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Original Article
Effects of Tamoxifen Therapy on Plasma Lipid Profile
in Patients of Breast Cancer
Sapna Gupta+, VR Tandon+, B Kapoor+, A Gupta*, GD Gupta**, V Khajuria+
Abstract
Aim : To evaluate the effects of tamoxifen therapy on plasma lipid profile in patients of breast cancer.
Method : A total of 55 postoperative patients of breast cancer were given tablet tamoxifen 20mg orally daily for
6 months. Estimation of plasma lipid by standard method was carried out in both pre-menopausal and
postmenopausal new patients of early stage breast cancer at 0 day, 3rd month and 6th months of therapy.
Results : Suggested that in pre-menopausal and postmenopausal patient’s TC and LDL-c levels were reduced
significantly, whereas, TG, VLDL-c and HDL-c were not altered. Comparison of the effects of tamoxifen in
pre-menopausal and postmenopausal patients on lipid profile revealed that fall in TC and LDL-c was
significantly higher at both 3 and 6 months in postmenopausal patients.
Conclusion : The study demonstrates that tamoxifen to favorably alter the markers of cardiovascular risk in
both pre-menopausal and postmenopausal patients of breast cancer. ©
B
INTRODUCTION
reast cancer is one of the commonest causes of cancer
mortality in females. Treatment of breast cancer is
complex and involves surgery, radiotherapy,
chemotherapy and hormonal therapy depending on the
stage and estrogen receptor status of the disease in the
individual patient. Tamoxifen, has been the main stay
of hormonal treatment of all phases of breast cancer and
represents a major therapeutic advance for clinical
practice.1
Originally it has been classified as anti-estrogen but
subsequent experience has shown that it has agonistic
activity on bone, liver and endometrium and hence now
classified as selective estrogen receptor modulator. It
shares the beneficial effects of estrogens on
cardiovascular risk factors by decreasing total cholesterol
(TC) and low-density lipoprotein cholesterol (LDL-c) both
in pre-menopausal2 and postmenopausal women.3-5
Whereas, it produces no significant change in
triglyceride(TG),2,6-8 high density lipoprotein cholesterol
(HDL–c)8,9 and very low-density lipoprotein cholesterol
(VLDL-c) 10 levels in pre-menopausal 2,6 and
postmenopausal 7,8 women. However, varying and
+Post Graduate Department of Pharmacology and
Therapeutics; *Post Graduate Department of Radiotherapy
and oncology; **Post Graduate Department of Radiodignosis
and Imaging, Government Medical College, Jammu (J&K)
India - 180001.
Received : 29.9.2005; Revised : 26.12.2005; Accepted : 6.2.2006
© JAPI • VOL. 54 • MARCH 2006
contrary results are also available in this regards as,
many authors10,6 failed to show any change in TC and
LDL-c after tamoxifen therapy. Similarly, Sharma, et al6,
Miyauchi, et al5 and Atalay, et al9 contrary to above
findings have reported tamoxifen to increases the levels
of TG. As well as, Bruning, et al2 showed increase in
HDL levels contrary to above mentioned reports in both
pre-menopausal and postmenopausal patients.
Most of the reports regarding the effects of tamoxifen
on lipid profile originate from outside India and there is
paucity of data regarding these effects in India and the
data whatsoever available is controversial. Thus, in view
of these contrary and varying reports it becomes even
more important to evaluate the effect of tamoxifen therapy
on lipid profile in patients of breast cancer. Moreover,
knowing its relationship with cardiovascular risk factors
will lead to better clinical understanding. Therefore, the
present study has been undertaken to assess the effect of
tamoxifen therapy on plasma lipid profile in premenopausal and postmenopausal patients of breast
cancer.
MATERIAL AND METHODS
A prospective, non-randomized study over a period
of one year was conducted in the Post Graduate
Department of Pharmacology and Therapeutics in
collaboration with Department of Radiotherapy and
Oncology and the Postgraduate Department of Radiodiagnosis and Imaging, Government Medical College,
Jammu in postoperative patients of breast cancer. A total
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183
of 55 pre-menopausal and postmenopausal patients of
breast cancer (35 to 75 years) participated in this study.
The study was approved by institutional ethics
committee. Written informed consent was obtained from
all patients after explaining the nature and purpose of
study. All patients were subjected to a detailed history,
clinical and gynecological examination. Patients with
normal routine laboratory tests, urine test, biochemical
tests like (LFT, RFT, and blood sugar) and ECG were
included in the study.
Any patient with unexplained uterine bleeding,
preexisting endometrial cancer, diabetes mellitus,
thyroid function abnormalities or other
endocrinopathies were excluded. Patients receiving
other medications, likely to interfere with the drug under
study or serum lipid profile, three months prior to the
trial and patients taking concomitant chemotherapy or
estrogenic hormones or who had undergone
hysterectomy or oophorectomy were also excluded.
Patients were given tablet tamoxifen 20mg (Tamoxifen
citrate–Dabur India Ltd.) per oral daily for 6 months.
Lipid profile was done in new patients of early stage
breast cancer who were to be started on tamoxifen as an
adjuvant therapy. A total of 55 patients of breast cancer
participated in this study and finally 49 patients
completed the study. Out of total 49 patients 14, were
pre-menopausal and 35 were postmenopausal patients.
Each patient was kept under treatment for six months
and had to undergo three post registration visits at 0
day, 3 months and at 6 months. During first (0 day) visit,
serum TC, LDL-c, TG, VLDL-c and HDL-c were recorded
and were considered as pre-drug values. During follow
up visit at 3 months and at 6 months, same parameters
were reassessed. All adverse effects experienced during
the trial were also recorded.
Estimation of plasma lipid: Subjects were asked to
report after an overnight fasting. Three ml of venous
blood was withdrawn and allowed to clot at room
temperature. Plasma was obtained by centrifugation at
3000 revolutions per minute. Plasma lipids were
estimated by standard enzymatic method in a
semiautomatic analyzer (ERBA – CHEM PRO). Total
cholesterol was estimated by cholesterol oxidase
peroxidase method (CHOD/PAP method) using
cholesterol reagent set provided by Ranbaxy Labs Ltd.
Triglycerides were estimated by GPO – ESPAS method
using Enozokit-triglycerides kit procured from Ranbaxy
Labs. Ltd. Whereas, LDL–c kit from Diagnostic Systems
International was used for the estimation of LDL–c by
select F.S.(fluid stable) method and HDL–c kit from Dr.
Reddy’s Lab was used for estimation of HDL–c by PEG
precipitation and enzymatic method. VLDL was
estimated using the Friedwald’s formula as: VLDL =
TG/5.
Statistical analysis : The data was expressed in Mean
± SEM or percentage. The results obtained (Mean ± SEM)
were analyzed by applying unpaired-t-test for
evaluation of intergroup significance. The intragroup
significance was assessed using paired-t-test. Chi–
square test was used for the data expressed in percentage.
Adverse effects were analyzed using chi-square test.
RESULTS
Effect of tamoxifen on plasma lipids (Table 1).
Pre-menopausal patients (mean age 37.92 ± 1.30
years)
After drug administration there was decrease in total
cholesterol by 6.57mg/dl at 3 months (P< .05) and by
9.93 mg/dl at 6 months (P < 0.01).Where as, there was
decrease in LDL Cholesterol by 7.14 mg/dl (P<0.05) at 3
months and by 8.93 mg/dl (P< 0.01) at 6 months, in
comparison to pre drug treatment. The peak fall in total
cholesterol and LDL-c was observed at 6 months. No
significant change in triglyceride levels up to 6 months
Table 1 : Effect of tamoxifen on plasma lipids in pre-menopausal and postmenopausal patients of breast cancer.
S.
Parameters
No.
Pre Menopausal (n = 14)
3 months
mean ±SEM
(MCFB)
6 months
mean ±SEM
(MCFB)
0 day
(baseline)
mean ±SEM
3 months
mean ±SEM
(MCFB)
6 months
mean ±SEM
(MCFB)
173.21±11.85*
(-6.57)
110.07±11.6*
(-7.14)
146.7±15.08
(+1.35)
29.5±3.00
(+0.43)
46.07±2.43
(+0.07)
169.85±11.07**
(-9.93)
108.28±11.5**
(-8.93)
145.5±15.07
(+0.15)
29.1±3.01
(+0.03)
45.85±2.98
(-0.15)
212.62±5.49
††202.2±5.44***
(-10.42)
†††141.2±4.47***
(-12.5)
147.6±7.24
(+1.00)
29.52±1.45
(+0.2)
42.94±1.85
(+0.17)
††196.2±5.02***
(-16.42)
†132.51±4.79***
(-21.26)
149.2±7.29
(+2.6)
30.42±1.62
(+1.1)
43.42±1.83
(+0.65)
1
TC (mg/dl)
179.78± 1.80
2
LDL–c
(mg/dl)
TG (mg/dl)
117.21±10.9
3
4
5
VLDL–c
(mg/dl)
HDL–c
(mg/dl)
Post Menopausal (n = 35)
0 day
(baseline)
mean ±SEM
145.35±15.45
29.07±3.09
46±2.00
153.77±5.06
146.6±7.23
29.32±1.44
42.77±2.04
Values are expressed as mean ? SEM (mean change from base line-MCFB); For inter group significance *P<0.05; **P<0.01;
***P<0.001was considered significant in comparison to base line (0 day) using paired t-test. Whereas, †p<0.05, †† p<0.01, †††
p<0.001 was considered significant using unpaired-t-test for evaluation of inter group significance (for comparison of premenopausal and postmenopausal data)
184
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© JAPI • VOL. 54 • MARCH 2006
study period was observed, though there was trend
towards increase in triglyceride levels by1.35 mg/dl and
0.15 mg/dl after 3 and 6 months respectively. After drug
administration the increase in levels of VLDL-c was
observed by 0.43 mg/dl at 3 months and by 0.03 mg/dl
at 6 months. However, observed small increase in VLDLc values were not statistically significant in comparison
to base line. Similarly, no statistically significant change
in the levels of HDL-c was observed after 3 and 6 months
of therapy. Although a slight increase (0.07 mg/dl) at 3
months and a slight decrease (0.15mg/dl) at 6 months
were observed. These changes were statistically
insignificant throughout the trial.
Postmenopausal Patients (mean age 54.31 ± 1.23
years)
In postmenopausal patients also, after tamoxifen
therapy there was significant reduction in total
cholesterol levels by 10.42 mg/dl at 3 months (P<0.001)
and by16.42 mg/dl (P< 0.001) at 6 months. The peak
reduction in the total cholesterol values occurred at 6
months . LDL-c also significantly decreased by 12.5 mg/
dl at 3 months (P < 0.001) and by 21.26 mg/dl at 6 months
(P < 0.001), with the peak decrease in the LDL-c at 6
months.
After therapy there was increase in triglycerides by
1.00 mg/dl at 3 months and by 2.6 mg/dl at 6 months
but these values were statistically non significant in
comparison to pre drug treatment. No Significant change
even in VLDL-c levels was observed during 6 months
study period, though there was trend towards increase
in VLDL-c levels (0.2 mg/dl, 1.1 mg/dl) after 3 and 6
months respectively. Similar increase in HDL-c levels
from baseline value was observed (0.17 mg/dl, 0.65 mg/
dl) after 3 and 6 months respectively, but it was
statistically non significant.
Comparative effects of tamoxifen on plasma lipids in
pre-menopausal and post-menopausal patients
(Table 1)
Comparison of the effects of tamoxifen in
premenopausal and postmenopausal patients on lipid
profile revealed that in both groups of patients,
tamoxifen caused significant fall in TC and LDL-c.
However, fall was significantly higher in
postmenopausal patients at both 3 and 6 months (P <
0.01) in case of TC and with (P < 0.001 and P < 0.05) at 3
months and 6 months in case of LDL-C. Whereas,
statistically non-significant difference was recorded in
case of TG, VLDL-c and HDL-c at both 3 and 6 months of
the therapy between the two groups.
Adverse effects profile of tamoxifen therapy in premenopausal and post menopausal breast cancer patients
is shown in Table 2. When these adverse effects were
compared among pre-menopausal and post menopausal
breast cancer patients they did not differ in significant
manner statistically.
© JAPI • VOL. 54 • MARCH 2006
Table 2 : Incidence of adverse effects with tamoxifen
S. Parameter
No.
1
2
3
4
5
6
Hot flashes
Night sweating
Vaginal discharge
Pruritis vulvae
Endometrial Polyp
Simple cystic
hyperplasia
without cytological
atypia
Premenopausal
(n = 14)
Postmenopausal
(n = 35)
14.28%
7.14%
7.14%
14.28%
—
—
17.75%
11.24%
7.10%
5.91%
3.55%
1.77%
# Non significant using chi square test
DISCUSSION
In the present study, effects of tamoxifen were
evaluated and compared on plasma lipid profile in premenopausal and postmenopausal patients of early stage
breast cancer. Tamoxifen was found to cause significant
reduction in TC and LDL-c in both pre-menopausal and
postmenopausal patients. Similar observations have
been made on premenopausal2 and postmenopausal
women3-5 in past also. The favorable effects on these
parameters are compatible with estrogen agonistic effects
of tamoxifen in both pre-menopausal and
postmenopausal patients as estrogens lower LDL-c by
up regulating apo B-100 receptors.11
However, our findings on pre-menopausal women
differ from Caleffi et al10 and Sharma et al6 who failed to
show any change in these parameters. This disparity
may be due to the fact that although tamoxifen increases
estrogen levels in pre-menopausal patients but at the
same time peripheral competition for estrogen receptors
may lead to abrogation of the effect of increased estradiol
on target tissues.
No change in TG was observed in pre-menopausal
patients while numerical increase was observed in
postmenopausal patients. Rise in TG is a
pharmacological effect resulting from the hepatic first
pass effect of estrogens.11 However, tamoxifen does not
share this estrogen agonist effect. Our findings on premenopausal2,6 and postmenopausal7,8 women are in
conformity with the previous studies which failed to
show any effect on TG. However, our findings on
postmenopausal women are contrary to the findings of
Sharma et al6, Miyauchi et al5 and Ataley et al9 who have
reported that being estrogenic, tamoxifen increases the
levels of triglycerides.
Levels of HDL-c at both 3 and 6 months did not show
any change in both pre-menopausal and
postmenopausal patients. Estrogens are known to
increase HDL-c and particularly HDL2 sub-fraction,
which is protective against the development of
atherosclerosis by inhibiting hepatic lipase activity.11
This action of estrogens is not shared by tamoxifen.
Similar findings have been reported by numerous
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185
authors.3, 9 However, Bruning et al2 showed increase in
HDL levels in both pre-menopausal and
postmenopausal patients. No alteration in VLDL-c was
observed in both pre-menopausal and postmenopausal.
Similar observation has been made on pre-menopausal
women by Caleffi et al.10
Comparison of the effects of tamoxifen in premenopausal and postmenopausal patients on lipid
profile revealed that in both groups of patients,
tamoxifen caused significant fall in TC and LDL-c levels.
However, fall was significantly higher in
postmenopausal patients. TC and LDL-c are modifiable
risk factors for CAD.12 A 1% fall in total cholesterol is
associated with 1.5% to 3% fall in subsequent rate of
CAD.13 Reduction in LDL-c levels in women results in
46% lower risk of cardiovascular events.14 This implies
that tamoxifen is beneficial in both pre-menopausal and
postmenopausal patients in reducing the cardiovascular
risk factors. Raised triglycerides and VLDL-c are other
CAD risk factors. No change was observed in these
parameters in both pre-menopausal and
postmenopausal patients. Bruning, et al2 reported similar
findings. Rise in HDL-c levels is protective against
cardiovascular disease. For every 1mg/dl rise in HDL-c
levels, the relative risk of CAD decreases by 2% - 3%.15 In
the present study tamoxifen had no significant effect on
HDL-c in both pre-menopausal and postmenopausal
patients.
Besides these, other adverse effects were also observed
during the study and they were - hot flashes in 14.28%
and 17.75%, night sweating in 7.14% and 11.24%,
vaginal discharge in 7.14% and 7.10%, puritis vulvae in
14.28% and 5.91% in pre-menopausal and
postmenopausal patients respectively. When these
adverse effects were compared none of them differed
significantly. This may probably be due to gross
difference in number of pre-menopausal and
postmenopausal patients evaluated in the present study.
These findings are in agreement with the previous
findings.16
Hence, the findings of present study suggest that
tamoxifen favorably alters the surrogate end points of
cardiovascular disease i.e. lipid profile and is well
tolerated in both pre-menopausal and postmenopausal
patients. ER/PR status was not done in our study
because of non-availability of this facility in our
institution. Furthermore, no CVS end-point was
evaluated in our study, which remains the limitations of
the present study.
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