Outcome In Epithelial Ovarian Cancer Research Articles

SEOM–GEICO clinical guideline on epithelial ovarian cancer (2023)

In recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.

Association between BMI and oncologic outcomes in epithelial ovarian cancer: a predictors-matched case-control study.

We aimed to study the association between obesity and survival in ovarian cancer (OC) patients, accounting for confounders as disease stage, histology, and comorbidities. Retrospective matched case-control study of consecutive patients, with epithelial OC. Obese (body mass index [BMI] ≥ 35 kg m-2) patients were matched in a 1:4 ratio with patients having lower BMIs (BMI < 35 kg m-2) based on disease stage, cytoreduction state, tumor histology and ASA score. We compared the 3-year and total recurrence-free survival and overall survival through Kaplan-Meier survival curves and Cox proportional hazards. Overall, 153 consecutive patients were included, of whom 32 (20.9%) had a BMI ≥ 35. and 121 a BMI < 35. The median follow-up time was 39 months (interquartile range 18-67). Both study groups were similar in multiple prognostic factors, including American Society of Anesthesiologists physical status, completion of cytoreduction, histology and stage of disease (p = 0.981, p = 0.992, p = 0.740 and p = 0.984, respectively). Ninety-five (62.1%) patients underwent robotic surgery and conversion rate from robotic to laparotomy was similar in both groups 2 (6.3%) in obese group vs. 6 (5.0%) in lower BMI patients, p = 0.673. During the follow-up time, the rate of recurrence was similar in both groups; 21 (65.6%) in obese group vs. 68 (57.1%), p = 0.387 and the rate of death events was similar; 16 (50.0%) in obese group vs. 49 (40.5%), p = 0.333). The 3-year OS was higher in the obese group (log rank p = 0.042) but the 3-year RFS was similar in both groups (log rank p = 0.556). Median total OS was similar in both groups 62 months (95% confidence interval 25-98 months) in obese vs. 67 months (95% confidence interval 15-118) in the lower BMI group, log rank p = 0.822. Median RFS was similar in both groups; 61 months (95% confidence interval 47-74) in obese, vs. 54 (95% confidence interval 43-64), log rank p = 0.842. In Cox regression analysis for OS, including obesity, age, laparotomy and neoadjuvant treatment - only neoadjuvant treatment was independently associated with longer OS: odds ratio 1.82 (95% confidence interval 1.09-3.05) and longer RFS: odds ratio 2.16 (95% confidence interval 1.37-3.41). In the present study on consecutive cases of ovarian cancer, obesity did not seem to be associated with outcome, except for an apparent improved 3-year survival that faded away thereafter.

Are preoperative serum cancer antigen 125 levels a prognostic factor for outcome in epithelial ovarian cancer? A systematic review.

Most patients with epithelial ovarian cancers (EOC) present with advanced-stage disease because of non-specific symptoms and lack of reliable strategies for early diagnosis. Cancer antigen 125 (CA-125) is suggested as a useful prognostic biomarker, its serum level is raised in over 80.0% of patients with EOC. Primary debulking surgery (PDS) followed by chemotherapy is the conventional treatment, but neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) is offered to patients with unresectable disease. There are inconsistencies regarding the role of preoperative CA-125 serum levels to adopt in stratifying patients for treatment choice that offers the most benefit. This review aimed to determine the role of preoperative CA-125 levels in predicting optimal cytoreduction and the association between optimal cytoreduction and survival outcome in patients with EOC. Three electronic databases CINAHL, Cochrane library and PubMed were searched for potentially relevant articles from 2016 to 2021 on the role of preoperative CA-125 levels in predicting optimal cytoreduction and survival in patients with epithelial ovarian carcinomas. In patients who underwent NACT-IDS, a lower preoperative CA-125 value is a predictor of optimal cytoreduction and an increase in preoperative CA-125 value is consistently associated with a decrease in optimal cytoreduction. There was insufficient data to assess overall survival. However, a raised preoperative CA-125 level is poor predictor of chance of achieving optimal cytoreduction and the rate of optimal cytoreduction was a weak predictor of overall survival in women who had primary debulking surgery.

Survival outcomes of epithelial ovarian cancer treated at a tertiary-level hospital in India.

One needs to choose wisely between primary neoadjuvant chemotherapy and primary cytoreductive surgery in ovarian cancer. The aim was to determine the recurrence free survival and overall survival after surgery for epithelial ovarian cancer and also the risk factors for recurrence and death. Electronic medical records of 322 women operated for ovarian, fallopian or primary peritoneal cancer between 2011 and 2015table were reviewed. Descriptive statistics were used to describe patients and their clinical outcomes. Cox proportional hazard models were used for risk factor analysis. Adjusted hazard ratios were obtained for recurrence and death, adjusted for stage, primary treatment modality, residual disease and histology. Kaplan-Meier curves were drawn for probability of recurrence-free survival and overall survival. The log rank test was used to compare survival probabilities. The majority were stage III or stage IV (78%), serous histology (71%) and high grade (64%). Primary cytoreduction was done in 48% and interval cytoreduction in 52%. The median duration of follow up (survival) was 77 months (95% CI 72-82). There were 179 known recurrences (55.6 %). The estimated median time to recurrence was 22 (95% CI 14.5- 29.5) months. The independent risk factors for recurrence were neoadjuvant chemotherapy [HR 2.14, 95% CI 1.48-3.09], stage III/IV [HR 2.75; 95% CI 1.40-5.41], high grade serous histology [HR 1.69; 95% CI 1.12-2.54] and sub-optimal debulking [HR 3.15, 95% CI 2.19-4.55]. There were 78 known deaths (24.2 %) with a mean time to death of 24.3 (SD 16.1) months. The independent risk factors for death were sub-optimal debulking [HR 3.07; 95% CI 1.78-5.29] and stages III and IV cancer [HR 3.07; 95% CI 1.14-8.27]. Most ovarian cancers recur within 2 years. Risk factors for mortality are advanced stage and sub-optimal debulking. Maximal efforts at down staging and surgical resection will increase survival.

Prevalence of viral DNA in high-grade serous epithelial ovarian cancer and correlation with clinical outcomes.

Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.

RIPK1 polymorphisms and expression levels: impact on genetic susceptibility and clinical outcome of epithelial ovarian cancer

BackgroundThe aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome.MethodsThree hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively.ResultsFor rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15–1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12–2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03–5.88, and OR = 1.64, 95%CI 1.04–2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18–0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02–0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients.ConclusionsOur results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Genome-wide expression profiling reveals novel biomarkers in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is the most aggressive and frequent malignancy detected among women worldwide. The pathophysiology of OC should, therefore be better understood to identify diagnostic, prognostic, and predictive novel biomarkers necessary for early detection, management, and prognostication. In this study, we aimed to investigate transcriptomic landscape and biomarker through RNA-seq data analysis. Further analysis by Protein Protein network identified top 10 Differentially Expressed Genes (DEGs). KEGG pathway enrichment analysis revealed the significant enrichment of DEGs in basal cell carcinoma, cell cycle and FoxO signalling pathway. The RNA-seq results of 10 DEGs were validated by QRT-PCR and TCGA database. Correlation studies were also performed between gene expression and clinical characteristics followed by survival analysis. Finally, 8 DEGs (CDKN1A, BCL6, CDC45, WNT2, TLR5, AQP5) including two novel DEGs (CSN1S1 and NKILA) were identified showing significant correlations with EOC characteristics. These may serve as interesting biomarkers and novel treatment targets and warrant further investigation into the functional outcome of EOC.

Patterns of Treatment and Outcomes in Epithelial Ovarian Cancer: A Retrospective North Indian Single-Institution Experience.

Ovarian cancer (OC) is ranked as the third most common gynecologic cancer in various Indian cancer registries. In India, OC is seen in the younger age group, with a median age < 55 years being reported by most of the studies. The majority of patients are diagnosed in advanced stage (70%-80%), where the long-term (10-year) survival rate is poor, estimated at 15%-30%. The aim of this study was to evaluate clinical epidemiology, treatment patterns, and survival outcomes in patients with epithelial OC. This was a retrospective analysis of patients with epithelial OC who were treated at Sher-i-Kashmir Institute of Medical Sciences, Srinagar, over a period of 9 years, from January 2010 to December 2018. OC constituted 2.94% of all cancers registered. Epithelial OC constituted 88.4% of all OCs, with a median age 50 years. More than two third of patients belonged to rural background and the majority (76.9%) of the patients were in stage III or IV at the time of diagnosis. The main presenting symptoms were abdominal distension/bloating (46.5%) and gastrointestinal disturbances (35.2%). The most common histologic types were serous (65.9%) followed by mucinous carcinoma (15%). Median overall survival for the whole study cohort was 30 months (95% CI, 28.0 to 31.9). Median overall survival for stage I, II, III, and IV was 72, 60, 30, and 20 months, respectively. Most of the patients presented in advanced stage of the disease and have poor outcome. Delay in diagnosis and improper management before registering in tertiary cancer center and lack of tertiary care facilities are the root causes of poor outcomes. The general population and primary care physicians need to be made aware of OC symptoms.

Characteristics and immunological changes of tumor-infiltrating lymphocytes during neoadjuvant chemo-immunotherapy in epithelial ovarian cancer (251)

<b>Objectives:</b> Epithelial ovarian cancer (EOC) is an aggressive gynecologic malignancy with a poor prognosis. Even after standard-care treatment, most patients eventually relapse and thus show a low survival rate. It is well known that tumor-infiltrating lymphocytes (TILs) are associated with survival outcomes in EOC. However, characteristics and dynamic changes of TILs during treatment courses have not been well investigated in EOC. In this study, we examined the characteristics of TILs from ovarian cancer patients and their dynamic changes during neoadjuvant chemotherapy (NACT) or neoadjuvant chemoimmunotherapy (NACI). <b>Methods:</b> We isolated peripheral blood mononuclear cells (PBMCs) and TILs from treatment-naïve (<i>n</i>=18) or post-NACT treated (<i>n</i>=22) or post-NACI treated EOC patients (<i>n</i>=8). NACT was paclitaxel plus carboplatin, and NACI was NACT with durvalumab plus tremelimumab. Immunologic characteristics and functions of CD8, CD4, and regulatory T (Treg) cells in each group were compared using flow cytometry. <b>Results:</b> The percentages of CD8 TILs of post-NACT and post-NACI were increased, but conventional CD4 and Foxp3⁺ Treg were decreased after NACT and NACI. Therefore, CD8/Treg cells ratio was increased in post-NACT and post-NACI. When we examined the memory differentiation status of CD8 and CD4 TILs, there was no significant difference among treatment-naïve, post-NACT, and post-NACI. The percentages of central memory and effector memory were not significantly different. In addition, comparing expressions of immune checkpoints, including PD-1, CTLA-4, and TIGIT on TILs, there was no significant difference among them. However, 4-1BB⁺ and Ki-67⁺ cells in CD8 and Treg cells were significantly decreased after NACT or NACI. It meant that tumor-reactive proliferating CD8 TILs and Treg cells were decreased after NACT. Next, we examined expressions of TCF-1 and TOX in PD-1+CD8 TIL in post-NACT or post-NACI to investigate changes of exhaustion status, and it was revealed that TCF-1⁺ cells were increased and TOX⁺ cells were decreased after NACT or NACI. However, cytokine production capacity (IFN-γ and TNF-α) of CD8 TILs was not different. In the case of Treg cells, suppressive CD45RA-Foxp3^high Treg cells and CCR8⁺ Treg cells were significantly decreased after NACT or NACI. In addition, comparing post-NACT with post-NACI, CCR8⁺ Treg cells were more significantly decreased in post-NACI. <b>Conclusions:</b> The current study investigated immunologic changes after NACT and NACI in ovarian TILs. According to a decrease in tumor burden during chemotherapy, the immunologic tumor-microenvironment changed to favor antitumor immunity. Furthermore, Treg cells with more suppressive properties (CCR8⁺ or 4-1BB⁺ Treg cells) were more decreased after NACI. Further studies are ongoing on the effect of NACI on Treg cells and their clinical significance in EOC.

Transmembrane Phosphatase with TEnsin Homologue (TPTE) Expression in Epithelial Ovarian Cancer

Background: TPTE is a ‘Cancer Testis’ antigen that could be a candidate for targeted immunotherapy of epithelial ovarian cancer.&#x0D; Objective: To determine the prevalence of expression and the impact of TPTE on clinical and survival outcomes in epithelial ovarian cancer.&#x0D; Methods: Relevant medical information of 173 ovarian cancer patients (including Fallopian and primary peritoneal) managed at a Cancer Centre were retrieved. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to detect the expression of TPTE in the tumours. TPTE expression was correlated with the clinicopathologic and survival outcomes of the patients.&#x0D; Results: TPTE was expressed by 45.1% (78/173) of the tested tumours. There was no significant difference in age between TPTE-positive and negative women (p = 0.93). TPTE expression was not significantly associated with the stage of the disease (p = 1.00), grade of disease (p = 0.71) and histology of the tumour (p = 0.17). There was no significant association between TPTE expression and the ease of optimum debulking (44.5% vs 44.3%, p = 0.54). TPTE expression was also not associated with a better response to therapy (p = 0.05). However, it was associated with slightly longer but not statistically significant progression-free survival (27.5 vs 20.6-months, p = 0.14) and overall survival (49.2 vs 28.0 months, p = 0.11).&#x0D; Conclusion: This study shows that TPTE is expressed at a moderate frequency in epithelial ovarian cancers, and its expression is associated with marginally better survival outcomes.

Genetic Variation of PD-L1 Gene Affects its Expression and Is Related to Clinical Outcome in Epithelial Ovarian Cancer.

ObjectiveThis study aims to investigate the effect of polymorphisms of programmed cell death-ligand 1 (PD-L1) on the risk and patient’s outcomes of epithelial ovarian cancer (EOC).MethodsTotally, 568 patients and 532 healthy women were included. Three polymorphisms in the PD-L1 gene, rs2297136, rs4143815 and rs4742098, were genotyped by the polymerase chain reaction/ligase detection reaction (PCR-LDR). Survival analysis was performed in 234 patients (received primary debulking surgery followed by platinum-based chemotherapy).ResultsPatients with the rs2297136 AG + GG genotypes had shorter progression-free survival (PFS) (hazard ratio (HR)=1.44, 95% CI=1.03-2.01) and overall survival (OS) (HR=1.55, 95% CI=1.06-2.27) than those with the AA genotype. Moreover, the mRNA and protein expression levels of PD-L1 in EOC tissues with the rs2297136 AG + GG genotypes were remarkably higher than those with the AA genotype (P=0.032 and P=0.047, respectively). Survival analysis showed that high expression of PD-L1 mRNA was remarkably associated with worse 10-year PFS (HR=1.55, 95% CI=1.28-1.88) and OS (HR=1.51, 95% CI=1.00-2.28) in EOC patients.ConclusionsThe rs2297136 may not only effectively influence the expression of PD-L1, but also is significantly associated with EOC patients’ outcomes.

Predictive value of preoperative inflammatory markers and serum CA 125 level for surgical outcome in Indonesian women with epithelial ovarian cancer.

It is essential in the management of ovarian cancers to identify the patients who will benefit from primary complete cytoreductive surgery and those who will rather benefit from neoadjuvant chemotherapy. To evaluate the predictive value of preoperative inflammatory markers, i.e. platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), red cell distribution width (RDW), and serum CA125 level for surgical outcome in epithelial ovarian cancer. A retrospective study was carried out in Sanglah Hospital, Denpasar, Bali. A total of 54 patients with epithelial ovarian cancer who underwent primary exploratory laparotomy from January 2018 to November 2019 was recruited. Data about clinical characteristics, preoperative inflammatory markers, serum CA125 level, and surgical outcome (optimal vs. suboptimal) was collected from the medical records. Predictive value of the markers were evaluated using ROC curve to determine their accuracy (area under the curve, sensitivity, specificity, positive and negative predictive value). Mean age, parity, and tumor size did not differ between the study groups (p> 0.05). The group with suboptimal outcome had significantly higher PLR, NLR, MLR, and RDW value (p< 0.05). Using the ROC curve, a cut off value was determined for each predictor, i.e. PLR: 196.50, NLR: 3.34, MLR: 0.24, RDW: 13.19, CA125: 300.85. AUC for each predictor were as follows: PLR 0.718 (95% CI: 0.578-0.859), NLR 0.676 (95% CI: 0.529-0.823), MLR 0.700 (95% CI: 0.560-0.839), RDW 0.712 (95% CI: 0.572-0.852), CA125 0.593 (95% CI: 0.436-0.750). Sensitivity, specificity, and accuracy for predicting suboptimal outcome were as follows: PLR (74.2%, 69.6%, 72.2%), NLR (64.5%, 60.9%, 62.9%), MLR (74.2%, 59.1%, 66.7%), RDW (74.2%, 60.9%, 68.5%), CA125 (54.8%, 60.9%, 57.4%). We have some limitations such as small numbers of sample, we generalized whole kinds of ovarian cancer, and this study does not describe follow-up features. Preoperative serum inflammatory markers (PLR, MLR, and RDW) may serve as useful markers to predict the surgical outcome with fair accuracy in patients with epithelial ovarian cancer.

Abstract PO-132: Upregulated LYL1 promotes epithelial ovarian cancer (EOC) cell growth and metastasis

Abstract Approximately 90% of ovarian cancer (OC) is Epithelial ovarian Cancer (EOC) subtype and claims ~15,000 lives in the United States annually, making it the deadliest reproductive cancer in women. There are few treatment options for EOC, amongst them include surgical resection of tumors or debulking, and chemotherapy alone or combination. In general, the survival rate of patients with EOC is about 48% and this has not changed in last few decades. According to recent reports from American Cancer Society and SEER, racial disparity in ovarian cancer not only exists for African American (AA) patients, but is worsening over the past few years. African American (AA) patients presents with more advanced disease and develop chemoresistance frequently, and as such, they experience worse survival. Thus identifying the cause of this discrepancy, or more importantly, describing which AA patients are at the highest risk of therapeutic relapse would alter our current treatment strategies and improve overall disease free survival rate. Therefore, the central focus of this proposal is to delineate the molecular and genetic mechanisms contributing to racial disparity of AA patients. Therefore, the overall objective of our studies are to identify the etiology of racial disparity in ovarian cancer and define the molecular networks that contribute this discrepancy in outcomes. Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) is a polypeptide that harbors basic helix-loop-helix transcription factor, a DNA binding motif and dysregulated in many cancers including EOC. Analysis of TCGA data for EOC revealed that LYL1 gene amplification in about 12% patients and associated with poor prognosis. Interestingly, further analysis of LYL1 copy number alteration in different ethnicities disclosed LYL1 amplification in about 36% of the African American (AA) EOC patients. Importantly, EOC patients with low LYL1 (n=1640) expression has better survival probability compared to patients with overexpressed LYL1 (n=202). This discrepancy in survival probability is much more prominent in AA EOC patients. As this is an intriguing observation, we evaluated the levels of LYL1 expression in different EOC cell lines in comparison with fallopian tube epithelial cells. Our data shows, upregulation of LYL1 in most of the EOC cell lines compared to normal fallopian tube epithelial cells. To examine the upregulated LYL1 in EOC cell lines, we performed siRNA mediated downregulation, and evaluated their clonogenic, migration invasion potential. Consistent with the TCGA data, knocking down LYL1 in EOC cells significantly attenuated their clongenic, migration and invasion potential. Furthermore, ectopic overexpression of LYL1 in EOC cells that shows deep deletion of the gene, exhibited increased clonogenicity, invasion and migration. Collectively, our studies indicate an important role for LYL1 in EOC tumor progression and metastatic phenotypes, and could be a biomarker for disparities in EOC outcomes. Citation Format: Damieanus Ochola, Shirisha Jonnalagadda, Swetha Peddibhotla, Tasmin Omy, Mark Reedy, Palle Komaraiah. Upregulated LYL1 promotes epithelial ovarian cancer (EOC) cell growth and metastasis [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-132.

SPME-LC/MS-based serum metabolomic phenotyping for distinguishing ovarian cancer histologic subtypes: a pilot study

Epithelial ovarian cancer (EOC) is the most common cause of death from gynecological cancer. The outcomes of EOC are complicated, as it is often diagnosed late and comprises several heterogenous subtypes. As such, upfront treatment can be highly challenging. Although many significant advances in EOC management have been made over the past several decades, further work must be done to develop early detection tools capable of distinguishing between the various EOC subtypes. In this paper, we present a sophisticated analytical pipeline based on solid-phase microextraction (SPME) and three orthogonal LC/MS acquisition modes that facilitates the comprehensive mapping of a wide range of analytes in serum samples from patients with EOC. PLS-DA multivariate analysis of the metabolomic data was able to provide clear discrimination between all four main EOC subtypes: serous, endometrioid, clear cell, and mucinous carcinomas. The prognostic performance of discriminative metabolites and lipids was confirmed via multivariate receiver operating characteristic (ROC) analysis (AUC value > 88% with 20 features). Further pathway analysis using the top 57 dysregulated metabolic features showed distinct differences in amino acid, lipid, and steroids metabolism among the four EOC subtypes. Thus, metabolomic profiling can serve as a powerful tool for complementing histology in classifying EOC subtypes.

Landscape of Immune Microenvironment in Epithelial Ovarian Cancer and Establishing Risk Model by Machine Learning.

Background Epithelial ovarian cancer (EOC) is an extremely lethal gynecological malignancy and has the potential to benefit from the immune checkpoint blockade (ICB) therapy, whose efficacy highly depends on the complex tumor microenvironment (TME). Method and Result We comprehensively analyze the landscape of TME and its prognostic value through immune infiltration analysis, somatic mutation analysis, and survival analysis. The results showed that high infiltration of immune cells predicts favorable clinical outcomes in EOC. Then, the detailed TME landscape of the EOC had been investigated through “xCell” algorithm, Gene set variation analysis (GSVA), cytokines expression analysis, and correlation analysis. It is observed that EOC patients with high infiltrating immune cells have an antitumor phenotype and are highly correlated with immune checkpoints. We further found that dendritic cells (DCs) may play a dominant role in promoting the infiltration of immune cells into TME and forming an antitumor immune phenotype. Finally, we conducted machine-learning Lasso regression, support vector machines (SVMs), and random forest, identifying six DC-related prognostic genes (CXCL9, VSIG4, ALOX5AP, TGFBI, UBD, and CXCL11). And DC-related risk stratify model had been well established and validated. Conclusion High infiltration of immune cells predicted a better outcome and an antitumor phenotype in EOC, and the DCs might play a dominant role in the initiation of antitumor immune cells. The well-established risk model can be used for prognostic prediction in EOC.

Loss of muscle mass during cancer therapy is associated with poor oncologic outcomes in epithelial ovarian cancer

<h3>Objectives:</h3> Sarcopenia, a loss of muscle mass and function, is a risk factor for decreased survival in advanced epithelial ovarian cancer (EOC). Little is known about the effect of primary treatment for EOC on sarcopenia and how this relates to patient outcomes. Our aim was to determine the change in sarcopenia measures over the course of primary EOC treatment and if changes are associated with overall survival. <h3>Methods:</h3> We utilized an institutional EOC surgical database to identify patients diagnosed with stage IIIC or IV EOC who received primary debulking surgery (PDS) and adjuvant chemotherapy at our institution. Patients were included if they had pre and post-treatment computerized tomography (CT) scans available. Patient CT scans were analyzed for body composition, including skeletal muscle area and skeletal muscle index (SMI, skeletal muscle area normalized for patient height). Sarcopenia was defined as a SMI <39 cm²/m². Percent change in body composition measures and change in sarcopenia were analyzed for association with death and disease progression based on fitting Cox proportional hazards models. <h3>Results:</h3> We identified 116 patients who underwent PDS followed by adjuvant chemotherapy from 2006-2016 at a large volume single institution. Most patients (73%) had 6 cycles of adjuvant platinum-based chemotherapy. A post-treatment CT scan was obtained at a median of 25 days following the last day of treatment. Overall, there was a decrease in the mean skeletal muscle area and skeletal muscle index, with a percent change of 2.6% from pre- to post-treatment CT scans. Almost half of patients (54/116; 47%) were sarcopenic at some point during their treatment. Of the 116 patients, 62 (53%) were never sarcopenic, 5 (4%) were initially sarcopenic but not at the time of post-treatment scan, 28 (24%) were sarcopenic on both CT scans, and 21 (18%) were only sarcopenic at the time of post-treatment CT scan.The 21 patients who became sarcopenic during the course of treatment were more likely to have an American Society of Anesthesiologists physical status score more than 2 (62% vs 43%), preoperative albumin <3.5 g/dL (24% vs 14%), stage IV disease (48% vs 21%) and to have undergone a high complexity surgery (57% vs 33%). Developing sarcopenia during treatment was associated with both an increased risk of disease progression (HR=1.43; 95% CI 0.85-2.40; p=0.18) and death (HR=1.78; 95% CI 1.00-3.18; p=0.05) when compared to all others (Figure). The development of sarcopenia following treatment was the strongest predictor of death compared to the 4 aforementioned factors. <h3>Conclusions:</h3> We observed that sarcopenia changes during the course of treatment among EOC patients who underwent curative intent PDS and adjuvant chemotherapy. Patients who develop sarcopenia following treatment appear to be at increased risk for poor oncologic outcomes. The cause of sarcopenia in EOC is unclear, and may reflect worse tumor biology or other patient specific factors.

Nuclear HKII-P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer.

Simple SummaryHexokinase II (HKII) is a key glycolysis enzyme associated with tumorigenesis, but its molecular mechanism and pathophysiological role in chemoresistant ovarian cancer remain elusive. In this study, we delineate the novel mechanism showing that activated phosphorylated-p53 (P-p53 Ser15) is required for the regulation of HKII intracellular trafficking and metabolic regulation in chemosensitive ovarian cancer, but not in chemoresistant ovarian cancer harboring p53 mutation. We have observed that increased nuclear HKII-P-p53 (Ser15) interaction is likely associated with chemosensitivity and better survival outcomes in epithelial ovarian cell lines, human primary epithelial ovarian cancer cells, and tumor sections. Nuclear HKII-P-p53 (Ser15) interaction may function as a promising prognostic biomarker, enabling prediction of patients with poor prognosis for deciding better clinical strategies.In epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII-P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII-P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.

Abstract 2137: Differential gene expression identifies a transcriptional regulatory network involving ESR1and PITX1 in invasive epithelial ovarian cancer

Abstract The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in invasive processes, but the molecular factors that drive aggressive behavior remain nebulous. In this study, we analyzed two types of EOC at opposite ends of the invasiveness spectrum, high-grade serous ovarian cancers (HGSOCs) and serous borderline tumors (SBTs). We identified differentially expressed genes to guide follow on studies of regulatory networks. Initially, in a discovery sample set, we generated transcriptome sequences to identify 11 differentially expressed genes in SBTs and HGSOCs, and a nonoverlapping set of 17 differentially expressed genes stage II and stage III HGSOCs. We validated the classification performance of these gene expression signatures on a validation set of SBT and HGSOC with classification rates of 94 and 98% using the 11-gene and 17-gene sets, respectively. Transcription factor binding sites enriched in the differentially expressed gene promoter regions were examined by Chip-seq analysis in ovarian cancer and other cell lines. We identified a suite of transcription factors implicated in the differential regulation associated with invasiveness, including ERα, RARA, PITX1, FOXA1/FOXF1, and BHLHE41/E40. These data implicate estrogen responsive gene regulatory networks in ovarian cancers and suggest that dynamic regulatory interactions determine malignant EOC outcomes. Citation Format: Yichao Li, Sushil Kumar Jaiswal, Rupleen Kaur, Dana Alsaadi, Xiaoyu Liang, Frank Drews, Julie A. DeLoia, Thomas Krivak, Hanna M. Petrykowska, Valer Gotea, Lonnie Welch, Elnitski Laura. Differential gene expression identifies a transcriptional regulatory network involving ESR1and PITX1 in invasive epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2137.

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

An international, multicenter, real-world analysis of epithelial ovarian cancer treatment and outcomes.

5531 Background: Few major studies have examined and compared the management and outcomes of patients from diagnosis to death between countries. We have established an international collaboration across Europe and South Korea to compare treatment and outcomes in Epithelial Ovarian Cancer (EOC). Methods: Patients diagnosed with EOC between January 2012 and December 2018 (age ≥18), were included for analysis. Data from medical records from five European and a single South Korean treatment centre were extracted, standardised to a common data model and analysed at each centre using a common script developed in R. Time to each progression/recurrence event (defined as time to next treatment) and overall survival have been estimated using Kaplan Meier methodology and outcomes stratified by categories of interest. Changes in the use of anti-cancer therapies over time and the incidence of BRCA mutations and incidence/timing of second breast cancers have also been examined. Results: A total cohort of 2925 patients was identified with a median age at each centre of 53 to 67 years. Advanced disease (FIGO stage III - IV) (range 57% to 84%) and high-grade serous morphology (38% to 70%) were most common at each centre. The timing of surgery (primary, interval debulking or delayed) and the proportion of patients undergoing surgery varied with stage. Patients with stage I disease where most likely to undergo surgery (range 73% to 100%) and stage IV the least (range 39% to 84%). Median overall survival for high grade serous cancers ranged from 1.9 to 4.9 years, and for the whole cohort from 2.1 to 5.5 years. Median time to next treatment at first relapse for the whole cohort ranged from 14 to 22 months. Second breast cancers were noted in 6 to 17% of patients and the majority of these occurred before the diagnosis of EOC at a median time of 96 to 118 months prior to diagnosis of EOC. Additional data on treatment pathways, BRCA status and outcomes by line of therapy for each centre will be presented. Conclusions: Preliminary analysis of results across this network suggests a variation in patient populations between sites and substantial differences in both treatments and outcomes. The establishment of a common data model and the use of a common analytic script between sites across six different countries allows for detailed exploration of the factors influencing differences in patient management and treatment outcomes in ovarian cancer patients.