Long-term follow-up of postmenopausal breast cancer patients following discontinuation of tamoxifen therapy

BACKGROUND: There is a need to evaluate the extent of endometrial pathologies that might develop in postmenopausal breast cancer patients following discontinuation of tamoxifen (TAM) therapy. METHODS: The medical records of 153 postmenopausal breast cancer patients who remained untreated following discontinuation of tamoxifen therapy were evaluated for various clinical features, for endometrial thickness measurements, as detected by transvaginal ultrasonography, and for various endometrial pathologies detected. The last endometrial thickness measurement performed before discontinuation of tamoxifen was compared with endometrial thickness measured following discontinuation of tamoxifen. RESULTS: Patients were followed for 37.5+/-31.3 months. There was a gradual and significant decrement of endometrial thickness measured at the last ultrasonographic study performed before cessation of tamoxifen, compared to that observed in all four ultrasonographic studies performed following discontinuation of tamoxifen (P=0.001). Endometrial thickness gradually and significantly decreased in correlation with the time intervals of the four ultrasonographic studies performed following discontinuation of tamoxifen (P=0.001). Overall, 40 hysteroscopies were performed in 38 (24.8%) patients. No tissue was obtained in 18 (11.8%) patients. Overall endometrial pathologies were diagnosed in 22 (14.4%) patients. Benign endometrial polyps were the most frequent endometrial pathology recovered: 17 (11.1%) patients. No endometrial malignancy was diagnosed. The rate of endometrial pathologies considerably decreased with the extension of time following discontinuation of tamoxifen therapy. CONCLUSIONS: Long-term follow-up of postmenopausal breast cancer patients who remained untreated following discontinuation of TAM therapy did not reveal any malignant endometrial pathology. Only few benign endometrial pathologies were diagnosed, which became fewer in time.     

HER-2/neu oncogene in uterine carcinosarcoma on tamoxifen therapy

HER-2/neu is an oncogene located on chromosome 17, encoding a type 1 tyrosine kinase growth factor receptor. HER-2/neu is overexpressed in 25-30% of breast cancers, increasing the aggressiveness of the tumor. We describe HER-2/neu overexpression and her-2/neu oncogene amplification in a case of uterine carcinosarcoma occurring in a 46-year-old women who had undergone mastectomy and a 2-year postoperative treatment with tamoxifen for invasive breast cancer. This is the first study demonstrating HER-2/neu expression and her-2/neu oncogene amplification in a uterine carcinosarcoma that has developed in a patient given tamoxifen therapy. It still needs to be clarified whether HER-2/neu overexpression increases the aggressiveness of carcinosarcoma, or whether HER-2/neu has a direct role in its pathogenesis, as described in breast cancers. Our observation of the her-2/neu oncogene amplification does not shed light on the prognostic impact of uterine carcinosarcoma following tamoxifen therapy, but it may indicate the need for further studies of HER-2/neu overexpression in a larger series of uterine carcinosarcoma patients, and it may permit us to hypothesize about a therapeutic concept, including the inhibition of HER-2/neu by humanized monoclonal antibodies also in uterine carcinosarcoma patients.     

三苯氧胺联合米非司酮对早孕绒毛LIF表达的影响

目的探讨三苯氧胺联合米非司酮行药物流产缩短流产后出血时间的可能机制,为临床防治药物流产后出血过多提供理论依据。方法将非意愿妊娠7周内要求药物流产的宫内早孕妇女60例随机分成米非司酮＋三苯氧胺组（A组）和米非司酮组（B组）,并以30例负压吸宫流产为对照组（C组）。实时定量PCR方法检测绒毛组织中白血病抑制因子（leukemia inhibitory factor,LIF）mRNA的表达。结果A、B、C组绒毛组织中的LIF的mRNA的表达量依次升高。结论米非司酮抑制LIF在绒毛组织的表达可能是其抗早孕机制之一,而三苯氧胺可进一步加强米非司酮的这一作用,这可能是米非司酮联合三苯氧胺缩短药物流产后出血时间的机制之一。     

Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

OBJECTIVES:Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats.RESULTS:The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001).CONCLUSIONS:According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.     

Absence of uterine tumours in CD-1 mice treated neonatally with subcutaneous tamoxifen or 4-hydroxyoestradiol

The effects of subcutaneous dosing of neonatal CD-1 mice with tamoxifen on days 1-5 after birth at doses of 0, 5, 10, 25 or 50 microg/pup or with 4-hydroxyoestradiol at 2 microg/pup have been investigated. Animals were culled at 1.5, 3, 6, 12 and 18 months after dosing and changes in uterine and ovarian pathology examined. Results showed both compounds to result in uterine hypoplasia relative to controls. At 18 months after dosing in the uterus, there was a fairly marked atrophy of the muscle layer, mild to moderate glandular hyperplasia of the endometrium even though these irregularly shaped glands did not penetrate through the myometrium and no adenocarcinomas were detected. At 18 months after dosing, oviducts showed mild focal adenomatous changes characterized by penetration epithelial hyperplasia, changes similar to those previously reported as 'diverticulosis and salpingitis isthmica nodosa' following diethylstilbestrol treatment of mice. At this time, both tamoxifen and 4-hydroxyoestradiol also affected the ovaries which showed a paucity of follicles and no corpora lutea, suggesting that there had been disruption to the oestrus cycle, particularly with tamoxifen at the highest dose where the ovaries of mice contained no developing follicles. At 18 months, control mice were cycling normally. Results failed to substantiate that tamoxifen and 4-hydroxyoestradiol are uterine carcinogens in this neonatal mouse model.     

Morphometric analysis of the pelvis in mice treated neonatally with tamoxifen

The pelves of male and female C57BL/Tw mice given five daily injections of 100 μg tamoxifen, 50 μg dihydrotestosterone (DHT), or 2 μg diethylstibestrol (DES) from the day of birth were examined morphometrically and histomorphometrically. Total areas of the pelvis, ilium, ischium, and pubis were significantly smaller in neonatally tamoxifentreated mice than in the controls. There was no significant difference in length of the ischium between tamoxifen-treated and control mice of both sexes. However, lengths of ilium and pubis, and widths of ilium, pubis, and ischium in tamoxifen-treated male and female mice were significantly smaller than in the respective controls. In contrast, neonatal treatment with DHT or DES did not affect the shape of the pelvis of either sex. In the neonatally tamoxifen-treated females, the number of osteoblasts and osteoclasts per 200 μm trabecular surface length and per 10,000 μm² subperiosteal area of pubic bone section was smaller than in the controls. Inhibition of ossification persisted in the junction of the pubis and ischium of pelves treated with tamoxifen in vitro. These results suggest that neonatally administered tamoxifen mainly retards the growth of the ilium and pubis in mice by changing the activities of osteoclasts and osteoblasts, and that tamoxifen acts directly on the neonatal mouse pubis to inhibit its ossification. © 1993 Wiley-Liss, Inc.     

The potential in breast tissue engineering for the combined effects of linoleic acid and tamoxifen

Literature to date has strongly suggested that linoleic acid (LA) enhances mammary cancer cell proliferation when used in the range of 0·5–20 μg/ml. In contrast, the current in vitro studies show that deoxyribonucleic acid (DNA) levels of estrogen receptor-positive (ER⁺) MCF7 breast cancer cells were diminished following treatment with 30 μg/ml (100 μM) LA. MCF7 cells, when treated for 6 days with LA, consumed significantly less glucose than untreated controls (P-value<0·01). MFC7 cells treated with 30 μg/ml LA and 10 μM tamoxifen had even lower levels of DNA and lower glucose uptake. The same combination treatment of tamoxifen and LA was applied to a noncancerous mammary cell line, MCF10A, and did not have a significant effect on MCF10A DNA concentrations. Linoleic acid and its byproducts are important to cell proliferation and tissue reconstruction and, in combination with tamoxifen, can provide a uniquely different approach to soft tissue engineering. That is, LA and tamoxifen-loaded scaffolds may provide a viable reconstructive approach for patients undergoing lumpectomy and mastectomy by encouraging natural breast healing while limiting the ability of ER⁺ cancer cells to regrow. This approach could allow the suppression of estrogen-dependent mammary carcinomas while allowing natural cell proliferation after a mastectomy or lumpectomy.     

Gynecologic consequences of long-term, unopposed estrogen replacement therapy

We evaluated the gynecologic risks of unopposed, long-term estrogen use in postmenopausal women. Our medical record review showed that unopposed estrogen users (mean dose, 0.9 mg of conjugated estrogens) had a significantly higher (P < 0.001) incidence of abnormal vaginal bleeding, curettage, hysterectomy, and endometrial cancer. The ratios of occurrence of these events among users compared with non-users were 7.8, 4.9, 6.6 and 7.7. The prevalence of hysterectomy reached 28.2% of users compared with 5.3% of non-users, and endometrial carcinoma developed in 9.9% of users compared with 1.4% of non-users.     

Managing menopausal symptoms and depression in tamoxifen users: implications of drug and medicinal interactions

Objective

Tamoxifen, a medication used in the treatment of breast cancer, often induces menopausal symptoms. Certain medications and natural supplements taken or prescribed to alleviate tamoxifen-induced hot flashes and depressive states in women with breast cancer interact with tamoxifen. This paper reviews potentially problematic interactions and offers treatment recommendations.

Methods

Medline (1950-June 1, 2010), Embase Classic + Embase (1947-June 1, 2010) and PsycINFO (1967-June 1, 2010) were searched through Ovid. The word “tamoxifen” was searched with “depression” and then with “menopaus*” and “symptoms”, with “treatment” as a limit. “Tamoxifen” was later searched with the MeSH terms “drug interaction” or “drug incompatibility”.

Results

Venlafaxine is efficacious for the treatment of hot flashes and depression and safe to use in combination with tamoxifen. Gabapentin is also efficacious in treating tamoxifen-induced hot flashes and, since it does not interact with cytochrome P450 system, is likely safe to use in patients using tamoxifen. Desvenlafaxine and pregabalin may be alternatives to venlafaxine and gabapentin, respectively, although desvenlafaxine has not yet been studied in this population. Paroxetine, fluoxetine and bupropion are strong CYP2D6 inhibitors which should be avoided in tamoxifen users. Fluvoxamine and nefazodone both inhibit CYP3A, which could potentially affect the metabolism of tamoxifen. Clonidine can be an alternative agent but may carry significant side effects. Evidence of medicinal products for the treatment of tamoxifen-induced hot flashes is equivocal at best.

Conclusions

Clinicians should remain cautious about using strong inhibitors and/or inducers of cytochrome 2D6 and 3A4 concomitantly with tamoxifen. Use of natural menopausal supplements and diets rich in isoflavones should not be encouraged in tamoxifen users until more data is available. There are however safe treatments for hot flashes and depression in tamoxifen users.     

Effects of septal lesion on lordosis response induced by estradiol in middle-aged and old female rats

Long-Evans female rats were divided into three age groups: 10 young rats (5 months of age), 7 middle-aged rats (10-13 months of age) and 6 old rats (21-27 months of age). The rats were ovariectomized and immediately implanted subcutaneously with a silastic capsule filled with estradiol benzoate (E2). Lordosis response was compared in each animal before and after the septal lesion. Serum E2 levels were 197 +/- 27 pg/ml (mean +/- SEM), 192 +/- 81 pg/ml and 405 +/- 83 pg/ml in young, middle-aged and old rats respectively. When serum E2 levels were adjusted by analysis of covariance, LQ (lordosis quotient) was 42, 36 and 61 in young, middle-aged and old rats respectively before the septal lesion and 98, 68 and 88 respectively after the septal lesion. The extent of potentiation of lordosis after the septal lesion was less in middle-aged and old rats than young rats. These results indicate that an enhanced lordosis response in aged rats is partly due to high circulating E2 levels and partly due to disinhibition of the septal region on lordosis.     

Evaluation of long-term oral levodopa therapy in chronic congestive heart failure

Summary To evaluate the long-term effects of orally administered levodopa, 11 patients with chronic congestive heart failure (NYHA III–IV) were studied during maintenance therapy (30±1 days) and after withdrawal from levodopa. The daily levodopa dose was 4 g in six patients; because of side effects the levodopa dose was reduced to 2–3 g in the remaining patients. After withdrawal of levodopa, mean pulmonary capillary wedge pressure and mean right atrial pressure increased significantly (from 19±2 to 24±3 and from 7±2 to 9±2 mmHg, respectively). Effective renal plasma flow was 329±57 during levodopa therapy and decreased significantly to 252±27 ml/min after withdrawal of levodopa. The number of ventricular premature contractions and couplets increased during levodopa therapy and decreased again significantly after withdrawal of levodopa. No significant differences between on and off levodopa were observed in resting heart rate, arterial blood pressure, cardiac index, stroke work index, systemic vascular resistance, sodium and water excretion, or creatinine clearance. Seven patients improved on levodopa therapy by one NYHA class; four of these seven patients deteriorated again by one NYHA class after withdrawal of levodopa. Regarding both clinical and hemodynamic changes after withdrawal of levodopa, three patients were classified as responders to long-term levodopa therapy. All three responders received 4 g levodopa per day. Average dopamine plasma level was 5.3±0.8 ng/ml in the responder group and 2.0±0.5 ng/ml in the nonresponder group.Long-term administration of oral levodopa is associated with beneficial clinical and hemodynamic response in only a minority of patients with chronic congestive heart failure.     

High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1.73 m(2)] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1.73 m(2)) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from -1.05 ml/min per month to -0.15 ml/min per month (P = 0.024) and proteinuria decreased from 2.4 g/l to 1.0 g/l (P = 0.015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5.2 years (median; range 0.4-8.8) after the first IVIg pulse, and after 1.3 years (median; range 0.8-2.4) in the control group (P = 0.043). In Kaplan-Meier analysis, the median renal survival time with IVIg was prolonged by 3.5 years (IVIg 4.7 years versus control 1.2 years; P = 0.006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.     

Alteration of dopamine metabolism in different brain regions of the rabbit by estradiol and tamoxifen

Tamoxifen citrate, a mixed estrogen agonist-antagonist, and estradiol 17-beta administered separately for 14 days significantly reduced dopamine and dihydroxyphenylacetic acid in the cortex and hypothalamus regions of the brain in immature female rabbits. In addition to these areas, estradiol also reduced dopamine and dihydroxyphenylacetic acid in the striatum but tamoxifen treatment significantly reduced only dihydroxyphenylacetic acid concentration in the striatum. When estradiol and tamoxifen were injected together, dopamine and dihydroxyphenylacetic acid concentrations were reduced only in the cortex. Specific binding of [3H]spiperone to dopamine receptors was significantly increased by both estradiol and tamoxifen in the hypothalamus but only tamoxifen increased dopamine binding in the striatum. A low dose of tamoxifen, either alone or in combination with estradiol, increased uterine weight, but a higher dose of tamoxifen was neither an estrogen agonist nor antagonist. These studies indicate that estradiol and tamoxifen alter dopamine metabolism in the various regions of brain differentially. The estrogen agonist activity of tamoxifen does not correspond to antidopaminergic action of estradiol in the striatum.     

Anticipations and experiences of menopause in a Danish female general population cohort born in 1936

Summary Introduction: Few studies on menopause consider the impact of sociopsychological factors on women's experiences of menopause. Objective: To focus on women's experiences of menopause: complaints, health, attitudes and stereotypes of menopause and ageing. Design: Prospective population study, initiated in 1976 with follow-ups in 1981, 1987 and 1996 with a high participation rate, a representative sample of all women born in 1936 and living in the County of Copenhagen. Study methods: Questionnaires and personal interviews: sociodemographic data, menopause, general health, sexuality, ageing. Results: The strongest predictors of the way in which women experienced menopause, including sexuality, were their general health earlier in life, their social circumstances and their expectations of menopausal changes. The biological changes had significant correlation to hot flushes. Menopause was seen as a symbol of ageing. Only a minority suffered from serious problems, typically originating earlier in life.     

他莫昔芬诱发的脂肪肝病人肝/脾CT值与BMI及P3/P2的相关性

目的：探讨他莫昔芬诱发的脂肪肝病人的肝/脾CT值与体重指数（BMI）及孕三醇（P₃）/孕二醇（P₂）的相关性。方法：56名乳腺癌采用保守疗法的病人给予他莫昔芬前后每年测肝/脾CT值及终止服药后她们尿中孕三醇/孕二醇的水平。结果：（Fisher）精确测试结果显示体重指数>23.6 kg/sqm与肝/脾CT<0.9密切相关；孕三醇/孕二醇<1与肝/脾CT<0.9密切相关。结论：服用他莫昔芬的病人BMI超过23.6 kg/sqm及尿中孕三醇/孕二醇比值小于1是脂肪肝发展的危险信号。     

Association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment

The aim of the study was to evaluate the association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. We evaluated the CYP2D6 genetic polymorphisms in 766 breast cancer patients. Among them, 110 patients whose samples were prospectively collected before surgery and treated with tamoxifen were included to evaluate the association between CYP2D6 and outcomes. The genotypes of CYP2D6 were categorized as extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) according to the activity score. The clinicopathologic features of 110 patients were not significantly different among the three groups except for the T-stage and nodal status. The high T-stage and axillary metastasis were more frequent in the PM group. While recurrence-free and overall survival in the PM group was poorer than the other groups, there was no significant difference between the EM and the IM group. The difference between the PM and the other groups on univariate analysis disappeared on multivariate analysis. These conflicting results suggest that the clinical value of CYP2D6 polymorphisms is still unclear and more large-sized and comprehensively designed trials are necessary.     

Hormone therapy with tamoxifen reduces plasma levels of NT-B-type natriuretic peptide but does not change ventricular ejection fraction after chemotherapy in women with breast cancer

The objective of this study was to evaluate the effect of tamoxifen on the plasma concentration of NT-pro-B-type natriuretic peptide (NT-proBNP) in women undergoing chemotherapy for breast cancer and to correlate changes in NT-proBNP with the left ventricular ejection fraction (LVEF). Over a period of 12 months, we followed 60 women with a diagnosis of breast cancer. The patients were separated into a group that received only chemotherapy (n=23), a group that received chemotherapy + tamoxifen (n=21), and a group that received only tamoxifen (n=16). Plasma levels of NT-proBNP were assessed at 0 (T0), 6 (T6), and 12 (T12) months of treatment, and echocardiography data were assessed at T0 and T12. Plasma NT-proBNP levels were increased in the chemotherapy-only group at T6 and T12, whereas elevated NT-proBNP levels were only found at T6 in the chemotherapy + tamoxifen group. At T12, the chemotherapy + tamoxifen group exhibited a significant reduction in the peptide to levels similar to the group that received tamoxifen alone. The chemotherapy-only group exhibited a significant decrease in LVEF at T12, whereas the chemotherapy + tamoxifen and tamoxifen-only groups maintained levels similar to those at the beginning of treatment. Treatment with tamoxifen for 6 months after chemotherapy significantly reduced the plasma levels of NT-proBNP and did not change LVEF in women with breast cancer.