Factor In Epithelial Ovarian Cancer Research Articles

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis

BackgroundThe canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context.MethodsWe assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression.ResultsAmong 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p = 0.004) and death (HR: 1.70, p = 0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors.ConclusionsThis is the first study to demonstrate that p52, a major component of non-canonical NF-κB signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-κB signaling should be explored as novel ovarian cancer therapies are needed.

The Combination of Plasma Fibrinogen Concentration and Neutrophil Lymphocyte Ratio (F-NLR) as a Prognostic Factor of Epithelial Ovarian Cancer.

ObjectiveGrowing epidemiological evidence supports that coagulation cascades and cancer-associated inflammation are associated with recurrence and survival of epithelial ovarian cancer (EOC). This study aimed to assess the clinical significance of the combination of plasm fibrinogen and neutrophil lymphocyte ratio (F-NLR) score to predict EOC prognosis, including recurrence, disease-free survival (DFS), and overall survival (OS).Patients and MethodsWe retrospectively enrolled 281 EOC patients who underwent surgery at our institution. According to receiver operating characteristic curve, cut-off values of fibrinogen and NLR were set at 3.44 g/L and 2.46, respectively, to predict recurrence. The F-NLR score was then classified into three groups as follows: F-NLR score of 2: both hyperfibrinogenemia (>3.44 mg/dL) and high NLR (>2.46), F-NLR score of 1: either hyperfibrinogenemia or high NLR, and F-NLR score of 0: neither of the abnormalities. Continuous and categorical variables were compared using T-test and chi-square test among F-NLR groups. The Cox hazard regression model was used to assess prognostic factors. Both DFS and OS curves were generated by Kaplan–Meier method.ResultsThe analyses showed that F-NLR was significantly associated with clinical stage (P=0.000), lymphatic metastasis (P=0.001), and carbohydrate antigen (CA) 125 level (P=0.048). The F-NLR (hazard ratio=2.211; 95% confidence interval=1.251–6.394; P=0.002) was demonstrated as an independent prognostic factor for survival of EOC. The DFS rates in F-NLR groups 0, 1, and 2 were 68.5%, 47.7%, and 31.7%, respectively (P=0.000); the OS rates in previous groups were 75.9%, 51.4%, and 34.2% (P=0.000) and the 5-year survival times (mean±SD, months) were 64.24±24.21, 60.27±22.65, and 46.09±20.32, respectively. By subgroup analysis, the F-NLR was significantly associated with DFS and OS among patients with advanced tumor stage (Stage III or IV) or lymphatic metastasis.ConclusionThe pre-operative F-NLR score, a novel inflammation-based grading system, was a promising prognosis predictor for EOC patients, especially those with advanced clinical stage and those with lymph node metastasis.

Abstract A15: Noncanonical NF-kappaB signaling is associated with poor ovarian cancer prognosis

Abstract Objective: Mediated by a family of transcription factors, the canonical and noncanonical nuclear factor-kappaB (NF-kB) signaling pathways have key roles in inflammation, innate immunity, and cancer development and progression. As prior ovarian cancer studies have evaluated only canonical NF-kB transcription factors in relation to survival, this study was undertaken to evaluate both canonical and noncanonical NF-kB pathway components in tumor samples from epithelial ovarian cancer cases from the Vanderbilt Tissue Repository for Ovarian Cancer (TROC). Methods: We abstracted clinical data from electronic medical records and assayed p65 (representing the canonical NF-kB pathway) and p52 (representing the noncanonical NF-kB pathway) by immunohistochemistry for 197 TROC samples. Nuclear and cytoplasmic staining in tumor cells was semiquantified by H-scores and dichotomized at median values. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional-hazards regression. Results: Median cytoplasmic and nuclear p65 and p52 H-scores were significantly higher among high-grade and serous cases; median p52 H-scores were also significantly higher among late-stage cases and patients treated with chemotherapy (all Wilcoxon rank sum p<0.05). In unadjusted regression models, higher nuclear p65 and higher nuclear p52 were associated with approximately 40% and 70% shorter PFS and OS, respectively, but these associations were attenuated by adjustment for age, stage, tumor type, race, chemotherapy, and residual disease. In multivariable adjusted models, higher cytoplasmic p52 was associated with more than 50% shorter PFS (HR 1.68, 95% CI 1.18-2.39) and OS (HR 1.53, 95% CI 1.06-2.21). Furthermore, when cytoplasmic and nuclear staining were combined, and mutually adjusted models included both p52 and p65, only p52 remained associated with worse PFS (HR 1.57, 95% CI 1.10-2.37) and OS (HR 1.51, 95% CI 1.05-2.15). Conclusions: This is the first study to demonstrate that p52, representing noncanonical NF-kB signaling, may be an independent prognostic factor for epithelial ovarian cancer. Approaches to inhibit noncanonical NF-kB signaling should be explored as novel therapies for ovarian cancer are needed. Citation Format: Demetra Hufnagel, Andrew J. Wilson, Jamie Saxon, Dineo Khabele, Timothy Blackwell, Marta A. Crispens, Fiona Yull, Alicia Beeghly-Fadiel. Noncanonical NF-kappaB signaling is associated with poor ovarian cancer prognosis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A15.

Abstract B37: Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer

Abstract Improving risk prediction and prevention strategies through identifying new susceptibility genes for non-high-grade serous ovarian cancer (non-HGS) would represent an important advance in reducing incidence and mortality. Epithelial ovarian cancer (EOC) has five main histotypes that have distinct pathologies, molecular changes, clinical characteristics, and tissues of origin. They are classified as high-grade serous (HGS), low-grade serous (LGS), clear-cell (CCC), endometrioid (END), and mucinous (MUC). A family history of breast or ovarian cancer is the strongest single risk factor for EOC. Germline mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2 confer EOC risks of 44% and 17% by age 80, respectively. Only 40% of the excess familial risk is known, suggesting there are many other susceptibility genes yet unidentified. The non-HGS histotypes are poorly studied due to limited sample size within individual studies. Thus, families of cases with non-HGS tumors have few risk prediction options. Whole-exome sequencing (WES) analysis was performed on 251 non-HGS cases (56 LGS, 55 CCC, 117 END, 23 MUC). Cases were screened negative for BRCA1/2 mutations and selected for a family history of ovarian or breast cancer, or young onset (<45 years) of ovarian cancer. WES identified 1,278 genes with rare predicted truncating mutation in at least one case. Predicted truncating mutations in cases were compared to 171,584 controls from the Exome Aggregation Consortium (ExAC) and the Genome Aggregation Database (gnomAD). Gene-set enrichment analysis showed enrichment for genes involved in the DNA repair pathway (p=3.08 × 10−7). Twenty-five candidate genes (including 4 DNA repair genes) were selected for validation by targeted sequencing. Five genes important in HGS (BRIP1, FANCM, PALB2, RAD51C, RAD51D) as well as two additional candidates (XRCC2 and XRCC3) were also sequenced. Targeted sequencing was performed on 1,779 cases (669 END, 356 CCC, 327 LGS, 427 MUC) and 1,863 controls from studies in the Ovarian Cancer Association Consortium (OCAC). Library preparation and target enrichment was performed using the Fluidigm Juno System and Illumina sequencing was performed on a NovaSeq 6000 Sequencing System. A case-control analysis of predicted truncating variants in the 32 genes was performed. Using a minimum alternate allele frequency of 30%, we identified a higher frequency of mutations in non-HGS cases than controls in ERCC6 (p=0.034) and IL31RA (p=0.034). ERCC6 is involved in DNA repair and IL31RA is a cytokine receptor. Sanger sequencing validation of variants to confirm these results is ongoing. Several other genes showed suggestive higher frequencies of mutations in cases than controls. A larger case control analysis will be performed to confirm those findings. Identifying novel susceptibility genes for non-HGS may have clinical impact by reducing disease-associated mortality through improving risk prediction, identifying prevention strategies, and developing new targeted treatments. Citation Format: Marina Pavanello, Ed Dicks, Honglin Song, Amir Ariff, Adelyn Bolithon, Maria P. Intermaggio, Mark Pinese, Kirsten Moysich, Kunle O. Odunsi, Ellen Goode, David D. Bowtell, Peter Fasching, Jennifer A. Doherty, Francesmary Modugno, Susanne K. Kjær, Penelope M. Webb, Anna Wu, Anna deFazio, Ovarian Cancer Association Consortium, Paul James, Deepak Subramanian, Ian Campbell, Simon A. Gayther, Paul D.P. Pharoah, Susan J. Ramus. Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B37.

Progranulin expression induced by follicle-stimulating hormone in ovarian cancer cell lines depends on the histological subtype

Epithelial ovarian cancer (EOC) is a heterogeneous disease that can be categorized into four major histological subtypes. Its etiology remains poorly understood due mainly to this heterogeneity. Follicle-stimulating hormone (FSH) has been implicated as a risk factor in EOC and has been suggested that may influence the development of specific subtypes. In addition, FSH regulates different aspects of ovarian cancer tumorigenesis. FSH downstream target genes in EOC have not been fully identified. Progranulin (PGRN) overexpression is associated with cell proliferation, invasion, chemoresistance, and shortened overall survival in ovarian cancer. Recently, we demonstrated that PGRN expression is regulated through the PI3K signaling pathway in clear cell ovarian carcinoma (CCOC) cells. In contrast, we also demonstrated that PGRN synthesis in serous ovarian cancer (SOC) cells is regulated via PKC but not by the PI3K signaling pathway. Several studies have demonstrated that FSH induces PKC and PI3K activation. Thus, this study was to investigate the effect of FSH on PGRN production in the CCOC cell line TOV-21G as compared to the SOC cell lines SKOV3 and OVCAR3. Cultured TOV-21G, SKOV3, and OVCAR3 cells were incubated with different concentrations of FSH for 48h. PGRN mRNA and protein expression were assessed by RT-PCR and Western blotting, while PGRN secretion was measured by ELISA. PGRN mRNA and protein expression, as well as PGRN secretion, significantly increased after FSH stimulation in TOV-21G but not in SKOV3 and OVCAR3 cells. These data indicate that FSH induces PGRN expression and secretion only in CCOC cells. Establishing specific features for CCOC could reveal potential diagnostic and therapeutic targets.

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity.

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

Expression and clinical significance of WWOX, Elf5, Snail1 and EMT related factors in epithelial ovarian cancer.

Expression and clinical significance of WW domain-containing oxidoreductase (WWOX), Elf5, Snail1 and epithelial-mesenchymal transition (EMT) related factors in epithelial ovarian cancer were investigated. Ovarian cancer tissues of 300 epithelial ovarian cancer patients and the adjacent normal tissues were analyzed. Immunohistochemical method was used to detect the expressions of WWOX, Elf5, Snail1 and EMT marker molecules in the specimens. The relationship between the indicators and clinicopathological parameters, and prognosis of patients with ovarian cancer was analyzed. The relationship between WWOX, Elf5, Snail1 and EMT marker molecules E-cadherin, N-cadherin and vimentin in ovarian cancer tissues was analyzed. The expression levels of WWOX, Elf5, Snail1 and EMT marker molecules in epithelial ovarian cancer tissues were significantly different from those in adjacent normal tissues, and were related to surgical pathological stage, pathological grade and lymph node metastasis. High expressions of WWOX and Elf5 were related to the survival rate of patients. The survival rate of patients with positive expression was significantly higher than that of negative expression. FIGO stage, pathological grade, lymph node metastasis and expression of WWOX and Elf5 were all independent factors affecting postoperative prognosis in ovarian cancer patients. In conclusion, the expression levels of WWOX, Elf5, Snail1 and EMT related factors in epithelial ovarian cancer tissues are consistent and different. The expression levels of WWOX and Elf5 are related to the survival and prognosis of patients with epithelial ovarian cancer.

Identifying modifiable and non-modifiable risk factors of epithelial ovarian cancer—can we get it better?

Ovarian cancer is the fifth most common cancer in women worldwide, with an estimated lifetime risk of one in 54–75, and one in 100 of ovarian cancer-related mortality (1). The role of irreversible and reversible risk factors in development of epithelial ovarian cancer (EOC) has been researched extensively, with a heavy focus on genetic factors and family history of breast/ovarian cancer.

Soluble Programmed Death Receptor Ligands sPD-L1 and sPD-L2 as Liquid Biopsy Markers for Prognosis and Platinum Response in Epithelial Ovarian Cancer.

Introduction: Response to platinum-based therapy is a major prognostic factor in epithelial ovarian cancer (EOC) and reliable prognostic biomarkers are urgently needed to identify patients at high risk. Since ligands of the Programmed Death Receptor-1 (PD-L1 and PD-L2) play a crucial role within the tumor microenvironment for tumorigenesis, we investigated levels of sPD-L1 and sPD-L2 in liquid biopsies of serum samples, and correlated the results with the clinical status, presence of circulating tumor cells (CTCs) and disease outcome in primary EOC patients.Methods: sPD-L1 and sPD-L2 were determined by ELISA in patients (N = 83) and healthy females (N = 29). Gene expression analysis of EpCAM, MUC-1, CA-125, and ERCC1 was performed by RT-PCR after CTCs enrichment.Results: sPD-L1 was significantly (p = 0.0001) increased and sPD-L2 decreased (p = 0.003) in EOC patients compared to controls. While enhanced sPD-L1 was associated with residual tumor burden (p = 0.022), reduced sPD-L2 levels were related to platinum-resistance (p < 0.01) and the presence of ERCC1+ CTCs (p < 0.0001). High sPD-L1 levels were associated with a reduced 5 year overall survival (OS, p = 0.003) and progression-free survival (PFS, p = 0.019). Strikingly, sPD-L1 levels >6.4 pg/ml were indicative of a reduced OS (p = 0.035) and PFS (p = 0.083) in platinum-sensitive patients, while OS and PFS in platinum-resistant patients did not differ when patients were stratified to this cut-off.Conclusions: Our study highlights sPD-L1 and sPD-L2 as complementary biomarkers reflecting clinical status, treatment response and disease outcome of EOC patients. Especially, sPD-L1 may facilitate the identification of high-risk patients with unfavorable disease outcomes despite platinum-sensitivity arguing for additional therapeutic approaches. As sPD-L1 and sPD-L2 are easily accessible via liquid biopsy, the inclusion of sPD-L1 and sPD-L2 in addition to CTC investigation as markers for risk assessment during patient therapy planning and follow-up appears to be a valuable approach.

Long non-coding RNA LINC01627 is a prognostic risk factor for epithelial ovarian cancer.

Ovarian malignancies are commonly diagnosed cancers of the female reproductive system. Recent studies have revealed that long non-coding RNAs (lncRNAs) can regulate a variety of oncological processes. In the present study, ovarian cancer expression datasets were searched in the GEO database using the GPL570 platform. Differential lncRNA expression between normal ovarian tissues and ovarian tumors were analyzed using the R package ‘limma’, and patient prognosis was accessed using the package ‘survival’. Four databases, GSE14001, GSE18520, GSE38666 and GSE40595, were used for the analysis. A total of 64 lncRNAs were highly expressed and 4 were downregulated within these four databases. Prognostic analysis of the 68 lncRNAs in the four databases was performed, and revealed that the expression of long intergenic non-protein coding RNA 1627 (LINC01627) was negatively associated with patient prognosis in GSE19829 and GSE62193; there was no association between LINC01627 expression and patient's prognosis in GSE18520 or GSE63885. To investigate the proposed association between LINC01627 and patient prognosis, meta-analysis revealed that the total hazard ratio was 1.38 and the 95% confidence interval was between 1.04 and 1.83. Subgroup analysis revealed that LINC01627 may predict patient prognosis in high-grade, advanced and serous epithelial ovarian cancer, which was a risk factor for prognosis. Further assessment was performed in clinical samples and ovarian cancer cells, where the knockdown of LINC01627 inhibited the proliferative and migratory capacities of HO8910 and HEY cells. Collectively, the present results suggested that lncRNA LINC01627 may serve an oncogenic role in the development of epithelial ovarian tumors.

Abstract 1573: Non-canonical NF-kappaB signaling in the tumor microenvironment in relation to ovarian cancer survival

Abstract Introduction: Despite advances in treatment, ovarian cancer associated mortality has not substantially improved over the last 50 years. Understanding mechanisms that underlie disease progression is crucial to the development of new treatments for ovarian cancer. Mediated by a family of transcription factors, the canonical and non-canonical nuclear factor-kappaB signaling pathways have known roles in cell proliferation, as well as immune, inflammatory, and neoplastic processes. Non-canonical NF-kappaB signaling requires processing of a cytoplasmic p100/RelB dimer to a mature p52/RelB complex, capable of nuclear translocation to activate transcription of target genes. Prior studies on canonical NF-kappaB expression and ovarian cancer survival have been inconsistent, but no studies to date have evaluated the role of non-canonical NF-kappaB transcription factors. Methods: We conducted immunohistochemical staining for p52, a component of the non-canonical NF-kappaB signaling pathway, on a clinically annotated tissue microarray of ovarian tumors collected from 1994-2004 at the Vanderbilt University Medical Center. Nuclear and cytoplasmic p52 staining in tumors was semi-quantified by H-score and expression was dichotomized at median values. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional-hazards regression. Results: Among 194 ovarian cancer cases, p52 expression was predominantly cytoplasmic, with a relatively smaller proportion of tumor cells showing nuclear staining (median H-scores: 135.6 vs. 1.0). Cytoplasmic and nuclear p52 H-scores were significantly higher among high grade, advanced stage, and serous tumors (all Wilcoxon rank sum p&amp;lt;0.01). Kaplan-Meier survival analysis showed that cases with high nuclear p52 expression had significantly shorter time to disease progression (5-year PFS high vs. low: 72% vs. 17%, log-rank p&amp;lt;0.001). In regression models that included adjustment for age, stage, grade, and histologic subtype, high nuclear p52 was associated with a more than two-fold shorter PFS (HR 2.30, 95% CI 1.44-4.67). Significance of this finding was unaltered by additional adjustment for race, debulking, and platinum sensitivity (HR 2.26, 95% CI 1.15-4.45). In contrast, significant associations between high nuclear p52 and worse OS, and all associations for cytoplasmic p52 staining were attenuated after adjustment for clinical covariates. Conclusions: This is the first study to demonstrate that nuclear p52, representing active non-canonical NF-kappaB signaling, may be an independent prognostic factor for epithelial ovarian cancer. Thus, interventions that inhibit non-canonical NF-kappaB signaling should be explored as novel therapies to limit ovarian cancer progression. Citation Format: Demetra Hufnagel, Andrew J. Wilson, Jamie Saxon, Timothy Blackwell, Dineo Khabele, Marta A. Crispens, Alicia Beeghly-Fadiel, Fiona Yull. Non-canonical NF-kappaB signaling in the tumor microenvironment in relation to ovarian cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1573.

Old age as a poor prognostic factor in epithelial ovarian cancer: What is the best age cutoff?

Old age as a poor prognostic factor in epithelial ovarian cancer: What is the best age cutoff?

Epithelial ovarian cancer risk: A review of the current genetic landscape.

Ovarian cancer is the fourth most common cause of cancer‐related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk‐reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome‐wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained. This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately.

Gender differences in prognostic value of immune-related biomarkers in colon cancer patients randomized to surgery or surgery and adjuvant chemotherapy treatment.

3603 Background: HLA-A*02, a common allele in the Scandinavian population, is a negative prognostic factor in epithelial ovarian cancer. It is a strong predictor of patient outcome, only inferior to clinical staging. This prognostic trait in epithelial ovarian cancer is stronger by the presence of the gene compared with the expression of its protein, MHC class I. Microsatellite instability (MSI) is used as a biomarker for prognosis and is suggested an increased tumor mutational burden which can make the tumor more susceptible for T cell mediated immunotherapy. Our aim was to analyze the prognostic markers HLA-A*02 genotype, MHC class I on tumor cells, the CD8+ lymphocyte infiltration and MSI status in colon cancer patients with randomized treatment. Methods: Clinical information and primary tumors were collected from 520 colon cancer patients and followed for overall survival for 120 months. Patients hade stage II and III colon cancer and were randomized to surgery alone or surgery and adjuvant chemotherapy. HLA-A*02 genotype was determined by conventional PCR. MHC class I, MSI status and CD8+ lymphocyte infiltration were determined by immunohistochemistry. Results: Female patients with a stage III tumor and HLA-A*02 genotype had a better outcome if they had received adjuvant chemotherapy instead of just surgery (p = 0.03), whereas this was not the case for patients with other HLA-A genotypes or in the male patients where HLA-type did not correlate to outcome. MHC class I expression did not act as a prognostic factor, however the presence of CD8+ lymphocytes in the invasive margin and inside the tumor was a positive prognostic factor for overall survival (p = 0.01), although only statistically significant in the male patients (p = 0.03). 21% patients had a tumor with MSI (23% of the female and 19% of the male patients respectively). MSI tumors had a slightly better outcome and this was irrespective of gender and HLA-type. Conclusions: The prognostic traits of HLA-A*02 appear in this colon cancer cohort to act differently in male and female patients. Also CD8+ infiltration is different between genders. These findings suggest that men and women may have two different immune responses to malignancy.

Prognostic value of monocyte to lymphocyte ratio (MLR) in epithelial ovarian cancer (EOC).

e17066 Background: Identifying high-risk early-stage EOC patients (p) is a major issue. Also, controversy about the role of neoadjuvant chemotherapy prior to surgery in advanced EOC is still ongoing. A high MLR is related to poorer outcomes in several cancers, and also in ovarian cancer according to limited retrospective series. We explored the clinical value of MLR in a cohort of EOC p. Methods: We included all EOC p diagnosed in our center, from January 2008 to April 2017, who had undergone radical treatment. Overall survival (OS) was assessed by Kaplan Meyer. Maximally selected rank statistics was used to determine the MLR cut-off value for the greatest OS discrimination. The hazard ratio (HR) of death of MLR was explored by multivariate Cox regression models, adjusted by age at diagnosis, stage I/II versus (vs) III/IV, high grade serous carcinomas (HGSC) vs other, primary surgery vs interval surgery after neoadjuvant chemotherapy (PS, IS), residual disease &lt; 1 vs &gt; 1cm, year of diagnosis, and hemoglobin, neutrophils, platelets and MLR at diagnosis. Results: 124 p were included. Median age at diagnosis was 58.7 years; 55.6% were HGSC;67.7% stage III/IV; 69.3% received PS; 14.3% had residual disease &gt; 1cm. Median OS was 75 months. MLR was the laboratory parameter that more significantly impacted on OS in our model (p = 0.02). Optimal MLR cut-off was 0.38. The MLR &gt; 0.38 group (MLR-hi) had a higher-risk of death (HR = 2.9; 95% IC: 1.3–6.5) with respect to those with MLR &lt; = 0.38 (MLR-lo). Median OS were 100 and 35 months, respectively. In the MLR-lo group, median age at diagnosis was 56.9 years (vs 61.9 in the MLR-hi, p 0.047), 44.8% were HGSC (vs 61.2%, p 0.134), and 49.97% were stages I/II (vs 14.2%, p 0.001). MLR-hi p who had undergone PS or IS had similar OS (p = 0.63). In contrast, among MLR-lo p, PS showed significantly higher OS than IS (p &lt; 0.0001). Conclusions: In our cohort, MLR was an independent prognostic factor in EOC. Its potential role to identify high-risk early-stage p and to predict worse outcomes after PS among advanced-stage p need to be explored in larger cohorts.

Visceral adiposity as a predictor of survival in patients with epithelial ovarian cancer receiving platinum and taxane-based chemotherapy.

e17031 Background: Obesity has been linked to worse outcomes in epithelial ovarian cancer (EOC), due to underlying metabolic dysfunction. Visceral fat (i.e. central obesity) compared to subcutaneous fat is more metabolically active and has been linked to higher rates of obesity-related comorbidities such as hypertension and diabetes, but less is known of the impact of increased visceral adiposity on EOC outcomes. Thus, our goal was to evaluate if visceral adiposity, as determined by computed tomography (CT) morphometric measurements, was associated with worse outcomes in EOC patients undergoing platinum and taxane-based chemotherapy. Methods: EOC patients diagnosed between 12/2004 and 5/2016 who received neoadjuvant or adjuvant treatment with platinum and taxane-based chemotherapy were included. Data on age, stage, grade, histology, BMI, comorbidities, treatment approaches and outcomes were collected. CT images closest to the time of diagnosis were retrospectively evaluated for mid-waist visceral fat volume (VFV), mid-waist subcutaneous fat volume (SFV) and the ratio of mid-waist VFV/SFV. Visceral adiposity is commonly defined as a VFV/SFV ≥ 0.4. Cox regression models were used to analyze time-to-event outcomes. Results: Two hundred fifty-eight EOC patients were evaluated. Seventy-five percent of patients were diagnosed with Stage III or IV disease, with high grade serous as the most common histology (72%). Median age at diagnosis was 62.4 years. Approximately 65% were obese; the median BMI was 26.8 (IQR 23.1 – 32.6). The median VFV/SFV ratio was 0.46 (IQR 0.32 – 0.70). Patients were categorized into those with a VFV/SFV ratio greater than 0.4 or a ratio less than 0.4. When comparing these two groups, there was no difference in progression free survival (PFS) for women with a VFV/SFV ratio greater or less than 0.4 (p = 0.22). However, a VFV/SFV ratio of greater than 0.4 was associated with worse overall survival (OS) (p = 0.01). Conclusions: We found that visceral adiposity, defined as a VFV/SFV ratio greater than 0.4, appeared to be associated with decreased OS, but not PFS. These findings suggest that body fat distribution may be an important prognostic factor for EOC and should be further explored as we expect the obesity epidemic to continue and influence EOC oncologic outcomes.

CD133, CD44, and ALDH1A1 as cancer stem cell markers and prognostic factors in epithelial ovarian cancer

BACKGROUND Ovarian cancer is a heterogeneous disease, and most patients are diagnosed at an advanced stage. Epithelial ovarian cancer type II is characterized by rapid tumor growth and is genetically more labile than type I. This study was aimed to demonstrate the prognostic value of CSC by using the markers CD133, CD44, and ALDH1A1 in EOC.METHODS Clinicopathological and demographic data were collected from medical records. The markers CD133, CD44, and ALDH1A1 were examined with flow cytometry and immunohistochemistry. Cancer stem cell (CSC) marker expression in patients with ovarian cancer types I and II were related to chemotherapy and survival. In multivariate analysis, the prognosis model was tested for ten months.RESULTS The largest demographic consisted of patients aged ≥45 years, with stage I, poor differentiation, and type II, of which there were 40 samples (72.7%), 23 samples (41.8%), 30 samples (54.5%), and 16 samples (29.1%), respectively. There is a high correlation between the 10-month chemotherapy response and the 4 variables, i.e., age ≥45 years, type II, stage III–IV, and CD44, with an ROC of 80.75% and a post-test probability of 82.5%. Using the ROC curve, the highest chemoresistance score was 0.841, based on the combination of CSCs markers and clinicopathological factors, that is stage III–IV, age ≥45 years, poor differentiation, type II, negative CD133, high CD44, and high ALDH1A1.CONCLUSIONS CSC (CD133, CD44, and ALDH1A1) markers and clinicopathological factors are prognostic of epithelial ovarian cancer.

Stromal tumor-infiltrating lymphocytes evaluated on H&E-stained slides are an independent prognostic factor in epithelial ovarian cancer and ovarian serous carcinoma.

Studies on tumor-infiltrating lymphocytes (TILs) in epithelial ovarian cancer (EOC) have focused on the clinical significance of inflammatory cells of specific subtypes that are identifiable using immunohistochemistry. However, the subtypes of inflammatory cells that reportedly affect patient survival and prognosis have differed from study to study, and few studies have examined TILs using hematoxylin and eosin (H&E) staining. Therefore, the present study aimed to identify the clinical importance of general stromal TILs in EOC by using H&E staining to apply breast cancer recommendations from the International TILs Working Group 2014 on breast cancer using H&E staining. Stromal TILs in 256 EOC cases from Pusan National University Hospital and 475 cases of high-grade serous carcinoma from The Cancer Genome Atlas dataset were assessed. Stromal TILs were evaluated using H&E-stained slides according to the breast cancer recommendations of the International Working Group 2014, and patients were classified into low and high stromal TIL groups according to their stromal TIL values. The associations of these groups with clinicopathologic factors were assessed, and it was confirmed that group membership correlated with survival and prognosis. According to the χ2 assessment, the stromal TIL group was associated with tumor grade. Furthermore, the stromal TIL group was associated with overall survival according to Kaplan-Meier analysis with the log-rank test. Finally, the stromal TIL group was an independent prognostic factor according to univariate and multivariate Cox regression analyses. In cases of EOC, the evaluation of general stromal TILs on H&E-stained slides could be used to predict prognosis.

Clinical relationships between the rs2212020 and rs189897 polymorphisms of the ITGA9 gene and epithelial ovarian cancer

To better understand the role of integrin subunit alpha 9 (ITGA9) gene polymorphism in epithelial ovarian cancer (EOC), we investigated the distribution of ITGA9 gene polymorphisms (rs2212020 and rs189897) and revealed whether these polymorphisms were associated with a curative effect in EOC. It was found that rs2212020 and rs189897 were correlated significantly with EOC incidence. The frequency of the C allele of rs2212020 was significantly higher in EOC patients than in the control group (P = 0.009, χ2 = 6.857). The population with the C allele of rs2212020 had a higher EOC risk than the population with the T allele (hazard ratio = 1.97, 95.0% CI = 1.178-3.299). Further, our results showed that the CC genotype was a risk factor for EOC. Regarding the association between ITGA9 and the sensitivity to platinum-based chemotherapy in EOC, there were no statistically significant differences in the frequencies of the rs189897 and rs2212020 polymorphisms between the chemosensitive group and the control group. In multivariate analysis, the patients with the TT genotype of rs189897 had longer progression free survival (PFS) than the patients without this genotype (P = 0.010, OR = 2.491). The AT genotype of rs189897 was a risk factor for PFS in EOC. These findings suggested that rs189897 and rs2212020 could play important roles in EOC diagnosis and prognosis.

Optimal cutoff age for predicting prognosis associated with serous epithelial ovarian cancer: what is the best age cutoff?

ObjectiveElderly age is one of the poor prognostic factors in epithelial ovarian cancer (EOC), but the optimal age cut-off is not known. The present study sought to identify the ideal age cutoff that represents a negative prognostic factor in EOC, considering the geriatric assessment.MethodsHazard ratios (HRs) with p-values were calculated using all possible age cutoffs with stage, histology, grade, optimality and comorbidities as covariates in multivariate Cox regression model. The trends of p-value and HR by age cutoff were further evaluated in a subgroup of histology and in The Cancer Genome Atlas (TCGA) dataset. In addition, propensity score-matching analysis using the identified age cutoff was performed.ResultsAn age of 66 years was shown to be the most significant cutoff for defining old age with independent prognostic power (HR=1.45; 95% confidence interval=1.04–2.03; p=0.027). This result was also observed with the analyses of serous histology subgroup and with the analysis of a TCGA dataset with serous EOC. In survival analysis, patients aged ≥66 years had significantly worse overall survival compared with younger individuals (56 months vs. 87 months; p=0.006), even following propensity score matching (57 vs. 78 months; p=0.038).ConclusionAn age of 66 years is the best cutoff to define elderly age in serous EOC patients considering the geriatric assessment, and this information can be used in the administration of individualized therapies in elderly EOC patients.