Tamoxifen In Breast Cancer Research Articles

Baseline Endometrial Assessment Before Tamoxifen for Breast Cancer in Asymptomatic Menopausal Women

Baseline Endometrial Assessment Before Tamoxifen for Breast Cancer in Asymptomatic Menopausal Women

A multimarker model to predict outcome in tamoxifen-treated breast cancer patients.

This study was designed to produce a model to predict outcome in tamoxifen-treated breast cancer patients based on clinicopathologic features and multiple molecular markers. This was a retrospective study of 324 stage I to III female breast cancer patients treated with tamoxifen for whom standard clinicopathologic data and tumor tissue microarrays were available. Nine molecular markers were studied by semiquantitative immunohistochemistry and/or fluorescence in situ hybridization. Cox proportional hazards analysis was used to determine the contributions of each variable to disease-specific and overall survival, and machine learning was used to produce a model to predict patient outcome. On a univariate basis, the following features were significantly associated with worse survival: high pathologic tumor or nodal class, histologic grade, epidermal growth factor receptor, ERBB2, MYC, or TP53; absent estrogen receptor (ER) or progesterone receptor; and low BCL2. CCND1 and CDKN1B did not reach statistical significance. On a multivariate basis, nodal class, ER, and MYC were statistically significant as independent factors for survival. However, the benefit of ER-positive status was moderated by BCL2, ERBB2, and progesterone receptor. BCL2 and TP53 also interacted as an independent risk factor. A kernel partial least squares polynomial model was developed with an area under the receiver operating characteristic curve of 0.90. Our data show the predictive value of BCL2, ERBB2, MYC, and TP53 in addition to the standard hormone receptors and clinicopathologic features, and they show the importance of conditional interpretation of certain molecular markers. Our multimarker predictive model performed significantly better than standard guidelines.

Cáncer de endometrio con evolución desfavorable en paciente tratada con tamoxifeno

Endometrial cancer is the most common gynecological malignancy and accounts for 6% of all cancers in women. An increased incidence has also been found in association with tamoxifen treatment, as in the case described herein. We present the case of a 54-year-old woman who was treated with tamoxifen for breast cancer. The patient was subsequently diagnosed with endometrial cancer. The clinical course was unfavorable with abdominopelvic disease recurrence.

Talking about tamoxifen

Thank you for Andrew Herxheimer's thoughtful editorial.1 As the source for his reference to the deepening of the voice associated with tamoxifen use, 2 I feel I should add a personal note to the discussion. First, I wish to modify his statement slightly, to read: ‘The sometimes irreversible deepening of the singing voice that has been reported to occur with long-term use of tamoxifen for breast cancer is an example of a side effect that prescribers, manufacturers, and drug regulators seem to have considered trivial and have not investigated’ [my emphasis]. My own experience, of serious voice problems 2–3 weeks after starting to take 40 mg a day of tamoxifen in 1987, led me to enquire further of other women, in particular members of the charity Breast Cancer Care (then the Breast Care and Mastectomy Association). I found that similar problems had been reported to the then Director, Jinty Blanckenhagen, who had also notified the manufacturer, ICI Pharmaceuticals. However, this side-effect had not made it to the data sheet. So I conducted a small pilot study among readers of the BCMA newsletter, Network. I invited singers to write in if they had noticed any voice changes. Of the 10 who wrote in, seven had noticed changes similar to my own: mainly croakiness and a lowering of pitch. 2 To me this confirmed that my experience was not unique and I imagined that the drug company would wish to know about it. So early in 1992 I wrote to them, with copies to various other bodies such as the Committee on Safety of Medicines, as well as some eminent breast cancer specialists. The result astonished me. I was living in West Sussex at that time, and a senior member of the ICI medical team flew from Macclesfield to Gatwick, accompanied by another member of staff who seemed to have a Public Relations role, to see me in my home. It felt as if the object of this expensive exercise was to persuade me to shut up. This I did not do, but this particular side effect has still not been listed in the British National Formulary. The problem may be partly dose-related, and now the standard dose is 20 mg, not 40 mg. But I believe that the effect is real and that singers should know about it before embarking on tamoxifen treatment, which is only likely to benefit those with ER+ tumours. It is particularly important to mention it in any trials of tamoxifen for ‘prevention’.

Tamoxifen Treatment for Breast Cancer and Risk of Endometrial Cancer: A Case-Control Study

Tamoxifen Treatment for Breast Cancer and Risk of Endometrial Cancer: A Case-Control Study

Tamoxifen Treatment for Breast Cancer and Risk of Endometrial Cancer: A Case–Control Study

Tamoxifen Treatment for Breast Cancer and Risk of Endometrial Cancer: A Case–Control Study

Tamoxifen and the Risk of Endometrial Cancer in Japanese Women with Breast Cancer

There is ongoing debate about whether tamoxifen for breast cancer is associated with a risk of endometrial cancer in Japanese women. We conducted a study to investigate this further. We conducted a retrospective hospital-based cohort study. A total of 674 consecutive patients underwent surgery for primary breast cancer between January 1989 and December 1998. By December 2003, endometrial cancers had been diagnosed in six of these patients. Based on medical records, we evaluated the potential risk factors for endometrial cancer, including age, menopausal status, obesity, parity, diabetes mellitus, hypertension, and tamoxifen. The 674 patients were divided into three groups based on the cumulative duration of tamoxifen use (A, <2 years vs B, 2-5 years vs C, >5 years). To examine the relationships between endometrial cancer and tamoxifen (and other factors), the hazards ratio (HR), 95% confidence interval (CI), and two-sided P value for endometrial cancer associated with each variable were calculated by the Cox regression method. Endometrial cancer was found in 1/318 (0.31%) patients in group A, 3/247 in group B, and 2/109 in group C. In a multivariate analysis no variable was significant, but tamoxifen use for longer than 5 years (group C) was closely correlated with endometrial cancer (HR = 7.92, CI = 0.69-90.89, P = 0.096). Although our data did not reach significance, they support a link between long-term tamoxifen and the development of endometrial cancer in Japanese women with breast cancer.

Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study

Tamoxifen treatment for breast cancer increases proliferation of the endometrium, resulting in an enhanced prevalence of endometrial pathologies, including endometrial cancer. An exploratory study was performed to begin to understand the molecular mechanism of tamoxifen action in the endometrium. Gene-expression profiles were generated of endometrial samples of tamoxifen users and compared with matched controls. The pathological classification of samples from both groups included atrophic/inactive endometrium and endometrial polyps. Unsupervised clustering revealed that samples of tamoxifen users were, irrespective of pathological classification, fairly similar and consequently form a subgroup distinct from the matched controls. Using SAM analysis (a statistical method to select genes differentially expressed between groups), 256 differentially expressed genes were selected between the tamoxifen and control groups. Upon comparing these genes with oestrogen-regulated genes, identified under similar circumstances, 95% of the differentially expressed genes turned out to be tamoxifen-specific. Finally, construction of a gene-expression network of the differentially expressed genes revealed that 69 genes centred around five well-known genes: TP53, RELA, MYC, epidermal growth factor receptor and beta-catenin. This could indicate that these well-known genes, and the pathways in which they function, are important for tamoxifen-controlled proliferation of the endometrium.

Centrally active nonhormonal hot flash therapies

Given the problems associated with hormonal therapy, and the prominent problem of hot flashes in menopausal women, there is a need for nonhormonal agents to alleviate hot flashes. Several compounds that appear to act on the central nervous system have been investigated. Potential mechanisms for their effects on hot flashes have been described. Bellergal (no longer available on the US market, where it was known as Bellergal-S), a combination preparation sedative that consists of low-dose phenobarbital, ergotamine tartrate, and levorotatory alkaloids of belladonna, is an old agent that was popular approximately 20 years ago; however, there is limited suggestion of efficacy for this agent. Clonidine, an older antihypertensive drug, is another centrally active agent that has been studied. Randomized trials have demonstrated that it clearly works for reducing hot flashes, but the magnitude of efficacy is somewhat limited. Toxicity from this agent limits its utility in the clinic. Methyldopa is another centrally active agent that has been studied but to a more limited degree. It appears to have minimal efficacy and too much toxicity to make it clinically useful. Anecdotal observations from a number of sources suggested that newer antidepressants can alleviate hot flashes. This led to pilot trials of venlafaxine and paroxetine, with results suggesting benefit from both drugs. Subsequently, randomized, placebo-controlled, double-blind clinical trials of venlafaxine, paroxetine, and fluoxetine were conducted. All 3 of these clinical trials demonstrated statistically significant reductions in hot flashes with these newer antidepressants compared with placebo. Pilot trials of citalopram and mirtazapine, 2 other newer antidepressants, have also suggested efficacy. Toxicity evaluations have suggested that these agents are, again, well tolerated by the majority of patients. A recent trial, however, was unable to demonstrate any benefit for fluoxetine or citalopram over a placebo. Anecdotal observations also suggested that gabapentin was helpful for alleviating hot flashes. This led to pilot trials that again suggested efficacy. Subsequently, 2 large placebo-controlled, randomized, double-blind clinical trials were conducted. Both of these demonstrated statistically significant efficacy for gabapentin compared with a placebo. This drug is relatively well tolerated by most patients. Thus, centrally active nonhormonal agents clearly do decrease hot flashes in women. The most efficacious and clinically appropriate agents for use are newer antidepressants and gabapentin. Continued evaluation of the efficacy and toxicity of these agents is ongoing.

Dégénérescence maligne de polypes endométriaux sous tamoxifène

To review and describe the anatomoclinical cases of the endometrial cancers arising on polyps during a hormonotherapy by tamoxifen for breast cancer. In the surgical inventory 1990-2002 of the benign or malignant uterine lesions investigated by hysteroscopy with dilatation & curettage (D&C) and/or hysterectomy, 108 single or multiple endometrial polyps were encountered and histologically analyzed. A malignant transformation of polyp was found in 5 instances, meaning a rate of 4.6% i.e. 5/108: 4 cases of adenocarcinoma, 1 case of sarcoma. The existence of endometrial polyps - symptomatic or not - does not seem compatible with the prolonged use of tamoxifen treatment owing the estrogen agonist potential effects of tamoxifen and its well-known hyperplastic and carcinogenic properties for the endometrium. The increased risk of endometrial cancer developing in polyps in this iatrogenic context is estimated between 2.5% and 10% in the literature.

Development of uterine sarcoma after tamoxifen treatment for breast cancer: report of four cases

Development of uterine sarcoma after tamoxifen treatment for breast cancer: report of four cases

Development of uterine sarcoma after tamoxifen treatment for breast cancer: report of four cases

Tamoxifen (TAM) is widely used in the treatment of breast cancer, and its paradoxical effects on female genital system are well known. During the past 10 years, many descriptions of nonepithelial uterine malignancies related to long-term TAM usage have been reported in the literature. Four uterine sarcoma patients who had history of TAM usage for previous breast cancer are presented in this study. The mean time of exposure to TAM was 6 (range 3-11) years, and the mean cumulative dose of drug was 43.82 g. All patients were postmenopausal, and the mean age was 66 (range 61-73) years at the time of the diagnosis of the uterine malignancy. Two (50%) patients had uterine malignant mixed müllerian tumor, and two (50%) had leiomyosarcoma. In one (25%) patient was diagnosed with endometrial biopsy made for a postmenopausal vaginal bleeding; the others (75%) were asymptomatic and their diseases were diagnosed during the pelvic examination and transvaginal ultrasonography. All patients underwent surgery +/- adjuvant therapy (chemotherapy and/or radiation therapy), and two (50%) patients died because of the sarcoma. In consequence, early detection of TAM-related uterine sarcoma is required for orderly gynecological examination in patients having history of TAM usage for previous breast cancer.

Elevated metallothionein (MT) expression in invasive ductal breast cancers predicts tamoxifen resistance.

Elevated expression of the low molecular weight metallothionein (MT) proteins can be found typically in breast cancer cases with less favourable prognosis. The MT gene has been described to be potentially down-regulated by estrogen receptor alpha. The present study is aimed at examining the predictive value of MT expression for results of tamoxifen treatment in breast cancer in relation to steroid receptor status. Sixty patients with primary invasive ductal breast cancers with post-operative tamoxifen treatment were enrolled in the study. In paraffin sections of the studied tumours immmunohistochemical reactions were performed using antibodies directed against MT, estrogen receptors (ER) and progesterone receptors (PgR). Results of the immunohistochemical reactions and of clinical observations were analysed using multivariate progression analysis based on the Cox proportional hazard model. Elevated MT expression was demonstrated to be typical for cases with documented relapse of the disease (P<0.001) or terminated by death (P=0.03). Decreased ER expression was found to be typical for cases of a higher grade (P=0.02) and cases terminated by death (P=0.006). The multivariate analysis showed that elevated MT expression was characteristic for cases with shorter overall survival time (P=0.04). The data showed that MT carried an independent, and also independent from ER status, unfavourable predictive value as far as results of tamoxifen treatment were concerned.

Cáncer uterino en pacientes tratadas con tamoxifeno por un cáncer de mama

Objective To evaluate the incidence of uterine cancer in women with breast cancer who had been treated with Tamoxifen. Material and methods We evaluate 463 women who were treated with 20mg of Tamoxifen daily for a hormone dependent breast cancer, and followed up for 6 years. Results We detected 7 uterine cancers (1.55% of the study population and 2.52 ‰ women a year). Of these, 5 were endometrial carcinomas, a malignant heterologous mixed mesodermal tumour and one endometrial stromal sarcoma. Only the rapid growth of what we believed to be a uterine myoma, detected by ultrasound, allowed us to diagnose the endometrial stromal sarcoma. The other 6 tumours were detected by the appearance of vaginal bleeding, in spite of the annual controls carried out on the study group. Conclusions We find a higher incidence of uterine cancer in women with Tamoxifen treated breast cancer, but it is not the double of the general population. We found mainly endometrial carcinomas, although there were also 2 sarcomas (an endometrial stromal sarcoma and a malignant heterologous mixed mesodermal tumour).

Baseline Endometrial Assessment Before Tamoxifen for Breast Cancer in Asymptomatic Menopausal Women

Editor’ Note: The following abstracts of articles from leading journals have been selected on the basis of their importance to the practice of obstetrics and gynecology.

Ovarian Cyst Formation in Patients Using Tamoxifen for Breast Cancer

The purpose of this study was to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A retrospective review of tamoxifen-treated women with breast cancer who were followed up in the outpatient clinic at Ankara Oncology Hospital between January 2002 and December 2004 was performed. Tamoxifen doses and duration, post-treatment menstrual function, adjuvant therapy, ultrasonographic and hormonal [follicle-stimulating hormone and serum estradiol (E(2))] data, details of gynecologic surgical procedure and histopathology were recorded. Twenty-nine of 150 tamoxifen-treated patients (19.3%) had ovarian cysts. Cysts were detected in 28 of 57 pre-menopausal women (49.1%) and 1 of 93 post-menopausal women (1.1%). Patients with ovarian cysts had higher serum E(2) levels compared with patients without cysts (24 versus 345 pg/ml; P < 0.001). Patients with ovarian cysts had <1 year amenorrhoea duration (P < 0.001) compared with the patients without cysts. Adjuvant standard chemotherapy did not have relationship between the development of ovarian cysts. Multivariant analysis showed that cyst development is related to high E(2) levels (P < 0.05). Patients still having a menstrual cycle during tamoxifen had high risk (58.33%) of developing ovarian cysts. We have described an association between pre-menopausal patients using tamoxifen with high E(2) level and ovarian cyst enlargement.

In vitro and in vivo Effects of Combination of Trastuzumab (Herceptin) and Tamoxifen in Breast Cancer

Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.

Tumor-Specific Expression of Vascular Endothelial Growth Factor Receptor 2 but Not Vascular Endothelial Growth Factor or Human Epidermal Growth Factor Receptor 2 Is Associated With Impaired Response to Adjuvant Tamoxifen in Premenopausal Breast Cancer

Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance. Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors. VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER-positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor-positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status. Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor-positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

Can Molecular Markers Predict When to Implement Treatment with Aromatase Inhibitors in Invasive Breast Cancer?

Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)-negative patients. We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer-related relapse on tamoxifen) was done. HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P= 0.017). HER1-3-positive and/or PR-negative patients combined as a "high-risk" group were significantly more likely to relapse on tamoxifen in univariate (P < 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status. We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.

Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women

Objective. The aim of this study is to estimate the prevalence of endometrial pathology before the start of tamoxifen therapy in menopausal breast cancer patients. Methods. Ninety-one gynecologically asymptomatic patients, suffering from estrogen receptor-positive breast cancer and scheduled for adjuvant tamoxifen, underwent pretreatment endometrial assessment. In all patients, a transvaginal ultrasonography was carried out; a double-layered endometrial stripe measuring above 4 mm was considered as abnormal. In these patients, outpatient hysteroscopy and endometrial biopsy were performed. Pathologic findings were considered the reference test in estimating the prevalence of endometrial morbidity. Results. In 34 patients (37.3%) a thickened endometrium was an indication for hysteroscopic and pathologic assessment. Endometrial polyps, simple hyperplasias, and complex atypical hyperplasias were found in 10 (10.9%), 4 (4.3%), and 3 (3.2%) patients, respectively, leading to an overall prevalence of baseline endometrial morbidity of 18.6%. Established individual risk factors for development of endometrial pathology, such as body mass index, age at menarche and menopause, and parity, did not significantly differ in patients with and without endometrial abnormalities. Only patients' age (63.8 ± 8.6 and 52.2 ± 11.8; P = 0.03) and endometrial thickness (10.5 ± 3.5 and 3.9 ± 3.0; P > 0.001) were significant predictive factors of endometrial pathology. Conclusions. Menopausal women with estrogen receptor-positive breast cancer appear to have high risk of baseline subclinical endometrial abnormalities; therefore, an endometrial assessment, before the start of tamoxifen therapy, is always recommended in such patients.