A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients.

Background: There is mounting evidence that a personal history of endometriosis is associated with an increased risk of ovarian cancer. Previous studies have shown that ovarian cancer patients with a prior diagnosis of endometriosis had more favorable outcomes than women without this condition, likely due to increased surveillance resulting in earlier detection. However, most of these studies were relatively small in size and did not consider histological subtypes in their analyses. Given the increased recognition of the importance of histology in ovarian cancer prognosis, we examined the association between history of endometriosis and overall survival among women diagnosed with ovarian cancer in a large multi-national sample. Methods: We utilized data from 10 case-control studies participating in Ovarian Cancer Association Consortium and used age- and stage-adjusted Cox- proportional hazards models to estimate associations between history of endometriosis and overall survival among patients diagnosed with invasive epithelial ovarian carcinoma. Analyses were also conducted separately for histological subtypes of ovarian cancer (low grade serous, high grade serous, mucinous, endometriod and clear cell). We also examined the associations within strata of menopausal status and body mass index (BMI) categories. Results: A personal history of endometriosis was inversely associated with risk of death (hazard ratio (HR)=0.84; 95% confidence interval (CI) 0.74-0.95) among all ovarian cancer patients (n=7033). We observed strong risk reductions among patients with low-grade serous disease (n=214; HR=0.48; 95% CI 0.24-0.95), but not among patients with high-grade serous tumors (n=3273; HR=0.97; 95% CI 0.83-1.14). Furthermore, patients with clear cell tumors (n=555) had a 40% risk reduction (HR=0.60; 95% CI 0.39-0.91). No significant associations were observed for patients with mucinous (n=356) or endometriod (n=1072) ovarian cancer, although the HRs were well below the null value (HR=0.82; 95% CI 0.33-1.05, and HR=0.70; 95% CI 0.47-1.05, respectively). When we considered BMI as a potential effect modifier, we observed that the survival benefit associated with a personal history of endometriosis was restricted to normal weight women (HR=0.70; 95% CI 0.58-0.85) and absent among overweight (HR=1.02; 95% CI 0.82-1.28) and obese (HR=1.08; 95% CI 0.82-1.40) patients. The relationship between a personal history of endometriosis and ovarian cancer outcomes did not differ between premenopausal and postmenopausal patients. Conclusion: Our results suggest that history of endometriosis is associated with overall survival among women diagnosed with invasive ovarian cancer, particularly among clear cell and low grade serous carcinomas, including after control for stage of disease. Despite being underpowered to adequately assess between endometriosis and outcomes for patients with mucinous and endometrioid tumors, there was a trend towards improved survival for those with a personal history of endometriosis. These findings underscore the importance of examining prognostic indicators for ovarian cancer among distinct histological subgroups, as well as to distinguish between low-grade serous and high-grade serous disease. Moreover, the constellation of changes caused by endometriosis to induce ovarian cancer may alter the tumor microenvironment and change the ultimate disease prognosis. Future studies are needed to determine the role of endometriosis in the tumor environment and ovarian cancer prognosis. Citation Format: Albina N. Minlikeeva, Jo L. Freudenheim, C. Leigh Pearce, J.Brian Szender, Ovarian Cancer Association Consortium, Kirsten B. Moysich. Personal history of endometriosis and survival in ovarian cancer patients: A pooled analysis of 10 studies from the Ovarian Cancer Association Consortium. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B24.

BackgroundActivation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands.Methodology/Principal FindingsWe performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8.Conclusions/SignificanceOur results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets.

To establish prediction models for 2-year overall survival of ovarian cancer patients with metastasis. In total, 4,929 participants from Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into the training set (n = 3,451) and the testing set (n = 1,478). Univariate and multivariable regression were conducted in the training set to identify predictors for 2-year overall survival of metastatic ovarian cancer patients. The C-index was calculated for assessing the performance of the models. The nomogram for the model was plotted. The prediction value of the model was validated in the testing set. Subgroup analysis were performed concerning surgery and chemotherapy status of patients and the metastatic site of ovarian cancer in the testing set. The calibration curves were plotted and the decision curve analysis (DCA) were conducted. At the end of follow-up, 2,587 patients were survived and 2,342 patients were dead within 2 years. The 2-year survival rate was 52.5%. The prediction models were constructed based on predictors including age, radiation, surgery and chemotherapy, CA125, and bone, liver, and lung metastasis. The prediction model for 2-year overall survival of ovarian cancer patients with metastasis showed good predictive ability with the C-index of the model of 0.719 (95% CI: 0.706-0.731) in the training set and 0.718 (95% CI: 0.698-0.737) in the testing set. In terms of patients with bone metastasis, the C-index was 0.740 (95% CI: 0.652-0.828) for predicting the 2-year overall survival of ovarian cancer patients. The C-index was 0.836 (95% CI: 0.694-0.979) in patients with brain metastasis, 0.755 (95% CI: 0.721-0.788) in patients with liver metastasis and 0.725 (95% CI: 0.686-0.764) in those with lung metastasis for predicting the 2-year overall survival of ovarian cancer patients. The models showed good predictive performance for 2-year overall survival of metastatic ovarian cancer patients.

To explore the variation in ovarian cancer survival in Denmark in the period 1978-2002 in relation to time since diagnosis, age at diagnosis, period of diagnosis, stage and histology. Register-based cohort study. Denmark in the period 1978-2002. Using the nationwide Danish Cancer Registry, we included a total of 13,035 women diagnosed with invasive ovarian cancer in Denmark in the period 1978-2002. Excess mortality risk analyses of five-year relative survival of ovarian cancer patients diagnosed in the period 1978-2002 with follow-up through 2006 were made based on data from the NORDCAN database. Five-year relative survival, excess mortality rate (ER) and relative excess mortality risk (RER) after an ovarian cancer diagnosis. The relative survival of Danish ovarian cancer patients slightly increased in the period 1978-2002. The ERs were highest in the first year following diagnosis, in particular in the first three months, and among older patients, even for localized and regional tumors. The pattern remained the same when stratified by histological subgroup. Older age at diagnosis, earlier period of diagnosis, more advanced stage at diagnosis and being diagnosed with undifferentiated carcinoma predicted poorer survival among Danish ovarian cancer patients diagnosed in the period 1978-2002. The survival of Danish ovarian cancer patients has slightly increased from 1978 through 2002. Despite this, the mortality rate of ovarian cancer in Denmark is still higher than in the other Nordic countries. Explanations for these differences are still to be identified.

High glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status. Whole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis. Combined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2. In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed. Increased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.

Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified.

Objective: In this study, we aimed to identify the prognostic factors of survival and recurrence in ovarian and uterine serous cancer patients. Materials and methods: This was a retrospective study conducted at Tepecik Research and Education Hospital, İzmir, Turkey, between January 2002 and January 2019. The medical files of 2,027 endometrial and 821 ovarian patients who underwent examination for endometrial cancer and epithelial ovarian cancer were examined retrospectively by the same author. The data of eligible 385 and 49 patients diagnosed with ovarian and uterine serous carcinoma, respectively, were identified for analysis from the hospital database. Descriptive, univariate, and multivariate Cox regression and binary logistic regression analyses of patients were performed. Results: The mean age of ovarian serous cancer patients (n = 385) was 53.9 ± 10.9 years. The mean age of uterine serous cancer patients (n = 49) was 67.2 ± 10.6 years. A total of 81 ovarian serous cancer patients (21.0%) had stage 1, while 24 (6.2%) had stage 2, and 31 (8.1%) had stage 4 disease. A total of 26 uterine serous carcinoma patients (53.1%) had stage 1 disease, 6 (12.2%) had stage 2, 10 (20.4%) had stage 3, and 7 (14.3%) had stage 4 disease. For ovarian serous patients, stage, grade, optimality, neoadjuvant chemotherapy, adjuvant chemotherapy cycle number, and recurrence had impact on both overall and disease-free survival (p &lt; 0.05). For uterine serous cancer patients, optimality was the only prognostic factor for both survival and recurrence (p = 0.01 and p = 0.01, respectively). Conclusion: In ovarian serous cancer patients, we found that disease stage, grade, optimality, neoadjuvant chemotherapy, and adjuvant chemotherapy cycle number had impact on overall and disease-free survival in both univariate and multivariate Cox regression analysis, whereas disease stage and optimality were the only significant prognostic factors for recurrence in ovarian serous cancer patients. However, in patients with uterine serous carcinomas, optimal surgery was the only independent prognostic factor both for survival and recurrence.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Impact:&lt;/b&gt; These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. &lt;i&gt;Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Impact:&lt;/b&gt; These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. &lt;i&gt;Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Acid ceramidase (ASAH1) is a key player in sphingolipid metabolism and signaling. It has prognostic value for several cancers, but histotype-specific analyses of ovarian cancer are not yet available. We used three retrospective TMA cohorts encompassing a total of 1106 ovarian cancers with follow-up data for immunohistochemical analysis of acid ceramidase (ASAH1) expression. Patients with sub-optimal debulking and persistent residual tumor after surgery introduced bias in the prognostic analysis and were excluded from further studies. Overall, we detected an association of ASAH1 expression with better prognosis in ovarian cancer patients. ASAH1 expression differed between histological ovarian cancer histotypes with most frequent expression in endometrioid and clear cell ovarian cancer, which are both associated with good prognosis. Stratified subgroup analyses within these histotypes did not reveal significant survival differences, but the power of the analysis may be limited by smaller sample sizes. In contrast to breast cancer, we found only a modest concordance between estrogen receptor status and ASAH1 expression within the endometrioid ovarian cancer histotype. In an exploratory analysis of estrogen receptor negative endometrioid ovarian cancer, ASAH1 expression was associated with significantly better overall survival (P = 0.007). Acid ceramidase is most frequently expressed in endometrioid and clear cell histotypes and could add independent prognostic value to estrogen receptor in endometrioid ovarian cancer. Modulating sphingolipid metabolism may lead to novel therapeutic intervention strategies for this disease.

Ovarian cancer patients who carry germ-line BRCA1 mutations may have improved survival compared with ovarian cancer patients without these mutations. To evaluate this hypothesis, the authors compared survival in ovarian cancer patients who had a history of prior breast cancer with that of patients without such a history. Specifically, they used data from the population-based US Surveillance, Epidemiology, and End Results (SEER) Program to assess time to death from ovarian cancer among ovarian cancer patients with and without a prior breast cancer. All 25,637 White women diagnosed with invasive epithelial ovarian cancer in SEER registries between 1973 and 1995 were included. Of these, 824 women had had a prior breast cancer diagnosis. The ovarian cancer death rate among women with prior breast cancer was significantly lower than that of women with ovarian cancer only, adjusted for age and stage at ovarian cancer diagnosis. The survival advantage was most pronounced among older women and among those whose ovarian cancers were more advanced at the time of diagnosis. These results lend indirect support to prior findings of improved ovarian cancer survival in BRCA1 mutation carriers.

ObjectiveAt present, there is still a lack of reliable biomarkers for ovarian cancer (OC) to guide prognosis prediction and accurately evaluate the dominant population of immunotherapy. In recent years, the relationship between peripheral blood markers and tumor‐infiltrating immune cells (TICs) with cancer has attracted much attention. However, the relationship between the survival of OC patients and intratumoral‐ or extratumoral‐associated immune cells remains controversial.MethodsIn this study, four machine‐learning algorithms were used to predict overall survival in OC patients based on peripheral blood indicators. To further screen out immune‐related gene and molecular targets, we systematically explored the correlation between TICs and OC patient survival based on The Cancer Genome Atlas database. Using the TICs score method, patients were divided into a low immune infiltrating cell group and a high immune infiltrating cell group.ResultsThe results showed that there was a significant statistical significance between the peripheral blood indicators and the survival prognosis of OC patients. Survival analysis showed that TICs play a crucial role in the survival of OC patients. Four core genes, CXCL9, CD79A, MS4A1, and MZB1, were identified by cross‐PPI and COX regression analysis. Further analysis found that these genes were significantly associated with both TICs and survival in OC patients.ConclusionsThese results suggest that both peripheral blood markers and TICs can be used as prognostic predictors in patients with OC, and CXCL9, CD79A, MS4A1, and MZB1 may be potential therapeutic targets for OC immunotherapy.

BackgroundOvarian cancer greatly threatens the general health of women worldwide. Implementation of predictive prognostic biomarkers aids in ovarian cancer management.MethodsUsing online databases, the general expression profile, target-disease associations, and interaction network of PAWR were explored. To identify the role of PAWR in ovarian cancer, gene correlation analysis, survival analysis, and combined analysis of drug responsiveness and PAWR expression were performed. The predictive prognostic value of PAWR was further validated in clinical samples.ResultsPAWR was widely expressed in normal and cancer tissues, with decreased expression in ovarian cancer tissues compared with normal tissues. PAWR was associated with various cancers including ovarian cancer. PAWR formed a regulatory network with a group of proteins and correlated with several genes, which were both implicated in ovarian cancer and drug responsiveness. High PAWR expression denoted better survival in ovarian cancer patients (OS: HR = 0.84, P = 0.0077; PFS, HR = 0.86, P = 0.049). Expression of PAWR could predict platinum responsiveness in ovarian cancer and there was a positive correlation between PAWR gene effect and paclitaxel sensitivity. In 12 paired clinical samples, the cancerous tissues exhibited significantly lower PAWR expression than matched normal fallopian tubes. The predictive prognostic value of PAWR was maintained in a cohort of 50 ovarian cancer patients.ConclusionsHigh PAWR expression indicated better survival and higher drug responsiveness in ovarian cancer patients. PAWR could be exploited as a predictive prognostic biomarker in ovarian cancer.

70P - mTORC1 and its downstream effectors predict poor outcome in primary epithelial ovarian cancer

Bevacizumab (BV) plus chemotherapy is broadly used in advanced ovarian cancer (OC). However, the efficacy of BV-based regimens for advanced OC patients is not satisfactory. Therefore, it is urgent to explore the predictive genetic biomarkers for BV.Tumor tissues from advanced OC patients receiving BV-based regimens were analyzed with a 150-gene targeted panel for next generation sequencing. The associations between gene alterations or clinicopathology features and progression-free survival (PFS) were analyzed by Kaplan–Meier curves or Cox regression. The association of the genetic alteration in potential predictive genes and expressions of 11 vascular endothelial growth factor-related genes were analyzed in The Cancer Genome Atlas cohort using 292 OC cases.Sixty two Chinese advanced OC patients treated with BV-based therapy were included. The median PFS of was 6.9 months, and objective response rate was 14.5%. In multivariate Cox regression analysis, the status of endothelial growth factor receptor (EGFR) (hazard ratio = 6.39, 95% confidence interval [CI] 2.25–18.13, P < .001) and human epidermal growth factor receptor 2 (HER2) (hazard ratio = 3.58, 95% CI 1.27–10.08, P = .016) were significantly correlated with PFS. MYC Proto-Oncogene amplification seemed to have a positive trend (hazard ratio = 0.21, 95% CI 0.05–1.02, P = .052). Moreover, EGFR and HER2 alterations were not prognostic factors of overall survival for OC in The Cancer Genome Atlas OC cohort. The vascular endothelial growth factor-related signature analysis indicated vascular endothelial factor A expression was upregulated with EGFR alterations (P = .034) which may be involved in BV resistance, and HER2 alterations were associated with hypoxia inducible factor 1 subunit alpha overexpression significantly (P = .029).EGFR or HER2 alterations are negative predictors of PFS for OC patient treated with BV plus chemotherapy. Therefore, the clinicians may consider to use alternative regimens such as anti-EGFR or anti-HER2 targeted therapy instead of BV-based regimens on these patients when standard care fail.