Faculty Bibliography

OBJECTIVE:Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. METHODS:NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C+BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. RESULTS:In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p<0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p<0.05). Synergistic tumor growth suppression (p<0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. CONCLUSION/CONCLUSIONS:Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.

OBJECTIVE:Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity. METHODS:Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan-Meier methods. RESULTS:High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts. CONCLUSIONS:Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.

OBJECTIVES/OBJECTIVE:The aim of this study is to compare response to chemotherapy and survival between patients with transitional call carcinoma of the ovary (TCCO) and papillary serous ovarian cancer (PSOC). METHODS:We identified women with both pure and mixed TCCO who were treated between 2000 and 2010. Each case was matched to two women with PSOC by age, grade, stage, and year of diagnosis. Correlation between categorical variables was assessed with chi square test. The Kaplan-Meier survival analysis was used to generate overall survival data (OS). Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS:Eighty-one women diagnosed with TCCO were selected as cases and compared to 162 controls. Women with TCCO had a lower rate of platinum resistance compared to controls (9% vs. 25%; p=0.01). When multivariate logistic regression was used to control for other factors independently associated with platinum resistance, patients with TCCO had a significantly lower risk of platinum resistance compared to PSOC. Median progression-free survival was not significantly different (27 months vs. 22 months; p=0.15) for women with TCCO and PSOC, respectively. Median OS, however, was significantly different at 83 months vs. 52 months for the TCCO and PSOC groups, respectively (p=0.01). A Cox proportional hazards model identified optimal cytoreduction, transitional cell histology, age, stage, and platinum and paclitaxel chemotherapy as independent predictors of OS. CONCLUSIONS:Patients with TCCO are less likely to demonstrate resistance to platinum chemotherapy and have improved overall survival when compared to patients with PSOC.

OBJECTIVE:To investigate the relationship of age and tumors associated with endometriosis and outcome of different histologies of epithelial ovarian cancer arising from endometriosis. STUDY DESIGN/METHODS:We identified cases of epithelial ovarian cancers with clear cell, endometrioid, or mixed clear cell and endometrioid histologies from January 2001 to March 2009. Tumors were classified as either "arising in" endometriosis, "associated with" endometriosis or "controls" (not associated with endometriosis). We collected information regarding patient demographics, past medical history, presentation at diagnosis, treatment, and outcome. RESULTS:Of 140 patients identified, 42 (30.0%) had clear cell, 92 (65.7%) had endometrioid, and 6 (4.3%) had mixed. Of those, 28.6% of tumors were associated with endometriosis (n = 40), 37.1% were arising in endometriosis (n = 52), and 34.3% were controls (n = 48). Premenopausal women had tumors that were more likely arising from or associated with endometriosis as compared to tumors in postmenopausal women (p = 0.005). Premenopausal patients were also more likely to present with early stage disease as compared to postmenopausal women (80.4% vs. 63.6%, p = 0.04) and better overall survival (p < 0.008). Survival analyses of the entire cohort showed that improved survival was associated with stage (p < 0.001), grade (p < 0.001), endometrioid histology (p < 0.005), and with tumors associated with or arising in endometriosis (p < 0.04). Multivariate analysis controlling for menopausal status showed the presence of endometriosis was no longer associated with a survival advantage (p = 0.08). CONCLUSION/CONCLUSIONS:The association with endometriosis does appear, at least in endometrioid tumors, to provide a survival benefit. Overall, menopausal status, stage, and grade are more powerful variables associated with improved survival.

BACKGROUND:The purpose of this study is to examine changes over time in survival for African American (AA) and white women diagnosed with cervical cancer (CC). METHODS:Surveillance, Epidemiology, and End Results (SEER) Program data from 1985 to 2009 were used for this analysis. Racial differences in survival were evaluated between African American (AA) and white women. Kaplan-Meier and Cox proportional hazards survival methods were used to assess differences in survival by race at 5-year intervals. RESULTS:The study sample included 23,368 women, including 3886 (16.6%) who were AA and 19,482 (83.4%) who were white. AA women were older (51.4 versus 48.9 years; P<.001) and had a higher rate of regional (38.3% versus 31.8%; P<.001) and distant metastasis (10.7% versus 8.7%; P<.001). AA less frequently received cancer-directed surgery (32.4% versus 46%; P<.001), and more frequently radiotherapy (36.3% versus 26.4%; P<.001). Overall, AA women had a hazard ratio (HR) of 1.41 (95% confidence interval=1.32-1.51) of cervical cancer (CC) mortality compared with whites. Adjusting for SEER registry, marital status, stage, age, treatment, grade, and histology, AA women had an HR of 1.13 (95% confidence interval=1.05-1.22) of CC-related mortality. After adjusting for the same variables, there was a significant difference in CC-specific mortality between 1985 to 1989 and 1990 to 1994, but not after 1995. CONCLUSIONS:After adjusting for race, SEER registry, marital status, stage, age, treatment, grade, and histology, there was a significant difference in CC-specific mortality between 1985 to 1989 and 1990 to 1994, but not after 1995.

OBJECTIVE:The purpose of this study was to compare the distribution of the first site of recurrence in patients with epithelial ovarian cancer (EOC) who received first-line treatment with bevacizumab compared with patients who did not receive bevacizumab. METHODS:From the Cancer Registry database at our institutions, we identified a group of patients with recurrent EOC who underwent treatment from January 1, 2005, to December 31, 2010. Each patient record was evaluated to classify the site of first recurrence. Correlation between categorical variables was assessed with χ² test. RESULTS:Two hundred ninety-two patients with advanced EOC (stage III or IV) who originally responded to chemotherapy and had a recurrence were identified. Of these, 37 (12.5%) had received postoperative chemotherapy bevacizumab, and 255 (87.5%) did not. Compared with those not treated with bevacizumab, there was a lower incidence of liver recurrence (0% vs 9%; P = 0.05) and a higher rate of lung and/or pleural recurrence (22% vs 5%; P = 0.001) and recurrence at distant sites (22% vs 9%; P = 0.03) in patients who received bevacizumab. There was no difference in the incidence of ascites at the time of recurrence between these groups. CONCLUSIONS:Patients who received bevacizumab as part of primary treatment for EOC had a higher rate of lung and/or pleural recurrence and a lower rate of liver recurrence. There was no difference in the rate of ascites at the time of recurrence.

Objectives. To characterize clinical outcomes in patients with intermediate or high-risk endometrial carcinoma who underwent surgical staging with or without para-aortic lymphadenectomy. Methods. This is a retrospective cohort study of patients with intermediate or high-risk endometrial adenocarcinoma who underwent surgical staging with (PPALN group) or without (PLN) para-aortic lymphadenectomy. Data were collected, Kaplan-Meier curves were generated, and univariate and multivariate analyses performed to compare differences in adjuvant therapy, disease recurrence, disease-free survival (DFS), and overall survival (OS). Results. 118 patients were included in the PPALN group and 139 in the PLN group. Patients in the PPALN group were more likely to receive adjuvant vaginal brachytherapy (25.4% versus 11.5%, OR = 2.5, P = 0.03) and less likely to receive adjuvant multimodal combination therapy (17.81% versus 28.8%, OR = 0.28, P = 0.002). DFS was improved in the PLN group as compared to PPALN (80% versus 62%, P = 0.02). OS was equivalent (P = 0.93). Patients in the PPALN group who had less than 10 para-aortic nodes removed were twice as likely to recur than patients who had 10 or more para-aortic nodes or patients in the PLN group (HR 2.08, CI 1.20-3.60, P = 0.009). Conclusions. Patients in the PLN group were more likely to receive multimodal adjuvant therapy and had better DFS than the PPALN group. Pelvic lymphadenectomy followed by adjuvant radiation and chemotherapy may represent an effective treatment option for patients with intermediate or high-risk disease. If systematic para-aortic lymphadenectomy is performed and less than 10 para-aortic lymph nodes are obtained, multimodality adjuvant therapy should be considered to improve DFS.

OBJECTIVE:The aim of the study is to review a single institution's experience with gastrostomy tubes (GTs) performed for malignant bowel obstruction from gynecologic cancers. METHODS:Women with gynecologic cancers who underwent venting GT placement from 2000 to 2008 were identified and clinical data were extracted. Logistic regression and spearman correlational coefficients were used to determine relationships between variables. Survival analysis was performed using the Kaplan-Meier method and a Cox proportional hazard model. RESULTS:We identified 115 women who underwent GT placement, the majority of whom were diagnosed with ovarian cancer (84%). Median time from cancer diagnosis to GT placement was 2.2 years. Median survival following GT placement was 5.6 weeks. A majority (56%) developed GT complications requiring GT revision. While burden of disease as assessed on CT scan by the validated peritoneal cancer index (PCI) was not associated with survival, low CA-125 within one week of GT placement was associated with improved survival (p<0.01). TPN was administered in 36% of women, was associated with concurrent chemotherapy (p<0.001) and a 5 week survival benefit (p<0.01). Chemotherapy after GT was administered in 40% of women and was associated with a 10 week survival benefit (p<0.001). Age-adjusted multivariate analysis identified chemotherapy as the only independent variable associated with survival. CONCLUSIONS:Women with malignant bowel obstructions from gynecologic cancers requiring palliative GT placement had a guarded prognosis measured in weeks. Gastrostomy tubes near the end of life had a high rate of complications requiring medical intervention. Chemotherapy after GT was associated with TPN administration, and both were associated with a modest extension in survival.

OBJECTIVE:The purpose of this study was to identify the clinical factors associated with time to hCG remission among women with low-risk postmolar GTN. METHODS:This study included a non-concurrent cohort of 328 patients diagnosed with low-risk postmolar GTN according to FIGO 2002 criteria. Associations of time to hCG remission with history of prior mole, molar histology, time to persistence, use of D&C at persistence, presence of metastatic disease, FIGO score, hCG values at persistence, type of first line therapy and use of multiagent chemotherapy were investigated with both univariate and multivariate analyses. RESULTS:Overall median time to remission was 46 days. Ten percent of the patients required multi-agent chemotherapy to achieve hCG remission. Multivariate analysis incorporating the variables significant on univariate analysis confirmed that complete molar histology (HR 1.45), metastatic disease (HR 1.66), use of multi-agent therapy (HR 2.00) and FIGO score (HR 1.82) were associated with longer time to remission. There was a linear relationship between FIGO score and time to hCG remission. Each 1-point increment in FIGO score was associated with an average 17-day increase in hCG remission time (95% CI: 12.5-21.6). CONCLUSIONS:Complete mole histology prior to GTN, presence of metastatic disease, use of multi-agent therapy and higher FIGO score were independent factors associated with longer time to hCG remission in low-risk GTN. Identifying the prognostic factors associated with time to remission and effective counseling may help improve treatment planning and reduce anxiety in patients and their families.