Anastrozole versus tamoxifen treatment in postmenopausal women with endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology.

PURPOSE: To investigate the effect of switching from adjuvant tamoxifen to anastrozole (Arimidex) treatment in postmenopausal women with endocrine-responsive breast cancer and histologically proven tamoxifen-induced benign endometrial pathology. EXPERIMENTAL DESIGN: Two hundred twenty-six postmenopausal women who had received adjuvant tamoxifen 20 mg/d (> or =12 months, < or =48 months) and developed abnormal vaginal bleeding and/or an asymptomatic endometrial thickness >10 mm [measured by transvaginal ultrasound (TVUS)] were subjected to hysteroscopy and dilation and curettage (D&C). Thereafter, 171 patients were randomized in a phase III study to continue tamoxifen treatment (n = 88) or switch to anastrozole 1 mg/d (n = 83). Patients were monitored for < or =42 months using TVUS at 6-monthly intervals. RESULTS: At study entry, there were no significant differences in vaginal bleeding, endometrial thickness, and histologic findings between the two treatment groups. Throughout the treatment period, there was no significant difference in recurrent vaginal bleeding between groups [anastrozole, 4 of 83 (4.8%); tamoxifen, 9 of 88 (10.2%); P = 0.18]. Six months after randomization, the mean endometrial thickness for patients who switched to anastrozole was significantly reduced compared with those who continued tamoxifen treatment (P < 0.0001). Significantly fewer anastrozole patients required a repeat hysteroscopy and D&C compared with those on tamoxifen [4 of 83 (4.8%) and 29 of 88 (33.0%), respectively; P < 0.0001]. Repeat hysteroscopy and D&C revealed endometrial atrophy in all 4 cases in the anastrozole group and 14 polyps, 8 hyperplasias, and 7 atrophies in the tamoxifen group. CONCLUSIONS: Switching from tamoxifen to anastrozole treatment significantly reduced the need for a second hysteroscopy and D&C due to recurrent vaginal bleeding or thickening of the endometrium in postmenopausal breast cancer patients with tamoxifen-induced endometrial abnormalities.     

Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound.

PURPOSE: To study the value of transvaginal ultrasound (TVS) in endometrial screening of postmenopausal breast cancer patients treated with tamoxifen. PATIENTS AND METHODS: In 247 tamoxifen-treated (20 to 30 mg/d for >/= 2 years) women and 98 controls, the endometrium was prospectively followed-up by means of TVS every 6 months for up to 5 years. Patients with homogeneous endometrium of more than 10-mm thickness were then scanned repeatedly every 3 months. RESULTS: The mean endometrial thickness was 3.5 +/- 1.1 mm before treatment and increased to a maximum of 9. 2 +/- 5.1 mm after 3 years of tamoxifen application (P: <.0001), which was significantly (P: <.0001) thicker compared with controls. Fifty-two asymptomatic patients with thickened or morphologically suspect endometrium underwent hysteroscopy and dilatation and curettage (D&C), resulting in four uterine perforations. Histopathologically, atrophy was found in 38 patients (73.1%), polyps in nine, hyperplasia in four, and endometrial cancer in one case. In 20 screened patients who reported vaginal bleeding, five atrophies (25%), five polyps, four hyperplasias, and two endometrial cancers were found. Before hysteroscopy and D&C were performed, 36 (69.2%) of 52 asymptomatic and four (20%) of 20 symptomatic patients were scanned by repeated TVS over 2 to 30 months. Invasive diagnostic procedures were significantly (P: <.05) more frequent in younger and obese patients. In the controls, one asymptomatic polyp and one symptomatic hyperplasia were found. CONCLUSION: In tamoxifen-treated patients, TVS offered a high false-positive rate, even with a cutoff value of 10 mm for endometrial thickness and repeated TVS scans. Increased iatrogenic morbidity and only one asymptomatic endometrial carcinoma do not warrant endometrial screening by TVS in tamoxifen-treated patients.     

Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening.

PURPOSE: Tamoxifen is the most commonly prescribed adjuvant therapy for women with breast cancer. It has agonist activity on the endometrium and is associated with an increased risk of endometrial cancer. The aim of this study was to evaluate whether screening with transvaginal ultrasound (TV USS) with or without hysteroscopy is worthwhile. PATIENTS AND METHODS: A total of 487 women with breast cancer, 357 treated with tamoxifen and 130 controls, were screened with TV USS, and endometrial thickness was measured. Women with thickened endometrium underwent outpatient hysteroscopy. RESULTS: Length of time on tamoxifen ranged from 5 to 191 months (mean, 66 months), and endometrial thickness ranged from 1 to 38 mm (mean, 7.3 mm). Women treated with tamoxifen had significantly thicker endometrium than did controls (P <.0001). There was a statistically significant (P <.0001) positive correlation between length of time on tamoxifen and endometrial thickness. One hundred forty-five women had endometrium greater than 5 mm on USS, and 134 underwent successful outpatient hysteroscopy, 61 of whom had atrophic endometrium, resulting in a 46% false-positive scan rate. The remaining women all had benign features to explain the USS findings. CONCLUSION: TV USS detects a high incidence (41%) of apparent endometrial thickening in women treated with tamoxifen, although 46% had atrophic endometrium on further assessment, and none of the remaining asymptomatic women had significant lesions. Length of time on tamoxifen relates to endometrial thickening as measured by TV USS. TV USS is a poor screening tool because of the high false-positive rate. The low frequency of significant findings suggests that endometrial screening in asymptomatic women is not worthwhile.     

Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients.

BACKGROUND: Tamoxifen may induce uterine abnormalities of clinical concern. Our aim was to compare early uterine changes occurring in postmenopausal breast cancer patients treated in first-line with tamoxifen or third generation aromatase inhibitors. We also assessed the effect of aromatase inhibitors on tamoxifen-induced uterine changes. PATIENTS AND METHODS: Seventy-seven consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. Transvaginal ultrasonography (TVUS) was carried out before and after 3 months of therapy. No interventions were done on pre-existing asymptomatic uterine abnormalities seen on baseline sonography. RESULTS: After 3 months of therapy, tamoxifen significantly increased endometrial thickness and uterine volume. Additionally, tamoxifen induced endometrial cysts and polyps, and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathologies seen under tamoxifen. Furthermore, aromatase inhibitors decreased endometrial thickness and uterine volume in patients previously treated with tamoxifen. CONCLUSIONS: Our study demonstrates that tamoxifen induces uterine abnormalities from as early as 3 months of therapy. In contrast, these abnormalities are not seen in patients on aromatase inhibitors. Furthermore, our data indicate that tamoxifen therapy followed by an aromatase inhibitor may lead to a reduction in endometrial pathologies associated with tamoxifen.     

Classification of benign endometrial glandular cells in cervical smears from postmenopausal women

BACKGROUND: The Bethesda System recommends reporting benign endometrial cells in cervical smears from postmenopausal (PMP) women as a glandular cell abnormality. However, PMP women on hormone replacement therapy (HRT) sometimes may experience endometrial shedding. The significance of such a finding has not been investigated in detail. METHODS: The authors evaluated 85 PMP women with cervical smears that contained benign endometrial glandular cells. Clinical information, including vaginal bleeding and the use of HRT or tamoxifen, was recorded, and follow-up was obtained. RESULTS: Thirty-three PMP women were not on HRT, and 11 women were symptomatic. Twenty women underwent endometrial biopsy: Two symptomatic patients had endometrial adenocarcinoma, and 3 symptomatic patients and 1 asymptomatic patient had endometrial polyps. The frequency of abnormal findings was 18%. Forty-seven PMP women received HRT; 15 were symptomatic. Twenty-two patients underwent endometrial biopsy: 1 symptomatic patient had cystic hyperplasia, and 2 symptomatic patients and 1 asymptomatic patient had an endometrial polyp. The frequency of abnormal findings was 8.5%. No one type of HRT was correlated with specific findings. Five PMP women were on tamoxifen, and two of them were symptomatic. Four patients underwent endometrial sampling: Two of them had an endometrial polyp, which was symptomatic in one patient. CONCLUSIONS: These data confirm that benign endometrial glandular cells in cervical smears from PMP women may indicate endometrial pathology, especially if vaginal bleeding is present. Although atypical endometrial hyperplasia or carcinoma was not identified in the group of PMP women on HRT, endometrial abnormalities of a lesser degree were present in 8.5% of patients. Thus, the authors favor continued classification of benign endometrial glandular cells in cervical smears of PMP women, whether or not they are on HRT, as a glandular cell abnormality.     

The effect of tamoxifen on the endometrium

Summary Tamoxifen is one of the most important treatments for breast cancer, especially in postmenopausal patients. It acts primarily as an anti-estrogenic agent, due to its cytoplasmic estrogen receptor binding capacity. However, it also exerts a mild estrogenic effect. Since the prolonged use of estrogen has been reported to increase the rate of benign and malignant changes in the endometrium, we evaluated whether there is a correlation between tamoxifen therapy and endometrial benign and malignant conditions. The study group comprised 95 patients with breast cancer who were treated with tamoxifen. No control group was examined. Patients underwent vaginal ultrasonography and endometrial biopsy in order to evaluate any changes in the endometrium occurring during tamoxifen therapy. Pathological changes were observed in 14 patients, 13 of whom were treated with tamoxifen for more than 12 months. Of these women, 3 were diagnosed with endometrial cancer, 3 had mild dysplasia, 3 had endometrial hyperplasia, and 4 had a benign endometrial polyp. Our findings indicate a significant correlation between long-term tamoxifen administration and endometrial proliferation. We therefore recommend that women treated with tamoxifen for more than 12 months have an annual vaginal ultrasonography and endometrial biopsy.     

Tamoxifen and the endometrium: findings of pelvic ultrasound examination

The need for endometrial surveillance in breast cancer patients undergoing adjuvant treatment with tamoxifen is still controversial. In this study, 164 asymptomatic breast cancer patients (110 on treatment with tamoxifen, 20 mg/day, and 54 controls) were examined with pelvic ultrasound and endometrial biopsy. No differences in ultrasound and biopsy findings were observed in the pre- and perimenopausal group between patients treated with tamoxifen and controls. Postmenopausal patients on tamoxifen had a significantly thicker endometrium (mean ± SD, 7.2 ± 8.5 vs. 1.5 ± 4.3 mm, p=0.00002) and significantly larger uterine volume (mean ± SD, 63.2 ± 39.9 vs. 43.7 ± 38.8 cm³, p=0.0001) than controls. Fifty-four percent of patients on tamoxifen had an endometrial thickness 5 mm, often with multiple irregular sonolucencies suggesting the presence of cysts. Ultrasound findings, however, did not correlate with the presence of endometrial abnormalities on biopsy, and no endometrial cancer or atypical hyperplasia were found. This lack of correlation makes questionable the use of routine sonography in asymptomatic breast cancer patients on tamoxifen. Obtaining routine endometrial samples, on the other hand, may be difficult in some patients because of cervical stenosis or refusal. Until the benefits of endometrial surveillance will be proved, asymptomatic patients should not be submitted routinely to ultrasound examination or biopsy, but encouraged to report promptly any abnormal vaginal bleeding.     

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

This prospective study assessed the endometrial effects of fulvestrant, a pure estrogen-receptor antagonist, in postmenopausal women with breast cancer. This single-center study enrolled postmenopausal patients who had an intact uterus at baseline with progressive metastatic breast cancer on tamoxifen followed by an oral aromatase inhibitor (AI). Fulvestrant (250 mg) was administered every 28 ± 3 days via IM injection. Transvaginal ultrasonography (TVUS) was performed at baseline and after 3 months of therapy. Primary and secondary endpoints were changes from baseline in double endometrial thickness (DET) and uterine volume (UV), respectively. No interventions were performed on any asymptomatic uterine abnormalities that were detected at baseline. In total, 32 women were enrolled. Five patients had no repeat TVUS because of early progression before 3 months, leaving 27 evaluable patients for final analysis. After 3 months therapy, mean DET had significantly decreased by 23.08% (P = 0.010). Mean UV also decreased by 10.88%, although this change was not significant (P = 0.119). After 3 months of therapy, none reported vaginal bleeding, there were no changes noted in most of the uterine pathologies present at baseline and no new uterine abnormalities were detected. We observed that 3 months of fulvestrant treatment resulted in a significant decrease in endometrial growth and a non-significant decrease in UV in postmenopausal women with metastatic breast cancer previously exposed to tamoxifen and AIs. Furthermore, no new uterine pathologies were detected, indicating that fulvestrant behaves as a pure antiestrogen at the uterine level.     

Increased Risk of Endometrial Abnormalities in Breast Cancer Patients Taking Tamoxifen: The Need for Gynaecologic Surveillance

Objective: To evaluate the risk of abnormally thickened endometrium associated with tamoxifen treatment in ‍postmenopausal breast cancer patients. ‍Methods: Two groups of asymptomatic postmenopausal breast cancer patients were recruited in the study. The ‍first consisted of 70 patients taking 20mg/day of tamoxifen for at least 6 months. The second group included 140 ‍patients without tamoxifen treatment. Endometrial evaluation using transvaginal ultrasonography (TVS) was ‍conducted for all patients. Fractional curettage was carried out for patients whose endometrial thickness was greater ‍than 5 mm on TVS. ‍Results: The prevalence of abnormally thickened endometrium (greater than 5 mm on TVS) was significantly ‍higher in patients receiving tamoxifen (58.57% VS 10.71 %, P = 0.0001). Patients undergoing tamoxifen treatment ‍had a 5.61 relative risk of developing abnormally thickened endometrium (95% CI= 2.65 -11.86). ‍Conclusion: Tamoxifen significantly increases the risk of developing abnormally thickened endometrium in ‍postmenopausal breast cancer patients. There is, thus, a true need for gynaecologic surveillance in such patients to ‍early detect neoplastic change of endometrium that may arise as a result of tamoxifen use.‍ ‍     

Uterine Malignancy following Tamoxifen Use in Breast Cancer Patients in Iran: Case Series and Literature Review

Background: This study evaluated tumor characteristics and survival in women with breast cancer whosubsequently developed uterine cancer. Methods: Information about endometrial cancer in tamoxifen usersfollowing breast cancer refered to the gynecologic oncology clinic of Vali-Asr hospital between 1997-2007 wasevaluated. Results: Among 330 patients with endometrial cancer, 5 were in women previously diagnosed withbreast cancer. Two cancers were malignant mixed Mullerian tumors of the uterus (MMMT), 2 were endometrioidadenocarcinomas, and one was a papillary clear cell carcinoma. Patients received tamoxifen for 4-8 years. Theendometrial cancers occurred 2-11 years after initial treatment for the breast cancers. Four of the endometrialcancers featured abnormal uterine bleeding and one of them had increased vaginal discharge and all werediagnosed on endometrial curetting. All patients received standard surgical staging for endometrial cancer andall except one were stage I. At laparotomy of one patient, an advanced stage MMMT was found with diffusedperitoneal spread and ascites. In spite of the surgery, she died of disease, 3 months later. The other patientsremain recurrence-free for breast cancer and uterine cancer after 6-120 months. Conclusion: Breast cancerpatients who use tamoxifen and have early stage endometrial cancers demonstrate a good prognosis. Abnormaluterine bleeding or vaginal discharge is the most important symptom.     

Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women

To assess and compare the gynaecological consequences of the use of 2 antioestrogens we examined 167 postmenopausal breast cancer patients before and during the use of either tamoxifen (20 mg/day, n = 84) or toremifene (40 mg/day, n = 83) as an adjuvant treatment of stage II-III breast cancer. Detailed interview concerning menopausal symptoms, pelvic examination including transvaginal sonography (TVS) and collection of endometrial sample were performed at baseline and at 6, 12, 24 and 36 months of treatment. In a subgroup of 30 women (15 using tamoxifen and 15 toremifene) pulsatility index (PI) in an uterine artery was measured before and at 6 and 12 months of treatment. The mean (+/-SD) follow-up time was 2.3 +/- 0.8 years. 35% of the patients complained of vasomotor symptoms before the start of the trial. This rate increased to 60.0% during the first year of the trial, being similar among patients using tamoxifen (57.1%) and toremifene (62.7%). Vaginal dryness, which was present in 6.0% at baseline, increased during the use of tamoxifen (26.2%) and toremifene (24.1%). Endometrial thickness increased from baseline (3.9 +/- 2.7 mm) to 6.8 +/- 4.2 mm at 6 months (P< 0.001), and no difference emerged between the 2 regimens in this regard. Before the start of the antioestrogen regimen, the endometrium was atrophic in 71 (75.5%) and proliferative in 19 of 94 (20.2%) samples; 4 patients had benign endometrial polyps. During the use of antioestrogen altogether 339 endometrial samples were taken (159 in tamoxifen group, 180 in toremifene group). The endometrium was proliferative more often in the tamoxifen group (47.8%) than in the toremifene group (32.2%) (P< 0.0001). 20 patients had a total of 24 polyps (17 in tamoxifen and 9 in toremifene group, P< 0.05) during the use of antioestrogens. One patient in the toremifene group developed endometrial adenocarcinoma at 12 months, and one patient had breast cancer metastasis on the endometrium. Tamoxifen failed to affect the PI in the uterine artery, but toremifene reduced it by 15.0% (P< 0.05) by 12 months. In conclusion, tamoxifen and toremifene cause similarly vasomotor and vaginal symptoms. Neither regimen led to the development of premalignant endometrial changes. Our data suggest that so close endometrial surveillance as used in our study may not be mandatory during the first 3 years of use of antioestrogen treatment.     

Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients

Objective Aromatase inhibitors may decrease endometrial thickness in breast cancer patients previously having short-term tamoxifen treatment. There is a necessity to find out if aromatase inhibitors can also decrease endometrial thickness in patients previously treated with long-term tamoxifen treatment. Methods Prospective comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 36 postmenopausal breast cancer patients, with further measurements, performed following aromatase inhibitors administration. Results There was a significant decrement of endometrial thickness, following 36.2 ± 16.8 months of tamoxifen treatment, from a mean value of 9.1 ± 5.8 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.0 ± 5.0 mm, measured following 5.8 ± 5.8 months of aromatase inhibitors therapy (P = 0.001). A second ultrasonographic measurement performed in 8 patients following of additional 7.5 ± 4.0 months of aromatase inhibitors treatment revealed further decrement of mean endometrial thickness to 4.8 ± 2.1 mm (P = 0.002 compared to baseline). In 28 patients (77.8%), endometrial thickness was reduced following the administration of aromatase inhibitors, in four patients (11.1%) there was no change in endometrial thickness and four (11.1%) patients demonstrated an increase of endometrial thickness. Conclusions Aromatase inhibitors may reverse endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients.     

Indication of hysteroscopy in tamoxifen treated breast cancer patients

The aim of this study was to indicate the patients treated with tamoxifen for breast cancer in which hysteroscopy with biopsy should be considered mandatory. 414 breast cancer patients who underwent hysteroscopy with bioptic evaluation were enrolled in the study. 334 subjects were treated with 20 mg of tamoxifen daily as adjuvant therapy for six up to a hundred months. Of the remaining 80 control patients, which had not received tamoxifen, 30 were in premenopause (Group IA) and 50, in postmenopause (Group IIA). The tamoxifen-treated patients were subdivided in premenopausal (Group IB = 72 patients) and in postmenopausal (Group IIB = 262 patients) groups. All patients were further classified in asymptomatic or symptomatic groups considering whether uterine bleeding was absent or present. The evaluation of the endometrial mucosa was performed by office hysteroscopy. In group IIB patients presenting uterine bleeding, malignant lesions were found in 7.8% of the cases. The incidence of premalignant and malignant lesions in IIB patients treated for longer than 3 years (11.7%) was higher than that observed in IIB patients treated for less than 3 years (1.3%). There was a significant difference in terms of endometrial pathology between Group IIB (32.8%) and Group IIA (8%) (p < 0.001); and between Group IIB (32.8%) and Group IB (13.9%) women (p = 0.003). Among IA and IIA patients there were no cases of endometrial hyperplasia or cancer; on the contrary, in IB and IIB women, 2 and 22 cases of atypical hyperplasia were observed, respectively. All cases of endometrial cancer were observed in Group IIB and had a diagnosis of poor prognosis. In conclusion the hysteroscopy with biopsy should be considered the first diagnostic procedure to perform in tamoxifen-treated postmenopausal patients presenting uterine bleeding and in postmenopausal women treated for longer than 3 years. In premenopause, hysteroscopy should be proposed to women with ultrasonographic abnormalities and/or with uterine bleeding to patients at high risk for endometrial cancer.     

Hysteroscopic assessment of menopausal breast-cancer patients taking tamoxifen; there is a bias from the mode of endometrial sampling in estimating endometrial morbidity?

The aim of this study is to evaluate the accuracy of hysteroscopy in detecting tamoxifen-associated endometrial morbidity. Ninety-eight menopausal breast cancer patients taking tamoxifen underwent hysteroscopy because of an endometrial thickness above 4 mm measured by Transvaginal Ultrasonography. Thirty-one women recorded uterine bleeding while 67 were asymptomatic. Hysteroscopies with operative facilities were performed, mainly in out-patient setting. Hysteroscopic findings were matched with histopathology derived from various modalities of tissue collection as suction-curettage, oriented-streak curettage, hysteroscopically-targeted biopsies or polypectomies and hysterectomies. Accuracy of hysteroscopy to estimate a normal or abnormal endometrium was calculated. Abnormal endometrium was detected in 35 patients (64.5% in symptomatic and 22.3% in asymptomatic women, P < 0.001). We found six carcinomas, 18 polyps and 11 hyperplasias. Hysteroscopy showed sensitivity and specificity of 89.2 and 98.4%, respectively. By blind sampling, tissue collection was too scant to give a diagnosis in 29.1% of patients and in 80.5% of patients in whom hysteroscopy showed cystic atrophy the pathologist failed to confirm this condition. Moreover, eight endometrial polyps (36.3%) detected by hysteroscopy were missed. Conversely, by tissue sampling under vision no inadequate specimen was sent to the pathologist and all hysteroscopies showing cystic atrophy and polyps were pathologically confirmed. From literature data, the detection-rate of endometrial pathology in tamoxifen users varies from the lowest to the highest prevalences whether blind or hysteroscopically-targeted modalities of tissue sampling were used, respectively. Hysteroscopy with targeted sampling appears to be the most effective method to assess the endometrial lining. In our experience it is safe, well tolerated and it should be considered the reference test to assess a thickened endometrium in women under tamoxifen.     

Tamoxifen therapy for breast cancer and endometrial cancer risk.

BACKGROUND: Tamoxifen is effective in treating breast cancer, reduces breast cancer incidence among high-risk women, and is associated with increased endometrial cancer risk. This study was designed to examine the possible modifying effects of endometrial cancer risk factors on the tamoxifen-endometrial cancer association. METHODS: We conducted a case-control study of endometrial cancer (324 case patients and 671 individually matched control subjects) nested within a population-based cohort of patients with breast cancer diagnosed from 1978 through 1992 within four regions of the United States. We obtained information on breast cancer treatment and endometrial cancer risk factors through interviews and reviews of medical records. All P values reported are two-sided. RESULTS: Endometrial cancer risk was associated with tamoxifen therapy for breast cancer (odds ratio = 1.52; 95% confidence interval [CI] = 1. 07-2.17). Risk increased with duration of tamoxifen use (P for trend =.0002). Women with more than 5 years of exposure to tamoxifen had 4. 06-fold greater odds of developing endometrial cancer than nonusers (95% CI = 1.74-9.47). Prior use of estrogen replacement therapy (ERT) increased risk associated with tamoxifen use (P for homogeneity of trends <.0001). Risk associated with tamoxifen use was stronger among heavier women than among thinner women, although trends did not differ statistically (P =.10). Tamoxifen dose-response effects were more pronounced among women with both previous ERT exposure and higher body mass index than among women in other risk groups. CONCLUSIONS: ERT use and obesity, both established endometrial cancer risk factors and markers of estrogen exposure, substantially modify the association between tamoxifen use and endometrial cancer risk among patients with breast cancer. Women with positive ERT histories and those who are obese, when prescribed tamoxifen, may warrant closer surveillance for endometrial cancer than women without such histories.     

Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study.

PURPOSE: To compare the efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) with that of tamoxifen as first-line therapy for advanced breast cancer (ABC) in postmenopausal women. PATIENTS AND METHODS: This randomized, double-blind, multicenter study evaluated the efficacy of anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with tumors that were hormone receptor-positive or of unknown receptor status who were eligible for endocrine therapy. The primary end points were time to progression (TTP), objective response (OR), and tolerability. RESULTS: A total of 668 patients (340 in the anastrozole arm and 328 in the tamoxifen arm) were randomized to treatment and followed-up for a median of 19 months. Median TTP was similar for both treatments (8.2 months in patients who received anastrozole and 8.3 months in patients who received tamoxifen). The tamoxifen:anastrozole hazards ratio was 0.99 (lower one-sided 95% confidence limit, 0.86), demonstrating that anastrozole was at least equivalent to tamoxifen. Anastrozole was also as effective as tamoxifen in terms of OR (32.9% of anastrozole and 32.6% of tamoxifen patients achieved a complete response [CR] or partial response [PR]). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 56.2% and 55.5% for patients receiving anastrozole and tamoxifen, respectively. Both treatments were well tolerated. However, incidences of thromboembolic events and vaginal bleeding were reported in fewer patients treated with anastrozole than with tamoxifen (4.8% v 7.3% [thromboembolic events] and 1.2% v 2.4% [vaginal bleeding], respectively). CONCLUSION: Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Together with the lower observed incidence of thromboembolic events and vaginal bleeding, these findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with ABC.     

Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)—a randomised controlled trial of exemestane versus continued tamoxifen after 2–3 years tamoxifen

BackgroundThe antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen.Patients and methodsSonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2–3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (≥5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation.ResultsThe analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67).ConclusionSwitching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.     

Surveillance for Endometrial Cancer in Postmenopausal Breast Cancer Patients Taking Tamoxifen

Objective: To determine the prevalence of endometrial thickening and endometrial pathologies in postmenopausal ‍breast cancer patients taking tamoxifen. ‍Materials and Methods: A total of 37 postmenopausal breast cancer patients receiving 20 mg/day of tamoxifen ‍treatment for at least 6 months at Srinagarind hospital were included in the study. Thorough history taking and ‍physical examination as well as transvaginal ultrasonography were conducted for all patients. Fractional curettage ‍was carried out in those whose endometrial thickness was found to be greater than 5 mm. ‍Results: Among 37 patients included in this study, the mean age was 56.35 years. The mean body weight and ‍mean body mass index was 60.88 kg and 26.03 kg/m2, respectively. The majority of patients (75.68%) had stage II ‍disease. The mean + SD of endometrial thickness found in this study was 7.53 + 5.16 mm. The prevalence of thickened ‍endometrium (defined as ET > 5mm from TVS) was 59.46%. Among the 19 patients for whom fractional curettage ‍was conducted, the majority (73.69%) exhibited inadequate endometrium for evaluation. Atrophic endometrium ‍and other unremarkable changes were found in 21.05% of patients and it is important to note that endometrial ‍adenocarcinoma was detected in 1 case (5.26%). ‍Conclusion: The prevalence of thickened endometrium in postmenopausal breast cancer patients taking tamoxifen ‍found in this study was extraordinarily high. These is, however, a discrepancy between the value and that for ‍endometrial abnormalities detected histologically. ‍     

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo.

Tamoxifen (tam) is used extensively for treatment of patients with breast cancer and is being evaluated for chemoprevention in healthy women. It has, however, been reported to increase the risk of endometrial cancer in post-menopausal women, probably by an oestrogenic effect on the endometrium. It also causes endometrial cysts and polyps. The aims of this study were to identify the incidence of endometrial thickening, polyps and cysts by transvaginal ultrasound (TVUS) screening of a population of post-menopausal healthy women in the Royal Marsden tamoxifen chemoprevention trial and to evaluate the possible benefit from the use of intermittent norethisterone (NE) in women with persistent changes. Since 1990, we have undertaken regular TVUS, using an endovaginal B mode probe, of the 463 post-menopausal women in the trial randomized to tam (20 mg day(-1)) or placebo (plac), without breaking the randomization code. Endometrial thickening (ET) was defined as > or = 8 mm at the widest point across the myometrial cavity in the longitudinal plane, including any stromal changes. Cystic changes were defined as more than one hypoechogenic area > 1 mm. Polyps were identified using saline hydrosonography. Oral NE (2.5 mg day(-1)) was used for 21 days out of 28 for three consecutive cycles by women with persistent endometrium > or = 8 mm, including cystic and polypoid changes. TVUS was repeated after the three courses to evaluate any change caused by NE and endometrial biopsies, including hysteroscopy, was performed on those women with persistent abnormalities. A persistent ET > or = 8 mm was identified in 56 (24%) of the 235 women on tamoxifen compared with only 5 (2%) of 228 women on placebo (P <0.0005). Stromal changes, including cysts, were detected in 36 (15%) and polyps in 26 (11%) of the women on tamoxifen compared with only two (< 1%) of the women on placebo (P << 0.0005). After 3 months of cyclical norethisterone, 39 of 47 women (83%) on tamoxifen had persistent ultrasound changes. However, 45 (96%) had a progesterone withdrawal bleed. Hysteroscopy was performed in 39 women on tamoxifen (28 endometrial biopsy, 15 polypectomy), five of whom had histological evidence of a proliferative endometrium and a further three had an atypical hyperplastic endometrium (one of whom had a focus of invasive carcinoma). The cysts and polyps which were detected in women on tam could not be reversed by NE and were presumably stromal and not of malignant risk. However, 96% of the women had withdrawal NE bleeding, indicating an oestrogenically primed endometrium which could be a mechanism for an increased risk of endometrial cancer. Further studies are required to ascertain whether a progestin would protect against this risk. As in other studies, these results indicate that any increased risk of endometrial cancer caused by tamoxifen is low, and that TVUS screening is probably not justified for asymptomatic women on tamoxifen.     

乳腺癌患者术后服用三苯氧胺后子宫内膜病变的临床病理分析

目的分析乳腺癌患者术后服用三苯氧胺(tamoxifen,TAM)后子宫内膜的病理变化。方法研究组为服用TAM出现阴道不规则出血或B型超声提示子宫内膜异常患者69例;对照组为同时期非乳腺癌因绝经后出血就诊的患者60例。TAM组又分为绝经前、后两组(20例、49例)及根据服用TAM时间(T)长短,分为T≤1年组、1年＜T＜2年组、T≥2年组,进行宫腔镜检查及子宫内膜活检。结果TAM组子宫内膜息肉及子宫内膜增生明显高于对照组(P<0.001,P<0.05)。绝经后TAM组较绝经前TAM组更易发生子宫内膜病变(P<0.01),且子宫内膜重度不典型增生和子宫内膜癌均发生在绝经后组。随着用药时间的延长,子宫内膜病变的发生增加(P<0.01),且子宫内膜癌均发生在服药2年后。结论乳腺癌患者使用TAM治疗发生子宫内膜病变的风险增加,尤其对于绝经后使用且用药2年以上的妇女。