DW4TR: A Data Warehouse for Translational Research.

The linkage between the clinical and laboratory research domains is a key issue in translational research. Integration of clinicopathologic data alone is a major task given the number of data elements involved. For a translational research environment, it is critical to make these data usable at the point-of-need. Individual systems have been developed to meet the needs of particular projects though the need for a generalizable system has been recognized. Increased use of Electronic Medical Record data in translational research will demand generalizing the system for integrating clinical data to support the study of a broad range of human diseases. To ultimately satisfy these needs, we have developed a system to support multiple translational research projects. This system, the Data Warehouse for Translational Research (DW4TR), is based on a light-weight, patient-centric modularly-structured clinical data model and a specimen-centric molecular data model. The temporal relationships of the data are also part of the model. The data are accessed through an interface composed of an Aggregated Biomedical-Information Browser (ABB) and an Individual Subject Information Viewer (ISIV) which target general users. The system was developed to support a breast cancer translational research program and has been extended to support a gynecological disease program. Further extensions of the DW4TR are underway. We believe that the DW4TR will play an important role in translational research across multiple disease types.

Influence of gynecologic oncologists on the survival of patients with endometrial cancer.

PURPOSE: Despite a lack of evidence for survival benefit, the American College of Obstetrics and Gynecology has recommendations for referral to gynecologic oncologists for the treatment of endometrial cancer. Therefore, we propose to determine the influence of gynecologic oncologists on the treatment and survival of patients with endometrial cancer. PATIENTS AND METHODS: Data were obtained from Medicare and Surveillance, Epidemiology, and End Results (SEER) databases from 1988 to 2005. Kaplan-Meier and Cox proportional hazard methods were used for analyses. RESULTS: Of 18,338 women, 21.4% received care from gynecologic oncologists (group A) while 78.6% were treated by others (group B). Women in group A were older (age > 71 years: 49.6% v 44%; P < .001), had more lymph nodes (> 16) removed (22% v 17%; P < .001), presented with more advanced (stages III to IV) cancers (21.9% v 14.6%; P < .001), had higher-grade tumors (P < .001), and were more likely to receive chemotherapy for advanced disease (22.6% v 12.4%; P < .001). In those with stages II to IV disease, the 5-year disease-specific survival (DSS) of group A was 79% versus 73% in group B (P = .001). Moreover, in advanced-stage (III to IV) disease, group A had 5-year DSS of 72% versus 64% in group B (P < .001). However, no association with DSS was identified in stage I cancers. On multivariable analysis, younger age, early stage, lower grade, and treatment by gynecologic oncologists were independent prognostic factors for improved survival. CONCLUSION: Patients with endometrial cancer treated by gynecologic oncologists were more likely to undergo staging surgery and receive adjuvant chemotherapy for advanced disease. Care provided by gynecologic oncologists improved the survival of those with high-risk cancers.

Dietary vitamin D exposure prevents obesity-induced increase in endometrial cancer in Pten+/- mice.

The possibility that dietary vitamin D(3) (VD(3)) exposure inhibits endometrial carcinogenesis in an animal model and modifies the enhanced risk of endometrial carcinoma associated with obesity was investigated. At 4 weeks of age, Pten(+/-) and wild-type mice were each divided into four treatment groups and fed AIN93G control diet, or AIN93G-based diet containing either 25,000 international units of VD(3) per kilogram of diet, 58% fat to induce obesity (high fat), or high fat and 25,000 international units of VD(3) per kilogram of diet. Mice were kept on these diets until they were sacrificed at week 28. Although VD(3) did not affect endometrial cancer risk, it inhibited obesity-induced increase in endometrial lesions. Specifically, high-fat diet increased focal glandular hyperplasia with atypia and malignant lesions from 58% in the control diet-fed Pten(+/-) mice to 78% in obese mice. Dietary VD(3) decreased the incidence of endometrial pathology in obese Pten(+/-) mice to 25% (P < 0.001). VD(3) altered the endometrial expression of 25-hydroxylase, 1α-hydroxylase, and vitamin D receptor in the wild-type and Pten(+/-) mice. Estrogen receptor-α mRNA levels were higher (P < 0.014) and progesterone receptor protein levels in the luminal epithelium were lower (P < 0.04) in the endometrium of control diet-fed Pten(+/-) than wild-type mice, but the expression of these receptors was not affected by the dietary exposures. VD(3) reversed the obesity-induced increase in osteopontin (P < 0.001) and significantly increased E-cadherin expression (P < 0.019) in the endometrium of obese Pten(+/-) mice. Our data confirm the known association between obesity and endometrial cancer risk. Dietary exposure to VD(3) inhibited the carcinogenic effect of obesity on the endometrium. This protective effect was linked to a reduction in the expression of osteopontin and increase in E-cadherin.

A GOG 210 aCGH study of gain at 1q23 in endometrioid endometrial cancer in the context of racial disparity and outcome.

The goal of this study was to identify recurrent regions of genomic gain or loss in endometrial cancer of the endometrioid type in the context of racial disparities in mortality for this disease. Array comparative genomic hybridization (aCGH) analysis was performed on 80 frozen primary tumors from the Gynecologic Oncology Group (GOG)-210 bank using the RPCI 19K BAC arrays. The 80 patients included 20 African American (AA) Stage I, 20 White (W) Stage I, 20 African American (AA) Stage IIIC/IV, and 20 White (W) Stage IIIC/IV. A separate subset of 220 endometrial cancers with outcome data was used for validation. A 1.6-Mbp region of gain at 1q23 was identified by aCGH in all AA patients and high grade W patients, but not W low grade patients. In the validation arm of 220 patients copy number gain at this region was validated using FISH and locus specific BACs. The number of AA patients in the validation arm was too small to confirm the aCGH association with racial disparity. Kaplan-Meier curves for survival showed a significant difference for gain at 1q23 versus no gain (log rank P = 0.0014). When subdivided into various groups of risk by stage and grade the survival curves showed a decreased survival for high grade and/or stage tumors, but not for low grade and/or stage endometrioid tumors. Univariate analyses for gain at 1q23 showed a significant association (P = 0.009) with survival. Multivariate analysis for gain at 1q23 did not show a significant association with survival (P = 0.14).

Cancer incidence in the U.S. military population: comparison with rates from the SEER program.

The U.S. active-duty military population may differ from the U.S. general population in its exposure to cancer risk factors and access to medical care. Yet, it is not known if cancer incidence rates differ between these two populations. We therefore compared the incidence of four cancers common in U.S. adults (lung, colorectal, prostate, and breast cancers) and two cancers more common in U.S. young adults (testicular and cervical cancers) in the military and general populations. Data from the Automated Central Tumor Registry (ACTUR) of the Department of Defense and the nine cancer registries of the Surveillance, Epidemiology and End Results (SEER) of the National Cancer Institute for the years 1990 to 2004 for persons with ages 20 to 59 years were analyzed. Incidence rates were significantly lower in the military population for colorectal cancer in White men, lung cancer in White and Black men and White women, and cervical cancer in Black women. In contrast, incidence rates of breast and prostate cancers were significantly higher in the military among Whites and Blacks. Incidence rates of testicular cancer did not differ between ACTUR and SEER. Although the numbers of diagnoses among military personnel were relatively small for temporal trend analysis, we found a more prominent increase in prostate cancer in ACTUR than in SEER. Overall, these results suggest that cancer patterns may differ between military and nonmilitary populations. Further studies are needed to confirm these findings and explore contributing factors.

Biological significance of prolactin in gynecologic cancers.

There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers.

HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients.

PURPOSE: To evaluate HER-2 expression and amplification in a large cohort of endometrial cancer with complete surgical staging and outcome data. PATIENTS AND METHODS: A tissue microarray was constructed of 483 patients with endometrial cancer of diverse histologic type and stage and tested for HER-2 expression and amplification using current standards of practice. There was outcome data for 83% of all patients and 81% with complete surgical staging. RESULTS: Both expression and amplification of HER-2 was associated with high-grade (P = .0001) and high stage (P = .0001) endometrial cancer. The highest rate of HER-2 expression and amplification was seen in serous carcinoma (43% and 29%), while grade 1 endometrioid adenocarcinoma showed the lowest levels (3% and 1%). For all histologic types, the rate of HER-2 expression and amplification was remarkably different (P < .0001) for grade 3 cancers (31% and 15%) versus grade 2 (7% and 3%) and grade 1 cancers (3% and 1%), with similar results for endometrioid type (P < .0001). Both HER-2 expression and amplification correlated with disease-specific survival and progression-free survival in univariate analyses. By multivariate analysis HER-2 expression in the presence of amplification (P = .012) correlated with overall survival, but not expression in the absence of amplification. Overall survival was significantly shorter (P = .0001) in patients who overexpressed (median, 5.2 years) and/or showed amplification of HER-2 (median, 3.5 years) versus those that did not (median of all cases, 13 years). CONCLUSION: Our results would suggest that HER-2 is an important oncogene in high grade and stage endometrial cancer, but plays only a minor role in the much more common low grade and stage tumors that encompass the majority of clinical practice.