Steroid-converting enzymes in human ovarian carcinomas.

Anti-estrogen therapies for treating ovarian carcinoma have had mixed outcomes suggesting some tumors may be estrogen-dependent. We assayed the activity levels of 17beta-hydroxysteroid dehydrogenase (17beta-HSD), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD/3-KSR) and estrone sulfatase in a series of ovarian epithelial carcinomas. 17beta-HSD activity ratios with estradiol (E(2)) and testosterone (T), and inhibition by isoform-specific inhibitors were used to estimate the contributions of 17beta-HSD isoforms. Activity levels were highest for estrone sulfatase, followed, respectively by 17beta-HSD, 3alpha-HSD/3-KSR, and 3beta-HSD. E(2)/T activity ratios varied widely between samples. A 17beta-HSD type 1 inhibition pattern was observed in 23% of the samples and a type 2 pattern in 25%. E(2) formation from estrone sulfate (E(1)S) was detected in 98% (47/48) of the samples. 17beta-HSD type 1, type 2 and type 5 mRNA was detected in matched primary tumor and metastases. Evaluation of 17beta-HSD and sulfatase activity levels, activity ratios and inhibition patterns may help predict tumor response to endocrine therapy.

Estrone sulfatase activity in patients with advanced ovarian cancer.

INTRODUCTION: We sought to identify whether the sulfatase pathway was present in ovarian cancer specimens and then to determine whether a clinical correlation existed between sulfatase activity and survival. MATERIALS AND METHODS: Enzymatic activity was assessed in advanced ovarian cancer specimens via thin layer chromatography and standardized against total protein. All enzyme activities are reported in pmol/mg protein/30 min. Kaplan Meier curves of progression-free and overall survival were constructed to compare outcomes between patients with low sulfatase activity and high sulfatase activity. Median survival rates were compared using the log-rank test for survival curves. Differences in proportions between patients with low sulfatase activity versus high sulfatase activity were compared with the z-test or chi-square analysis as appropriate. RESULTS: 37 specimens from patients with advanced stage ovarian cancer were analyzed. Enzymatic activity was detected in all specimens except one. Median progression-free survival was 23.5 months for patients with low sulfatase activity compared to 6.9 months for patients with high sulfatase activity (p=0.008). Median overall survival favored the low sulfatase group (50.8 vs. 30.6 months respectively), though statistical difference was not detected (p=0.16). No other difference in clinical characteristics between patients with high or low sulfatase activity was detected. CONCLUSIONS: Sulfatase activity is widely present in ovarian cancer specimens. Increased sulfatase activity is associated with worse progression-free survival in patients with advanced stage ovarian cancer. The sulfatase pathway is a potential therapeutic target in the treatment of ovarian cancer.

Testing of two binary grading systems for FIGO stage III serous carcinoma of the ovary and peritoneum.

OBJECTIVE: A variety of histologic grading systems for ovarian carcinoma have been used, but there is no widely accepted system. Binary grading systems are inherently superior to the more common three-grade systems because they are more reproducible and they correspond to the number of options in the binary treatment decision for which grade is considered important: the use of or withholding of chemotherapy. METHODS: One hundred thirteen unselected FIGO stage III serous carcinomas of the ovary and peritoneum were tested with two grading systems: a binary system recently proposed by investigators at MD Anderson Cancer Center (MDACC) and a new binary system we formulated at the Washington Hospital Center (WHC). Both of these systems are based on nuclear grade. The WHC system has a higher threshold of nuclear size for diagnosing high-grade tumors. RESULTS: The WHC system separated the cases into 89 high-grade and 24 low-grade tumors. The median survival rates were 30 and 49 months for high and low grade respectively, and the actuarial survival curves were not significantly different (P > 0.10). The MDACC system separated the cases into 103 high-grade and 10 low-grade tumors. With this system, low-grade tumors were significantly more likely than high grade to be stage IIIA (P < 0.05) and occurred at a mean age of 57 years compared to 65 years for high-grade tumors (P < 0.05). Low-grade tumors were suboptimally debulked in 10% of cases compared to 27% for high-grade tumors (P > 0.05). The median survival for high-grade tumors was 34 months, and the median for low grade has not been reached. The actuarial survival curves were not significantly different (P = 0.065). CONCLUSION: The MDACC grading system appears more promising than the WHC system. The MDACC system separates a small (9% of advanced stage serous carcinomas) but distinctive well-differentiated tumor which usually has the appearance of invasive low-grade (micropapillary) serous carcinoma. The rarity of this tumor, however, will require a larger series to demonstrate prognostic value. The WHC system, which was designed to enlarge the low-grade group to a size that would be more meaningful in clinical practice, did not demonstrate a survival difference. The failure of the WHC system suggests that attempts to enlarge the low-grade group using histologic features alone are unlikely to be successful. The potential for confounding of grade with substage, volume of residual disease and patient age are issues that may impede determination of the independence of tumor grade in prognosis, and more data, especially for low-grade tumors, are needed.