- Email: [email protected]
Serum and tissue miR-21 as a predictor of future malignancy in endometrial hyperplasia without atypia
Abstracts / Gynecologic Oncology 145 (2017) 2–220
CA-125 concentration suggesting the involvement of this pathway in CA-125 regulation. Moreover, an additive effect was shown when costunolide and BIBR 1532 were combined with the previous inhibitors. A decrease in telomerase expression and activity was obtained after gene silencing of CA-125 by the 3 cell lines, along with a decrease in PI3k, Akt, and mTOR gene expression, which may explain the possible implication of this signaling pathway in the modulation of hTERT by CA-125. Conclusion: Both inhibition of telomerase and PI3K/Akt/mTOR signaling pathway decreased the CA-125 secretion, while inhibition of CA-125 decreased hTERT expression and activity suggesting a mutual modulation and a substantial role of CA-125 in cancer initiation and progression.
doi:10.1016/j.ygyno.2017.03.186
159 - Poster Session Impact of ascites volume on clinical outcomes in epithelial ovarian cancer: A cohort study J.B. Szendera, T. Emmonsa, K. Morrella, S. Belliottib, D. Dicksonb, A. Khana, P.C. Mayora, S.B. Lelea, P.J. Fredericka, E. Zsirosa, K. Odunsia, K. Enga, B.H. Segala. aRoswell Park Cancer Institute, Buffalo, NY, USA, b University at Buffalo, Buffalo, NY, USA Objective: To investigate the relationship between pretreatment ascites volume and outcomes in patients with ovarian, fallopian tube, or primary peritoneal cancer (EOC). In addition, the impact of intraperitoneal administration of cell-free ascites (CFA) on tumor progression was evaluated in murine syngeneic EOC. Method: For patients undergoing primary debulking surgery (PDS) for EOC between 2005 and 2015, clinicopathologic parameters were obtained from a database maintained at our institution. Progression-free (PFS) and overall survival (OS) were recorded. Ascites volume was dichotomized at 2000 mL, and comparisons for high- and low-volume ascites were made. We additionally evaluated the effect of intraperitoneal administration of CFA versus
Fig. 1.
79
PBS on tumor progression in syngeneic murine EOC. Banked ascites supernatants harvested from a prior group of tumor-bearing mice were coadministered with tumor cells and at various times after tumor challenge. Results: Out of 512 patients identified as undergoing PDS, 398 (77.7%) had ascites present at surgery. Patients with ascites greater than 2,000 mL had significantly shorter PFS (19.4 vs 14.1 months, P b 0.001) and OS (41.7 vs 25.4 months, P b 0.001). After adjusting for stage, presence of ascites was significantly associated with ability to achieve optimal cytoreduction. There was a volumedependent effect of ascites on both PFS and OS. EOC-bearing mice administered CFA reached endpoint significantly earlier than those receiving PBS alone. (See Fig. 1.) Conclusion: Patients with larger volume ascites at the time of surgery were less likely to have complete surgical resection (R0) and had worse overall prognosis. These results suggest that pretreatment high-volume ascites could be a prognostic biomarker for advanced EOC. Furthermore, worse outcomes in mice support an ascites-driven model tumor progression. Additional research is warranted to identify cell-free ascites constituents that drive tumor progression and may be potential therapeutic targets.
doi:10.1016/j.ygyno.2017.03.187
160 - Poster Session Serum and tissue miR-21 as a predictor of future malignancy in endometrial hyperplasia without atypia C.H. Laia, R.C. Wub, C.Y. Linb, L.Y. Yangb,c, S.M. Jungd, A. Chaob. a Chang Gung Memorial Hospital and Chang Gung University, Kueishan, Taoyuan, Taiwan, bChang Gung Memorial Hospital, Taipei, Taiwan, c Asian Gynecologic Oncology Group, Taoyuan, Taiwan, dChang Gung Memorial Hospital, Taoyuan, Taiwan Objective: The conventional criteria of predicting risk of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) is based on the degree of architectural crowding and nuclear atypia. We aim to investigate the predictive markers for risk of developing EC in women with EH without atypia. Method: EC patients with preceding simple or complex hyperplasia (SH/CH) without atypia were compared to SH/CH without progression to EC using miRNA array, followed by reverse transcription and quantitative real-time PCR, Western blot, and immunohistochemistry (IHC). Results: Thirty miRNAs (P b 0.001, fold change N4) including miR21 were significantly overexpressed in patients with SH/CH lesions (case, n = 4) who subsequently turned to EC compared to those who did not (control, n = 4). In the validation phase on an independent set, miR21was confirmed higher in patients who had a history of SH/CH without atypia and subsequently developed EC (n = 3 vs n = 12, P = 0.0038). Upregulation of miR21 correlated with increased expression of miR21-targeted PTEN (n = 8 vs n = 23, P = 0.022) and BCL2 (n = 8 vs n = 23, P = 0.0006) at the protein level using IHC analysis. Interestingly, serum miR21 level of cases was also significantly higher than in control. These results identified miR21, both at tissue level and serum level, to be a potential biomarker for predicting future EC. External validation on larger independent cohorts (EC vs non-EC) is ongoing. (See Fig. 1.) Conclusion: MiR21 may become a useful serum biomarker for early prediction of patients with EH who are at risk of developing EC.
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Abstracts / Gynecologic Oncology 145 (2017) 2–220
Objective: The spectrum of toxicities associated with angiogenesis inhibitors bears a striking resemblance to the clinical syndrome of preeclampsia. Recent studies suggest that alterations in soluble angiogenic factors play a critical role in the development of preeclampsia. We sought to explore whether these proteins are predictive of the development of antiangiogenic class-specific toxicities. Method: Serum was collected from gynecologic cancer patients at baseline and sequential time points after initiating a therapeutic regimen containing bevacizumab. Nine candidate biomarkers were detected and quantified using enzyme-linked immunosorbent assays and a dual-detector reader. χ2 and Wilcoxon rank sum tests were used to compare clinical and serum predictors between subjects with and without toxicity. Results: In this preliminary analysis, 12 of 50 total subjects were evaluated. The median age of subjects was 60 years (range 42–68); 67% had ovarian cancer, and 58% were receiving primary therapy. The median number of cycles received was 15 (range 3–21). Seven of 12 patients (58%) discontinued therapy because of toxicity such as venous thromboembolism, hypertensive urgency, congestive heart failure, and bowel perforation. Proteinuria (P = 0.039), higher VEGF-A levels (P = 0.046), and higher epidermal growth factor (EGF) levels (P = 0.106) at baseline were associated with cessation of antiangiogenic therapy. Age, hypertension, use of chemotherapeutic agents in addition to bevacizumab, number of cycles, and history of prior antineoplastic treatment did not appear to increase risk of toxicity. Other serum analytes (PDGF AB, sTIE-2, sVEGFR-1, sVEGFR-2, VEGF-C, and endoglin) were also not predictive. Conclusion: VEGF-A and EGFs have been implicated in the development of both essential hypertension as well as pregnancy-related hypertensive disorders. Elevated baseline levels of these analytes may provide early indication that a patient will experience class-specific drug toxicity. Validation of serum angiogenic proteins in a larger cohort of patients exposed to angiogenesis inhibitors is warranted. Changes in prospectively collected serum makers over time may provide insight into the etiology of angiogenesis-inhibitor toxicity as well. doi:10.1016/j.ygyno.2017.03.189
162 - Poster Session Clinical challenges associated with universal screening for Lynch syndrome associated endometrial cancer A.S. Bruegla, K.L. Ringb, B. Fellmanc, D. Urbauerc, M.S. Danielsc, R. Broaddusc. aOregon Health and Science University, Portland, OR, USA, b University of Virginia, Charlottesville, VA, USA, cThe University of Texas MD Anderson Cancer Center, Houston, TX, USA
Fig. 1.
doi:10.1016/j.ygyno.2017.03.188
161 - Poster Session Clinical and serum predictors of anti-angiogenic toxicity R. Ruskina, M. Rowlandb, D.N. Dhanasekarana, M. Jayaramana, K. Moxleyc. aThe University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, bThe University of Oklahoma, Norman, OK, USA, cThe University of Oklahoma, Oklahoma City, OK, USA
Objective: Universal tumor testing to screen for Lynch syndrome is becoming increasingly common for endometrial cancer patients. Several studies have been published describing the utility of universal screening and its ability to detect the majority of patients with germline mutations associated with Lynch syndrome. However, there have been no studies examining the challenges that can be encountered when universal tumor testing is employed. The purpose of this study was to prospectively identify the challenges associated with implementing universal screening. Method: Endometrial cancer patients (n = 213) prospectively underwent microsatellite instability (MSI) and immunohistochemistry (IHC) testing for expression of DNA mismatch repair proteins. Patients with low (MSI-L) or high (MSI-H) levels of tumor MSI, or IHC loss of MLH1 (and absent MLH1methylation), MSH2, MSH6, or PMS2 were referred to a genetic counselor. Results: Various clinical and diagnostic challenges that can occur with universal tissue testing for Lynch syndrome were identified.
CA-125 concentration suggesting the involvement of this pathway in CA-125 regulation. Moreover, an additive effect was shown when costunolide and BIBR 1532 were combined with the previous inhibitors. A decrease in telomerase expression and activity was obtained after gene silencing of CA-125 by the 3 cell lines, along with a decrease in PI3k, Akt, and mTOR gene expression, which may explain the possible implication of this signaling pathway in the modulation of hTERT by CA-125. Conclusion: Both inhibition of telomerase and PI3K/Akt/mTOR signaling pathway decreased the CA-125 secretion, while inhibition of CA-125 decreased hTERT expression and activity suggesting a mutual modulation and a substantial role of CA-125 in cancer initiation and progression.
doi:10.1016/j.ygyno.2017.03.186
159 - Poster Session Impact of ascites volume on clinical outcomes in epithelial ovarian cancer: A cohort study J.B. Szendera, T. Emmonsa, K. Morrella, S. Belliottib, D. Dicksonb, A. Khana, P.C. Mayora, S.B. Lelea, P.J. Fredericka, E. Zsirosa, K. Odunsia, K. Enga, B.H. Segala. aRoswell Park Cancer Institute, Buffalo, NY, USA, b University at Buffalo, Buffalo, NY, USA Objective: To investigate the relationship between pretreatment ascites volume and outcomes in patients with ovarian, fallopian tube, or primary peritoneal cancer (EOC). In addition, the impact of intraperitoneal administration of cell-free ascites (CFA) on tumor progression was evaluated in murine syngeneic EOC. Method: For patients undergoing primary debulking surgery (PDS) for EOC between 2005 and 2015, clinicopathologic parameters were obtained from a database maintained at our institution. Progression-free (PFS) and overall survival (OS) were recorded. Ascites volume was dichotomized at 2000 mL, and comparisons for high- and low-volume ascites were made. We additionally evaluated the effect of intraperitoneal administration of CFA versus
Fig. 1.
79
PBS on tumor progression in syngeneic murine EOC. Banked ascites supernatants harvested from a prior group of tumor-bearing mice were coadministered with tumor cells and at various times after tumor challenge. Results: Out of 512 patients identified as undergoing PDS, 398 (77.7%) had ascites present at surgery. Patients with ascites greater than 2,000 mL had significantly shorter PFS (19.4 vs 14.1 months, P b 0.001) and OS (41.7 vs 25.4 months, P b 0.001). After adjusting for stage, presence of ascites was significantly associated with ability to achieve optimal cytoreduction. There was a volumedependent effect of ascites on both PFS and OS. EOC-bearing mice administered CFA reached endpoint significantly earlier than those receiving PBS alone. (See Fig. 1.) Conclusion: Patients with larger volume ascites at the time of surgery were less likely to have complete surgical resection (R0) and had worse overall prognosis. These results suggest that pretreatment high-volume ascites could be a prognostic biomarker for advanced EOC. Furthermore, worse outcomes in mice support an ascites-driven model tumor progression. Additional research is warranted to identify cell-free ascites constituents that drive tumor progression and may be potential therapeutic targets.
doi:10.1016/j.ygyno.2017.03.187
160 - Poster Session Serum and tissue miR-21 as a predictor of future malignancy in endometrial hyperplasia without atypia C.H. Laia, R.C. Wub, C.Y. Linb, L.Y. Yangb,c, S.M. Jungd, A. Chaob. a Chang Gung Memorial Hospital and Chang Gung University, Kueishan, Taoyuan, Taiwan, bChang Gung Memorial Hospital, Taipei, Taiwan, c Asian Gynecologic Oncology Group, Taoyuan, Taiwan, dChang Gung Memorial Hospital, Taoyuan, Taiwan Objective: The conventional criteria of predicting risk of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) is based on the degree of architectural crowding and nuclear atypia. We aim to investigate the predictive markers for risk of developing EC in women with EH without atypia. Method: EC patients with preceding simple or complex hyperplasia (SH/CH) without atypia were compared to SH/CH without progression to EC using miRNA array, followed by reverse transcription and quantitative real-time PCR, Western blot, and immunohistochemistry (IHC). Results: Thirty miRNAs (P b 0.001, fold change N4) including miR21 were significantly overexpressed in patients with SH/CH lesions (case, n = 4) who subsequently turned to EC compared to those who did not (control, n = 4). In the validation phase on an independent set, miR21was confirmed higher in patients who had a history of SH/CH without atypia and subsequently developed EC (n = 3 vs n = 12, P = 0.0038). Upregulation of miR21 correlated with increased expression of miR21-targeted PTEN (n = 8 vs n = 23, P = 0.022) and BCL2 (n = 8 vs n = 23, P = 0.0006) at the protein level using IHC analysis. Interestingly, serum miR21 level of cases was also significantly higher than in control. These results identified miR21, both at tissue level and serum level, to be a potential biomarker for predicting future EC. External validation on larger independent cohorts (EC vs non-EC) is ongoing. (See Fig. 1.) Conclusion: MiR21 may become a useful serum biomarker for early prediction of patients with EH who are at risk of developing EC.
80
Abstracts / Gynecologic Oncology 145 (2017) 2–220
Objective: The spectrum of toxicities associated with angiogenesis inhibitors bears a striking resemblance to the clinical syndrome of preeclampsia. Recent studies suggest that alterations in soluble angiogenic factors play a critical role in the development of preeclampsia. We sought to explore whether these proteins are predictive of the development of antiangiogenic class-specific toxicities. Method: Serum was collected from gynecologic cancer patients at baseline and sequential time points after initiating a therapeutic regimen containing bevacizumab. Nine candidate biomarkers were detected and quantified using enzyme-linked immunosorbent assays and a dual-detector reader. χ2 and Wilcoxon rank sum tests were used to compare clinical and serum predictors between subjects with and without toxicity. Results: In this preliminary analysis, 12 of 50 total subjects were evaluated. The median age of subjects was 60 years (range 42–68); 67% had ovarian cancer, and 58% were receiving primary therapy. The median number of cycles received was 15 (range 3–21). Seven of 12 patients (58%) discontinued therapy because of toxicity such as venous thromboembolism, hypertensive urgency, congestive heart failure, and bowel perforation. Proteinuria (P = 0.039), higher VEGF-A levels (P = 0.046), and higher epidermal growth factor (EGF) levels (P = 0.106) at baseline were associated with cessation of antiangiogenic therapy. Age, hypertension, use of chemotherapeutic agents in addition to bevacizumab, number of cycles, and history of prior antineoplastic treatment did not appear to increase risk of toxicity. Other serum analytes (PDGF AB, sTIE-2, sVEGFR-1, sVEGFR-2, VEGF-C, and endoglin) were also not predictive. Conclusion: VEGF-A and EGFs have been implicated in the development of both essential hypertension as well as pregnancy-related hypertensive disorders. Elevated baseline levels of these analytes may provide early indication that a patient will experience class-specific drug toxicity. Validation of serum angiogenic proteins in a larger cohort of patients exposed to angiogenesis inhibitors is warranted. Changes in prospectively collected serum makers over time may provide insight into the etiology of angiogenesis-inhibitor toxicity as well. doi:10.1016/j.ygyno.2017.03.189
162 - Poster Session Clinical challenges associated with universal screening for Lynch syndrome associated endometrial cancer A.S. Bruegla, K.L. Ringb, B. Fellmanc, D. Urbauerc, M.S. Danielsc, R. Broaddusc. aOregon Health and Science University, Portland, OR, USA, b University of Virginia, Charlottesville, VA, USA, cThe University of Texas MD Anderson Cancer Center, Houston, TX, USA
Fig. 1.
doi:10.1016/j.ygyno.2017.03.188
161 - Poster Session Clinical and serum predictors of anti-angiogenic toxicity R. Ruskina, M. Rowlandb, D.N. Dhanasekarana, M. Jayaramana, K. Moxleyc. aThe University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, bThe University of Oklahoma, Norman, OK, USA, cThe University of Oklahoma, Oklahoma City, OK, USA
Objective: Universal tumor testing to screen for Lynch syndrome is becoming increasingly common for endometrial cancer patients. Several studies have been published describing the utility of universal screening and its ability to detect the majority of patients with germline mutations associated with Lynch syndrome. However, there have been no studies examining the challenges that can be encountered when universal tumor testing is employed. The purpose of this study was to prospectively identify the challenges associated with implementing universal screening. Method: Endometrial cancer patients (n = 213) prospectively underwent microsatellite instability (MSI) and immunohistochemistry (IHC) testing for expression of DNA mismatch repair proteins. Patients with low (MSI-L) or high (MSI-H) levels of tumor MSI, or IHC loss of MLH1 (and absent MLH1methylation), MSH2, MSH6, or PMS2 were referred to a genetic counselor. Results: Various clinical and diagnostic challenges that can occur with universal tissue testing for Lynch syndrome were identified.