- Email: [email protected]
Identification of molecular targets in vulvar cancers
112
Abstracts / Gynecologic Oncology 141 (2016) 2–208
still observed in black patients with ovarian cancer. Based on these data, tumor biology plays a role in ovarian cancer racial disparity, and continued research is needed for determining the cause of this racial disparity.
270 – Poster HPV vaccination rates and attitudes: A cross-sectional survey of college men and women C. Nicol, L. Duska, P. Hornsby, A. Pannone, R.G. Bernheim. University of Virginia, Charlottesville, VA, USA
doi:10.1016/j.ygyno.2016.04.300
OF
TE
DP
Objectives: The effect of MMR loss on the prognosis of endometrial cancer (EC) is controversial. Correlations between MMR-related protein expression and clinicopathologic factors of EC in African American (AA) versus white women were analyzed. Methods: A retrospective review of EC (n = 578) between 1995 and 2013 was conducted to analyze clinicopathologic parameters (Table 1). Immunohistochemical evaluation of MMR protein expression (MLH1, PMS2, MSH2, and MSH6) was performed on tumor tissue microarray. Absence of nuclear staining of any of the 4 proteins in tumor cells with positive lymphocytes (internal control) was considered as MMR loss. Data were analyzed using the Fisher’s exact test and Kaplan-Meier survival analysis. Results: MMR loss was identified in 116/578 patients (20%) with the highest frequency of loss in both MLH1 and PMS2 (47%), PMS2 (30%), MSH6 (14%), and both MSH2 and MSH6 (9%). White women with MMR loss had significantly higher-grade cancer and shorter disease-free interval (187 vs 594 months). AA women with MMR loss had endometrioid histology (P = .001), higher grade (P = .042), tumor size of 2 cm or greater (P = .019), and tendency toward myometrial invasion compared with AA women with intact MMR. Disease-free interval was similar for AA and white women with MMR loss (190 vs 187 months). Conclusions: Although EC is reported to have worse prognosis in AA than white women, our study showed no difference between AA women and white women who had MMR loss.
RO
269 – Poster Prognostic value of loss of MMR protein expression in endometrial carcinoma in African American and White women S. Sakra, E. Abdulfataha, A.R. Munkarahb, R.T. Morrisa, M.A. Elshaikhb, V. Pardeshic, R. Ali-Fehmia. aWayne State University School of Medicine, Detroit, MI, USA, bHenry Ford Health System, Detroit, MI, USA, cKarmanos Cancer Center/Wayne State University, Detroit, MI, USA
Objectives: Human papillomavirus (HPV) vaccination rates remain low, especially among young adults. The objective of the study was to measure the rate of HPV vaccination among college men and women, and to assess attitudes toward HPV vaccination and their association with vaccination status and intent. Methods: A random sample of 3,000 college men (18–21 years) and women (18–26 years) were asked to complete an online survey including questions about HPV vaccination status and intention and the modified Carolina HPV Immunization Attitudes Scale (CHIAS). (See Table 1.) Results: Overall, 67.6% of students had received at least 1 HPV vaccination; this proportion was higher for women (74.7%) than for men (51.0%). Male and female attitudes toward vaccination were not significantly different for 14 of 17 CHIAS items. Barriers score was the factor most strongly associated with vaccination intent “today” and also strongly associated with vaccination intent for “the next 6 months.” In contrast to the other factors, higher Barriers scores were actually associated with greater vaccination intent both “today” and “in the next 6 months.” Conclusions: The rate of HPV vaccination among college students was higher than expected, with rates double the national average for 18- to 26-year-old women (74.7% vs 34.5%) and 20 times higher than the national average for 18- to 21-year-old men (51.0% vs 2.4%). Men and women report similar attitudes to HPV vaccination. Even among a college population, barriers remain a significant factor in nonvaccination. Decreasing cost and access barriers is essential to improving HPV vaccination rates among young adults. Additional studies are needed to validate CHIAS among male populations.
RR
EC
Table 1 CHIAS Barrier Factor Items.
UN
CO
Table 1
doi:10.1016/j.ygyno.2016.04.301
doi:10.1016/j.ygyno.2016.04.302
271 – Poster Identification of molecular targets in vulvar cancers P.H. Thakera, M. Palisoula, S.K. Reddyb, R. Feldmanb. aWashington University School of Medicine in St. Louis, St. Louis, MO, USA, bCaris Life Sciences, Irving, TX, USA Objectives: Vulvar cancer may comprise only 5% of gynecologic malignancies but its incidence has been increasing. Given its rarity, there is a paucity of data surrounding treatment guidelines and targets for new therapies. We retrospectively examined a database of molecularly profiled patients for insight into the molecular alterations that contribute to vulvar pathogenesis with the hopes of identifying molecular targets for this rare disease. Methods: A total of 143 vulvar cancer patients were included in the study and tested at a central laboratory (Caris Life Sciences, Phoenix, AZ). Tests included 1 or more of the following: gene sequencing (Sanger or next-generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (chromogenic/ fluorescence in situ hybridization [ISH]). The 2-tailed Fisher’s exact test
Abstracts / Gynecologic Oncology 141 (2016) 2–208
OF
doi:10.1016/j.ygyno.2016.04.304
273 – Poster The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer M.M. Boisena, C. Andersenb, M. Sikorab, T. Mac, G. Tsengc, A. Vladd, E. Elishaeva, U. Chandrane, R.P. Edwardsa, S. Oesterreicha. aMageeWomens Hospital of UPMC, Pittsburgh, PA, USA, bUniversity of Pittsburgh/Magee-Women's Hospital, Pittsburgh, PA, USA, cUniversity of Pittsburgh, Pittsburgh, PA, USA, dMagee-Womens Research Institute, Pittsburgh, PA, USA, eUniversity of Pittsburgh/Magee-Women's Hosiptal, Pittsburgh, PA, USA
DP
doi:10.1016/j.ygyno.2016.04.303
1.55–10.10, P = .004) and residual disease (HR 2.67, 95% CI 1.29– 5.52, P = .008) were significant factors. Conclusions: Older EOC patients completed fewer cycles of IP/ intravenous chemotherapy without any significant increase in toxicity, dose delays or dose modifications, and comparable survival to younger patients. The numeric increase in neuropathy higher than grade 2 is a point of concern, especially in a more vulnerable population. The population of older patients receiving IP chemotherapy in this study were on clinical trial and likely to be healthier than the general elderly population. IP chemotherapy appears well tolerated and effective among older patients and is likely underutilized outside clinical trials.
RO
was performed to test where proportions of positive results were different by subgroup (P ≤ .05). Results: The study cohort had a median age of 65 years, consisted of 84% (120/143) squamous (SCC) and 16% (23/143) adenocarcinoma (ADC) histologies, and 46% of patients had metastatic disease (stage IV). Targeted hot-spot sequencing identified variants in the following genes, in descending order of frequency: TP53 (34%), PIK3CA/BRCA2 (8% each), HRAS/FBXW7 (5%-6% each) and ERBB4/ GNAS (3% each). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS, and BRAF also occurred (n = 1 each). Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancer types (e.g., PIK3CA: exon 9 [E545K]; RAS: G13D, Q61L; BRCA2: S1667X; BRAF: R443T; and FBXW7: E471fs). Additional drug targets are identifiable using IHC and ISH methodologies, including cMET (32% IHC, 2% ISH), PDL1 (16%), PTEN loss (45%), HER2 (6% IHC, 2% ISH), and hormone receptors (AR, 6%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2, and GNAS, with an increased presence in ADC (P b .05 for all). Conclusions: Molecularly guided precision medicine could provide alternative, targeted treatment options for vulvar cancer patients especially because of the easy accessibility for repetitive biopsy.
113
Objectives: To investigate estrogen receptor (ER) signaling as a potential mechanism of malignant transformation of endometriosis into endometriosis-associated ovarian cancer (EAOC). Methods: Tissue samples of normal endometrium (n = 23), and benign (n = 19), atypical (n = 11), and concurrent (n = 9) endometrioisis and endometriosis-associated cancers (n = 20) were collected. To evaluate ER signaling, a 236-gene signature of estrogenregulated genes (the “E2sig”) was developed. RNA was isolated from each tissue specimen and expression of the E2sig was measured on the NanoString nCounter platform. Analysis of variance (ANOVA) and unsupervised clustering were used to identify differentially regulated genes and distinct gene expression profiles across samples. These profiles were compared with gene expression datasets of estrogen regulation using Gene Expression Omnibus (GEO). Gene Set Enrichment Analysis (GSEA) against the Molecular Signatures Database was performed to assess whether the pattern of gene expression was consistent with ER activity. Results: ANOVA revealed 158 differentially expressed genes (q b 0.05) and unsupervised clustering of this subset identified 4 distinct gene clusters. Cluster 1 includes genes with increasing expression from benign endometriosis to EAOC and best represents genes involved in malignant transformation. The most notable genes in this cluster are FGF18 and ESR2 (ERβ). Clusters 2 and 3 include genes that are highly expressed and underexpressed in EAOC compared with endometriosis, respectively. Cluster 4 includes genes with an incremental decrease in expression from benign endometriosis to EAOC and includes ESR1 (ERα)) and several downstream ER targets (e.g., PGR, GREB1). Compared with datasets of classic ERα signaling profiles identified in GEO, profiles of EAOC differed significantly. Likewise, GSEA analysis did not identify any ER-related signatures activated in EAOC and among those ownregulated genes, GSEA identified signatures consistent with endocrine resistance and loss of ER function. (See Fig. 1.) Conclusions: Gene expression data suggest classic ER signaling decreases in the progression of endometriosis to EAOC. The gene expression pattern in EAOC is more consistent with profiles of endocrine resistance. FGF18 and ESR2 may play an important role in malignant transformation.
TE
272 – Poster Is intraperitoneal chemotherapy as effective within the elderly population for the treatment of epithelial ovarian cancer? A.K. Crima, M. Rowlanda, R. Ruskina, J. Dvorakb, M. Greenwadeb, A. Waltera, J. Gillenb, K. Dingc, K.N. Moorec, C.C. Gundersonc. aThe University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK, USA, bUniversity of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, cThe University of Oklahoma, Oklahoma City, OK, USA
UN
CO
RR
EC
Objectives: Intraperitoneal (IP) chemotherapy for the treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial advantage in overall survival, and is now considered the standard of care. As the US population ages, evaluating these treatments, specifically for patients with this condition, is of utmost importance. This study aims to compare the toxicity and benefits of IP chemotherapy in patients of ages 70 years and older with those younger than 70 years. Methods: We performed a single institution retrospective review of patients diagnosed with stage IIA-IIIC EOC from 2000 to 2013 who received IP chemotherapy. Clinicopathologic characteristics were extracted, and survival was calculated. SAS version 9.3 was used for descriptive statistics and multivariate analyses. Results: A total of 133 patients were included, with 100 patients being younger than 70 years and 33 patients aged 70 years or older. Race, stage, histology, and performance status were similar. Residual disease did not differ (P = .23). All patients received a platinum/ taxane doublet for frontline chemotherapy. Clinical trial enrollment was similar (89% vs 90%, P = 1.00) despite age. In trial-enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, P = .002) but had similar dose delays (0.9 vs 0.3, P = .17) and dose modifications (1.00 vs 0.93, P = .91). Median progressionfree survival (27 vs 31 months) and overall survival (71 and 62 months) were not statistically different. Grade 4 heme toxicities (P = 1.0), and grade 3 and higher non-heme toxicities (6.1% vs 6.7%, P = 1.0) were similar between groups. Although not statistically significant, neuropathy grade higher than 2 trended higher in the older group (100 vs 86%; P = .18). Upon multivariate analysis for overall survival, age less than 70 years (HR 0.697, 95% CI 0.36–1.26, P = .23) was not predictive, but stage (IIIC vs lower: HR 3.95, 95% CI
Abstracts / Gynecologic Oncology 141 (2016) 2–208
still observed in black patients with ovarian cancer. Based on these data, tumor biology plays a role in ovarian cancer racial disparity, and continued research is needed for determining the cause of this racial disparity.
270 – Poster HPV vaccination rates and attitudes: A cross-sectional survey of college men and women C. Nicol, L. Duska, P. Hornsby, A. Pannone, R.G. Bernheim. University of Virginia, Charlottesville, VA, USA
doi:10.1016/j.ygyno.2016.04.300
OF
TE
DP
Objectives: The effect of MMR loss on the prognosis of endometrial cancer (EC) is controversial. Correlations between MMR-related protein expression and clinicopathologic factors of EC in African American (AA) versus white women were analyzed. Methods: A retrospective review of EC (n = 578) between 1995 and 2013 was conducted to analyze clinicopathologic parameters (Table 1). Immunohistochemical evaluation of MMR protein expression (MLH1, PMS2, MSH2, and MSH6) was performed on tumor tissue microarray. Absence of nuclear staining of any of the 4 proteins in tumor cells with positive lymphocytes (internal control) was considered as MMR loss. Data were analyzed using the Fisher’s exact test and Kaplan-Meier survival analysis. Results: MMR loss was identified in 116/578 patients (20%) with the highest frequency of loss in both MLH1 and PMS2 (47%), PMS2 (30%), MSH6 (14%), and both MSH2 and MSH6 (9%). White women with MMR loss had significantly higher-grade cancer and shorter disease-free interval (187 vs 594 months). AA women with MMR loss had endometrioid histology (P = .001), higher grade (P = .042), tumor size of 2 cm or greater (P = .019), and tendency toward myometrial invasion compared with AA women with intact MMR. Disease-free interval was similar for AA and white women with MMR loss (190 vs 187 months). Conclusions: Although EC is reported to have worse prognosis in AA than white women, our study showed no difference between AA women and white women who had MMR loss.
RO
269 – Poster Prognostic value of loss of MMR protein expression in endometrial carcinoma in African American and White women S. Sakra, E. Abdulfataha, A.R. Munkarahb, R.T. Morrisa, M.A. Elshaikhb, V. Pardeshic, R. Ali-Fehmia. aWayne State University School of Medicine, Detroit, MI, USA, bHenry Ford Health System, Detroit, MI, USA, cKarmanos Cancer Center/Wayne State University, Detroit, MI, USA
Objectives: Human papillomavirus (HPV) vaccination rates remain low, especially among young adults. The objective of the study was to measure the rate of HPV vaccination among college men and women, and to assess attitudes toward HPV vaccination and their association with vaccination status and intent. Methods: A random sample of 3,000 college men (18–21 years) and women (18–26 years) were asked to complete an online survey including questions about HPV vaccination status and intention and the modified Carolina HPV Immunization Attitudes Scale (CHIAS). (See Table 1.) Results: Overall, 67.6% of students had received at least 1 HPV vaccination; this proportion was higher for women (74.7%) than for men (51.0%). Male and female attitudes toward vaccination were not significantly different for 14 of 17 CHIAS items. Barriers score was the factor most strongly associated with vaccination intent “today” and also strongly associated with vaccination intent for “the next 6 months.” In contrast to the other factors, higher Barriers scores were actually associated with greater vaccination intent both “today” and “in the next 6 months.” Conclusions: The rate of HPV vaccination among college students was higher than expected, with rates double the national average for 18- to 26-year-old women (74.7% vs 34.5%) and 20 times higher than the national average for 18- to 21-year-old men (51.0% vs 2.4%). Men and women report similar attitudes to HPV vaccination. Even among a college population, barriers remain a significant factor in nonvaccination. Decreasing cost and access barriers is essential to improving HPV vaccination rates among young adults. Additional studies are needed to validate CHIAS among male populations.
RR
EC
Table 1 CHIAS Barrier Factor Items.
UN
CO
Table 1
doi:10.1016/j.ygyno.2016.04.301
doi:10.1016/j.ygyno.2016.04.302
271 – Poster Identification of molecular targets in vulvar cancers P.H. Thakera, M. Palisoula, S.K. Reddyb, R. Feldmanb. aWashington University School of Medicine in St. Louis, St. Louis, MO, USA, bCaris Life Sciences, Irving, TX, USA Objectives: Vulvar cancer may comprise only 5% of gynecologic malignancies but its incidence has been increasing. Given its rarity, there is a paucity of data surrounding treatment guidelines and targets for new therapies. We retrospectively examined a database of molecularly profiled patients for insight into the molecular alterations that contribute to vulvar pathogenesis with the hopes of identifying molecular targets for this rare disease. Methods: A total of 143 vulvar cancer patients were included in the study and tested at a central laboratory (Caris Life Sciences, Phoenix, AZ). Tests included 1 or more of the following: gene sequencing (Sanger or next-generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (chromogenic/ fluorescence in situ hybridization [ISH]). The 2-tailed Fisher’s exact test
Abstracts / Gynecologic Oncology 141 (2016) 2–208
OF
doi:10.1016/j.ygyno.2016.04.304
273 – Poster The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer M.M. Boisena, C. Andersenb, M. Sikorab, T. Mac, G. Tsengc, A. Vladd, E. Elishaeva, U. Chandrane, R.P. Edwardsa, S. Oesterreicha. aMageeWomens Hospital of UPMC, Pittsburgh, PA, USA, bUniversity of Pittsburgh/Magee-Women's Hospital, Pittsburgh, PA, USA, cUniversity of Pittsburgh, Pittsburgh, PA, USA, dMagee-Womens Research Institute, Pittsburgh, PA, USA, eUniversity of Pittsburgh/Magee-Women's Hosiptal, Pittsburgh, PA, USA
DP
doi:10.1016/j.ygyno.2016.04.303
1.55–10.10, P = .004) and residual disease (HR 2.67, 95% CI 1.29– 5.52, P = .008) were significant factors. Conclusions: Older EOC patients completed fewer cycles of IP/ intravenous chemotherapy without any significant increase in toxicity, dose delays or dose modifications, and comparable survival to younger patients. The numeric increase in neuropathy higher than grade 2 is a point of concern, especially in a more vulnerable population. The population of older patients receiving IP chemotherapy in this study were on clinical trial and likely to be healthier than the general elderly population. IP chemotherapy appears well tolerated and effective among older patients and is likely underutilized outside clinical trials.
RO
was performed to test where proportions of positive results were different by subgroup (P ≤ .05). Results: The study cohort had a median age of 65 years, consisted of 84% (120/143) squamous (SCC) and 16% (23/143) adenocarcinoma (ADC) histologies, and 46% of patients had metastatic disease (stage IV). Targeted hot-spot sequencing identified variants in the following genes, in descending order of frequency: TP53 (34%), PIK3CA/BRCA2 (8% each), HRAS/FBXW7 (5%-6% each) and ERBB4/ GNAS (3% each). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS, and BRAF also occurred (n = 1 each). Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancer types (e.g., PIK3CA: exon 9 [E545K]; RAS: G13D, Q61L; BRCA2: S1667X; BRAF: R443T; and FBXW7: E471fs). Additional drug targets are identifiable using IHC and ISH methodologies, including cMET (32% IHC, 2% ISH), PDL1 (16%), PTEN loss (45%), HER2 (6% IHC, 2% ISH), and hormone receptors (AR, 6%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2, and GNAS, with an increased presence in ADC (P b .05 for all). Conclusions: Molecularly guided precision medicine could provide alternative, targeted treatment options for vulvar cancer patients especially because of the easy accessibility for repetitive biopsy.
113
Objectives: To investigate estrogen receptor (ER) signaling as a potential mechanism of malignant transformation of endometriosis into endometriosis-associated ovarian cancer (EAOC). Methods: Tissue samples of normal endometrium (n = 23), and benign (n = 19), atypical (n = 11), and concurrent (n = 9) endometrioisis and endometriosis-associated cancers (n = 20) were collected. To evaluate ER signaling, a 236-gene signature of estrogenregulated genes (the “E2sig”) was developed. RNA was isolated from each tissue specimen and expression of the E2sig was measured on the NanoString nCounter platform. Analysis of variance (ANOVA) and unsupervised clustering were used to identify differentially regulated genes and distinct gene expression profiles across samples. These profiles were compared with gene expression datasets of estrogen regulation using Gene Expression Omnibus (GEO). Gene Set Enrichment Analysis (GSEA) against the Molecular Signatures Database was performed to assess whether the pattern of gene expression was consistent with ER activity. Results: ANOVA revealed 158 differentially expressed genes (q b 0.05) and unsupervised clustering of this subset identified 4 distinct gene clusters. Cluster 1 includes genes with increasing expression from benign endometriosis to EAOC and best represents genes involved in malignant transformation. The most notable genes in this cluster are FGF18 and ESR2 (ERβ). Clusters 2 and 3 include genes that are highly expressed and underexpressed in EAOC compared with endometriosis, respectively. Cluster 4 includes genes with an incremental decrease in expression from benign endometriosis to EAOC and includes ESR1 (ERα)) and several downstream ER targets (e.g., PGR, GREB1). Compared with datasets of classic ERα signaling profiles identified in GEO, profiles of EAOC differed significantly. Likewise, GSEA analysis did not identify any ER-related signatures activated in EAOC and among those ownregulated genes, GSEA identified signatures consistent with endocrine resistance and loss of ER function. (See Fig. 1.) Conclusions: Gene expression data suggest classic ER signaling decreases in the progression of endometriosis to EAOC. The gene expression pattern in EAOC is more consistent with profiles of endocrine resistance. FGF18 and ESR2 may play an important role in malignant transformation.
TE
272 – Poster Is intraperitoneal chemotherapy as effective within the elderly population for the treatment of epithelial ovarian cancer? A.K. Crima, M. Rowlanda, R. Ruskina, J. Dvorakb, M. Greenwadeb, A. Waltera, J. Gillenb, K. Dingc, K.N. Moorec, C.C. Gundersonc. aThe University of Oklahoma, Stephenson Cancer Center, Oklahoma City, OK, USA, bUniversity of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, cThe University of Oklahoma, Oklahoma City, OK, USA
UN
CO
RR
EC
Objectives: Intraperitoneal (IP) chemotherapy for the treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial advantage in overall survival, and is now considered the standard of care. As the US population ages, evaluating these treatments, specifically for patients with this condition, is of utmost importance. This study aims to compare the toxicity and benefits of IP chemotherapy in patients of ages 70 years and older with those younger than 70 years. Methods: We performed a single institution retrospective review of patients diagnosed with stage IIA-IIIC EOC from 2000 to 2013 who received IP chemotherapy. Clinicopathologic characteristics were extracted, and survival was calculated. SAS version 9.3 was used for descriptive statistics and multivariate analyses. Results: A total of 133 patients were included, with 100 patients being younger than 70 years and 33 patients aged 70 years or older. Race, stage, histology, and performance status were similar. Residual disease did not differ (P = .23). All patients received a platinum/ taxane doublet for frontline chemotherapy. Clinical trial enrollment was similar (89% vs 90%, P = 1.00) despite age. In trial-enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, P = .002) but had similar dose delays (0.9 vs 0.3, P = .17) and dose modifications (1.00 vs 0.93, P = .91). Median progressionfree survival (27 vs 31 months) and overall survival (71 and 62 months) were not statistically different. Grade 4 heme toxicities (P = 1.0), and grade 3 and higher non-heme toxicities (6.1% vs 6.7%, P = 1.0) were similar between groups. Although not statistically significant, neuropathy grade higher than 2 trended higher in the older group (100 vs 86%; P = .18). Upon multivariate analysis for overall survival, age less than 70 years (HR 0.697, 95% CI 0.36–1.26, P = .23) was not predictive, but stage (IIIC vs lower: HR 3.95, 95% CI