Molecular clustering of endometrial carcinoma based on estrogen-induced gene expression.

Identification of biomarkers potentially provides prognostic information that can help guide clinical decision-making. Given the relationship between estrogen exposure and endometrial cancer, especially low grade endometrioid carcinoma, we hypothesized that high expression of genes induced by estrogen would identify low risk endometrioid endometrial cancers. cDNA microarray and qRT-PCR verification were used to identify six genes that are highly induced by estrogen in the endometrium. These estrogen-induced biomarkers were quantified in 72 endometrial carcinomas by qRT-PCR. Unsupervised cluster analysis was performed, with expression data correlated to tumor characteristics. Time to recurrence by cluster was analyzed using the Kaplan-Meier method. A receiver operating characteristic (ROC) curve was generated to determine the potential clinical utility of the biomarker panel to predict prognosis. Expression of all genes was higher in endometrioid carcinomas compared to non-endometrioid carcinomas. Unsupervised cluster analysis revealed two distinct groups based on gene expression. The high expression cluster was characterized by lower age, higher BMI, and low grade endometrioid histology. The low expression cluster had a recurrence rate 4.35 times higher than the high expression cluster. ROC analysis allowed for the prediction of stage and grade with a false negative rate of 4.8% based on level of gene expression in endometrioid tumors. We have therefore identified a panel of estrogen-induced genes that have potential utility in predicting endometrial cancer stage and recurrence risk. This proof-of-concept study demonstrates that biomarker analysis may play a role in clinical decision making for the therapy of women with endometrial cancer.

[Menopause in 2004: "hormone replacement therapy" is not what it used to be anymore]. / Ménopause en 2004: le "traitement hormonal substitutif" n'est plus ce qu'il était.

PURPOSE: The data concerning post-menopausal hormone replacement therapy (HRT) were recently completely modified. The aim of this review is to present the last studies about post-menopausal HRT and to describe new alternatives to this treatment. CURRENT KNOWLEDGE AND KEY POINTS: In May 2002, the women's health initiative (WHI) trial of post-menopausal HRT was interrupted earlier than expected. The studied hormonal formulation in this arm of the WHI trial was the association of conjugated equine estrogens and medroxyprogesterone. The reason for termination was an increased risk of breast cancer and myocardial infarction in the hormone-therapy group. Later, reports confirmed that this type of HRT could not be used any more for the primary prevention of coronary heart disease even if the absolute risk remained low. There is an increased risk for venous thromboembolism with post-menopausal estroprogestative replacement. This risk does not seem to exist with transdermal estrogens. The other WHI findings concerned the lack of protection against dementia and cognitive decline. On the contrary, osteoporotic hip fractures and colorectal cancers were reduced in the treated group. In April 2004, the estrogen only arm of the same WHI study was also prematurely interrupted because of an increase in the incidence of stroke. The risk of breast cancer was on the contrary not increased after 6.8 years, raising the question of the eventual role of progestins. PERSPECTIVES: The impact of the WHI trial on clinical practice was very important since then. The "Agence Francaise de sécurité sanitaire des produits de santé" (AFSSAPS) edited in May 2004 a public recommendation limiting indication for HRT to patients with severe climacteric symptoms. The treatment must now be prescribed for the shortest time and at the minimal dose. The patient has to be precisely informed about the risks with HRT and the practitioner has to re-evaluate his prescription annually. Hormonal or non-hormonal alternatives have also to be considered as phytoestrogens and tibolone for hot flashes, and raloxifene and diphosphonates for osteoporosis prevention. In any case, a healthy diet, exercise and smoking cessation should be encouraged.

Low-dose esterified estrogens (0.3 mg/day): long-term and short-term effects on menopausal symptoms and quality of life in postmenopausal women.

OBJECTIVE: To study the impact of low-dose unopposed esterified estrogens on menopausal symptoms and quality of life. METHODS: In a long-term, 2-year, randomized, double-blind, placebo-controlled study, 204 postmenopausal women were treated with esterified estrogens 0.3 mg daily or placebo. Menopausal symptoms were assessed with a modified Kupperman index at baseline, 3, 6 and thereafter every 6 months. In a second 12-week, open-label, short-term pilot study, 25 postmenopausal women with moderate to severe vasomotor symptoms were treated with esterified estrogens 0.3 mg daily for 12 weeks. Vasomotor symptoms and quality of life were assessed using the Greene scale and Quality of Life Menopause Scale (QUALMS). RESULTS: In the long-term study, significant (p < 0.05) reductions in total symptom scores were observed at each time point with esterified estrogens compared with placebo. Somatic symptom scores (hot flushes, night sweats, vaginal dryness) decreased significantly (p < 0.01) in patients treated with esterified estrogens 0.3 mg compared to baseline and placebo. In the short-term, open-label pilot study, the incidence of vasomotor symptoms was significantly (p < 0.01) reduced with esterified estrogens 0.3 mg from week 4 until the study end. Significant (p < 0.05) improvements versus baseline were seen in the somatic and vasomotor/sleep domains and in the total quality-of-life score. CONCLUSIONS: Esterified estrogens 0.3 mg given daily provide adequate menopausal symptom relief and improved quality of life in postmenopausal women.