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Articles |
Departments of
1
Oncology and
2
Pharmacology, Haukeland University Hospital, N-5021 Bergen, Norway.
a Author for correspondence. Fax 47-55-972046; e-mail Per.Lonning{at}onko.haukeland.no.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Numerous studies have shown that the antiestrogen agent tamoxifen not only induces remission in advanced breast cancer but also prolongs relapse-free as well as overall survival rates when administered to breast cancer patients in the adjuvant setting (3). However, long-term treatment with tamoxifen may cause undesirable side effects, such as an increased risk of endometrial carcinoma (4). This, combined with the favorable effects achieved with novel aromatase inhibitors in advanced breast cancer (5)(6), has led to increased interest in the use of aromatase inhibitors in the adjuvant setting.
A major concern related to the long-term use of aromatase inhibitors is the possible detrimental influence of estrogen suppression on cardiovascular risk factors. There is evidence that tamoxifen reduces the risk of cardiovascular morbidity when administered to patients with early breast cancer (7)(8). We found (9) that tamoxifen treatment, similar to estrogen substitution therapy (10), reduces plasma total homocysteine (tHcy)1 concentrations. Substantial evidence links increased plasma tHcy to an increased risk of cardiovascular disease (11)(12) and mortality (13).
Only one small study has compared the long-term effects of aminoglutethimide to placebo treatment in the adjuvant setting (14). This study suggested an increased incidence of cardiovascular events related to aminoglutethimide treatment.
In the present study, we explored possible effects of aminoglutethimide treatment on plasma tHcy in patients suffering from advanced breast cancer. To examine whether changes in plasma tHcy could be the result of plasma estrogen suppression, other biochemical effects of aminoglutethimide, or an effect of glucocorticoids administered in concert, we also evaluated possible alterations in plasma tHcy in patients treated with novel, selective aromatase inhibitors (formestane and exemestane) and in patients receiving progestins (megestrol acetate) in pharmacological doses. Megestrol acetate suppresses plasma estrogen but has also glucocorticoid agonistic effects (15).
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients treated with aminoglutethimide.
Thirty patients were
treated with aminoglutethimide 250 mg four times per day together with
cortisone acetate 50 mg twice per day for the first 2 weeks,
followed by aminoglutethimide 250 mg four times per day with cortisone
acetate 25 mg twice per day. (16). One patient
subsequently had her dose of aminoglutethimide reduced to 250 mg twice
per day because of toxic side effects.
Patients treated with exemestane or formestane.
Ten patients
were treated with exemestane, a novel steroidal aromatase inhibitor
(17). The drug was administered by the oral route in a
dose of 25 mg once daily. Twelve patients were treated with formestane
(18), another steroidal aromatase inhibitor. This drug
must be given parenterally, and was administered as intramuscular
injections of 250 mg every second week.
Patients treated with megestrol acetate.
Twenty-one patients
received the synthetic progestin megestrol acetate in a single daily
dose of 160 mg (19).
blood-sampling protocol
Previous endocrine therapy was terminated 
4 weeks before
enrollment in the protocol. Blood samples were collected before and at
different intervals (1–12 months) during treatment when the patients
attended the clinic for follow-up visits. Fasting blood samples were
collected into 10-mL EDTA-containing evacuated tubes, which were
centrifuged within 30 min at 0–2 °C. The plasma fractions were
stored at -20 °C until analysis. Red blood cell (RBC) folate was
determined in the pellet. In addition, blood was collected in vials
without additives to obtain serum for cobalamin and folate
determinations.
determination of tHcy, cysteine, cobalamin, and folate
in blood
Plasma tHcy and total cysteine (tCys) were determined by a
modification of an automated procedure based on derivation with
monobromobimane and HPLC separation (20). The CV of the
method with respect to tHcy as well as tCys previously had been found
to be ~3% (20), and had been confirmed by later
measurements (unpublished observations). On the basis of the Hordaland
Homocysteine study (21) with unpublished follow-up results,
the upper 95% limit of plasma Hcy for 70-year-old women is ~18
µmol/L, which is considered as the upper health-related reference
limit for plasma Hcy in our population.
Serum cobalamin was determined with a microparticle enzyme intrinsic factor assay on an IMx system from Abbott Laboratories. Serum and RBC folate were assayed using the Quantaphase folate RIA produced by Bio-Rad. Serum creatinine was determined using the alkaline picrate method in the CHEM 1 system (Technicon).
statistical methods
Previous studies by our group (9)(13) revealed that
plasma tHcy is best fitted to a log-normal distribution. Thus,
pretreatment concentrations are described by their geometrical mean
values with 95% confidence intervals, and values during treatment are
expressed as percentages of the pretreatment concentrations for the
same patients from whom we had obtained samples at the different time
intervals together with 95% confidence intervals of the mean. In
addition to confidence intervals, plasma tHcy concentrations obtained
before and during treatment were compared using the Wilcoxon
matched-pairs sign-rank test. The P values were corrected
for multiple comparison according to the Bonferroni rule. Correlations
were tested by the Pearson least-square method. All P values
are expressed as two-tailed.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. For the total group of patients, the mean pretreatment tHcy
was 12.6 µmol/L.
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Three patients in the group treated with formestane, two patients in the aminoglutethimide group, one patient in the exemestane group, and three patients in the megestrol acetate group had tHcy above the value defined as the upper health-related limit for postmenopausal women in our laboratory (18 µmol/L; see Patients and Methods). All patients had serum and RBC folate as well as serum cobalamin concentrations above the lower health-related limit. Two patients had slightly increased serum creatinine. Although there was a trend for a negative correlation between plasma tHcy and cobalamin (r = -0.36) and plasma tHcy and serum folate (r = -0.30) in the pretreatment samples from the aminoglutethimide-treated group, these correlations were not statistically significant (P >0.05). In the total population, a weak, nonsignificant correlation between RBC folate and plasma tHcy (r = -0.36; P >0.05) was seen, but not between plasma tHcy and any of the other indicators.
influence of endocrine treatment on plasma tHcy and the tHcy/tCys ratio
Treatment with aminoglutethimide was associated with a significant
change in plasma tHcy (Fig. 1
). Although short-term (1 month) treatment
with aminoglutethimide had no effect on tHcy, treatment for >2 months
was associated with a significant increase (mean increases of 24.5%
and 35.8%; P <0.025 and P <0.01 after 2 months
and 3–5 months, respectively). The mean plasma tHcy increased from
12.2 to 15.8 µmol/L after 3–5 months on treatment.
The selectivity of the increase in plasma tHcy during aminoglutethimide
treatment was further documented by an increase in the tHcy/tCys ratio
with no increase in tCys. Although treatment with
aminoglutethimide for 1 month had no significant influence on the
tHcy/tCys ratio, treatment for 2 months and 3–5 months caused a
significant increase (mean increases of 23.4% and 30.2%,
respectively; Fig. 1
).
All patients stopped previous endocrine treatment 4 weeks before
entering this study. However, we previously had demonstrated that
tamoxifen may be detected in human tissues for several months after
treatment is terminated (22). Thus, data for patients
treated with aminoglutethimide were re-analyzed after exclusion of the
five patients who had received tamoxifen as their last treatment
modality before aminoglutethimide. Also in this subgroup (n = 25),
aminoglutethimide was found to cause a significant increase (mean,
27.4–28.7%) in plasma tHcy (data not shown).
Exemestane and formestane belong to the same subgroup of selective, steroidal aromatase inhibitors and are thought to act by the same biochemical mechanisms. The two drugs were found to have no influence on plasma tHcy, and data from these patients were pooled for statistical analysis. Treatment with these aromatase inhibitors or treatment with the progestin megestrol acetate did not influence plasma tHcy concentrations (data not shown).
vitamins and creatinine values
To evaluate whether the increase in plasma tHcy caused by
treatment with aminoglutethimide could be the result of reduced
cobalamin or folate, which are cofactors in Hcy metabolism, we
determined serum cobalamin and folate and RBC folate before and during
aminoglutethimide therapy. Treatment with aminoglutethimide for 1–5
months caused a nonsignificant increase in all the three indicators
(Table 1
). No significant alterations in plasma creatinine values were
observed during aminoglutethimide treatment.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Previous findings suggested that an increased risk of cardiovascular diseases (14) associated with aminoglutethimide adjuvant treatment may be partly the result of an increase in plasma cholesterol and triglycerides (26). This increase in plasma cholesterol of ~15% (26) corresponds to an increase in the risk of myocardial infarction of ~35–50% (27); the increase in cardiovascular deaths in the adjuvant trial was higher, however, with eight patients in the aminoglutethimide treatment arm compared with only three placebo-treated patients (14). Although these results should be interpreted carefully because the number of events was small, they raise the possibility that factors other than an increase in plasma cholesterol may increase the risk of cardiovascular diseases in patients treated with aminoglutethimide.
The possibility that alterations in tHcy during treatment with aminoglutethimide could be secondary to alterations in blood lipids may be considered. However, most data thus far suggest only a weak correlation between plasma tHcy and plasma cholesterol (11)(12)(13)(28), and we consider these indicators in general to be independent risk factors for cardiovascular disease (29).
We found that treatment with aminoglutethimide caused a significant and substantial increase in plasma tHcy and the ratio of tHcy to tCys. Treatment with aminoglutethimide for 3–5 months was found to increase plasma tHcy by a mean of 3.7 µmol/L. Notably, a recent prospective analysis indicated that an increase in plasma tHcy of 4 µmol/L may increase the risk of coronary heart disease by ~40% (11).
It is difficult from our data to identify the mechanism by which aminoglutethimide increases plasma tHcy. The finding of a nonsignificant increase in cobalamin and folate refutes a hypothesis that aminoglutethimide may exert this effect by reducing the vitamin concentrations. In contrast to treatment with aminoglutethimide, we found that treatment with the steroidal aromatase inhibitors formestane and exemestane as well as treatment with progestins in pharmacological doses had fewer and nonsignificant effects on plasma tHcy. This may suggest that aminoglutethimide does not exert its effect on plasma tHcy by suppressing plasma estrogens. Megestrol acetate administered at a dose of 160 mg in a single daily dose has substantial glucocorticoid agonistic effects (15). Thus, our data suggest that the increase in plasma tHcy seen during administration of aminoglutethimide is not caused by cortisone acetate administered in concert. However, aminoglutethimide has additional biochemical effects, including induction of liver mixed function oxidases (30)(31). This should be considered as a mechanism whereby drugs may increase the plasma concentrations of tHcy and thereby increase cardiovascular risk. Notably, the observation that enzyme-inducing antiepileptic drugs also increase tHcy (32) support this notion.
In summary, our data show that aminoglutethimide treatment increases plasma tHcy in breast cancer patients. This effect may be of little importance in advanced breast cancer, but it may have significant implications in the adjuvant setting. The effect seems to be drug-specific and not related to estrogen suppression in general because similar alterations were not observed in patients treated with the steroidal aromatase inhibitors formestane and exemestane or the progestin megestrol acetate. Our findings emphasize the importance of a thorough evaluation of the pharmacodynamic profiles, including side effects, of drugs used for long-term treatment of early cancers.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The following articles in journals at HighWire Press have cited this article:
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  P. E. Lonning, J. Geisler, L. E. Krag, B. Erikstein, Y. Bremnes, A. I. Hagen, E. Schlichting, E. A. Lien, E. S. Ofjord, J. Paolini, et al. Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer J. Clin. Oncol., August 1, 2005; 23(22): 5126 - 5137. [Abstract] [Full Text] [PDF]
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 H. Refsum, A. D. Smith, P. M. Ueland, E. Nexo, R. Clarke, J. McPartlin, C. Johnston, F. Engbaek, J. Schneede, C. McPartlin, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion Clin. Chem., January 1, 2004; 50(1): 3 - 32. [Abstract] [Full Text] [PDF]
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