Estrogen receptor expression in an endometrial stromal sarcoma after tamoxifen therapy

INTRODUCTION: Several cases of low-grade endometrial stromal sarcomas in women with breast cancer have been reported to be associated with tamoxifen therapy. Estrogen receptor expression has been used to characterize the partial estrogenic action of tamoxifen on the endometrium and has been found in tamoxifen-associated endometrial pathologies. CASE: A low-grade endometrial stromal sarcoma in a woman with a history of breast cancer treated with adjuvant tamoxifen is presented. Steroid receptor studies performed on the tumor were negative for estrogen and positive for progesterone. CONCLUSION: The absence of estrogen receptor expression suggests that endometrial stromal sarcomas are not necessarily caused by the estrogenic properties of tamoxifen.     

Endometrial lesions in patients undergoing tamoxifen therapy.

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

Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment

Aberrant DNA methylation is an important molecular alteration commonly detected in various malignancies. Hypermethylation and expression silencing have been frequently found in multiple genes including those for steroid receptors, tumor suppressors, and DNA repair factors. Differential DNA methylation patterns are detected in type I and type II endometrial cancers, suggesting divergent epigenetic backgrounds and unique tumorigenic pathways. In this review, the implications of new findings in the field of epigenetics are discussed for endometrial cancer prevention, diagnosis, and treatment. DNA methylation-based assays may be explored as a useful adjunct diagnostic tool. Epigenetic modification reagents, including DNA methyltransferase and histone deacetylase inhibitors, when used alone or in combination with conventional chemotherapy, may be beneficial for endometrial cancer patients. Recent studies on epigenetic reactivation of the progesterone receptor provide a novel approach for re-sensitization of advanced, PR-negative endometrial cancers to progestational therapy.     

Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports

Abstract. Rose PG, Brandewie EV, Abdul-Karim FW. Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports.
Tamoxifen's agonist effect on the endometrium has been associated with an increased incidence of endometrial carcinoma. It has been suggested that this agonist effect may be averted by the concomitant use of a progestational agent. We report two patients with breast cancer receiving tamoxifen who developed endometrial carcinoma and atypical endometrial hyperplasia, respectively. In one patient, this occurred despite the use of concomitant megestrol acetate. In the other patient, tamoxifen-associated endometrial hyperplasia persisted and progressed despite cessation of tamoxifen and initiation of megestrol acetate therapy. These cases may have implications for strategies to avert tamoxifen induced endometrial neoplasia.     

The prognostic value and clinical utility of estrogen and progesterone receptors in endometrial carcinoma

In the United States, endometrial carcinoma is the most common gynecologic malignancy, and accounts for 4,900 deaths per year in the United States. While this disease has relatively good cure rates, there is motivation to describe other determinants, which may help in the treatment of this disease. Attempts have been made to correlate hormone receptor status with disease-free intervals and survival in patients with endometrial carcinoma. The weight of evidence seems to support that of the two hormone receptors, progesterone is the more significant predictor of patient outcome. If hormone receptors are to be used in the management of endometrial carcinoma, they should be determined by immunohistochemistry. In the adjuvant setting, patients with progesterone positive tumors are more amenable to treatment with progestational agents than are patients with receptor negative tumors. Future areas of research include the use of tamoxifen and selective estrogen receptor modulators in the chemoprevention and treatment of endometrial carcinoma.     

Down-regulation of bcl-2 is a potential marker of the efficacy of progestin therapy in the treatment of endometrial hyperplasia

OBJECTIVE: The objective of this study was to evaluate the expression of bcl-2, a regulatory protein in programmed cell death, in endometrial hyperplasia before and after progestational therapy. METHODS: Pre- and posttreatment paraffin-embedded endometrial tissue samples from 20 women with an initial diagnosis of endometrial hyperplasia were obtained from archived files. Cases were evaluated and classified as either complete resolution of hyperplasia or persistent hyperplasia in response to progestin treatment. Sections were examined for bcl-2, estrogen receptor, and progesterone receptor expression using immunohistochemistry and compared within the treatment response groups. RESULTS: Among the 20 women studied, 13 had complete regression of their hyperplasia with progestin treatment and 7 had evidence of persistent disease after therapy. Bcl-2 expression was significantly decreased after treatment from a mean reactivity score of 2.08 to 0.31 (P = 0.0005) in the group of patients whose hyperplasia completely regressed with progestin administration. Among the women who had persistent hyperplasia after therapy, no significant change was observed between pre- and posttreatment bcl-2 expression, with a mean reactivity of 1.86 to 1. 29, respectively (P = 0.075). Progestational therapy significantly decreased the status of estrogen receptors from a mean score of 2.08 to 0.46 (P = 0.0005) in completely resolved cases of hyperplasia and from 2.00 to 0.43 (P = 0.0025) in persistent hyperplasias. Treatment also significantly decreased the status of progesterone receptors from a mean reactivity score of 1.92 to 0.31 (P = 0.0005) in cases of regressed hyperplasia and from a mean reactivity of 1.86 to 0.29 (P = 0.005) in persistent cases of hyperplasia. CONCLUSIONS: Bcl-2 expression decreases following successful progestin treatment of endometrial hyperplasias, whereas it remains expressed in hyperplasias which persist despite progestational therapy. This suggests that bcl-2 expression may represent a component of the therapeutic effects exerted in the endometium during progestational therapy in the treatment of hyperplasia. The activity of the oncoprotein may be a potential measure of the progress of treatment.     

The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer

PURPOSE OF REVIEW: Hormone therapy has been palliative for advanced/ recurrent endometrial cancer. High remission rates are seen in well-selected stage I, grade 1 endometrial cancer of young women using hormone therapy (usually progestins) as fertility-preserving treatment. Many other hormones, such as gonadotropin-releasing hormone analogs (GnRHa), selective estrogen receptor modulators, aromatase inhibitors, intrauterine progestins, and others are potential modalities. This review updates the recent publications in this area. RECENT FINDINGS: Two reports investigating different scheduling of tamoxifen and progestins indicated that tamoxifen may be a valuable adjunct to progestin therapy. GnRHa has been used adjunctively to tamoxifen as second-line hormone therapy for fertility sparing after progestin failed. Aromatase inhibitors have shown their potential in treating endometrial cancer and endometrial hyperplasia as single agent or in combination with progestins. Intrauterine progestins seem efficacious in treating endometrial hyperplasia; its applications on endometrial cancer patients, however, have been limited to postmenopausal women with poor surgical risk. SUMMARY: Translational research based on molecular mechanisms is mandatory to a more appropriate utilization of hormone therapy. The role of dose, scheduling, route of administration of progestins as well as the addition of other hormonal agents should be further explored by well designed randomized controlled trials.     

Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma

OBJECTIVES: Tamoxifen is a nonsteroidal triphenylethylene derivate with a predominant antiestrogen activity, used in the endocrine treatment of breast and endometrial cancer. It is not known which endometrial carcinomas will respond favorably to tamoxifen and which ones will not. The aim of this study was to find out whether tamoxifen has an effect on hormone steroid receptors, hormone concentration, DNA content, and proliferative activity in endometrial cancer and to correlate the tamoxifen-induced changes with pathologic parameters such as clinical stage, tumor differentiation, depth of invasion, and histologic type. METHODS: Thirty postmenopausal women with endometrial carcinoma were treated with 30 mg of tamoxifen daily for 7-10 days after curettage. Steroid hormone receptors (estrogen and progesterone receptors), levels of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, progesterone, testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and DNA ploidy and proliferative activity were determined before and after therapy. The patients were also divided into favorable and unfavorable prognosis groups according to classical histological parameters. The patients in the favorable group consisted of patients with stage I disease, well and moderately differentiated tumors, favorable histologic type, and a depth of myometrial invasion of less than (1/3). The patients with only one of the unfavorable parameters (clinical stage II or III, poorly differentiated tumors, unfavorable histologic types, and deeper invasion of myometrium) were included in the unfavorable prognosis group. RESULTS: After the treatment, there was a net increase in the progesterone receptors and sex hormone binding globulin and a significant decrease in the estrogen receptors. The increase in progesterone receptors and decrease in estrogen receptors occurred in the patient group with favorable prognosis regarding histologic type, degree of differentiation, and clinical stage, but also in the unfavorable prognosis group regarding the depth of myometrial invasion. Statistically significant decrease in the follicle-stimulating hormone concentration was observed in the groups with favorable prognosis regarding histologic type, depth of myometrial invasion, and grade of differentiation. Concentration of sex hormone binding globulin was significantly increased in groups with favorable prognosis if histologic type and grade of differentiation were taken into account. On the other hand, there was a significant decrease in the concentration of luteinizing hormone in the group with unfavorable histologic type and also a decrease in progesterone concentration in patients with unfavorable prognosis regarding the grade of differentiation. There was no statistical significance either in the concentrations of other hormones measured or in the DNA analysis by flow cytometry. CONCLUSIONS: Our results revealed that tamoxifen can increase progesterone receptors and decrease estrogen receptors in endometrial cancer. The effect was most pronounced in tumors with favorable clinicopathologic parameters. We conclude that tamoxifen therapy can induce progesterone receptor synthesis even in tumors with low initial progesterone receptor levels, making such tumors potentially responsive to additional hormonal therapy with progesterone.     

Uterine Blutungen bei internistischen Grunderkrankungen

Clinical management of unscheduled uterine bleeds in women using hormone replacement therapy (HRT) involves reconsideration of the selected individual therapy. Special attention should be given to the dose of the estrogen and progestin, the adequacy of both the progestin phase and the regimen – sequential or continuous combined therapy. A progestin should be administered for at least 10 days. It is unknown whether tibolone is an alternative for women with irregular bleeding on continuous combined therapy. These considerations also apply to women with uterine myoma. Transvaginal sonography may help identify women with thickened endometrium demanding histopathological assessment. Various controlled clinical trials suggest different cut-off values for a “normal” endometrial thickness (double-layer). A threshold of 7 mm appears to offer a reasonable compromise between sensitivity and specificity. A single episode of bleeding in the presence of an endometrial thickness ≤ 4 mm may allow for follow-up without endometrial sampling. Adherence to HRT may be enhanced by selecting the lowest doses of estrogens and progestins, including progesterone, achieving alleviation of climacteric symptoms without compromising endometrial safety. Parenteral use of estrogens and progestins is preferable in women with impaired liver function, as this mode of administration avoids the first-pass effect. This relatively small group of women may be eligible for replacement therapy if hepatic function reaches an equilibrium prior to initiation of therapy. Scarce clinical data indicate that systemic lupus erythematosus appears to deteriorate in women using HRT. However, other studies suggest that biliary cirrhosis does not deteriorate in women on HRT. HRT is possible in women with chronic renal and bone diseases. The outlined management of uterine bleeding also applies to these women. Uterine bleeding may occur with use of tamoxifen and less frequently with raloxifene, which is approved for the prophylaxis and treatment of postmenopausal osteoporosis. Transvaginal sonography may identify women with uterine stimulation, as indicated by the presence of subendometrial cysts and thickened endometrium, and preselect patients for endometrial sampling to exclude hyperplasia and cancer. The sensitivity and specificity of a single measurement of endometrial thickness is limited and additional tests such as saline infusion sonography may enhance the predictive value of the ultrasound assessment. The baseline frequency of postmenopausal bleeding does not appear to be increased in women who use raloxifene. Preliminary data suggest that use of raloxifene is not associated with an increased risk of endometrial cancer as is tamoxifen. SERMs constitute a relative contraindication in women with severe impairment of liver function.     

Is levonorgestrel intrauterine system effective for treatment of early endometrial cancer? Report of four cases and review of the literature

BACKGROUND: Intrauterine progesterone therapy potentially provides a simple alternative treatment for women with Stage I Grade I endometrial cancers who are at high risk for surgery. The case histories of four women with early endometrial cancer primarily treated with levonorgestrel intrauterine system (Mirena) are reported and the literature reviewed. CASES: Four women had Stage I grade 1 endometrial adenocarcinoma with positive progesterone receptor. All were assessed to be in American Society of anaesthesiologists risk class IV. After insertion of mirena intrauterine system, one woman (25%) had complete histological regression of disease within 6 months. One of three women who did not respond to treatment subsequently had a vaginal hysterectomy, which showed endometrial cancer with superficial myometrial invasion. CONCLUSION: This report raises doubts about the effectiveness of intrauterine progesterone therapy as a definitive alternative for the treatment of early endometrial cancer.     

Tamoxifen and endometrial carcinoma: alterations in estrogen and progesterone receptors in untreated patients and combination hormonal therapy in advanced neoplasia

Estrogen receptors and progesterone receptors were measured in tumors from patients with previously untreated endometrial carcinoma before and after a 5-day course of tamoxifen citrate. On initial biopsy, 13 of 25 tumors (52%) were progesterone receptor-positive, whereas 21 of 25 tumors (84%) were progesterone receptor-positive after tamoxifen. Grades 1 and 2 tumors were more likely to demonstrate this increased incidence of measurable progesterone receptors. Considering these results, and the work of others who have shown that progesterone receptor-positive metastatic endometrial cancer is more responsive to progestin therapy than are progesterone receptor-negative tumors, we instituted a phase II clinical trial of tamoxifen plus progestin for patients with recurrent endometrial carcinoma. Thus far, however, the 33% total response rate achieved with the combination therapy has not been superior to standard progestin therapy.     

Tamoxifen, screening and new oestrogen receptor modulators

Tamoxifen is a selective oestrogen receptor modulator (SERM) with anti-oestrogenic properties in the breast and oestrogenic effects in tissues such as bone and the cardiovascular system. It is an excellent breast cancer drug for all stages of the disease. Its SERM profile makes it a valuable alternative to hormone replacement therapy, especially for women at high risk of breast cancer. Tamoxifen, however, increases the incidence of benign and malignant lesions of the uterus. Secondary prevention of these, early detection and treatment, is feasible but not cost-effective in breast cancer patients because potential endometrial risks do not outweigh beneficial effects in the breast. This may be different in healthy women with an as yet unknown benefit on breast cancer mortality.We review the literature on the importance of tamoxifen's endometrial lesions and balance available evidence on whether and how best to screen them. In a subset of tamoxifen users it seems advisable to assess the uterine cavity prior to intake with a yearly endometrial assessment as pointed out, starting 3 years after initiation of treatment. In most cases there is endometrial thickening on ultrasonographic assessment and additional tests such as hydrosonography or hysteroscopy are required to confirm an empty atrophic uterus as remains the case in most asymptomatic women on tamoxifen.Newer compounds, such as raloxifene, have a similar SERM profile to tamoxifen but are neutral on the uterus. This has recently been proven by 3 years of endometrial follow-up data. Longer endometrial safety will hopefully confirm these early findings. Whether other SERMs in development are better, and which of them is better for the breast, is to be demonstrated in ongoing studies.     

Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients

Tamoxifen citrate, a nonsteroidal antiestrogen with agonistic properties, is prescribed as an adjuvant to surgery in the treatment of breast cancer. Recent reports have suggested that tamoxifen has an estrogenic property and may be implicated in the development of endometrial carcinomas. Seven new cases are reported to the existing literature in which endometrial carcinomas developed in postmenopausal women on tamoxifen therapy for breast carcinomas.     

Modulation of endometrial steroid receptors and growth regulatory genes by tamoxifen

OBJECTIVE: We investigated tamoxifen's effects on the expression of growth regulatory genes in the endometrium to identify the mechanism by which tamoxifen induces proliferation. METHODS: Using immunohistochemical techniques, we analyzed 39 endometrial specimens for expression of Ki-67, lactoferrin, transforming growth factor-alpha, tumor necrosis factor receptor-II, adrenomedullin, estrogen receptors, and progesterone receptors. Twenty specimens were obtained from postmenopausal breast cancer patients treated with tamoxifen (20 mg/day) for at least 6 months to include two endometrial adenocarcinoma specimens. Five secretory phase, three proliferative phase, and seven atrophic endometrial specimens were used as controls. In addition, four endometrial adenocarcinoma specimens were reviewed from patients not treated with tamoxifen. Intensity of immunostaining was quantified using digitized imaging techniques. RESULTS: Overexpression of both estrogen receptors and progesterone receptors, and an elevated proliferative index were the most consistent effects observed in benign endometrial specimens from tamoxifen-treated patients compared with atrophic controls (P <. 003). This staining pattern was also evident in adenocarcinomas from patients who received tamoxifen. Benign endometrium from tamoxifen-treated patients also expressed transforming growth factor-alpha, tumor necrosis factor receptor-II, lactoferrin, and adrenomedullin at levels comparable with those found in proliferative endometrial specimens. CONCLUSION: These data provide further documentation that the uterotropic effects of tamoxifen may be due, at least in part, to the induction of estrogen receptors and progesterone receptors, as well as other genes associated with the proliferative phase. Furthermore, analysis of estrogen receptors, progesterone receptors, and Ki-67 may be useful in identifying postmenopausal individuals on tamoxifen, who are at increased risk for developing endometrial cancer.     

Hormonal treatment of endometrial cancer: past, present and future

The concept that hormonal therapy may be useful in the treatment of endometrial cancer antedated the pharmaceutical availability of progestational compounds. By 1959, initial studies demonstrated the ability of progestins to reverse endometrial hyperplasias. Thereafter, progestins and other hormonal agents have been used in various roles as treatment for endometrial cancers. This chapter reviews the use of hormonal agents for the treatment of primary and metastatic/recurrent endometrial cancer, as well as such treatment in an adjuvant setting. Major problems in enhancing the efficacy of endocrine therapy of cancers arising from hormonally responsive tissues are also considered. The regulations of steroid-hormone receptor expression in endometrial and breast cancers continues to be an active area of research interest.     

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

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

The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study

OBJECTIVE: To evaluate the risk of endometrial cancer in women who carry a deleterious mutation in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: Women known to carry a BRCA1 or BRCA2 mutation, aged 45 to 70, were identified from an international registry and were followed prospectively. A total of 857 women completed a baseline questionnaire and one or more follow-up questionnaires. Study subjects were followed until diagnosis of endometrial cancer, ovarian cancer, death or the date of completion of the last questionnaire. The expected number of endometrial cancers was calculated using age and country-specific incidence rates. RESULTS: After an average follow-up period of 3.3 years, six women were diagnosed with endometrial cancer, compared to 1.13 cancers expected (SIR=5.3, p=0.0011). Four of these six patients used tamoxifen in the past. The risk among women who were never exposed to tamoxifen treatment was not significantly elevated (SIR=2.7, p=0.17), but among the 226 participants who had used tamoxifen (220 as treatment and six for the primary prevention of breast cancer) the relative risk for endometrial cancer was 11.6 (p=0.0004). CONCLUSION: The main contributor to the increased risk of endometrial cancer among BRCA carriers is tamoxifen treatment for a previous breast cancer. The risk and benefits of prophylactic hysterectomy should be discussed with women with a BRCA mutation considering tamoxifen therapy.     

Anastrozole, an aromatase inhibitor, and medroxyprogesterone acetate therapy in premenopausal obese women with endometrial cancer: a report of two cases successfully treated without hysterectomy

BACKGROUND: Hormonal therapy for endometrial cancer is occasionally warranted in the premenopausal woman who is interested in maintaining fertility. Combining progesterone with an agent that eliminates the adipose production of estrogen will theoretically be more effective than progesterone alone. CASES: Two cases of reproductive-aged women with grade 1 endometrial cancer who were treated with medroxyprogesterone acetate and anastrozole daily for 3 and 6 months subsequently reverted to normal endometrium. CONCLUSION: Progesterone combined with the elimination of adipose production of estrogen may be an effective therapy in well-differentiated endometrial cancer in the obese premenopausal woman.     

Tamoxifen and giant endometrial polyps

Tamoxifen is a synthetic non-steroid anti-estrogen that has been used effectively for several years in the adjuvant treatment of breast cancer. Although its therapeutic effect is due to its anti-estrogenic properties, the drug also shows modest type B estrogen-receptor agonist activity during the menopausal period in which estrogens are at a low level. Owing to the fall in estrogen levels in menopause, tamoxifen provokes an up-regulation of both estrogen and progesterone receptors at an endometrial tissue is a direct consequence of this. This proliferation, which is the result of an inappropriate response of the basal layer and the basis for the onset of hyperplasia and polyps in the tissue. At standard therapeutic dosages, tamoxifen in postmenopausal women is associated with the onset of alterations in the vaginal and endometrial epithelium. Cases of endometrial hyperplasia, endometrial polyps, adenomyosis, endometriosis and fibromyomas are described in the literature. Endometrial polyps represent the most common pathology associated with TAM in women with previous breast cancer in menopause. The estrogenic stimulus to polyps following TAM treatment may be considerable, resulting in their growth to sizeable proportions, causing metrorrhagia and suspected neoplastic pathology. Two cases of patients receiving adjuvant treatment with tamoxifen for previous breast cancer, who presented two giant endometrial polyps of uncommon dimension, are reported.     

Endometrial carcinoma in tamoxifen-treated breast cancer patient: clinicopathological, immunohistochemical, and genetic analysis.

Endometrial polyps and endometrial neoplasms are a recognized complication of chronic tamoxifen treatment. This study describes an endometrial carcinoma that developed in a woman receiving low-dose tamoxifen treatment for breast cancer. Little is known about steroid receptor status, somatic alterations in oncogenes and tumor suppressor genes, and inherited susceptibility in endometrial carcinomas associated with tamoxifen use. In the present case, the endometrial carcinoma was negative for estrogen receptors and weakly positive for progesterone receptors. In addition, analysis of K-ras, c-erbB2/neu, cyclin D1, and p53 status revealed a codon 12 point mutation in the K-ras oncogene. The patient was determined not to be a carrier of germ-line mutations in cytochrome P-450 1A1 (CYP1A1), an estrogen-metabolizing gene previously associated with enhanced endometrial cancer risk, but she was a carrier of a methylenetetrahydrofolate reductase gene variant related with putative alterations in DNA methylation.