Estrogen receptor polymorphisms in tamoxifen-treated women with breast cancer.

In postmenopausal women with estrogen receptor (ER)-positive breast cancer, long-term tamoxifen administration has proved beneficial after surgical treatment and subsequent chemotherapy. One of the major adverse effects of tamoxifen is the development of endometrial pathology (polyps, endometrial hyperplasia and endometrial cancer). PvuII and XbaI polymorphisms of the estrogen receptor-alpha gene (ERalpha) and RsaI and AluI polymorphisms of the estrogen receptor-beta gene (ERbeta) have been associated with breast cancer. Thus the present study aimed to identify whether ER gene polymorphisms are associated with breast cancer stage or endometrial responsiveness to long-term tamoxifen treatment in 87 postmenopausal, tamoxifen-treated women with ER-positive breast cancer. The mean age of the patients was 58.7 +/- 4.7 years and the mean duration of tamoxifen treatment was 3.9 +/- 1.1 years. At diagnosis, the stage of breast cancer was determined as follows: 29 women (32%) at Stage I, 49 (58%) at Stage II and 9 (10%) at Stage III. The frequency distributions of the estrogen receptor polymorphisms in all women with breast cancer were not different from those predicted by the Hardy-Weinberg equilibrium hypothesis (p > 0.10). None of the ER polymorphisms studied was linked to either the presence of endometrial pathology or the stage of breast cancer.     

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.     

Tamoxifen in gynaecology

Tamoxifen, a nonsteroidal synthetic anti-oestrogen is the most widely used selective estrogen receptor modulator (SERM). Designed as a contraceptive it is most frequently used in prevention and treatment of breast cancer. Its role in gynaecology is limited to ovulation induction. Although it has a favourable effect on lipid profiles and increases bone density in postmenopausal women its use for these indications is not warranted. The practising gynaecologist will most likely be faced with the risks associated with long-term tamoxifen use: endometrial polyps, endometrial hyperplasia and endometrial cancer; venous thromboembolism, ovarian cysts and endometrioid ovarian cancers. Further insight into the oestrogen receptor (ER) tamoxifen induced changes could potentially identify new therapeutic opportunities.     

Antiestrogenic therapy in breast cancer and endometrial modifications

The aim of this retrospective study was to detect endometrial lesions in tamoxifen breast cancer users (menopausal state related). The meaning of genital bleeding during the treatment and the actual incidence of benign and malignant pathology of the endometrium related to length of treatment was also evaluated. Tamoxifen (TMX) is a nonsteroidal triphenylene derivate with clear antiestrogenic properties on the breast which is used as adjuvant treatment for breast cancer; potential adverse effects include endometrial lesions. Three hundred and sixty-six breast cancer patients were enrolled in this study; 292 patients were treated with 20 mg/daily of TMX as adjuvant therapy and the remaining 74 did not receive therapy. All patients were subdivided in premenopausal and postmenopausal, asymptomatic and symptomatic groups. All patients underwent ultrasound scans (to examine endometrial thickness) and hysteroscopic examinations before treatment and after one, three and five years. Endometrial biopsy under direct hysteroscopic vision was systematically performed. The pathological histology reports were classified under polyps, simple hyperplasia, complex hyperplasia, atypical hyperplasia, and carcinoma. A higher incidence of endometrial pathology was found only in symptomatic postmenopausal TMX treated patients (27.2% vs 19.5%) between the third and fifth year of treatment.     

Gynaecological Complications of Women Treated with Tamoxifen for Breast Cancer

Summary: We present 6 cases illustrating some of the gynaecological complications associated with tamoxifen treatment of women with breast cancer. The first 2 represent cases of myometrial hypertrophy secondary to tamoxifen use, a postmenopausal woman and a premenopausal women with recurrent carcinoma of the breast. The third is a case of probable ovulation induction in a perimenopausal woman with recurrent breast cancer who was commenced on tamoxifen 20 mg daily. The other 3 cases illustrate some of the endometrial effects associated with tamoxifen therapy in women with a history of breast cancer, namely cystic glandular hyperplasia, endometrial polyps and endometrial cancer.     

他莫昔芬对乳腺癌患者子宫内膜影响的前瞻性临床病理研究

目的:前瞻性研究他莫昔芬对乳腺癌患者子宫内膜的影响。方法:对2005年1月~2008年10月于温州医学院附属第二医院乳腺外科手术的155例乳腺癌患者进行随访,以阴道B超、宫腔镜及子宫内膜活检评价服用他莫昔芬前后子宫内膜情况。结果:可评价患者共135例,其中绝经前46例,绝经后89例。服用他莫昔芬后,未绝经组36例(78.26%)出现异常阴道流血,9例(19.56%)出现子宫内膜病变,绝经组22例(24.72%)发生异常阴道流血,出现子宫内膜病变29例(32.60%),其中术前绝经组18例(18/59,30.51%),化疗后绝经组11例(11/30,36.67%)。阴道B超对绝经后子宫内膜病变诊断的灵敏度为52.3%,特异度为90.2%,宫腔镜诊断相应的灵敏度为81.8%,特异度为100%。结论:他莫昔芬导致绝经后妇女子宫内膜病变发生增加,对绝经前妇女的影响还不确定。阴道B超可作为初步检测手段,宫腔镜检查可提高诊断的准确率。     

Uterine abnormalities in non menopausal women who received tamoxifen for breast cancer adjuvant therapy

OBJECTIVE: To elaborate a strategy of endometrial follow-up for premenopausal women treated with Tamoxifen as adjuvant hormonal treatment of breast cancer. PATIENTS AND METHODS: Retrospective study of 152 premenopausal patients treated with Tamoxifen in Nantes Comprehensive Cancer Center for a breast cancer from January 2003 to December 2005. Vaginal sonography was used in the follow-up of 70 of them. RESULTS: Endometrial hypertrophy was found in 26 patients. Sonohysterography and hysteroscopy allowed to find 11 polyps and three hyperplasias in the 19 women who were investigated. In our study, endometrial pathology was found in 20% of premenopausal women treated with Tamoxifen (polyps or hyperplasia). Uterine bleeding was found in half patient of this group. DISCUSSION AND CONCLUSION: Vaginal sonography monitoring could be proposed to premenopausal women treated with Tamoxifen among whom endometrial pathology is usual.     

Pretreatment and prospective assessment of endometrium in menopausal women taking tamoxifen for breast cancer

OBJECTIVES: To estimate the pretreatment incidence of endometrial pathology and to prospectively assess the endometrial morbidity emerging during tamoxifen intake for breast cancer. STUDY DESIGN: One-hundred and forty-six menopausal breast cancer patients, candidate to receive tamoxifen underwent endometrial assessment by Transvaginal Ultrasonography (TU) before the start of therapy. A double-layered endometrial stripe measuring more than 4mm indicated hysteroscopy and endometrial biopsy. Endometrial abnormalities detected before the start of tamoxifen were treated by operative hysteroscopy or by hysterectomy; no therapy and yearly hysteroscopic follow-up was scheduled for patients showing non-atypical hyperplasias. All women were asked to undergo TU on a yearly basis; during the follow-up period, indication for hysteroscopy and endometrial biopsy were the following: (i) an endometrial lining measured above 4mm at the first time, (ii) at least a 50% increase of endometrial thickness since the last finding in patients previously assessed by hysteroscopy, (iii) a recorded vaginal bleeding, and (iv) previous findings of endometrial hyperplasia. Histopathologic result from biopsy or hysterectomy was the reference test to establish the baseline prevalence of endometrial pathology and the emerging prevalences of morbidity after 12, 24, 36, 48 and 60 months of tamoxifen therapy. RESULTS: One-hundred and five patients were followed for 60 months, whereas 113, 126, 137 and 141 patients were evaluated up to 48, 36, 24 and 12 months, respectively. In 44 out of 146 patients, pretreatment TU showed an endometrium thicker than 4mm and in 31 (21.2%) of these patients abnormalities consisting of 16 endometrial polyps, seven polyps harboring simple hyperplasia, four simple hyperplasias, three atypical hyperplasias and one adenocarcinoma were found. During tamoxifen intake benign endometrial abnormalities were detected in 36 out of 114 assessable patients showing normal endometrium before the start of tamoxifen therapy (31.5%) and in seven out of 27 patients with baseline endometrial abnormalities (25.9%). Overall, an endometrial pathology emerged in 30.4% of patients during tamoxifen administration and in no patients we found an atypical lesion. CONCLUSIONS: In menopausal breast cancer patients the incidence of endometrial abnormalities before the start of tamoxifen therapy is high and includes 2.7% of atypical pathology. After the diagnosis and treatment of baseline atypical lesions were accomplished, no atypical endometrial lesion emerged after the start of tamoxifen administration. Based on these findings, we believe that pretreatment assessment of endometrium is recommended in all menopausal women candidate to receive tamoxifen therapy.     

乳腺癌患者服用三苯氧胺后子宫内膜病变150例临床病理分析

目的分析乳腺癌患者服用三苯氧胺(tamoxifen,TAM)后子宫内膜的病理变化,以期制定随访中的相应对策。方法对北京大学第一医院1993年1月至2008年8月乳腺癌患者术后服用三苯氧胺期间或停药后,因妇科问题而住院诊治者150例进行回顾性分析。结果绝经前53例,绝经后97例。与使用三苯氧胺有关的子宫内膜病理结果为:内膜息肉、内膜单纯性增生、内膜非典型增生和内膜癌的例数在绝经前组合计为10例(10/53,18.9%),在绝经后组中49例(49/97,50.5%)。子宫内膜非典型增生和子宫内膜癌均发生在绝经后组。乳腺癌患者服用三苯氧胺后,发生子宫内膜息肉等病理表现与患者是否绝经、是否有阴道出血这两个因素呈正相关,而与三苯氧胺服用时间、剂量及乳腺癌患病年限无明显相关性。结论应重视并加强对绝经后乳腺癌患者服用三苯氧胺期间和之后的随访工作,对绝经后服用三苯氧胺的患者,建议用药前进行妇科评估,包括B超了解子宫内膜厚度,并加强用药期间的随访工作。     

Endometrial lesions in patients undergoing tamoxifen therapy.

Forty-six nonhysterectomized women treated with tamoxifen during 6-36 months as adjuvant therapy for breast cancer underwent a hysteroscopy to assess the endometrial effects of this drug. Whereas the endometrium was normal among 23 patients, 13 presented with endometrial polyps, 8 with hyperplasia and 2 with adenocarcinoma. The rate of endometrial lesions was directly related to the cumulative dose of tamoxifen but it was not statistically different among patients receiving progestational therapy compared to patients who did not receive this therapy.     

Effects of tamoxifen on the human female genital tract: review of the literature

Tamoxifen is a non-steroidal triphenylethylene derivate, with clear antioestrogenic effects on the breast, that is orally administrated for the treatment of breast cancer and its prevention in a high-risk population. This article analyzes the effects of tamoxifen on the adult human female genital tract and considers its carcinogenicity in the gynaecological reproductive organs. It has been found that tamoxifen causes oestrogenic changes of the vaginal and cervical squammous epithelium and increases the incidence of cervical and endometrial polyps. The action of tamoxifen on the human endometrium in postmenopausal women is connected with simple oestrogenic effects including hyperplasia, while in others with endometrial cystic atrophy. In cases where tamoxifen induces endometrial polyps and hyperplasia, the extensive fibrosis accounts for difficulties in obtaining endometrial biopsy or resecting the polyps. In premenopausal patients tamoxifen disrupts the menstrual cycles and causes ovarian cysts, while in postmenopausal patients it induces ovarian cystic tumors and endometriomas. Also, postmenopausal patients treated with tamoxifen may develop endometriosis, adenomyosis and leiomyomata. In addition, randomized trials have shown a link between tamoxifen use in breast cancer patients and the development of endometrial carcinomas. Moreover, of note is the fact that the association of tamoxifen therapy with uterine mesenchymal neoplasms is higher than expected. In conclusion, the most worrying gynaecological side-effect of tamoxifen is the well-known increased risk of endometrial carcinomas. Women with breast cancer treated with tamoxifen should undergo annual gynaecological examination, but endometrial sampling should be obtained only in the event of endometrial bleeding.     

Transvaginal ultrasound and diagnostic hysteroscopy as a predictor of endometrial polyps: risk factors for premalignancy and malignancy

The aim of this study is to assess accuracy of transvaginal ultrasound (TVUS) and diagnostic hysteroscopy in diagnosing endometrial polyps and to determine premalignancy and malignancy rates in asymptomatic women. The study was designed to retrospectively analyze 438 women who underwent operative hysteroscopy in a day-care unit when endometrial polyp was suspected after TVUS and diagnostic hysteroscopy. Multivariate logistic regression modeling showed effects of age, previous breast cancer with tamoxifen treatment, and menopause with or without bleeding on pathologic results. The results indicate that positive predictive value of TVUS with diagnostic hysteroscopy was 79.9%. Premalignancy or malignancy occurred in 3.2% and was significantly related to menopause with abnormal bleeding (P < 0.001), which carried a 20-fold higher risk of pathology than any other group. Age was also a risk factor. It was concluded that TVUS with diagnostic hysteroscopy reliably evaluates endometrial polyps. The low incidence of endometrial tumors in asymptomatic (especially premenopausal) women suggests that their operative evaluation may not be cost effective. Larger studies are needed to support this tentative conclusion.     

Uterine Malignant Mixed Mullerian Tumor in a Patient on Long-Term Tamoxifen Therapy for Breast Cancer

A case of malignant mixed mullerian tumor of the uterus, heterologous type, in an 83-year-old woman on tamoxifen (TAM) therapy for 9 years for breast cancer is presented. Benign endometrial polyps were diagnosed on endometrial curettings for postmenopausal bleeding after the patient had been on TAM for 5 years. Recurrent postmenopausal bleeding developed 4 years later. Endometrial curettings and hysterectomy revealed a 10-cm polypoid malignant mixed mullerian tumor (MMMT) and endometrial polyps. There was no invasion of the myometrium or endocervix and no evidence of metastatic tumor in 13 pelvic lymph nodes, peritoneal washings, or omentum. TAM has been associated with the development of endometrial polyps, hyperplasia, and adenocarcinoma possibly mediated through its agonistic estrogenic properties. Only one other case of MMMT arising in patients on TAM therapy has been previously reported, but may also be a consequence of the estrogenic effects of TAM therapy.     

Uterine pathologies in patients undergoing tamoxifen therapy for breast cancer: ultrasonographic, hysteroscopic and histological findings

PURPOSE OF INVESTIGATION: To evaluate endometrial abnormalities by ultrasonography, hysteroscopy and biopsy in postmenopausal patients treated with tamoxifen as adjuvant therapy for breast cancer. METHODS: The study was carried out on 113 patients who underwent vaginal ultrasonography, hysteroscopy and endometrial biopsy. RESULTS: There was a significative relation between ultrasonographic and hysteroscopic features (p < 0.001); 58 polyps were diagnosed at hysteroscopy, although 35 were not found at ultrasonography. A significant relation between ultrasonographic and histological findings was also documented (p < 0.005). A significant relation between histological findings and symptomatology was found (p < 0.05), although pathologies were also present in asymptomatic women. CONCLUSIONS: These results show that long-term tamoxifen therapy in breast cancer patients is associated with a higher incidence of uterine pathology. No significant relation has been documented between duration of treatment and grade of endometrial lesion (p > 0.05). Ultrasonography alone is useful in asymptomatic patients because it selects patients with increased endometrial thickness who should undergo hysteroscopy. Hysteroscopy is more accurate in detecting polyps, hyperplastic and neoplastic changes. Asymptomatic tamoxifen treated women should be evaluated as symptomatic patients.     

Recurrent endometrial polyps in postmenopausal breast cancer patients on tamoxifen

OBJECTIVES: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure, with an incidence of up to 10.7% of malignancy. Some women tend to develop recurrent polyps. However, no one has yet described any risk factors for the development of recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. METHODS: We compared various clinical features of 64 postmenopausal breast cancer tamoxifen-treated patients with a primary endometrial polyp (Group I), with those of 27 similar patients with recurrent polyps (Group 2). RESULTS: Previous exposure to hormone replacement therapy was significantly more common and duration of tamoxifen treatment, up to the diagnosis of primary endometrial polyp, was significantly shorter in Group II patients (P = 0.0217 and P = 0.0148, respectively). Logistic regression analysis revealed that the combination of shorter tamoxifen exposure before the diagnosis of primary polyp, lower parity, lower menopausal age at the diagnosis of primary polyp, and higher years of tamoxifen treatment was found to increase significantly the risk of developing recurrent endometrial polyps. Any additional year of tamoxifen treatment may increase by fivefold the risk of developing recurrent polyps. There was no significant difference in ultrasonographic endometrial thickness measured before resection of the primary polyps in both groups and before the resection of recurrent polyps in Group II. CONCLUSIONS: Previous use of HRT, shorter duration of tamoxifen exposure, and additional years of tamoxifen treatment may significantly increase the risk of developing recurrent endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients.     

Cancer of the endometrium caused by antiestrogens]

Tamoxifen is the most widely used non-steroidal antiestrogen compound for adjuvant treatment of postmenopausal breast cancer. Tamoxifen has both antiestrogen and estrogen-agonistic activity, which depends on the target tissue involved owing its systemic distribution. Upon the endometrium the agonistic estrogenic effect, so-called "paradoxical" effect, is suggested to induce proliferative changes such as hyperplasia or carcinoma. The authors report four cases of endometrial cancer developed in postmenopausal patients with breast cancer receiving tamoxifen. According to the literature data, the relationship of the tamoxifen to the endometrial remains uncertain: women with breast cancer are at increased risk for this neoplasm sharing common aetiologic hormonal factors and, in most published case reports, the uterine cavity has not been checked up before starting tamoxifen administration.     

Transvaginal endometrial sonography in postmenopausal women taking tamoxifen

OBJECTIVE: To evaluate sonographic measurements of endometrial thickness in postmenopausal women taking adjuvant tamoxifen therapy for breast cancer, and to correlate sonographic and pathologic findings to symptoms and duration of tamoxifen therapy. METHODS: Medical records and sonograms of 80 postmenopausal women treated for breast cancer with adjuvant tamoxifen therapy were reviewed retrospectively. Endometrial thickness was recorded as a single-layer thickness and considered abnormal when greater than 2.5 mm for postmenopausal women. Sonographic endometrial thickness was correlated to histologic findings, symptoms, and duration of tamoxifen therapy. RESULTS: Fifty-seven of 80 postmenopausal women (69%) had single-layer endometrial thicknesses of 2.5 mm or greater, measured by transvaginal sonography, and 55 of 57 had endometrial biopsies or dilatations and curettage. Biopsies detected 24 cases of abnormal endometria, including endometrial carcinoma (two), breast carcinoma metastatic to the endometrium (one), endometrial polyps (13), tubal metaplasia (three), and benign endometrial hyperplasia (five). Using a single-layer endometrial thickness greater than 2.5 mm by transvaginal ultrasound, 21 of 24 (87.5%) women with abnormal endometria were detected. Women with abnormal pathologic findings had a significantly thicker mean single-layer endometrial thickness than those with normal findings, 7 mm versus 4 mm (P < .01). Twelve women had postmenopausal bleeding, all of whom had a single-layer endometrial thickness greater than 2.5 mm on transvaginal sonography. CONCLUSION: With a sensitivity of detecting endometrial abnormalities of 84%, transvaginal sonography was useful for studying postmenopausal tamoxifen-treated women.     

The progesterone test and transvaginal sonography as methods for the early discovery and screening of endometrial cancer in women in the postmenopause from some risk groups

We wanted to assess the effect of tamoxifen treated women with breast cancer, as well as to examine patients with diabetes blood hypertension, and obesity. The influence of Tamoxifen was searched over the endometrium in patients treated with it for 3 years. In this research work is assessed the effect of this medicament from this risk group. The second risk group were the women with high blood pressure, obesity and diabetes mellitus. We used transvaginal sonography and the progesterone test to find endometrial pathology and especially endometrial cancer in asymptomatic women-measuring the depth of the endometrium, and using abrasio probatoria separata in order to find endometrial cancer. With these tests we found polyps, hyperplasia, and early endometrial cancer. We wanted with progesteron test and vaginal sonography in these risk groups to find endometrial pathology and especially early endometrial cancer in asymptomatic women.     

The effects of tamoxifen therapy on the endometrium

From January 1992 to December 1998, 219 women (aged between 30 and 81 yrs; average 55 years) affected by breast cancer were treated. These women in addition to the usual adjuvant therapy, were treated with TAM 20 mg/day, for a period between 24 and 72 months (average 40). In this group there were 84 postmenopausal and 31 premenopausal women. In 8 fertile patients ovarian activity was suppressed with GnRh analogue therapy and one patient underwent attinic castration. Before performing TAM therapy, a hysteroscopic exam was done and patients were followed-up with an annual check-up. None had any endometrial side-effects after the first check-up. After two years, 31 women (26.9%) complained of endometrial alterations (hyperplasia, polyps and endometrial cancer). One women only after 6 years of follow-up, had metrorrhagia; an endometrial adenocarcinoma was found. We would like to point out the necessity of monitoring these patients with an annual check-up (transvaginal sonography and/or hysteroscopy).     

Ovarian cysts in postmenopausal tamoxifen-treated breast cancer patients with endometrial thickening detected by transvaginal sonography

OBJECTIVE: To investigate the frequency of ovarian cysts in tamoxifen-treated postmenopausal breast cancer patients with endometrial thickening detected by transvaginal sonography. METHODS: Medical records and transvaginal sonographies of 38 postmenopausal women treated for breast cancer with adjuvant tamoxifen therapy who had undergone endometrial sampling due to abnormal endometrial thickness were reviewed retrospectively. RESULTS: During the study period five of 38 tamoxifen-treated postmenopausal patients (13.2%) had ovarian cysts. The mean tamoxifen treatment interval of the patients with an ovarian cyst was 22.4 +/- 18.4 months (p = 0.17). The mean endometrial thickness of the patients with an ovarian cyst was 12.6 +/- 5.9 mm (p = 0.17). Endometrial biopsy detected six cases of abnormal endometria, including endometrial carcinoma (n = 1), endometrial polyp (n = 1) and simple endometrial hyperplasia without atypia (n = 4). Three patients with ovarian cysts underwent laparatomy revealing simple cysts on histopathological examination. Two patients with ovarian cysts declined laparatomy and are currently under follow-up. CONCLUSION: Ovarian cysts a common side-effect of tamoxifen treatment in postmenopausal tamoxifen-treated breast cancer patients. Transvaginal sonography should be performed to detect any concomitant endometrial pathology.