Agent In Postmenopausal Women Research Articles

Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?

Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?

DNA Adduct Formation in the Livers of Female Sprague−Dawley Rats Treated with Toremifene or α-Hydroxytoremifene

Toremifene, an analogue of tamoxifen in which the ethyl side chain has been replaced with a 2-chloroethyl substituent, is used as a chemotherapeutic agent in postmenopausal women with advanced breast cancer. Toremifene is metabolized in a manner similar to that of tamoxifen, with alpha-hydroxytoremifene being a predominant metabolite in incubations in vitro. DNA adducts have been detected previously in liver DNA upon the administration of toremifene to rats; however, the identity of these adducts is unknown. In the present study, we have characterized the DNA adducts produced by alpha-hydroxytoremifene and have compared the extent of hepatic DNA adduct formation in rats administered toremifene, alpha-hydroxytoremifene, or tamoxifen. alpha-Hydroxytoremifene was synthesized, further activated by sulfation, and then reacted with salmon testis DNA. After enzymatic hydrolysis to deoxynucleosides, HPLC analysis indicated the formation of two major DNA adducts, which were characterized as (E)- and (Z)-alpha-(deoxyguanosin-N2-yl)toremifene on the basis of 1H NMR and mass spectral analyses. To assess the formation of toremifene DNA adducts in vivo, female Sprague-Dawley rats were treated intraperitoneally with toremifene, alpha-hydroxytoremifene, or tamoxifen. 32P-Postlabeling analyses of hepatic DNA from the tamoxifen-treated rats indicated three DNA adducts at a total level of 2,200 +/- 270 adducts/108 nucleotides. DNA adducts were not detected (<5 adducts/108 nucleotides) in the livers of rats treated with toremifene. Two DNA adducts, of which the major one coeluted with the 3',5'-bis-phosphate of (E)-alpha-(deoxyguanosin-N2-yl)toremifene, were present at a level of 57 +/- 12 adducts/108 nucleotides in hepatic DNA from rats administered alpha-hydroxytoremifene. The low level of hepatic DNA adduct formation observed with both toremifene and alpha-hydroxytoremifene, as compared to that with tamoxifen, may be due to the limited esterification of alpha-hydroxytoremifene and/or the poor reactivity of alpha-sulfoxytoremifene.

Effect of Raloxifene on Bone Mineral Density in Premenopausal Women at Increased Risk of Breast Cancer

Raloxifene is a promising breast cancer prevention agent in postmenopausal women at increased risk for breast cancer. The effects of raloxifene in premenopausal women are unknown. We evaluated the effect of raloxifene in premenopausal women at increased risk for breast cancer on bone mineral density (BMD). This was a phase II clinical trial. This study was conducted at an academic medical center. Thirty-seven premenopausal women at increased risk for breast cancer enrolled in the trial. Thirty subjects began treatment and 27 were evaluable. Raloxifene (60 mg daily) and elemental calcium (500 mg daily) were given for 2 yr. Subjects were followed up off medications for 1 yr. The primary end point was the intrasubject percent change in BMD at 1 yr measured by dual-energy x-ray absorptiometry. The mean baseline lumbar spine density was 1.027 g/cm(2). Lumbar spine density decreased 2.3% at 1 yr (P < 0.00001) and 3.5% at 2 yr (P < .00001). Percent change from yr 2 to 3 was +1.4%. The mean baseline total hip bone density was 0.905 g/cm(2). Total hip density decreased 0.3% at 1 yr and 1.0% at 2 yr (P = 0.033). Percent change from yr 2 to 3 was +1.7%. Raloxifene use is associated with a decrease in BMD in premenopausal women at increased risk for breast cancer. The clinical significance of this decrease is unknown and is attenuated with stopping raloxifene.

Aromatase Inhibitors

SummaryThe new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER-and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.

The effects of tamoxifen on the endometrium, blood flow of the uterine arteries and serum lipoprotein (a) levels in postmenopausal women

The purpose of this study was to evaluate the effect of tamoxifen therapy on the endometrium by transvaginal color Doppler sonography and on lipid profile focusing on lipoprotein (a) [Lp(a)] levels. Seventy-five postmenopausal breast cancer patients were examined by transvaginal color Doppler sonography and serum Lp(a) levels. Lipid parameters were measured after overnight fasting. Forty of the patients were treated with tamoxifen (20-30 mg/day) for at least 1 year. The remaining 35 patients did not receive tamoxifen and were used as controls. Statistical analysis was performed using t-test and Mann-Whitney U-test (Systat version 5.0). The patients receiving tamoxifen had significantly thicker endometrium (7.9 ± 3.6 mm) compared to the control group (4.5 ± 1.8 mm) (p ≤ 0.001). The mean pulsatility index and resistance index of the uterine arteries in the tamoxifen group were 2.063 ± 0.49 and 0.83 ± 0.07, respectively, and were significantly lower than those of the control group (2.69 ± 0.16 and 0.88 ± 0.02) (p < 0.001). In addition, tamoxifen decreased total cholesterol (p < 0.001) and low-density lipoprotein cholesterol (p < 0.001) and apolipoprotein B (p < 0.05) significantly. Tamoxifen also increased high-density lipoprotein cholesterol (p < 0.05) and apolipoprotein A-I (p < 0.05). These results indicate that tamoxifen stimulates the endometrium and acts as an anti-atherogenic agent in postmenopausal women.

Tamoxifen: a review of pharmacoeconomic and quality-of-life considerations for its use as adjuvant therapy in women with breast cancer.

Extensive clinical experience, summarised in the recent overview of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), have confirmed that tamoxifen reduces the rate of both disease recurrence and mortality when administered as adjuvant therapy in women with early breast cancer. Tamoxifen is now established as the preferred adjuvant agent in postmenopausal women; in particular, patients with node-positive, estrogen receptor-positive breast cancer have the most to gain from tamoxifen therapy. Data from a decision-analysis model indicated that tamoxifen monotherapy had a cost-utility ration {$US6000 per additional quality-adjusted life-year (QALY), in 1989 dollars} 5 to 6 times lower than that cited as the cost-acceptability cut-off point in the US. While tamoxifen monotherapy is effective in postmenopausal women, the EBCTCG overview findings indicate that a combined regimen of tamoxifen and antineoplastic chemotherapy has superior efficacy in the same patient group. An issue of current interest is whether the added benefit offered by such a regimen can be justified in terms of added toxicity and cost. Data from a decision-analysis model indicate that combined therapy has a high incremental cost-utility ratio ($US58 000 per additional QALY, in 1989 dollars) compared with no therapy in postmenopausal women. However, the quality-of-life measures TWiST (Time Without Symptoms and Toxicity) and Q-TWiST (quality-adjusted TWiST) indicate that the early toxicity associated with a combined regimen appears to be justified given the superior long term benefits. Patient preference data from 1 study further indicate that the degree of benefit offered by a combined regimen would be acceptable to the majority (73%) of patients. Other areas where pharmacoeconomic analyses may help define more closely the optimal use of adjuvant tamoxifen is in patients at low risk of developing metastatic disease and in determining the optimal duration of therapy. Both areas require further clinical data. In conclusion, tamoxifen adjuvant monotherapy has a low cost-utility ratio in postmenopausal women with node-positive, estrogen receptor-positive breast cancer. Combined therapy in the same patient group has a high cost-utility ratio compared with no therapy but quality-of-life and patient preference data suggest that the costs may be justified. Firm conclusions relating to the use of the drug in other patient subgroups and the optimal duration of therapy await further research.

Tamoxifen Flare in Advanced Breast Cancer

The antiestrogen tamoxifen citrate is an effective antitumor agent in postmenopausal women with advanced breast cancer. The drug has produced relatively few and generally mild side effects. However, a not uncommon clinical phenomenon that may falsely suggest premature discontinuation of tamoxifen therapy has become evident to us and has not yet been sufficiently emphasized in the literature. We have designated this phenomenon as the tamoxifen flare. It consists of transient, at times severe, increase in pain with an apparent worsening of the patient's clinical status occurring within the first few weeks of therapy. In each of six patients experiencing this flare (45 patients treated) pain subsided despite continuation of tamoxifen therapy, followed by a partial remission lasting from six to 20 months.

Calusterone.

Androgens are effective therapeutic agents in postmenopausal women with metastatic breast cancer. Early studies with testosterone propionate showed objective regression rates of slightly more than 20%. Subsequent work with synthetic androgens has failed to show a significant reduction in toxicity or an increase in therapeutic efficacy over testosterone propionate. Calusterone (7 beta,17 alpha-dimethyltestosterone), in early clinical trials, showed both of these qualities and was believed by some to be the "ideal androgen." As with many new drugs, subsequent work failed to confirm these early findings, and most of the later data gathered on calusterone are inconsistent. We conclude from our knowledge at present that calusterone offers no real advantages or disadvantages over other androgens in the treatment of breast cancer.