Harriet O. Smith

Estrogen Signaling through the Transmembrane G Protein–Coupled Receptor GPR30

Steroids play an important role in the regulation of normal physiology and the treatment of disease. Steroid receptors have classically been described as ligand-activated transcription factors mediating long-term genomic effects in hormonally regulated tissues. It is now clear that steroids also mediate rapid signaling events traditionally associated with growth factor receptors and G protein-coupled receptors. Although evidence suggests that the classical steroid receptors are capable of mediating many of these events, more recent discoveries reveal the existence of transmembrane receptors capable of responding to steroids with cellular activation. One such receptor, GPR30, is a member of the G protein-coupled receptor superfamily and mediates estrogen-dependent kinase activation as well as transcriptional responses. In this review, we provide an overview of the evidence for the cellular and physiological actions of GPR30 in estrogen-dependent processes and discuss the relationship of GPR30 with classical estrogen receptors.

Incidence and survival rates for female malignant germ cell tumors.

OBJECTIVE: To evaluate 30-year, population-based trends in incidence and survival rates for malignant germ cell tumors originating within the female genital tract. METHODS: Surveillance, Epidemiology, and End Results data were used to identify malignant germ cell tumors (1973–2002). Overall and 5-year incidence rates, estimated annual percentage change, and survival rates were calculated and compared by age at diagnosis, race, stage, and histology. RESULTS: Of 1,262 cases, there were 414 (32.8%) dysgerminomas, 449 (35.6%) immature teratomas, 37 (2.9%) mature teratomas with malignant degeneration, and 362 (28.7%) mixed germ cell tumors. The 30-year, age-adjusted incidence rate per 100,000 women-years was 0.338, decreasing by 29.4% for dysgerminomas (P = .18) and by 31.5% for mixed germ cell tumors (P = .22). Other nonwhites had higher rates than whites and blacks, but dysgerminoma rates were higher in whites and other nonwhites than in blacks. Using the registries for expanded races, rates were higher for Asian/Pacific Islanders (P = .059) and Hispanics (P = .07). By age at diagnosis, 15–19 year olds had the highest rates and the only significant change in rates (37.5% increase, P = .008). The 5-year relative survival was 83.9%. Survival rates improved significantly over calendar time and varied by histologic subtype, race, stage of disease, and age at diagnosis. CONCLUSION: Over the past 30 years, germ cell tumor incidence rates have declined in women and differ from rising trends reported for testicular tumors. Survival rates have improved but were lower for older women and for nondysgerminoma subtypes. LEVEL OF EVIDENCE: II-3

Aggressive angiomyxoma of the female pelvis and perineum: Review of the literature

Aggressive angiomyxoma is an uncommon neoplasm which predominantly involves the pelvis and perineum of young White females. Misdiagnosis is common. Treatment typically involves surgery, and in spite of apparently complete resection, recurrences are common. Local spread into the adjacent fascia and musculature is frequently reported, and rarely, extension into intestine and bladder. The first reported case of pubic bone involvement, including its histology, radiologic features, and operative management, is discussed. Including this patient, 26 women with this tumor have been reported in the literature and are reviewed, along with 2 previously reported cases from the University of New Mexico Tumor Registry.

Gestational trophoblastic disease epidemiology and trends.

Introduction Gestational trophoblastic disease (GTD) comprises a spectrum of interrelated placental trophoblastic lesions that vary in predilection for spontaneous resolution, local invasion, and metastasis. All GTD variants arise following an antecedent pregnancy, usually, but not always, the one temporally related. Despite extensive epidemiological data spanning at least 50 years, the extent to which genetic and environmental factors including race, age, and geographic location influence the variably in reported differences in incidence rates for GTD throughout the world is uncertain. While multiple factors contribute, many of the differences in reported incidence rates can be accounted for by the following observations: ● GTD is an uncommon condition. Some variants (choriocarcinoma, placental site trophoblastic tumor) are exceedingly rare. ● Until recently, no uniform classification system with clear, precise, and reproducible definitions existed. Inconsistently applied terminology, such as destructive mole, transitional mole, invasive mole, and hydropic degeneration made meaningful comparisons across studies difficult or impossible. ● Rapid advances in radiographic and cytogenetic methodologies have greatly enhanced the characterization of ambiguous cases. However, there is enormous variability throughout the world, and within any given nation, in availability and application of newer technology. ● Census-based denominators that accurately and reproducibly reflect denominators of the population at risk were not available and their significance was not well understood. Incidence rates were typically derived using hospital-based recorded live births, pregnancies, and deliveries. ● Regional and national tumor registries that recorded all incidence cases by histologic subtype, with a mechanism for centralized reCorrespondence: Harriet O. Smith, MD, Professor and Director, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, 2211 Lomas Boulevard, N.E., Albuquerque, New Mexico. E mail: Hsmith@salud. unm.edu, Ph: (505) 272-6382, Fax: (505) 272-6385. CLINICAL OBSTETRICS AND GYNECOLOGY Volume 46, Number 3, 541–556

G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.

Insulin-like Growth Factor 2 Expression Modulates Taxol Resistance and Is a Candidate Biomarker for Reduced Disease-Free Survival in Ovarian Cancer

Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fishers exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05). Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance. Clin Cancer Res; 16(11); 2999–3010. ©2010 AACR.

Population-based study of microinvasive adenocarcinoma of the uterine cervix.

Objective To analyze lymph node status and survival rates of women with microinvasive cervical adenocarcinoma (International Federation of Gynecology and Obstetrics stages IA1 and IA2). Methods The Surveillance, Epidemiology, and End Results (SEER) Public-Use Database was used to identify cases of microinvasive cervical adenocarcinoma diagnosed between 1988 and 1997. Variables analyzed included stage, extent of surgery, lymph node status, radiation therapy, and age. Statistics included analysis of trends, analysis of variance, log-rank test, one-sided binomial confidence interval estimation, and power analysis. Results Among 301 reported cases, 131 had stage IA1 and170 IA2 disease. Simple hysterectomies were done in 54 women with IA1 and 64 with IA2 disease and radical hysterectomies were done in 50 and 83 women, respectively. Only one of 140 women who had lymphadenectomy had a single positive lymph node. There were four tumor-related deaths (one with IA1, and three with IA2 disease). There were no deaths among 96 women (47, IA1; 49, IA2) treated by simple hysterectomy alone. The mean follow-up was 46.5 months (range 1–119). The censored survival rate was 98.7% overall (99.2% IA1, 98.2% IA2). Power analysis estimated that 720 patients would be required in each group to detect a 2% difference in survival. Using one-sided 95% confidence interval estimations, the risk-adverse events rate for IA1 was no more than 3.57%, and 4.50% for IA2 disease. Conclusion Prognosis is excellent for microinvasive adenocarcinoma of the uterine cervix. In 96 cases (31.9%), simple hysterectomy alone proved adequate.

Trends in gestational choriocarcinoma: A 27-year perspective

OBJECTIVE To evaluate trends in incidence and survival rates for gestational choriocarcinoma with the use of population-based data. METHODS Overall and 5-year average age-adjusted incidence rates were computed with the Surveillance, Epidemiology, and End Results program public-use database. Differences by age at diagnosis, race, stage, registry, and over calendar time were compared by Poisson regression, and survival censored for deaths other than choriocarcinoma by log-rank tests and Coxs proportional hazard ratios. RESULTS Between 1973 and 1999, 450 cases were recorded. The annualized age-adjusted incidence rate for choriocarcinoma was 0.133 per 100,000 woman-years and decreased by 49.7% (2.8% per year). By race (whites, blacks, and others), incidence rates declined by 62.3%, 27.2%, and 54.3%, respectively. In the Poisson model evaluating incidence rates, age, race, registry, and stage were significant main effects. Compared with whites, the relative risk was higher for blacks (2.14, 95% confidence interval [CI] 1.60, 2.86) and others (2.30, 95% CI 1.67, 3.18). Rates were highest in Utah and lowest in Iowa. By age at diagnosis, rates were higher in 20–39-year-olds. The 5-year relative survival rate was 89.5%. Censored survival was significantly lower among blacks (whites 92.4%, blacks 84.9%, others 87.1%, P = .045), for advanced disease (localized 94.5%, regional 92.9%, distant 87.1%, P = .02), and with increasing age at diagnosis (P = .017). Age and calendar time significantly influenced censored survival independent of stage and registry. CONCLUSION Gestational choriocarcinoma incidence rates have declined and survivals have improved, but blacks continue to have higher incidence and lower survival rates.

Phase II evaluation of neoadjuvant chemotherapy and debulking followed by intraperitoneal chemotherapy in women with stage III and IV epithelial ovarian, fallopian tube or primary peritoneal cancer: Southwest Oncology Group Study S0009

OBJECTIVE Intraperitoneal (IP) chemotherapy prolongs survival in optimally reduced ovarian cancer patients. For patients in whom optimal debulking cannot be achieved, one could incorporate IP therapy post-operatively if the cancer was optimally debulked following neoadjuvant chemotherapy. We sought to evaluate overall survival (OS), progression-free survival (PFS), percent of patients optimally debulked and toxicity in patients treated with this strategy. METHODS Women with adenocarcinoma by biopsy or cytology with stage III/IV (pleural effusions only) epithelial ovarian, fallopian tube or primary peritoneal carcinoma that presented with bulky disease were treated with neoadjuvant intravenous (IV) paclitaxel 175 mg/m2 and carboplatin AUC 6 q 21 daysx3 cycles followed by surgery (if >/=50% decrease in CA125). If optimally debulked they received IV paclitaxel 175 mg/m2 and IP carboplatin AUC 5 (day 1) and IP paclitaxel 60 mg/m2 (day 8) q 28 daysx6 cycles. RESULTS Sixty-two patients were registered. Four were ineligible. Fifty-six were evaluated for neoadjuvant chemotherapy toxicities. One patient died of pneumonia. Five patients had grade 4 toxicity, including neutropenia (3), anemia, leukopenia, anorexia, fatigue, muscle weakness, respiratory infection, and cardiac ischemia. Thirty-six patients had debulking surgery. Two had grade 4 hemorrhage. Twenty-six patients received post-cytoreduction chemotherapy. Four had grade 4 neutropenia. At a median follow-up of 21 months, median PFS is 21 months and median OS is 32 months for all 58 patients. PFS and OS for the 26 patients who received IV/IP chemotherapy is 29 and 34 months respectively. CONCLUSIONS These results compare favorably with other studies of sub-optimally debulked patients.

Hormone replacement therapy in the menopause: A pro opinion

The preponderance of data support the benefits of HRT in estrogen-deprived and menopausal women to reduce the risks of osteoporosis and cardiovascular disease and to enhance quality of life and life expectancy. Controversies exist with regards to the risk-benefit ratio in women with a history of estrogen-dependent gynecologic tumors or breast cancer. Until these issues are resolved, physicians must carefully weigh, on an individual basis for each patient, the potential risks against the known benefits. Women should be counseled regarding the benefits of exercise, weight control, breast feeding, and cessation of cigarette smoking or excessive alcohol to reduce their risks of cancer, cardiac disease, and/or osteoporosis. HRT is not a panacea for an unhealthy lifestyle. When ERT is contraindicated, viable alternatives to retard bone loss and/or control vasomotor symptoms include calcium supplementation and progestin therapy. The role of tamoxifen as an alternative HRT in women at increased risk for breast cancer development is currently under investigation.