Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO).

BACKGROUND: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. METHODS: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. RESULTS: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. CONCLUSION: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. TRIAL REGISTRATION: Trial identification number (Clinical Trials.gov): NCT01965080.Nordic Society of Gynecological Oncology: NSGO-EC-0302.EudraCT number: 2004-001103-35.

Protein profiling of genomic instability in endometrial cancer.

DNA aneuploidy has been identified as a prognostic factor in the majority of epithelial malignancies. We aimed at identifying ploidy-associated protein expression in endometrial cancer of different prognostic subgroups. Comparison of gel electrophoresis-based protein expression patterns between normal endometrium (n = 5), diploid (n = 7), and aneuploid (n = 7) endometrial carcinoma detected 121 ploidy-associated protein forms, 42 differentially expressed between normal endometrium and diploid endometrioid carcinomas, 37 between diploid and aneuploid endometrioid carcinomas, and 41 between diploid endometrioid and aneuploid uterine papillary serous cancer. Proteins were identified by mass spectrometry and evaluated by Ingenuity Pathway Analysis. Targets were confirmed by liquid chromatography/mass spectrometry. Mass spectrometry identified 41 distinct polypeptides and pathway analysis resulted in high-ranked networks with vimentin and Nf-κB as central nodes. These results identify ploidy-associated protein expression differences that overrule histopathology-associated expression differences and emphasize particular protein networks in genomic stability of endometrial cancer.

Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized study.

The purpose of the study was to compare postoperative vaginal irradiation with surgery alone in low-risk International Federation of Gynecology and Obstetrics (FIGO) stage IA-IB endometrial carcinoma. The study was a prospective, randomized trial of 645 evaluable low-risk endometrial carcinoma patients from 6 European gynecologic cancer centers. All tumors were in FIGO stage IA-IB, of endometrioid histological type, and FIGO grade 1-2. High-dose-rate afterloading equipments (iridium [Ir] 192 or cobalt [co] 60) were used at 5 centers, and low-dose-rate (LDR) afterloading equipment (cesium [Cs] 137) at 1 center. Perspex vaginal applicators or ovoids were normally used, and the dose was specified at 5 mm from the surface of the applicator. Three to 6 fractions (3.0-8.0 Gy) were given, and the overall treatment time was 4 to 15 days. A total of 319 patients were treated with surgery plus vaginal irradiation (treatment group), and 326 patients with surgery alone (control group).Twenty-six recurrences (4.0%) were recorded in the complete series. The locoregional recurrence rate was 2.6%, whereas distant metastases occurred in 1.4%. The rate of vaginal recurrences was 1.2% in the treatment group versus 3.1% in the control group. The difference was not statistically significant (P = 0.114). Side effects were few and mild (grade 1-2). Dysuria, frequency, and incontinence were slightly more common after vaginal irradiation (2.8% vs 0.6%, respectively). Late intestinal problems were few and similar in the 2 groups. The conclusions were that the impact of postoperative brachytherapy on even the locoregional recurrence rate seems to be limited in patients with low-risk endometrial carcinoma. The overall recurrence rate and survival were similar in the 2 groups.

Palliation of bone pain in prostate cancer using chemotherapy and strontium-89. A randomized phase II study.

Strontium-89 is an established alternative for the alleviation of bone pain in prostate cancer. There are few data evaluating the effect on pain of palliative chemotherapy. The aim of this randomized phase II study was to assess and compare the analgesic efficacy of strontium-89 and chemotherapy (FEM=5-FU, epirubicin, and mitomycin C) in 35 patients with disseminated, hormone-refractory prostate cancer suffering from persisting bone pain despite analgesic treatment. In order to minimize the risk for imbalances regarding the two patient groups, a double-blind randomization was performed. A significant reduction in pain intensity and pain frequency was registered in both patient groups (P < 0.01 in both groups after 3 weeks). Side effects were generally mild in the strontium-89 group and significantly more severe in the FEM group. The effect of FEM on pain is surprising as chemotherapy has generally only limited effect on tumor growth in bone metastases due to prostate cancer. A possible explanation is that FEM has an inhibitory activity on the inflammatory component of metastases.

2-DE protein expression in endometrial carcinoma.

The objective of this study was to explore the protein expression pattern in normal endometrial mucosa (n = 5) and endometrial carcinoma (n = 15) of low (diploid) and high (aneuploid) malignancy potential by two-dimensional gel electrophoresis (2-DE). The specimens were evaluated for histopathologic subtype, stage and grade in relation to DNA ploidy. A match-set consisting of five samples from normal endometrium, eight diploid and seven aneuploid tumours was created. All the diploid and three of the aneuploid tumours were of endometrioid subtype, while the remaining four were of uterine seropapillary type. There were 192 protein spots differentiating diploid tumours from normal endometrium and 238 protein spots were separating aneuploid tumours from normal endometrium (p < 0.01). A cluster analysis based on 52 significantly deviating protein spots within the groups showed clustering and separation of the normal endometrium, diploid and aneuploid tumours. In conclusion this study showed significant differences in protein expression between normal endometrium and endometrial carcinoma as well as between endometrial carcinoma of low and high malignancy potential. In future studies these results may provide useful in finding new sensitive prognostic markers for endometrial cancer.

Prognostic factors in surgical stage I endometrial carcinoma.

The prognostic impact of DNA ploidy, MIB-1 and p53 was evaluated in relation to clinical and histopathological features in surgical stage I endometrial carcinoma (n = 284) and in the histopathological endometrioid subgroup (n = 257). Tumour material from 284 consecutive patients was analysed regarding image cytometric DNA ploidy and the immunohistochemical MIB-1 and p53 expression. Twenty-four tumours relapsed. In univariate analysis, histopathological subgroup (endometrioid vs. non-endometrioid), grade, DNA ploidy and p53 were highly significant prognostic factors (p < or = 0.001). MIB-1 was also significant (p = 0.039). In the endometrioid subgroup only DNA ploidy and p53 were significant (p < 0.001). In multivariate analysis of the entire material, ploidy and histopathological subgroup retained their significance (p = 0.001, p = 0.004), whereas only ploidy was significant in the endometrioid subgroup (p = 0.001). DNA ploidy was the strongest predictor of relapse-free survival and the only independent prognostic factor in the endometrioid subgroup.

Laminin-5 gamma 2 chain as an invasivity marker for uni- and multifocal lesions in the lower anogenital tract.

During recent decades it has become apparent that there are two types of vulvar disease: the classic type found in elderly women with unicentric and unifocal lesions, and the type found in younger women, in which precancerous and invasive changes develop in the anogenital lower tract in a multicentric and multifocal fashion, often over a long period of observation. The laminin-5 gamma 2 chain is an extracellular protein that is a component of the basement membrane. Recently its expression has been recognized as a marker in cervical cancer that permits identification of invasive capacity. The aim of our study was to determine if laminin-5 gamma 2 chain antibody can act as a sensitivity marker of invasive capacity in precancerous and invasive carcinoma in women with uni- and multifocal changes in the anogenital tract. The result showed that all patients in the older group of women with invasive carcinoma of the vulva had moderate to high positive expression of the laminin-5 gamma 2 chain. In the group of younger patients with multifocal precancerous changes observed over long periods, most of the patients with vulva intraepithelial neoplasia (VIN) 3 showed laminin-5 gamma 2 chain positivity already in the precancerous changes, and all of them developed invasivity during the period of observation. Normal epithelium without atypia was mostly negative or of low immunoreactivity of laminin-5. In conclusion, positive laminin-5 gamma 2 chain expression seems to indicate the invasiveness potential of precancerous lesions and is also expressed in all investigated invasive carcinomas of the anogenital tract.