Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

PURPOSE: In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. PATIENTS AND METHODS: Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. RESULTS: Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). CONCLUSION: Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.     

Hormonal and receptor status in postmenopausal women with endometrial carcinoma before and after treatment with tamoxifen

Twenty-four patients with endometrial carcinoma received tamoxifen (Nolvadex) for 7 days. Before and after administration, circulating hormones (estradiol, testosterone, progesterone, gonadotropins FSH and LH) were evaluated. Estrogen (ER) and progesterone receptors (PgR) in neoplastic tissue were also assayed. Our results show a net increase in PgR content and a significant decrease in gonadotropin levels after the treatment. The authors suggest that clinical trials be conducted using tamoxifen and progestins for adjuvant therapy after surgery of endometrial carcinoma and for the therapeutic approach of advanced carcinoma.     

Adjuvant therapy of breast cancer with tamoxifen and endometrial carcinoma]

Twenty cases of endometrial carcinoma are reported, observed in women who had received long term tamoxifen treatment as adjuvant therapy for breast cancer. Furthermore, a specific study was carried out on an homogeneous group of 790 women with an operable breast cancer, 318 receiving tamoxifen as adjuvant treatment. Five endometrium carcinoma were observed in the group under tamoxifen versus none in the other group. From an analysis of these cases, authors will carry out a case control study to evaluate the relative risk of endometrial carcinoma for patients under tamoxifen. They underline the importance of gynecologic follow up procedures for all women receiving this endocrine therapy.     

Risk of endometrial hyperplasia and carcinoma in breast cancer patients receiving adjuvant tamoxifen

The antiestrogen drug tamoxifen, which is widely used in adjuvant hormone therapy of breast cancer, presents certain risk of causing hyperplasia and endometrial carcinoma. Our clinical data on 1,969 breast cancer patients (stage I-III) (tamoxifen--947; control--1,022) showed a double rise in endometrial carcinoma risk in cases receiving hormone therapy. Endometrial carcinoma incidence in tamoxifen-treated patients was 3% while in the untreated ones--1.6% (p < 0.05). According to the endometrial tissue study in 439 breast cancer patients, proliferative effect of tamoxifen in the form of endometrial hyperplasia was 5--6 times in tamoxifen users. Meanwhile, endometrial carcinoma and hyperplasia risk increased during a much longer exposure to tamoxifen and in combination with such factors as obesity, diabetes mellitus, uterine myoma and estrogen-type colpocytological response. Hence, breast cancer patients need to undergo dynamic follow-up of the endometrium including ultrasonic examination of the small-pelvis organs and cytological study of ecto- and endocervical smears and endometrial aspirates.     

What do we know and what don't we know about tamoxifen in the human uterus

Since its introduction in the early seventies, the list of indications for the use of the antiestrogen tamoxifen has been continuously expanded. Tamoxifen is now used for the treatment of metastatic breast cancer and for long-term and often indefinite administration as an adjuvant therapy. Large clinical trials in three countries are now evaluating the efficacy of tamoxifen as a preventive agent. However, tamoxifen therapy has been associated with an increased incidence of endometrial carcinoma. Laboratory and clinical data available to date on this controversial issue can be summarized as follows:

1. Tamoxifen can have an estrogenic effect on endometrium in the presence of low estrogen levels.
2. Tamoxifen treatment is probably associated with an increased incidence of endometrial cancer; however, this association appears to be linked to higher tamoxifen doses (40mg/d).
3. It is not known whether tamoxifen causes or allows the identification of occult endometrial carcinoma.
4. At the present time there is evidence for a tumor promoting effect of tamoxifen on endometrial cancer at a dose of 20 mg per day.
5. Replacement of tamoxifen by ‘pure’ antiestrogens or coadministration of progestins with tamoxifen do not appear to offer benefit unless clinical trials demonstrate a reduced incidence of endometrial problems.
6. Patientsmust be evaluated for pre-exsisting endometrical carcinoma before starting tamoxifen therapy.
7. Close followup of long-term tamoxifen patients with endometrial biopsies is recommended with individuals who experience symptoms.

     

Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882)

To investigate the effect of adding tamoxifen to megestrol in the hormonal therapy for advanced endometrial cancer, 66 patients were entered in this study. Initially, 41 patients were randomized to either the standard progestin therapy of megestrol or to the combination of megestrol and tamoxifen between October 1982 and October 1984. The megestrol arm was terminated because of poor accrual and 25 patients were directly assigned to the combination arm. Among the 20 eligible cases on the megestrol arm, the response rate of 20% consisted of I complete response and 3 partial responses. The response rate on the megestrol plus tamoxifen arm was 19% with 1 (2%) complete response and 7 (17%) partial responses among 42 eligible cases. The median survival times were 12.0 months and 8.6 months, respectively. Only mild and moderate toxicities were observed on megestrol compared with more toxic complications observed on the combination of megestrol and tamoxifen, including a life-threatening case of pulmonary embolism. Although we could not carry out a comparative evaluation as intended, we conclude that the combination of megestrol and tamoxifen offers no clinical advantage over megestrol alone in the treatment of advanced endometrial carcinoma.     

Toremifene. where do we stand?

Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.     

The role of tamoxifen in the treatment and prevention of breast cancer.

Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. Tamoxifen was originally introduced for the treatment of advanced disease in postmenopausal women; however, the drug is now also available for the palliative treatment of premenopausal women with estrogen receptor (ER) positive disease. The proven efficacy of tamoxifen and the low incidence of side effects made the drug an ideal agent to test as an adjuvant therapy for women with node-positive breast cancer. Laboratory studies indicate that long-term treatment schedules may provide maximal benefit in preventing recurrence, and recent analysis of clinical trials demonstrates that between 2 and 5 years of adjuvant tamoxifen therapy provides a survival advantage for postmenopausal women with node-positive disease. Similarly, adjuvant studies in node-negative breast cancer have demonstrated an increase in the disease-free survival of both pre- and postmenopausal patients with ER-positive tumors. However, the extended use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy. Of special concern is the impact of tamoxifen on ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs. Fortunately, there are no reports about the teratogenicity of tamoxifen in the human, but it is important that physicians counsel women about the risk of pregnancy. Tamoxifen should not be used if a patient is pregnant. Initial concerns that the long-term administration of an antiestrogen would increase bone loss and increase the risks of coronary heart disease appear to be unwarranted. Tamoxifen has some estrogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and a decrease in circulating cholesterol. Indeed, a reduction in fatal myocardial infarction (MI) has been noted during 5 years of tamoxifen therapy, possibly the direct result of a prolonged reduction in circulating cholesterol. However, the estrogen-like qualities of tamoxifen that could be valuable as a hormone replacement therapy for all postmenopausal women following a diagnosis of breast cancer may also increase the risk for developing endometrial carcinoma. To date, there are only a few reports of endometrial carcinoma being diagnosed during adjuvant therapy with tamoxifen; however, any instances of uterine bleeding or spotting should be followed up with an endometrial biopsy. There are some concerns about large doses of tamoxifen promoting liver cancer in rats. These results are of particular concern if tamoxifen is to be used as a preventive in normal women.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prevention of Endometrial Cancer in Breast Cancer Patients Taking Tamoxifen : The Gynecologists' Role

Breast cancer is among the commonest malignant diseases in women. Over the past two decades tamoxifen has ‍been generally accepted as an endocrine therapy of choice for prevention of breast cancer recurrence. Although ‍tamoxifen was thought to have only a few adverse effects, several reports indicate that it is associated with an increase ‍incidence of proliferative and neoplastic changes in the endometrium, with a 1.3 to 7.5 relative risk of developing ‍endometrial carcinoma. The increased risk of endometrial cancer following the use of tamoxifen has stimulated ‍studies on endometrial diagnostic screening methods. During the past ten years several reports have shown the ‍benefits of transvaginal ultrasonography in detecting endometrial pathologies in patients receiving tamoxifen. ‍Sonohysterography has been claimed to be a useful diagnostic tool on differentiating space-occupying lesion, eg. ‍endometrial polyp, from abnormal endometrial-myometrial junction while the contribution of pulsed flow velocity ‍in diagnosis of endometrial pathologies seems to be inconclusive. More recently a few factors have been identified as ‍risk of developing endometrial cancer after tamoxifen use. These include pre-existing endometrial pathologies, obesity, ‍and prior ERT use. This information provides us a more sensible way in following breast cancer patients receiving ‍tamoxifen. It is proposed here that postmenopausal breast cancer patients intend to have tamoxifen treatment should ‍receive a “two - step evaluation”. The pretreatment evaluation is aimed to classify patients at risk of later development ‍of endometrial pathologies after being exposed to tamoxifen while the ongoing evaluation is designed to closely ‍follow the patents after the initiation of tamoxifen in hope that this will provide a tool for early diagnosis or hopefully ‍a protective measure against endometrial carcinoma associated with tamoxifen therapy.     

Chemotherapy and endocrine therapy of endometrial carcinoma

The main treatment of recurrent and advanced endometrial carcinoma are chemotherapy and/or endocrine therapy. Some of the combination chemotherapy, including Cis-platinum are useful in advanced and recurrent endometrial carcinoma, and progestational agents are available for adjuvant chemo-endocrine therapy after operation of endometrial carcinoma. Authors consider the literatures of the chemotherapy and endocrine therapy for endometrial carcinoma and describe our own cases.     

Long-term adjuvant tamoxifen therapy for breast cancer

Tamoxifen (ICI46,474) is a competitive inhibitor of estrogen action which has found ubiquitous application in the treatment of breast cancer. The drug is the front line endocrine therapy for breast cancer and is the proven treatment of choice for the adjuvant therapy of postmenopausal women with node-positive disease. Tamoxifen is available for the treatment of premenopausal patients with advanced disease, and is being evaluated in clinical trials as an adjuvant therapy for premenopausal patients with either node-positive or node-negative disease. Laboratory studies demonstrate that tamoxifen is a tumoristatic agent and long-term treatment strategies (chemosuppression) should be considered to apply the antiestrogen to its maximal therapeutic advantage. Optimal therapy with tamoxifen may also be achieved by treatment strategies to lower circulating estrogen levels in the premenopausal patient.Tamoxifen is a well tolerated drug, and long-term therapy does not appear to induce metabolic tolerance. Concerns about premature osteoporosis or cardiovascular disease appear to be unfounded because tamoxifen has an appropriate level of target site-directed estrogenic activity. Isolated reports about the growth or appearance of endometrial carcinoma during long-term adjuvant tamoxifen therapy must be balanced against the risks of withholding treatment to patients with a fatal disease.     

三苯氧胺对子宫内膜癌的潜在致癌作用机制

三苯氧胺是一种具有抗雌激素作用的非甾体类化合物,已成为各期乳腺癌患者的一线内分泌治疗药物。但最新的临床研究表明,使用三苯氧胺作为辅助治疗的乳腺癌患者并发子宫内膜癌的危险性增加。通常认为,三苯氧胺在乳腺组织中具有抗雌激素作用,但是在子宫内膜细胞中却表现出类雌激素作用。越来越多的临床试验正聚焦于三苯氧胺与子宫内膜癌的关系,三苯氧胺对子宫内膜的潜在致癌作用机制也成为当前研究的一项热点。     

Some specifics of tamoxifen's effect on the endometrium in menopausal cancer patients

The study has been concerned with evaluation of tamoxifen effect in menopause, the nature of hyperplastic developments taking place in the course of that therapy as well as risk of endometrial carcinoma. Out of 276 breast cancer patients, 135 received tamoxifen whereas the rest were in control. Therapy was found to cause hyperplasia of the basal endometrial stroma. That in turn was followed by such benign changes as endometrial polyp formation. They were represented by an enlarged middle M-echo in ultrasound examination. No enhanced risk of endometrial carcinoma was reported.     

Neues zur Epidemiologie und ?tiologie des Endometriumkarzinoms

Endometrial carcinoma can be distinguished into two types which differ in the clinical pathological features, prognosis, therapy, molecular genetics and risk. Type 1 carcinomas are often well differentiated, clinically less aggressive, estrogen associated and can be treated with anti-estrogens. On the molecular level changes in PTEN, KRAS and β-catenin can be found and in some cases, microsatellite instability (MSI) can be detected. By contrast, type 2 carcinomas most often have a poor prognosis, are not estrogen associated and have a tendency for early metastatic spread. The genes involved are p53 and p16. The precursor lesion of endometrioid carcinoma is atypical hyperplasia of the endometrium. The most likely precursor lesion of serous and clear cell carcinomas is endometrial glandular dysplasia. This lesion is strongly and diffusely positive for p53 and p16, as are invasive serous and clear cell carcinomas. Estrogens have a stimulatory effect on the endometrium, whereas gestagens have an anti-proliferative effect. The effect of tamoxifen on the endometrium is controversial but most likely depends on the hormonal status of the endometrium before therapy with tamoxifen was instituted. It is well known that different types of uterine tumors can develop after tamoxifen therapy. Some of them usually develop in association with hyperestrogenism but others are not associated with increased levels of estrogen. Other important risk factors for the development of endometrial carcinoma are long-term intake of estrogen without gestagen protection, hormonal therapy with gestagen intake for less than 12 days/month, metabolic syndrome with obesity, diabetes mellitus, diet with large amounts of fat, polycystic ovary (PCO) syndrome, nulliparity, early menarche and late menopause. A significant increase in risk for endometrial cancer can also be observed in cases with autosomal-dominant hereditary nonpolyposis colorectal (HNPCC) syndrome.     

Tamoxifen and endometrial adenocarcinoma

The authors report a case of endometrial carcinoma treated with tamoxifen introduced after normal initial uterine curettage. Based on recent experimental and clinical data, the importance of a gynecological follow-up in anti-estrogen therapy is emphasized.     

Effects of tamoxifen therapy on the expression of p27 protein in the endometrium of women with primary breast cancer

The cyclin-dependent kinase inhibitor, p27, has been shown to mediate cell growth arrest thereby significantly reducing the percentage of proliferating cells. It seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis. Our aim was to demonstrate the effects of tamoxifen therapy on the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. Fifty-three pre- and post-tamoxifen treatment endometrium samples were examined immunohistochemically using p27 antibody. Tamoxifen therapy (20 mg/day) for 60 days increased the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. We conclude that tamoxifen therapy does not seem to be directly involved in the carcinogenesis of endometrial carcinoma since the expression of p27 is not decreased.     

Effect of tamoxifen on steroid hormone receptors and creatine kinase activity in human endometrial carcinoma

Estrogen receptor (ER), progesterone receptor (PR) and creatine kinase (CK) were measured in cancerous tissue from 29 post-menopausal patients with endometrial carcinoma under basal conditions and after a short course of tamoxifen treatment. ER and PR were detected in nearly all tumors. CK was detected in all of the tumors examined. After tamoxifen, PR and CK increased simultaneously in 26% of cases, while they were either enhanced, decreased or unmodified in the remainder. No correlation could be found between increase of PR and tumor differentiation. CK, however, was enhanced only in the more differentiated cancers. These results indicate that only a percentage of endometrial cancers are responsive to tamoxifen. It is hypothesized that patients bearing these tumors are those likely to benefit from endocrine therapy.     

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.     

雌激素与抗雌激素制剂对子宫内膜癌细胞株化疗效应的研究

目的 探讨雌激素与抗雌激素制剂对子宫内膜癌细胞化疗效应的影响。方法 采用细胞凋亡ELISA方法检测雌激素、三苯氧胺与阿霉素相互作用后,ER( )RL-952子宫内膜癌细胞的凋亡水平。结果 阿霉素诱发：ER( )RL-952子宫内膜癌细胞产生一定的细胞凋亡水平,雌激素能阻断阿霉素的作用,使细胞凋亡水平下降,呈剂量依赖反应;三苯氧胺也能诱发细胞凋亡,与阿霉素作用后,促进子宫内膜癌细胞凋亡,高于三苯氧胺单一作用产生的细胞凋亡水平,并与三苯氧胺浓度剂量呈正相关。结论 雌激素能阻断阿霉素对子宫内膜癌细胞的细胞凋亡作用,而三苯氧胺能促进阿霉素的作用,三苯氧胺与阿霉素的联合应用有助于为子宫内膜癌临床治疗的选择提供依据。     

Risk factors of endometrial polyps resected from postmenopausal patients with breast carcinoma treated with tamoxifen

BACKGROUND: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. Up to 3% of these polyps may show malignant changes. However, to the authors' knowledge no one has described any risk factor for the development of this pathology in postmenopausal patients with breast carcinoma treated with tamoxifen. OBJECTIVE. The objective of this study was to evaluate whether risk factors can be identified for the development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen. METHODS: The authors reviewed the medical records of 54 postmenopausal patients with breast carcinoma in whom endometrial polyps were resected by hysteroscopy after at least 6 months of tamoxifen treatment (Group I). Demographic characteristics, health habits, risk factors for endometrial carcinoma, and clinical factors related to the primary breast disease were examined. The results were compared with those obtained from 210 similar patients in whom hysteroscopy did not reveal any endometrial pathology (Group II). RESULTS: Age at menopause was significantly older, duration of breast disease was significantly longer, and body weight was significantly heavier among Group I patients compared with Group II patients (P = 0.0162, P = 0.0026, and P = 0.0364, respectively). Endometrial thickness, measured by transvaginal ultrasonography, was significantly thicker in Group I patients (16.3 +/- 7.2 mm) compared with that detected in Group II patients (11.8 +/- 6.3; P = 0.0001). CONCLUSIONS: Various factors, such as older age at menopause, longer duration of breast disease, heavier weight, and thicker endometrium may contribute to the prediction of increased risk of development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen.