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Failure to Correct for Hysterectomy Prevalence Underestimates the Racial Disparity in US Cervical Cancer Mortality Rates
Abstracts / Gynecologic Oncology 143 (2016) 194–223
may benefit from addressing the barriers to health service utilization to eliminate these disparities.
doi:10.1016/j.ygyno.2016.08.257
Differential Expression of Cilia-Related Genes in Endometrioid Endometrial Carcinoma: Prognostic Implications and Therapeutic Opportunities E. Clair McClunga, Anders Berglundb, Eric Welshc, Yin Xiongd, Sharon Robertsona, Bernadette Boacd, Hye Sook Chona, Anthony Maglioccoa,d,e, Douglas Marchiona,d. aDepartment of Women’s Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, b Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, cBioinformatics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, d Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, eDepartment of Oncologic Sciences, Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA Objectives: Loss of cilia is associated with malignant transformation in multiple carcinomas. Cilia are involved in regulation of cell growth and differentiation, polarity, and cell cycle progression, as well as Hedgehog, Wnt, and mTOR signaling, as well as AURORA kinase activity. We present a signature describing differential expression of cilia-related genes, and we report correlations with pathologic features and clinical outcomes. Methods: We analyzed microarray gene expression data for 389 endometrioid endometrial adenocarcinomas collected from 12 institutions from 1998-2012. We reviewed sample collection data, pathology reports, and patient medical records to confirm that all included samples were collected from primary endometrioid endometrial carcinomas. Co-expression analysis and the PANTHER GO biological processes experimental tool were used to identify a 247-gene signature describing expression of cilia-related genes and pathways. The cilia-related gene signature was checked for correlation with signatures describing other cellular processes and signaling pathway expression. Tumor samples were labeled according to relative enrichment for cilia-related genes using PCA modeling. Sample PC1 scores were evaluated for correlation with clinical outcomes including age at diagnosis, stage, tumor size, and lymphovascular space invasion (LVSI). Association with recurrence and recurrence free survival were evaluated in a subset of 175 tumors with complete follow up data, derived from a single institution. Results: Key regulators of cilia formation including FOXJ1, and cilia structure- and dynein-associated proteins are represented in the signature. Cilia-related gene expression was not correlated with signatures describing cell cycle/proliferation. Low cilia-related PC1 scores were significantly associated with higher grade, stage III disease, pelvic and para-aortic lymph node involvement, and LVSI. Low cilia-related PC1 scores were associated with recurrence (p=.00598), with a non-significant trend toward decreased recurrence-free survival, with a median follow up of 33.3 months. Conclusion: Differential expression of cilia-related genes is linked to endometrial cancer differentiation, high risk features including LVSI and nodal metastasis, and development of recurrence. Importantly, the potential role for differences in cilia expression in modulating response to targeted therapies warrants further investigation.
doi:10.1016/j.ygyno.2016.08.258
201
Alligator or crocodile? Distinctions between uterine sarcoma and leiomyomata may be distinguishable after all I.M. Lazoa, A. Niiharab, L.-Y. Tuckera, M.Y. Yamamotoa, E.Z. Zaritskya, S.E. Lentzb. aThe Permanente Medical Group, bSouthern California Permanente Medical Group Objectives: Preoperative discrimination between benign uterine leiomyoma and possible uterine sarcomas has eluded clinicians when preparing for hysterectomy. We sought to discern clinical features that might increase preoperative suspicion of a potential uterine sarcoma. Methods: We conducted a case-control study of women undergoing hysterectomy for leiomyomata or abnormal uterine bleeding from 2006-2013. Patients diagnosed with unanticipated (occult) and presumed (known or suspected) uterine sarcoma were compared to age- and race-matched controls (1:2 ratio) who had benign pathology. Conditional logistic regression analyses were used to identify potential preoperative clinical factors associated with uterine sarcoma (all sarcoma, presumed sarcoma, occult sarcoma) with the threshold of significance set at P less than .05. Results: The total patient cohort was composed of 819 patients: 273 uterine sarcoma cases and 546 control cases. Of the sarcomas identified, 118 (43.2%) were occult. A lengthy list of predictors emerged when comparing the demographics of the cases and controls. After excluding the known or suspected sarcomas (155 patients), there were 4 characteristics that persisted as predictive of any malignancy in comparison to the controls. Solitary uterine masses (OR 6.1; 95% CI 2.0-18), uterine size increase in excess of 51% (OR 4.7; 95% CI 1.04-21.5), uterine weight N1000 gm (OR 4.0; 95% CI 1.04-15.8) and pelvic pain requiring narcotic medications (OR 21.7; 95% CI 2.3-206). A history of transfusion within 3 months of hysterectomy approached significance (OR 5.2; 95% CI 0.8-33.3). Other factors such as unplanned weight loss, recent venous thromboembolism, pain requiring emergency room or hospital admission and a history of blood transfusion were predictive of all sarcomas, but did not persist when predicting an unanticipated sarcoma. Conclusion: Our large case-control study identifies potential characteristics in hysterectomy patients that should raise the suspicion of clinicians for a potential uterine sarcoma. This collection of apparently mundane features persist in a large dataset when trying to predict the presence of an unrecognized sarcoma. While conventional wisdom teaches that size change is not predictive, it may be reasonable to reconsider this attitude. The association of these se common findings should be tested as a predictive model for uterine sarcoma to help direct patients to the most appropriate surgeon when considering hysterectomy.
doi:10.1016/j.ygyno.2016.08.259
Failure to Correct for Hysterectomy Prevalence Underestimates the Racial Disparity in US Cervical Cancer Mortality Rates A.L. Beavisa, P.E. Gravittb, A.F. Rositchc. aThe Kelly Gynecologic Oncology Service, Department of Gynecologic and Obstetrics, Johns Hopkins Medicine, Baltimore, MD, USA, bDepartment of Global Health, George Washington University Milken Institute School of Public Health, Washington, DC, USA, cDepartment of Epidemiology, The Bloomberg School of Health at Johns Hopkins, Baltimore, MD, USA Objectives: To determine the age-standardized and age-specific annual US cervical cancer mortality rates after correction for hysterectomy prevalence, and to evaluate disparities by age and race. Methods: Cervical cancer mortality estimates stratified by age, sex, state, and year for women 20 years and older were derived from the incidence-based mortality database publically available through
202
Abstracts / Gynecologic Oncology 143 (2016) 194–223
Surveillance, Epidemiology, and End Results (SEER) 18 from 20022012. Stratified hysterectomy prevalence was estimated using the Behavioral Risk Factor Surveillance System (BRFSS) survey and used to correct the denominator to include only women at risk in the agestandardized and age-specific mortality rates. Trends in mortality rates across time and age were analyzed using Joinpoint regression. Results: Overall, age-standardized cervical cancer mortality rates were higher after correction for hysterectomy prevalence: 3.0 per 100,000 before (95% confidence interval [CI]: 2.9, 3.1) and 4.4 per 100,000 after (95% CI: 4.3, 4.5). The uncorrected rates were higher in black versus white women (mortality rate ratio [MRR]: 1.79 (95%CI: 1.67, 1.92)), and this disparity was even more pronounced after correction (MRR: 2.12 (95%CI: 1.96, 2.30)). The corrected rates have plateaued in white women since 2004 and are decreasing by 2.2% per year in black women (p b0.05). Uncorrected and corrected agespecific cervical cancer mortality rates increased with increasing age in both races. Before correction, black women N40 years old had significantly higher rates than white women; after correction, the disparity started at age 30, and was more pronounced (figure). Black women N85 years old were the most affected: their uncorrected rate was 15.8 deaths per 100,000 (95%CI: 12.6, 19.0), compared to a corrected rate of 31.0 deaths per 100,000 (95%CI: 25.0, 37.2). In contrast, white women of the same age had uncorrected rates of 5.4 deaths per 100,000, and 9.7 per 100,000 after correction. Conclusion: National cervical cancer mortality rates and the racial disparity in these rates have been underestimated due to the prevalence of hysterectomy. Both age-specific and age-standardized mortality rates show a greater disparity between white and black women than previously appreciated; however, this disparity is decreasing over time. While this closing gap is promising, mortality rates in black women are double those in white women, a major public health concern that must be addressed.
model that provides tumor characteristics at a level of individual patient. Several studies in colon, pancreatic, and fallopian tube cancer models demonstrated that the organoid culture platform can be exploited for genomic and functional studies that can make individualized treatment assessment potentially feasible. The objective of our study was to assess the feasibility of applying tumor organoid culture for endocrine treatment and drug sensitivity in endometrial cancer. Methods: Endometrial cells were extracted from fragments of tumor retrieved from fresh hysterectomy specimen. The cells were cultured on basement membrane extract (BME) in serum-free medium. The bulk organoid cultures were maintained and passaged to allow subsequent testing, cryopreservation, histology and immunohistochemistry assessment. Initial screening assays were done using several variables including progestin, antiprogestin, aromatase inhibitor, selective estrogen receptor downregulator, tyrosine kinase inhibitors, Stat3 inhibitor, and chemotherapeutic agents. H&E and immunohistochemistry were performed on de-paraffinized sections for both endometrial tumor and organoid preparations. Results: We were able to successfully grow and propagate organoids from 7 endometrial cancer specimens in serum-free media. Small spherical structures formed within 24 hours and many continued to grow to larger, denser structures, here termed organoids. The efficiency of formation of progressively growing organoids (N100 microns at 2 weeks) was 20-30 organoids per 5,000 input cells, or around 0.5%. Uniform sensitivity across all specimen was noted to Stat3 inhibitor, BBI-608, further suggesting that stemness programing is involved in organoid formation. Sensitivity to different growth factor tyrosine kinase inhibitors were noted in several specimens, which may implicate importance of autocrine and paracrine sources of growth factor signaling for organoid growth. Some tumors were inhibited by Fulvestrant, implying an important role for ER signaling in some tumor organoids. Histologically, organoids closely resembled their tumors of origin and had similar IHC expression of ER, PR, lacked expression of stromal marker CD10 and all had strong expression of epithelial marker AE1/AE3. Tumors and organoids had similar growth fraction by Ki67. Conclusion: We demonstrate that tumor organoid cultures can be used as in-vitro model for development of endocrine profiles and drug sensitivity testing for individual tumors in endometrial cancer patients. The organoid model provides essential basis for further investigations of signaling routes involved in development and treatment of endometrial cancer. doi:10.1016/j.ygyno.2016.08.261
Cervical Cancer Screenings is Feasible and Cost-Effective in Women with Substance Abuse Disorders K. Rogg, R. Regn, W. Robinson. Tulane University School of Medicine
doi:10.1016/j.ygyno.2016.08.260
The Use of Tumor Organoid Culture For Drug Sensitivity Testing In Endometrial Cancer Is Feasible E. Girda, E. Huang, G. Leiserowitz, L. Smith. UC Davis Medical Center, Sacramento, CA Objectives: Stem cell derived organoid cultures have been successfully used in other tumor sites as a quick and affordable in vitro
Objectives: The purpose of this report is to determine the level of need, feasibility, and cost-effectiveness of a cervical cancer-screening program in a residential substance abuse facility for women. Methods: Papanicolau smear/Human Papilloma Virus(HPV) co-testing (Pap testing) was included with the Admission History and Physical exam on a trial basis for clients of a large, inner-city residential substance abuse facility for women. Data from these encounters, including demographics, pap smear history, liquid cytology and HPV results and sexually transmitted illness testing was collected in prospective fashion between 2012-2015, and reviewed as part of an ongoing Quality Improvement project. Results: 305/346 (88%) of appropriate clients accepted pap testing when offered. 256/346(74%) had not undergone testing within 3 years. 116/305(38%) had abnormal pap results. 113/305(37%) women were identified as having chlamydia, gonorrhea or syphilis.
may benefit from addressing the barriers to health service utilization to eliminate these disparities.
doi:10.1016/j.ygyno.2016.08.257
Differential Expression of Cilia-Related Genes in Endometrioid Endometrial Carcinoma: Prognostic Implications and Therapeutic Opportunities E. Clair McClunga, Anders Berglundb, Eric Welshc, Yin Xiongd, Sharon Robertsona, Bernadette Boacd, Hye Sook Chona, Anthony Maglioccoa,d,e, Douglas Marchiona,d. aDepartment of Women’s Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, b Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, cBioinformatics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, d Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA, eDepartment of Oncologic Sciences, Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA Objectives: Loss of cilia is associated with malignant transformation in multiple carcinomas. Cilia are involved in regulation of cell growth and differentiation, polarity, and cell cycle progression, as well as Hedgehog, Wnt, and mTOR signaling, as well as AURORA kinase activity. We present a signature describing differential expression of cilia-related genes, and we report correlations with pathologic features and clinical outcomes. Methods: We analyzed microarray gene expression data for 389 endometrioid endometrial adenocarcinomas collected from 12 institutions from 1998-2012. We reviewed sample collection data, pathology reports, and patient medical records to confirm that all included samples were collected from primary endometrioid endometrial carcinomas. Co-expression analysis and the PANTHER GO biological processes experimental tool were used to identify a 247-gene signature describing expression of cilia-related genes and pathways. The cilia-related gene signature was checked for correlation with signatures describing other cellular processes and signaling pathway expression. Tumor samples were labeled according to relative enrichment for cilia-related genes using PCA modeling. Sample PC1 scores were evaluated for correlation with clinical outcomes including age at diagnosis, stage, tumor size, and lymphovascular space invasion (LVSI). Association with recurrence and recurrence free survival were evaluated in a subset of 175 tumors with complete follow up data, derived from a single institution. Results: Key regulators of cilia formation including FOXJ1, and cilia structure- and dynein-associated proteins are represented in the signature. Cilia-related gene expression was not correlated with signatures describing cell cycle/proliferation. Low cilia-related PC1 scores were significantly associated with higher grade, stage III disease, pelvic and para-aortic lymph node involvement, and LVSI. Low cilia-related PC1 scores were associated with recurrence (p=.00598), with a non-significant trend toward decreased recurrence-free survival, with a median follow up of 33.3 months. Conclusion: Differential expression of cilia-related genes is linked to endometrial cancer differentiation, high risk features including LVSI and nodal metastasis, and development of recurrence. Importantly, the potential role for differences in cilia expression in modulating response to targeted therapies warrants further investigation.
doi:10.1016/j.ygyno.2016.08.258
201
Alligator or crocodile? Distinctions between uterine sarcoma and leiomyomata may be distinguishable after all I.M. Lazoa, A. Niiharab, L.-Y. Tuckera, M.Y. Yamamotoa, E.Z. Zaritskya, S.E. Lentzb. aThe Permanente Medical Group, bSouthern California Permanente Medical Group Objectives: Preoperative discrimination between benign uterine leiomyoma and possible uterine sarcomas has eluded clinicians when preparing for hysterectomy. We sought to discern clinical features that might increase preoperative suspicion of a potential uterine sarcoma. Methods: We conducted a case-control study of women undergoing hysterectomy for leiomyomata or abnormal uterine bleeding from 2006-2013. Patients diagnosed with unanticipated (occult) and presumed (known or suspected) uterine sarcoma were compared to age- and race-matched controls (1:2 ratio) who had benign pathology. Conditional logistic regression analyses were used to identify potential preoperative clinical factors associated with uterine sarcoma (all sarcoma, presumed sarcoma, occult sarcoma) with the threshold of significance set at P less than .05. Results: The total patient cohort was composed of 819 patients: 273 uterine sarcoma cases and 546 control cases. Of the sarcomas identified, 118 (43.2%) were occult. A lengthy list of predictors emerged when comparing the demographics of the cases and controls. After excluding the known or suspected sarcomas (155 patients), there were 4 characteristics that persisted as predictive of any malignancy in comparison to the controls. Solitary uterine masses (OR 6.1; 95% CI 2.0-18), uterine size increase in excess of 51% (OR 4.7; 95% CI 1.04-21.5), uterine weight N1000 gm (OR 4.0; 95% CI 1.04-15.8) and pelvic pain requiring narcotic medications (OR 21.7; 95% CI 2.3-206). A history of transfusion within 3 months of hysterectomy approached significance (OR 5.2; 95% CI 0.8-33.3). Other factors such as unplanned weight loss, recent venous thromboembolism, pain requiring emergency room or hospital admission and a history of blood transfusion were predictive of all sarcomas, but did not persist when predicting an unanticipated sarcoma. Conclusion: Our large case-control study identifies potential characteristics in hysterectomy patients that should raise the suspicion of clinicians for a potential uterine sarcoma. This collection of apparently mundane features persist in a large dataset when trying to predict the presence of an unrecognized sarcoma. While conventional wisdom teaches that size change is not predictive, it may be reasonable to reconsider this attitude. The association of these se common findings should be tested as a predictive model for uterine sarcoma to help direct patients to the most appropriate surgeon when considering hysterectomy.
doi:10.1016/j.ygyno.2016.08.259
Failure to Correct for Hysterectomy Prevalence Underestimates the Racial Disparity in US Cervical Cancer Mortality Rates A.L. Beavisa, P.E. Gravittb, A.F. Rositchc. aThe Kelly Gynecologic Oncology Service, Department of Gynecologic and Obstetrics, Johns Hopkins Medicine, Baltimore, MD, USA, bDepartment of Global Health, George Washington University Milken Institute School of Public Health, Washington, DC, USA, cDepartment of Epidemiology, The Bloomberg School of Health at Johns Hopkins, Baltimore, MD, USA Objectives: To determine the age-standardized and age-specific annual US cervical cancer mortality rates after correction for hysterectomy prevalence, and to evaluate disparities by age and race. Methods: Cervical cancer mortality estimates stratified by age, sex, state, and year for women 20 years and older were derived from the incidence-based mortality database publically available through
202
Abstracts / Gynecologic Oncology 143 (2016) 194–223
Surveillance, Epidemiology, and End Results (SEER) 18 from 20022012. Stratified hysterectomy prevalence was estimated using the Behavioral Risk Factor Surveillance System (BRFSS) survey and used to correct the denominator to include only women at risk in the agestandardized and age-specific mortality rates. Trends in mortality rates across time and age were analyzed using Joinpoint regression. Results: Overall, age-standardized cervical cancer mortality rates were higher after correction for hysterectomy prevalence: 3.0 per 100,000 before (95% confidence interval [CI]: 2.9, 3.1) and 4.4 per 100,000 after (95% CI: 4.3, 4.5). The uncorrected rates were higher in black versus white women (mortality rate ratio [MRR]: 1.79 (95%CI: 1.67, 1.92)), and this disparity was even more pronounced after correction (MRR: 2.12 (95%CI: 1.96, 2.30)). The corrected rates have plateaued in white women since 2004 and are decreasing by 2.2% per year in black women (p b0.05). Uncorrected and corrected agespecific cervical cancer mortality rates increased with increasing age in both races. Before correction, black women N40 years old had significantly higher rates than white women; after correction, the disparity started at age 30, and was more pronounced (figure). Black women N85 years old were the most affected: their uncorrected rate was 15.8 deaths per 100,000 (95%CI: 12.6, 19.0), compared to a corrected rate of 31.0 deaths per 100,000 (95%CI: 25.0, 37.2). In contrast, white women of the same age had uncorrected rates of 5.4 deaths per 100,000, and 9.7 per 100,000 after correction. Conclusion: National cervical cancer mortality rates and the racial disparity in these rates have been underestimated due to the prevalence of hysterectomy. Both age-specific and age-standardized mortality rates show a greater disparity between white and black women than previously appreciated; however, this disparity is decreasing over time. While this closing gap is promising, mortality rates in black women are double those in white women, a major public health concern that must be addressed.
model that provides tumor characteristics at a level of individual patient. Several studies in colon, pancreatic, and fallopian tube cancer models demonstrated that the organoid culture platform can be exploited for genomic and functional studies that can make individualized treatment assessment potentially feasible. The objective of our study was to assess the feasibility of applying tumor organoid culture for endocrine treatment and drug sensitivity in endometrial cancer. Methods: Endometrial cells were extracted from fragments of tumor retrieved from fresh hysterectomy specimen. The cells were cultured on basement membrane extract (BME) in serum-free medium. The bulk organoid cultures were maintained and passaged to allow subsequent testing, cryopreservation, histology and immunohistochemistry assessment. Initial screening assays were done using several variables including progestin, antiprogestin, aromatase inhibitor, selective estrogen receptor downregulator, tyrosine kinase inhibitors, Stat3 inhibitor, and chemotherapeutic agents. H&E and immunohistochemistry were performed on de-paraffinized sections for both endometrial tumor and organoid preparations. Results: We were able to successfully grow and propagate organoids from 7 endometrial cancer specimens in serum-free media. Small spherical structures formed within 24 hours and many continued to grow to larger, denser structures, here termed organoids. The efficiency of formation of progressively growing organoids (N100 microns at 2 weeks) was 20-30 organoids per 5,000 input cells, or around 0.5%. Uniform sensitivity across all specimen was noted to Stat3 inhibitor, BBI-608, further suggesting that stemness programing is involved in organoid formation. Sensitivity to different growth factor tyrosine kinase inhibitors were noted in several specimens, which may implicate importance of autocrine and paracrine sources of growth factor signaling for organoid growth. Some tumors were inhibited by Fulvestrant, implying an important role for ER signaling in some tumor organoids. Histologically, organoids closely resembled their tumors of origin and had similar IHC expression of ER, PR, lacked expression of stromal marker CD10 and all had strong expression of epithelial marker AE1/AE3. Tumors and organoids had similar growth fraction by Ki67. Conclusion: We demonstrate that tumor organoid cultures can be used as in-vitro model for development of endocrine profiles and drug sensitivity testing for individual tumors in endometrial cancer patients. The organoid model provides essential basis for further investigations of signaling routes involved in development and treatment of endometrial cancer. doi:10.1016/j.ygyno.2016.08.261
Cervical Cancer Screenings is Feasible and Cost-Effective in Women with Substance Abuse Disorders K. Rogg, R. Regn, W. Robinson. Tulane University School of Medicine
doi:10.1016/j.ygyno.2016.08.260
The Use of Tumor Organoid Culture For Drug Sensitivity Testing In Endometrial Cancer Is Feasible E. Girda, E. Huang, G. Leiserowitz, L. Smith. UC Davis Medical Center, Sacramento, CA Objectives: Stem cell derived organoid cultures have been successfully used in other tumor sites as a quick and affordable in vitro
Objectives: The purpose of this report is to determine the level of need, feasibility, and cost-effectiveness of a cervical cancer-screening program in a residential substance abuse facility for women. Methods: Papanicolau smear/Human Papilloma Virus(HPV) co-testing (Pap testing) was included with the Admission History and Physical exam on a trial basis for clients of a large, inner-city residential substance abuse facility for women. Data from these encounters, including demographics, pap smear history, liquid cytology and HPV results and sexually transmitted illness testing was collected in prospective fashion between 2012-2015, and reviewed as part of an ongoing Quality Improvement project. Results: 305/346 (88%) of appropriate clients accepted pap testing when offered. 256/346(74%) had not undergone testing within 3 years. 116/305(38%) had abnormal pap results. 113/305(37%) women were identified as having chlamydia, gonorrhea or syphilis.