Effects of Tamoxifen on the Cervix and Uterus in Women with Breast Cancer: Experience with Iranian Patients and a Literature Review

Objective: Invasive breast cancer is the most common malignancy in women. Due to the declining mortalityrate that is partly attributable to the use of screening mammography and effective adjuvant therapy, morewomen survive their breast cancers. The aim of this study was to evaluate the effects of tamoxifen on the genitaltract with particular attention to the uterus and cervix. Methods: We investigated the relationship betweentamoxifen and cervical or uterine cancer in Iran, reviewing all the studies performed by the Vali-Asr GynecologyOncology Clinic in Tehran. In addition, the available data on Medline from 1980 until 2009 were reviewed.Results: A total of 182 articles showed associations with gynecologic malignancies. Although as many as 121refered to links between the drug and endometrial abnormalities (polyps or cancers), 55 articles studied therelationship with changes of pap smears, four of which indicated isolated cervical metastasis followed tamoxifenuse in patients with breast cancer. Conclusion: In spite of the significant relationship between tamoxifen andendometrial cancers, cervix is rarely involved in breast cancer patients. However, vaginal bleeding or abnormalvaginal discharge has been reported in all cases before the diagnosis was made. To rule out genital tract malignancy,it is necessary, therefore, to have an annual pelvic exam, pap smear and early endometrial with endocervicalcurettage for tamoxifen users following a breast cancer in those with abnormal uterine bleeding or persistentvaginal discharge.     

Tamoxifen Use in Indian Women - Adverse Effects Revisited

Background: Tamoxifen is generally considered a safe drug for Indian womenwith breast cancer. Indian women seem to tolerate tamoxifen therapy better than western women, but thereare no data regarding safety and local adverse effect profiles in typical Indian populations. Methods and Results:A total of 3,000 case records of patients who had received tamoxifen daily for any period of time, betweenJanuary 1988 and December 2007, were identified for study. Hot flashes were reported by 800 (26%), mildvaginal dryness by 450 (15%) and vaginal discharge by 300 (10%), with vaginal bleeding experienced by 40(1.3%) patients. A total of 1,100 (36.6%) asymptomatic patients had a thickened endometrium(defined as >8mmin thickness) on ultrasonography. Endometrial curettage was performed in all of these. None of the patientsdeveloped endometrial carcinoma. Fatty infiltration of liver was found in 1,440 (48%) patients with a meantime interval for development of 7 months (range 6-30 months). Conclusions: Fatty infiltration of liver is foundin almost half of the Eastern Indian women who receive tamoxifen. Increased endometrial thickness, whichremains asymptomatic, was documented in more than one third of patients on ultrasound examination. Tamoxifenseems to have a negligible potential for causation of uterine malignancies in eastern Indian women. Rates ofhysterectomies in Indian patients on tamoxifen are substantially lower than those of western patients on tamoxifen.     

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.     

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.     

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.     

Tamoxifen and risk of large bowel cancer in women with breast cancer

Background: The increasingly consistent association between estrogen replacement therapy and colorectal cancer suggests that the anti-estrogen tamoxifen may also be associated with large bowel cancer incidence.Methods: Women with new diagnoses of breast cancer were identified from the Surveillance Epidemiology and End Results (SEER) Program, a set of geographically defined, population based cancer registries representing approximately ten percent of the U.S. population. Of 85,411 women with local or regional breast cancer diagnosed from 1983–90, 14,984 women were reported to have received hormonal therapy and 70,427 were not known to have received hormonal therapy. Subsequent cancer diagnoses were identified in this cohort beginning 6 months after initial breast cancer diagnosis until death, or December 31, 1994. Multivariate Cox proportional hazards models were used to estimate the risk of developing colorectal cancer and other second cancers according to hormonal therapy use.Results: Over the follow-up period 793 colorectal, 2,648 contralateral breast, 506 endometrial, 250 ovarian, 98 gastric, and 1,765 other cancers were identified in the study cohort. While overall there was no association between hormonal therapy use and colorectal cancer (relative risk (RR) 1.09, 95% confidence interval (CI) 0.88–1.35), in the period five or more years after diagnosis, risk was increased significantly by about 50% (95% CI 1.00–2.15). As expected, based upon clinical trials data, cancers of the contralateral breast were significantly decreased, and cancers of the uterine endometrium were significantly increased. No other meaningful associations were observed. When women were excluded for whom hormonal therapy might represent therapy other than tamoxifen (premenopausal women and those who received chemotherapy), this did not meaningfully alter these estimates.Conclusions: The results of this large population based cohort study suggest that tamoxifen therapy may modestly increase risk of large bowel cancer in women, but only after 5 years following initiation of breast cancer therapy.     

Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: Pooled results from three countries

Introduction

Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subsequently diagnosed with endometrial cancer.

Methods

We pooled case-patient data from the three largest case-control studies of tamoxifen in relation to endometrial cancer after breast cancer (1,875 patients: Netherlands, 765; United Kingdom, 786; United States, 324) and collected follow-up information on vital status. Breast cancers were diagnosed in 1972 to 2005 with endometrial cancers diagnosed in 1978 to 2006. We used Cox proportional hazards survival analysis to estimate hazard ratios (HRs) and 95% confidence intervals (CI).

Results

A total of 1,104 deaths occurred during, on average, 5.8 years following endometrial cancer (32% attributed to breast cancer, 25% to endometrial cancer). Mortality from endometrial cancer increased significantly with unfavorable non-endometrioid morphologies (P < 0.0001), International Federation of Gynaecology and Obstetrics staging system for gynecological malignancy (FIGO) stage (P < 0.0001) and age (P < 0.0001). No overall association was observed between tamoxifen treatment and endometrial cancer mortality (HR = 1.17 (95% CI: (0.89 to 1.55)). Tamoxifen use for at least five years was associated with increased endometrial cancer mortality (HR = 1.59 (1.13 to 2.25)). This association appeared to be due primarily to the excess of unfavorable histologies and advanced stage in women using tamoxifen for five or more years since the association with mortality was no longer significant after adjustment for morphological type and FIGO stage (HR = 1.37 (0.97 to 1.93)). Those patients with endometrioid tumors, who stopped tamoxifen use at least five years before their endometrial cancer diagnosis, had a greater mortality risk from endometrial cancer than endometrioid patients with no tamoxifen exposure (HR = 2.11 (1.13 to 3.94)). The explanation for this latter observation is not apparent.

Conclusions

Patients with endometrial cancer after breast cancer who received tamoxifen treatment for five years for breast cancer have greater endometrial cancer mortality risk than those who did not receive tamoxifen. This can be attributed to non-endometrioid histological subtypes with poorer prognosis among long term tamoxifen users.     

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.     

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.     

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.     

Endometrial cancer with congenital uterine anomalies: 3 case reports and a literature review

Background: Uterine malformation is a rare deformity in woman, and only a few cases concerning endometrial cancer arising in patients with congenital uterine anomalies have been reported. Herein, we present 3 cases of endometrial cancer with different congenital uterine anomalies, and review studies involving congenital uterine anomalies associated with endometrial cancer in the past 25 years, to identify similarities and differences in clinicopathologic characteristics and prognosis between endometrial cancer associated with uterine anomalies, and normal uterus. Cases: Case 1 was a 75-year-old gravida 1, para 0, woman with carcinosarcoma (mixed well-differentiated endometrial adenocarcinoma and undifferentiated sarcoma) of the right cavity (grade III, and at least stage II ) of a uterus didelphys. The tumor recurred within 7 months after surgery, salvage radiotherapy was unsuccessful; the patient died 8 months after the surgery. Case 2 was a 63-year-old gravida 5, para 3, woman with a bicornuate uterus and uterus papillary serous carcinoma of the right horn (grade III, stage IIIC). She did not respond to the chemotherapy post surgery and died within 4 months. Case 3 was a 60-year-old gravida 0, para 0, woman with a complete septate uterus and an oblique vaginal septum of the upper region of the vagina with endometrioid adenocarchcinoma of the left cavity (grade II, stage IA). No adjuvant therapy was administered and the patient had recovered 2 y after the surgery. Conclusion: Clinicians should be aware of the coexistence of uterine malignancies and uterine anomalies in patients presenting with persistent abnormal uterine bleeding, but with negative endometrial biopsy or failed in the operation of endometrial biopsy. In such cases, magnetic resonance imaging has an important role in the diagnosis of both malformation and malignancy, and an exploratory laparotomy should be performed to avoid delaying the diagnosis and treatment of cancers.     

Surveillance for uterine abnormalities in tamoxifen-treated breast carcinoma survivors: a community based study

BACKGROUND: Tamoxifen-treated breast carcinoma survivors are at elevated risk of endometrial carcinoma. Whether to recommend annual surveillance for uterine abnormalities in this population is currently under debate. METHODS: This study was a cross-sectional, community-based investigation of tamoxifen use and the frequency of surveillance for endometrial carcinomas in 541 women with breast carcinoma. Study participants whose breast carcinoma was diagnosed in 1994 were interviewed in 1998. Data were collected from a telephone interview and from a cancer registry record. Tests for uterine abnormalities, based on participant reports of endometrial biopsy and transvaginal ultrasound, were categorized according to frequency. Testing for uterine abnormalities was defined as irregular if women reported tests once every 3 years, on average, and as regular, if they reported annual tests. RESULTS: Forty-nine percent of respondents were current tamoxifen users, 12% were former tamoxifen users, and 39% reported never taking tamoxifen. Of respondents with a uterus (n = 385), 19% reported irregular and 30% regular testing for uterine abnormalities after their breast carcinoma diagnosis. Respondents more frequently reported transvaginal ultrasound (37%) than endometrial biopsy (29%). Women 65 years of age and older were significantly less likely to report regular surveillance for uterine abnormalities (16%) than those younger than 65 years (35%). Current tamoxifen users more frequently reported regular surveillance (43%) than either former (35%) or never tamoxifen users (15%). Multivariable analyses showed tamoxifen users were more likely to have regular (odds ratio [OR], 9.8; 95% confidence interval [CI], 4.4-21.8) or to have irregular testing for uterine abnormalities (OR, 3.9; 95% CI, 1.9-8.1) compared with women who never used tamoxifen, after adjustment for age, number of recent gynecologic visits, and gynecologic symptoms. CONCLUSIONS: The results of the current study indicate that half of the breast carcinoma survivors in this population were tested for uterine abnormalities. Although at increased risk, 38% of tamoxifen users never had a test. Clear guidelines need to be established for the type and frequency of testing for uterine abnormalities among tamoxifen-treated breast carcinoma patients.     

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial: an update

Until recently, tamoxifen was the only adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early-stage breast cancer. However, the first efficacy update from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial has introduced a choice of adjuvant therapy in this setting. After a median follow-up of 47 months, these data indicated that anastrozole continued to show superior efficacy compared with tamoxifen, including significantly greater disease-free survival, a longer median time to recurrence, and a reduced incidence of contralateral breast cancer. Anastrozole also exhibited a number of important tolerability benefits compared with tamoxifen, including reduced incidences of thromboembolic events, vaginal bleeding, and endometrial cancer. Additional ATAC subprotocols included the examination of bone mineral density and its associated sequelae, endometrial abnormalities, and quality of life. The results of these studies support the primary conclusions of the main efficacy and safety analyses: the efficacy benefits of anastrozole were not at the expense of quality of life, anastrozole was associated with reduced endometrial stimulation compared with tamoxifen, and only patients receiving tamoxifen had endometrial atypical hyperplasia. Anastrozole was associated with a modest loss of bone mineral density and an initial increase of fractures compared with tamoxifen. However, the fracture rate with anastrozole stabilizes after 2 years, and indirect comparison suggests that any increased fracture risk with anastrozole is modest. This review concludes that, based on the overall risk-benefit profile from the ATAC study, anastrozole is a rational alternative to tamoxifen for the adjuvant treatment of women with hormone-sensitive early-stage breast cancer.     

Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case-control study

Since tamoxifen is widely used in breast cancer treatment and has been proposed for the prevention of breast cancer, its endometrial iatrogenic effects must be carefully examined. We have investigated the association between endometrial cancer and tamoxifen use or other treatments in women treated for breast cancer in a case-control study. Cases of endometrial cancer diagnosed after breast cancer (n = 135) and 467 controls matched for age, year of diagnosis of breast cancer and hospital and survival time with an intact uterus were included. Women who had received tamoxifen were significantly more likely to have endometrial cancer diagnosed than those who had not (crude relative risk = 4.9, p = 0.0001). Univariate and adjusted analyses showed that the risk increased with the length of treatment (p = 0.0001) or the cumulative dose of tamoxifen received (p = 0.0001), irrespective of the daily dose. Women who had undergone pelvic radiotherapy also had a higher risk (crude relative risk = 7.8, p = 0.0001). After adjusting for confounding factors, the risk was higher for tamoxifen users (p = 0.0012), treatment for more than 3 years (all p < 0.03) and pelvic radiotherapy (p = 0.012). Women who had endometrial cancer and had received tamoxifen had more advanced disease and poorer prognosis than those with endometrial cancer who had not received this treatment. Our results suggest a causal role of tamoxifen in endometrial cancer, particularly when used as currently proposed for breast cancer prevention. Pelvic radiotherapy may be an additional iatrogenic factor for women with breast cancer. Endometrial cancers diagnosed in women treated with tamoxifen have poorer prognosis. Women who receive tamoxifen for breast cancer should be offered gynaecological surveillance during and after treatment. A long-term evaluation of the risk–benefit ratio of tamoxifen as a preventive treatment for breast cancer is clearly warranted. Int. J. Cancer 76:325–330, 1998.© 1998 Wiley-Liss, Inc.     

Tamoxifen and malignant epithelial-nonepithelial tumours of the endometrium: report of six cases and review of the literature.

AIMS: To review the use of tamoxifen in malignant epithelial-nonepithelial tumours of the endometrium. Tamoxifen has been widely used for almost 20 years as adjuvant therapy for breast cancer. Large clinical trials have pointed out that long-term tamoxifen therapy increases the risk of uterine cancers. These tumours include endometrial carcinomas, stromal sarcomas, leiomyosarcomas as well as malignant mixed (epithelial-nonepithelial) tumours. METHODS: We report here six more cases of malignant epithelial-nonepithelial tumours which, in addition to those reported in the literature, makes a total of 36 presented cases. The pathogenesis of such tumours remains unclear, but it has been claimed that unopposed oestrogenic stimulation due to the agonistic effect of tamoxifen might be involved, as in the case of endometrial carcinomas. Pelvic irradiation has also been incriminated, especiallly in women under 55 years of age. RESULTS: Among 21 endometrial malignant epithelial-nonepithelial tumours associated with tamoxifen, seven occurred in women less than 55 years old. Five of them had previous pelvic irradiation. The data from the literature and from our series suggest that tamoxifen might favour the occurrence of malignant epithelial-nonepithelial tumours in women with breast cancer aged over 55 years, whereas in younger women both pelvic irradiation and tamoxifen might participate.     

Outcomes in patients with primary breast cancer and a subsequent diagnosis of endometrial cancer : comparison of cohorts treated with and without tamoxifen

BACKGROUND: The study compared tumor characteristics and survival in women with breast cancer who subsequently developed endometrial cancer with or without a history of tamoxifen use. METHODS: The British Columbia Cancer Agency registry identified 163 women diagnosed with breast cancer between 1989-1999 who received a subsequent diagnosis of endometrial cancer. Of these, 55% (n = 90) had a history of tamoxifen use. Outcomes analyzed were breast cancer-specific survival (BCSS), endometrial cancer-specific survival (ECSS), and overall survival (OS). RESULTS: Median follow-up was 9.4 years. Distributions of age, menopausal status, body mass index, and comorbidities were similar in the tamoxifen-treated and nontamoxifen cohorts. Proportions of aggressive endometrial cancer subtypes including papillary serous, clear cell, and mixed mullerian tumors were higher in the tamoxifen cohort (28% vs14%, P = .03). Distributions of endometrial cancer grade and stage were similar in the 2 groups (P > .05). Hysterectomy and/or oophorectomy were the primary treatments for endometrial cancer in 99% of patients, with comparable pelvic control rates in the tamoxifen and nontamoxifen groups. At 10 years, patients in the tamoxifen group experienced lower BCSS compared with the nontamoxifen group (89% vs 97%, P = .02). No significant differences in ECSS and OS were observed between the 2 groups (ECSS 82% and 82%, P = .85; and OS 69% v. 66%, P = .85). CONCLUSIONS: In patients with breast cancer who developed a subsequent endometrial cancer, tamoxifen-treated patients had higher proportions of aggressive endometrial cancer subtypes, but almost all cases were amenable to surgery, thus resulting in similar endometrial cancer control and survival when compared with nontamoxifen treated patients.     

Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice

BACKGROUND: In patients with early-stage breast cancer, 5 years of treatment with the selective estrogen receptor modulator (SERM) tamoxifen reduces breast cancer recurrence and mortality, whereas more than 5 years of tamoxifen does not further reduce breast cancer recurrence and doubles the risk of endometrial cancer. We evaluated the effects on tumor growth of raloxifene, another SERM, after tamoxifen treatment in mouse models of breast and endometrial cancers. METHODS: Athymic, ovariectomized mice were bitransplanted with tumors derived from human breast cancer and endometrial cancer cells that either were tamoxifen-naive or had been exposed to tamoxifen for short (6 months) or long (>5 years) terms. The effects of raloxifene (two dose levels) and tamoxifen on tumor growth in the presence and absence of low-dose estrogen were evaluated. All statistical tests were two-sided. RESULTS: Raloxifene was less effective than tamoxifen in blocking the stimulatory effects of low-dose estrogen on the growth of tamoxifen-naive breast (P<.001) and endometrial (P =.001) tumors. Raloxifene and tamoxifen had similar inhibitory effects on the growth of short-term tamoxifen-exposed breast tumors. Raloxifene and tamoxifen had similar stimulatory effects on the growth of breast and endometrial tumors that had been exposed to at least 5 years of tamoxifen. However, neither drug blocked the stimulatory effects of estrogen on the growth of these tumors. Raloxifene was less effective than tamoxifen (P<.001) in blocking the stimulatory effects of estrogen on endometrial tumors that had been exposed to tamoxifen in the past. CONCLUSIONS: Raloxifene and tamoxifen had similar effects on these mouse models of tamoxifen-naive and tamoxifen-resistant breast and endometrial cancer. Treatment with raloxifene following 5 years of adjuvant tamoxifen may not further decrease breast cancer recurrence and may increase endometrial cancer incidence.     

Locally advanced breast cancer in the elderly: a major challenge requiring effective and appropriate treatment

AIMS AND BACKGROUND: Breast cancer is the most common tumor in women. As the population above 65 years increases, breast cancer will be a more substantial problem for elderly patients. This work reports our experience in the management of stage III and IV locally advanced breast cancer. METHODS: Nineteen patients over 65 years of age (mean, 70.3 years) with stage III and IV breast cancers, treated between 1990 and 2000, are considered. The management and outcome are evaluated. RESULTS: Nine patients had stage IIIA breast cancer, 7 stage IIIB and 3 stage IV. Sixteen underwent Madden mastectomy and 3 simple mastectomy. Patients at stage IIIB and 1 patient at stage IV with T4 tumor received neo-adjuvant chemotherapy. There were no significant postoperative complications. Sixteen patients were given tamoxifen and 10 patients adjuvant chemotherapy. Patients were followed for a median of 36.7 months (range, 6-72 months). In 8 patients with stage IlIl disease, metastasis developed. Two patients had local recurrence of disease. Of the patients at stage IIIA, 6 were free from disease (one died from unrelated causes) and 3 had recurrent disease (2 died). Of the patients at stage IIIB, 2 are disease free and 5 had recurrent disease and died. Of the patients at stage IV, only one is alive. CONCLUSIONS: Stage and individual characteristics of elderly women influence management. Patients should be managed adequately since most of them are fit enough to undergo treatment.