS,A. P. M. FOmU~ST,A. R. BOYNS, E. N. COLE and K. G~FFITHS, Plasma prolactin and breast cancer. Cancer (Philad.) 33, 1325 (1974). 15. G.V. GROOMand K. GRIFFITHS,J. Endocr. (1976). In press. 16. W. POWELL-JONES,D. A. JENNER, R. W. BLAMEY,P. DAVIESand K. GRIFFITHS, Influence of anti-oestrogens on the specific binding in vitro of [3H]oestradiol by cytosol of rat mammary tumours and human breast carcinomas. Biochem. J. 150, 71 (1975). 17. V . C . JORDON and S. KOEmCER, Tamoxifen (I.C.I. 46474) and the human carcinoma 8S oestrogen receptor. Europ. J. Cancer 11, 205 (1975). 18. V.C. JORDON,S. KOERNERand C. ROBISON,Inhibition of oestrogen stimulated prolactin release by anti-oestrogens. J. Endocr. 65~ 151 (1975). 19. R . I . NIeHOLSONand M. P. GOLDER,The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary turnouts. Europ. J. Cancer 11~ 571 (1975). 8.
723
Plasma Hormones in Patients with Advanced Breast Cancer Treated with Tamoxlfen M E R I E L P. GOLDER~, M. ELIZABETH A. PHILLIPS,, D. R. FAHMY~-, P. E. PREECE$, V. JONES§, J. M. H E N K § and K. GRIFFITHS~ Tenovus Institute for Cancer Research, Welsh National School of Medicine, Heath, Cardiff, CF4 4XX, Waler Abstract--Plasma concentrations of prolactin, FSH, L H and oestradiol-17[3 were measured in patients with advanced breast cancer being treated with tamoxifen. Plasma FSH levels dropped during the first month of treatment in patients who subsequently responded to therapy and in those who did not. After prolonged therapy plasma FSH in the responders ret~rrned to pre-treatment levels whereas those in the non-responders remained lower that,, the pre-treatment value. L H levels were lowered during tamoxifen therapy but there was no significant difference between the two group of patients. Plasma prolactin and oestradiol-17 fl concentrations were unaffected by treatment.
INTRODUCTION
prolactin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and oestradiol-171~ have been studied in patients with advanced breast cancer treated with the anti-oestrogen tamoxifen, (I.C.I. 46474). This compound has been used extensively in the treatment of the disease in recent years by other groups [3, 4]. There are however no reports of studies of plasma hormone changes in treated patients.
ALTHOUGH it iS well recognized that a large proportion of patients with recurrent breast cancer require palliative treatment, only approximately one third of these respond to hormone therapy, whether additive or ablative. The selection c,f the type of treatment given is largely empirical and a more scientific basis is required. Little is known regarding the biochemical effects of the hormonal therapy regimes which are used although it is accepted that these may involve a suppression of pituitary hormone secretion, a direct action on the tumour cells or an enhancement of the immune competence of the patient. Although a number of studies have been undertaken in an attempt to provide a scientific basis for the selection of therapy [1,2] little is known about the endocrine changes that occur during the treatment of patients with various hormone regimes or of the plasma hormone concentrations of those who respond 1:o therapy compared to those who do not. In this study, plasma concentrations of
MATERIAL AND M E T H O D S Patients Studies were carried out on patients attending the Combined Breast Clinic of the Departments of Surgery and Radiotherapy. All patients included in the study had either local or general carcinoma of the breast. They were either post-menopausal (in all cases more than two years since the last menstrual period) or had undergone oophorectomy. Thirty patients were treated with tamoxifen and of these 24 had sufficient blood samples taken for analysis. None had previously received any hormone treatment nor had undergone ablative endocrine surgery which would require maintenance therapy. None had received cytotoxic drugs. Blood samples were taken from the patient on the morning before the commencement of treatment. Subsequent samples were taken at 7 and 14 days a n d at one, two and three months later.
Accepted 22 March 1976. *Supported by the Tenovus Organization. ++Departmentof Surgery, UniversityHospital of Wales. §Velindre Hospital, Whitchurch, Cardiff, United Kingdom. 719
720
Merid P. Golder et al.
Treatment Patients were given tamoxifen (tram- (p-fidimethylamino- ethoxyphenyl) - 1, 2 - diphenylbut-l-ene, Nolvadex, I.C.I. Ltd., Macclesfield, Cheshire) 20 mg twice a day for a minimum of one month. Hormone assays Blood was collected into lithium sequestrene tubes, centrifuged at 4°C, separated, and the plasma stored at - 2 0 ° C until assayed. Protein hormones Prolactin was assayed by a double antibody radioimmunoassay using the method described by Cole & Boyns [5]. Results are expressed in terms of M R C Standard 71/222 and 1 m U is equal to 50 ng in this assay system. LH and FSH were assayed using methods described previously [6], L H is expressed in terms of M R C Standard 68•40 and FSH in terms of 2nd 1 R P - H M G where 1 m I U is equivalent to 230 ng. Plasma oestradiol-17fl Oestradiol-17fl was determined by a R I A procedure, using an antiserum raised against an oestradiol-6-[O-carboxymethyl]-oxime bovine serum albumin conjugate. Steroids were extracted with diethyl ether (the recoveries ranged from 95-105~o) and no purification procedures were incorporated in the assay since results, with and without chromatography, showed no significant difference. Free and bound steroid were separated using dextran' coated charcoal and the free steroid in a 500 #1 aliquot dissolved in 5 m l Aquasol (NEN Chemicals) and counted in a liquid scintillation counter. Data analysis The clinical response to tamoxifen was assessed three months after beginning therapy according to the criteria described by Forrest [7], and patients were grouped as responders or non-responders. Their pretreatment plasma hormone values were compared and are presented as median and range because the distributions for prolactin and oestradiol-17fl were markedly skewed. Within subjects, however, hormone concentrations approximated to a Gaussian distribution so that transformation of the data was not warranted. In order to minimize between subject variation hormone concentrations were first normalized by expressing each concentration as a fraction of the average for an individual. For both groups of patients at each time interval mean + S.E.M.
was calculated and the figures then scaled to make the pretreatment value 100. RESULTS
Three months after the start of treatment all patients were assessed clinically and classified as responders, non-responders or those with an equivocal response. For the purpose of analysis the two patients assessed as equivocal responders were grouped with the non-responders. The distribution of sites of the disease with which the patient presented was similar between the two groups of patients (Table 1). There were no differences between the ages, years post-menopausal and cancer free intervals in all the patients studied (Table
2). Table 1. Distribution of disease type in patients treated with tamoxifen Number of patients Disease type Responders Local General Local and General Total
5 1 4 10 (42%)
Non-responders 5 2 7 14 (58%)
Patients were assessed 3 months after start of treatment and classed as responders or non-responders.
Table 3 shows the pre-treatment plasma hormone concentrations of the patients treated with tamoxifen. The results indicate that the nature of the response of the patients to the anti-oestrogen treatment is not determined by differences in the hormonal status of the patient before commencement of hormone therapy. Plasma prolactin levels in the patients were unaffected by tamoxifen treatment (Fig. la). Although there was a wide range of concentrations before the start of therapy in both responders and non-responders, some patients having high prolactin levels and others very low levels, the values in the individual patients did not alter significantly during the treatment time and there was no difference between the two groups of patients. Plasma oestradiol-17p concentrations were also unaffected by tamoxifen treatment in either group of patients (Fig. lb). Gonadotrophin levels during treatment are shown in Fig. 2. Plasma FSH decreased in the
Plasma Hormones in Patients with Advanced Breast Cancer Treated with Tamoxifen Table 2.
72l
Distribution of patients treated with tamoxifen
N
Age (yr)
Time since L.M.P. (yr)
Cancer free Interval (yr)
Responders
10
64.5 (56-80)
14 (2-40)
2-0 (0-12)
Non-responders
14
61.5 (54-82)
14 (3-29)
1-5 (0-6)
Patients were assessed 3 months after starting treatment and classed as responders or non-responders. Values are expressed as the median and range. N ----number of patients in each sub-group. There are no differences between responders or non-responders, L M P ----Last Menstrual period. 0 ----Patients who presented with advanced disease.
Table 3.
Plasma Hormone concentrations before starting treatment with tamoxifen Plasma hormones
N Responders
10
Non.-responders
14
Prolactin (mU/ml)
Oestradiol- 17fl LH (pg/ml) (mlU/ml)
0" 13 (0-04-0"98) 0"21 (0.04-0.41)
27 (16-52) 25 (16-52)
FSH (mIU/ml
25 (15-48) 36 (17-50)
72 (33-112 80 (28-124
Results are expressed as Median and range. There are no differences between responders and non-responders. {a)
(a) 15o-
Prola(-fin
150-
e
g $
FSH
ioo-
I00"I(.0 b_
......... ~.°°-'"
o
o
o
5o-
50-
o
o-
2;
-; ,~
5~
.~
~
(b)
Oestradiol
- 17/~
5'6
.'2
'
LH
g
~
100-
"r _I
100-
i
50--
._o "~ 50-
ft. O-
~
2~
150-
(b) 150-
÷,:~
Days after starting treatment
Days after starting treatment
~
,
'
0
,
~'4
2'8
~6
.'2 '
Days after starting treatment
' ~ 4
2'8
~6
~1'2 '
Days .after starting treatment
Fig. 1. Response of plasma prolaain and oestradiol-17fl to tamoxifen therapy in responding and non-responding breast cancer patients. Values are expre.~sedas mean ± S.E,M. of normalised data, (see text for details of analyris). • - - - • responders 0 - " - - • non-responder$
Fig. 2. Response of plasma FSH and L H to tamoxifen therapy in responding and non-responding breast cancer patients. Values are expressedas mean + S.E.M. of normalised data. (see text for details of analysis). • - - - • responders • • non-responders *VFSHpretreatment value P < 0.05 t Non-responders v. responders P < 0-05
722
Meriel P. Golder et al.
first week of tamoxifen therapy and at o n e month was significantly lower (P ~ 0-05) than the pretreatment level in both responders and non-responders. However, within 2 and 3 months of the start of treatment, plasma FSH concentration in patients responding to tamoxifen had returned to the value found before tamoxifen treatment started, whereas in the non-responders, hormone concentrations were significantly lower (P < 0.05) than the basal level throughout the course of therapy. There was a significant difference (P ~ 0.05) between the FSH levels in the responders and nonresponders in the second and third month of treatment. By contrast, there was no difference between LH concentrations in the two groups of patients (Fig. 2b). After 1 week of treatment, plasma LH had decreased in both groups and remained significantly lower than the pretreatment value over the three-month period. DISCUSSION
The remission rate of approximately 40~o which was induced by tamoxifen treatment in this series of patients is similar to that obtained by other groups who have also used this agent in the treatment of advanced breast cancer [3, 4]. This proportion of patients showing an objective response is comparable with the results of other studies from this group using other single hormone agents [8]. Using clomiphene, a compound closely related chemically to tamoxifen, a response rate of approximately 40 ~o has also been observed [9]. Evidence from animal studies suggests that the rat mammary tumour, induced by the administration of dimethylbenz-anthracene is dependent o n the pituitary hormone prolactin [10, 11]. Although Murray [12] demonstrated elevated plasma prolactin levels in postmenopausal women with advanced breast cancer, other studies from the Tenovus Institute have, however, failed to demonstrate such a difference or any relationship between plasma prolactin concentration and breast disease [13, 14]. In this study, neither prolactin concentrations nor oestradiol-17fl levels altered during the course of tamoxifen therapy. The plasma prolactin c o n c e n t r a t i o n before treatment
ranged from low normal through to high normal values but in each patient levels were not affected by treatment. This result appears to be in contrast to the action of tamoxifen in the pre-menopausal woman, when tamoxifen administration caused a decrease in plasma prolacfin with a subsequent increase in oestradiol- 17fl concentration [ 15]. Plasma FSH concentrations were lowered during the first week of treatment with tamoxifen in patients who subsequently responded to therapy and in those who did not. Significantly reduced levels were maintained during the first month of treatment but after prolonged therapy, plasma FSH in the responders returned to pre-treatment levels whereas those in the non-responders remained lower than the pretreatment value. At two and three months after the start of tamoxifen administration, FSH concentrations, in the group of non-responders remained significantly lower than in the responders. Plasma FSH levels are also affected in a similar way when patients with advanced breast cancer were treated with clomiphene [9]. Both these compounds are generally regarded to be anti-oestrogens although the mechanism of action of neither is fully understood. Although tamoxifen is known to affect the binding of oestradiol-17fl to the cytoplasmic receptor protein in both the rat DMBA-tumour [16] and in human breast carcinoma [17], it would also seem to have some action on the hypothalamic-pituitary axis. The response of the rat to antioestrogen treatment appears to be dependent on dose since a large amount of tamoxifen administered over a long period of time can be oestrogenic and cause an elevation of prolactin levels (R. Nicholson & M. P. Golder, unpublished observations) whereas lower doses are antioestrogenic [18, 19]. In view of the use of tamoxifen in pituitarygonodal function tests in the pre-menopausal woman it will be interesting to study in greater depth pituitary function in post-menopausal women. A c k n o w l e d g e m e n t s - - W e thank Miss K. Baker for expert technical assistance.
We arc grateful to Professgr L. E. Hughes, Mr. M. Baum, and Dr. T. Priestman for allowing us to study patients under their care.
REFERENCES
.
R. D. BULBROOKand J. L. HAYWARD,Abnormal urinary steroid excretion a n d subsequent breast cancer. Lancet i, 519 (1967).
Plasma Hormones in Patients with Advanced Breast Cancer Treated with Tamoxifen
2. 3. 4. 5. 6. 7.
E.R. DE SOMBRE,S. SMITH, G. E. BLOCK,D. J. FERGUSONand E. V. JENSEN, Prediction of breast cancer response to endocrine therapy. Cancer Chemother. Rep. p. 39, (1974). M . P . CozaL C. T. A. JONES and I. D. H. TODD, A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of I.C.I. 46474. Brit. J. Cancer 25, 270 (1971). H . W . C . WARD, Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Brit. med. J. 1, 13 (1973). E . N . COLE and A. R. BOYNS, Radioimmunoassay for human pituitary prolactin using antiserum against an extract of human amniotic fluid. Horm. Res. 4, 261 (1973). G . V . GROOM, M. A. GROOM, I. D. COOKE and A. R. BOYNS,The secretion of immunoreactive luteinizing hormone and follicle stimulating hormone by the human foetal pituitary in organ culture..1. Endocr. 49, 335 (1971). A . P . M . FORREST, In: The Clinical Management of Advanoed Breast Cancer, p. 88, (Edited by C. A. F. JOSLINand E. N. GLEAVE). Alpha Omega Alpha, Cardiff
(1970).
v . JoN~s, A prospective trial of oestrogens, androgens and progestogens for the treatment of advanced carcinoma of the breast. In: The Clinical Management of Advanced Breast Cancer, p. 24, (Edited by C. A. F. JosuN and E. N. CLEAVE). Alpha Omega Alpha, Cardiff (1970). 9. M.P. GOLDER, M. E. A. PHILLIPS, P. E. PREECE, V. JONES, C. A. F. JOSUN and K. GR*FFITHS, Submitted for publication. 10. 0. n. PEARSON, R. L. MURRAY, G. MOZAFFERIAN and J. PENSKY, Prolactin and experimental breast cancer. In: Prolactin and Carcinogenesis, p. 154, (Edited by A. R. BOYNSand K. GRIFFITHS).Alpha Omega Alpha, Cardiff (1972). 11. A . R . BOYNS,R. BUCHAN,E. N. COLE, A. P. M. FORRESTand K. GRn~FITHS, Basal prolactin blood levels in three strains of rats with differing incidence of 7,12,dimethylbenz(a)anthracene-induced mammary tumours. Europ. J. Cancer 9, 169 (1973). 12. R . M . L . MURRAY,G. MOZAFFERIANand O. H. PEARSON,Prolactin levels with L-Dopa treatment in metastatic breast carcinoma. In: Prolactin and Carcinogenesis, p. 158. (Edited by A. R. BOX,NS and K. GRr~VITHS). Alpha Omega Alpha, Cardiff (1972). 13. A . R . BOYNS,E. N. COLE, K. GRIFFITI-IS,M. M. ROBERTS,R. BUCHAN,R. G. WILSON and A. P. M. FOREST, Plasma prolactin in breast cancer. Europ. J. Cancer 9, 99 (1973). 14. R . G . WILSON, R. BUCHAN,M. M. ROBERTS,A. P. M. FOmU~ST,A. R. BOYNS, E. N. COLE and K. G~FFITHS, Plasma prolactin and breast cancer. Cancer (Philad.) 33, 1325 (1974). 15. G.V. GROOMand K. GRIFFITHS,J. Endocr. (1976). In press. 16. W. POWELL-JONES,D. A. JENNER, R. W. BLAMEY,P. DAVIESand K. GRIFFITHS, Influence of anti-oestrogens on the specific binding in vitro of [3H]oestradiol by cytosol of rat mammary tumours and human breast carcinomas. Biochem. J. 150, 71 (1975). 17. V . C . JORDON and S. KOEmCER, Tamoxifen (I.C.I. 46474) and the human carcinoma 8S oestrogen receptor. Europ. J. Cancer 11, 205 (1975). 18. V.C. JORDON,S. KOERNERand C. ROBISON,Inhibition of oestrogen stimulated prolactin release by anti-oestrogens. J. Endocr. 65~ 151 (1975). 19. R . I . NIeHOLSONand M. P. GOLDER,The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary turnouts. Europ. J. Cancer 11~ 571 (1975). 8.
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