Survival In Ovarian Cancer Patients Research Articles

Development and validation of a nomogram to predict overall survival of epithelial ovarian cancer patients: a population-based study (381)

<b>Objectives:</b> To develop and validate a nomogram for the overall survival of epithelial ovarian cancer based on the National Union of Real- World Gynecological Oncology Research and Patient Management Platform (NUWA) in China. <b>Methods:</b> We enrolled patients with pathologically confirmed primary epithelial ovarian cancer in the NUWA platform between 2004 and 2018 as a training cohort to develop a nomogram. The cut-off for follow-up was December 2020. Patients with a history of other tumors or missing values of any variable were excluded. Variables were selected by univariate and multivariate Cox proportional hazard regression. Significant factors were applied to establish a nomogram to predict 3-year and 5-year survival, assessed by C-statistic and calibration curves. A testing cohort from SEER Database was applied to externally validate the nomogram by bootstrap resampling. Statistical analysis was conducted by SPSS version 26.0 (IL, USA) and R version 4.1.1 (www.r-project.org). <b>Results:</b> A total of 1262 primary epithelial ovarian cancer patients were filtered out from 5003 ovarian cancer patients in the NUWA platform. Total 10594 of 125682 patients in the SEER Database were screened out accordingly. Baseline age, histotype, histological grade, FIGO stage, longest diameter of the primary tumor, and residual disease after primary surgery were significant risk factors (<i>p</i><0.05). Compared with serous cancer, the hazard ratio (HR) of mucinous, endometrioid, clear cell, other epithelial cancer were 3.391 (95% CI: 2.201-5.223), 1.642 (95% CI: 1.045-2.580), 3.127 (95% CI: 2.134-4.582), and 2.071 (95% CI: 1.486-2.885), respectively. The HR of advanced stage and high grade of disease (FIGO stage III-IV vs I-II, High grade vs Low/moderate grade) were 1.921 (95% CI: 1.226-3.010) and 1.407 (95% CI: 1.048-1.889), respectively. Patients who received optimal (R1), suboptimal (R2) cytoreduction, and those who didn't receive primary debulking surgery had a higher risk of death compared to those without the residual disease (R0), with HRs of 5.530 (95% CI: 3.575-8.555), 7.757 (95% CI: 5.101-11.796) and 9.975 (95% CI: 5.831-17.063), respectively. For continuous variables, the HR of baseline age (years) was 1.024 (95% CI: 1.013-1.036), and the HR of the longest diameter of the primary tumor (cm) was 1.030 (95% CI: 1.007-1.054). The C-statistic values of the nomogram (Figure 1) in the training and testing cohorts were 0.771 (95% CI: 0.748-0.794) and 0.726 (95% CI: 0.718-0.734), respectively. The slopes of calibration curves of 3-year and 5-year survival in the training cohort were 1.165 (95% CI: 0.990-1.340) and 0.955 (95% CI: 0.920-0.990), respectively, whereas, in the testing cohort, these were 1.355 (95% CI: 1.108-1.602) and 1.374 (95% CI: 1.103-1.644), respectively. Fig. 1 <b>Conclusions:</b> The discrimination and goodness of fit of the nomogram indicated its predictive value for the survival of epithelial ovarian cancer in China. Furthermore, the nomogram also obtains certain values in external validation, which implies its feasibility in different populations.

Efficacy and safety of niraparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer using an individualized starting dose (PRIME Study): A randomized, double-blind, placebo-controlled, phase 3 trial (LBA 5)

<b>Objectives:</b> Niraparib, a potent poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor, demonstrated statistically significant improvement in progression-free survival (PFS) in advanced ovarian cancer (OC) patients (pts) with complete or partial response (CR/PR) after first-line platinum-based chemotherapy (1L CT) regardless of biomarker status in the global phase 3 PRIMA study. The PRIME study was conducted to evaluate the efficacy and safety of niraparib using an individualized starting dose as a maintenance treatment following CR/PR to 1L CT in Chinese pts with advanced OC. <b>Methods:</b> In this double-blind, placebo (PBO)-controlled, multicenter phase 3 study, pts with newly diagnosed, advanced (stage III-IV) OC (including high-grade serious or endometrioid ovarian, primary peritoneal, or fallopian tube cancer) with CR/PR to 1L CT were randomized 2:1 to niraparib or PBO once-daily. A starting dose of 200 mg once daily (QD) was used, except in pts with a baseline body weight of ≥ 77 kg and platelet count ≥ 150,000/μL who received 300 mg QD. Pts were stratified by gBRCA status (mutated [m]/non-gBRCAm), tumor HRD status (HRDpos, HRDneg [including not determined, missing] by BGI Genomics assay, receipt of neoadjuvant chemotherapy (yes/no), and best response to 1L CT (CR/PR). All randomized pts remained on assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, or lost to follow-up. The primary endpoint was PFS assessed by blinded independent central review, analyzed using a stratified log-rank test and a Cox proportional hazards model. The secondary endpoint included overall survival (OS). All efficacy outcome measures were analyzed based on the intention-to-treat (ITT) population. <b>Results:</b> Of the 384 randomized pts (niraparib, n=255; PBO, n=129); 125 (32.6%) were gBRCAm, 257 (66.9%) were HRd population (HRDpos/non-gBRCAm or gBRCAm) (data cutoff [DCO], 30 September 2021). The median follow-up was 27.5 months. Median PFS was significantly longer among pts who received niraparib compared with PBO (24.8 <i>vs</i> 8.3 months; hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.34–0.60; <i>P</i><0.001; Figure 1). All subgroup analysis demonstrated consistent treatment benefit with HRd population (HR 0.48) and HRp (HR 0.41). OS data was immature (as of DCO, number of OS events: 65[16.9 %] occurred; HR, 0.63; 95% CI, 0.38-1.03). The most common grade ≥ 3 adverse events in niraparib arm were anemia (18.0%), neutrophil count decreased (17.3%), and platelet count decreased (14.1%), 1.6%, 1.6%, and 0.8% in placebo arm, respectively. <b>Conclusions:</b> The PRIME study is the first phase 3 study to confirm the efficacy and safety of niraparib as a single agent in Chinese pts with newly diagnosed advanced OC as 1L maintenance therapy. Pts who received niraparib had a clinically meaningful and statistically significant improvement in PFS compared to those who received PBO, regardless of biomarker status. Niraparib was well tolerated and no new safety signals were identified.Fig. 1

HIPEC is associated with improved survival in stage III-IV ovarian cancer patients undergoing complete cytoreductive surgery: An NCDB-based analysis (561)

<b>Objectives:</b> To determine if hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with improved survival in patients undergoing cytoreductive surgery (CRS) for newly diagnosed stage III or stage IV ovarian cancer at Commission on Cancer (CoC)-accredited cancer programs in the United States. <b>Methods:</b> The National Cancer Database was queried for patients with stage III or stage IV ovarian cancer undergoing CRS+HIPEC between 2004 and 2017. A control population of patients from 38 HIPEC-performing institutions undergoing CRS only was obtained using propensity score matching and adjusted for facility volume, age, Charlson-Deyo-Comorbidity-Index (CDCI), and stage. All patients in this study underwent complete cytoreduction to no gross residual (NGR) disease. Univariate survival analyses were performed using the log-rank test and adjusted for covariates using Cox proportional hazards regression. All analyses were performed using IBM SPSS Statistics 27. <b>Results:</b> A total of 66 patients who underwent CRS+HIPEC and had available survival data were identified. An additional 66 patients who underwent CRS only at HIPEC performing institutions were included in all comparisons based on propensity score match parameters. Demographics for the CRS+HIPEC group versus the CRS only group revealed no significant difference between median age (58 vs 61 years old) or median CDCI (score 0 vs 0), while significant differences were observed in primary CRS (46% vs 76%) (p<0.001), interval CRS (54% vs 24%) (p<0.001), stage III (65% vs 82%) (p=0.007), and stage IV (35% vs 18%) (p=0.007). Patients undergoing CRS+HIPEC had a significantly higher median overall survival (OS) of 42.1 months (95% CI: 31.8-52.4 months) compared to patients undergoing CRS only, who had a median OS of 34.9 months (95% CI: 23.4-46.4 months, p=0.015). Fifty percent of patients undergoing CRS+HIPEC were still alive at 60 months compared to 30.3% of patients undergoing CRS only. On multivariable analysis, patients undergoing CRS+HIPEC were 38.9% less likely to die compared to those who underwent CRS alone (HR of death: 0.611, 95% CI 0.402-0.928, p=0.021). Fig. 1 <b>Conclusions:</b> On retrospective review of patients undergoing complete CRS for newly diagnosed stage III or stage IV ovarian cancer at CoC-accredited cancer programs in the United States, we found CRS+HIPEC to be associated with significantly improved survival compared to CRS only. These findings are especially notable given the higher proportion of stage IV patients in the CRS+HIPEC group. Thus, stage IV patients who respond well to neoadjuvant chemotherapy and can undergo complete interval CRS should also be considered for HIPEC.

The prognostic value of the chemotherapy response score in tubo-ovarian or primary peritoneal high-grade serous carcinoma (466)

<b>Objectives:</b> The purpose of the study was to evaluate the prognostic value of a two-tiered chemotherapy response score (CRS) system on progression-free and overall survival in high-grade serous ovarian cancer patients using traditional survival type analysis. <b>Methods:</b> Retrospective chart data were collected from all patients aged 18 and older with FIGO stage III or IV tubo-ovarian high-grade serous carcinoma undergoing neoadjuvant chemotherapy (NACT) at a single institution from January 2017 to January 2021. A two-tier scoring system was used in which patients were stratified to either CRS 1-2 (no or minimal response to neoadjuvant chemotherapy) or CRS 3 (appreciable or near-complete response). These data were used to compare progression-free and overall survival between the patients in each subgroup using survival analysis (log-rank test). Survival data were adjusted for covariates as appropriate with a Cox regression model. <b>Results:</b> We identified 80 women who met the inclusion criteria above; 97% (<i>n</i>=78) were Caucasian, and the mean age was 66 years (range: 25-87). Baseline demographic data were similar between patients with CRS 1-2 (<i>n</i>=58) and patients with CRS 3 (<i>n</i>=22). More women with CRS 3 underwent an aborted attempt at cytoreduction or surgery for bowel obstruction at the time of diagnosis (<i>n</i>=3 compared to none in the CRS 1-2 cohort). Overall, 74% (<i>n</i>=58) of patients achieved a partial response on platinum-based NACT. About 23% (<i>n</i>=5) of patients with CRS 3 had a complete response compared to only 12.5% (<i>n</i>=7) of CRS 1-2. Overall a greater percentage of patients in the CRS 3 group (95%, <i>n</i>=21) achieved optimal cytoreduction compared with patients in CRS 1-2 (74%, <i>n</i>=43). <i>BRCA1</i> or <i>2</i> mutation frequencies were similar in both CRS subgroups. The majority of women recurred (73%, <i>n</i>=59) regardless of the CRS subgroup. Ultimately five patients were excluded from the analysis of progression-free and overall survival due to pertinent missing information such as documented CRS or missing vital statistics. The mean time from diagnosis to recurrence was 16 months versus 19 months for CRS 1-2 compared to CRS 3, but this difference was not significant. Median time from interval debulking to recurrence was not different between groups (11 months for CRS 1-2 vs 13 months for CRS 3, p=0.21). There was no difference in overall survival between the two groups; mean survival was 35 months in CRS 1-2 versus 34 months in CRS 3 (p=0.86). <b>Conclusions:</b> Previous studies have suggested a difference in progression-free survival for women who had CRS 1-2 versus CRS 3, indicating that this scoring system can inform disease prognosis and may help to guide adjuvant treatment strategies. Our preliminary analysis revealed no statistically significant difference in progression-free or overall survival for patients with CRS 1-2 versus CRS 3 and did not replicate the findings of other studies, a discrepancy that warrants further investigation.

Protein expression profiling identifies a prognostic model for ovarian cancer

BackgroundOwing to the high morbidity and mortality, ovarian cancer has seriously endangered female health. Development of reliable models can facilitate prognosis monitoring and help relieve the distress.MethodsUsing the data archived in the TCPA and TCGA databases, proteins having significant survival effects on ovarian cancer patients were screened by univariate Cox regression analysis. Patients with complete information concerning protein expression, survival, and clinical variables were included. A risk model was then constructed by performing multiple Cox regression analysis. After validation, the predictive power of the risk model was assessed. The prognostic effect and the biological function of the model were evaluated using co-expression analysis and enrichment analysis.Results394 patients were included in model construction and validation. Using univariate Cox regression analysis, we identified a total of 20 proteins associated with overall survival of ovarian cancer patients (p < 0.01). Based on multiple Cox regression analysis, six proteins (GSK3α/β, HSP70, MEK1, MTOR, BAD, and NDRG1) were used for model construction. Patients in the high-risk group had unfavorable overall survival (p < 0.001) and poor disease-specific survival (p = 0.001). All these six proteins also had survival prognostic effects. Multiple Cox regression analysis demonstrated the risk model as an independent prognostic factor (p < 0.001). In receiver operating characteristic curve analysis, the risk model displayed higher predictive power than age, tumor grade, and tumor stage, with an area under the curve value of 0.789. Analysis of co-expressed proteins and differentially expressed genes based on the risk model further revealed its prognostic implication.ConclusionsThe risk model composed of GSK3α/β, HSP70, MEK1, MTOR, BAD, and NDRG1 could predict survival prognosis of ovarian cancer patients efficiently and help disease management.

Determination of Both TP53 Mutation Status and the Amount of p53 Protein has Limited Diagnostic Importance for Patients with Ovarian Cancer.

Ovarian cancer is one of the most aggressive types of gynecologic cancers. Many patients have a relapse within two years after diagnosis and subsequent therapy. Among different genetic changes generally believed to be important for the development of cancer, TP53 is the most common mutation in the case of ovarian tumors. Our work aims to analyze the outcomes of different comparisons based on the overall survival of ovarian cancer patients, the determination of TP53 status and the amount of p53 protein in tumor tissues. We analyzed and compared a collective of 436 ovarian patients' data. The extracted data include TP53 mutation status, p53 protein level and information on the overall survival. Values for p53 protein level in dependence of the TP53 mutation status were compared using the Independent Samples t-Test. Survival analyses were displayed by Kaplan- Meier plots, using the log-rank test to check for statistical significance. We have not found any statistically significant correlations between the determination of TP53 status or the amount of p53 protein in tumor tissues and the overall survival of ovarian cancer patients. In ovarian tumors the determination of both the TP53 status as well as the p53 protein amount has only limited diagnostic importance.

Predictors of early mortality risk in patients with epithelial ovarian cancer.

BackgroundTo improve the overall survival of epithelial ovarian cancer (EOC) patients, a more precise risk identification after completion of standard treatment will enhance patients' follow‐up surveillance and the use of individualized targeted therapy.AimThis study explored the potential risk predictors of early mortality in EOC patients who had standard treatment with debulking surgery and chemotherapy.MethodsThe study included 93 EOC patients who had standard treatment and were followed up between January 2011 and December 2020. The sociodemographic, clinical, and laboratory data of patients with EOC including the update on their 3‐year follow‐up status were retrospectively collected and analyzed. Early mortality is defined as the death of a patient within 3 years of completion of standard treatment. Patients' data were computed using descriptive statistics and the associations between patients' factors and the risk of early mortality were tested using the binary logistic regression model.ResultsEarly deaths occurred in 36 (38.7%) of patients with EOC. In the final multivariate analyses, early tumor relapse within 6‐months of treatment completion was the only independent risk factor that predicts early mortality in EOC patients (risk ratio = 8.6, 95% confidence interval: 3.3–24.5, p < 0.01).ConclusionOur study suggests that early tumor relapse may be a useful surrogate of early mortality in EOC. However, our findings should be interpreted with caution pending further corroboration through an adequately powered, prospective multicenter study.

The hyaluronan-related genes HAS2, HYAL1-4, PH20 and HYALP1 are associated with prognosis, cell viability and spheroid formation capacity in ovarian cancer

PurposeHyaluronan modulates tumour progression, including cell adhesion, cohesion, proliferation and invasion, and the cancer stem cell phenotype. In ovarian cancer, high levels of stromal hyaluronan are associated with poor prognosis. In this work, hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-4, PH-20, HYALP1) were examined with regard to different levels of gene expression and its influence on ovarian cancer patients’ survival. The impact of a siRNA depletion of HAS2 was investigated in vitro.MethodsUsing the Kaplan–Meier Plotter tool, we investigated the influence of hyaluronic synthases and hyaluronidases on the survival of a collective of 1435 ovarian cancer patients. Differences in gene expression between normal (n = 46) and cancerous (n = 744) ovarian tissue were examined using the TNMplot database. Following an evaluation of hyaluronan-related gene expression in the ATCC ovarian cancer panel, we studied SKOV3 and SW 626 ovarian cancer cells subjected to HAS2 siRNA or control siRNA treatment in terms of HAS1-3, HYAL2 and HYAL3 mRNA expression. We investigated the ability to form spheroids using the Hanging Drop method and the response to chemotherapy at different concentrations using the MTT Assay. By STRING analysis, interactions within the enzymes of the hyaluronic acid system and with binding partners were visualized.ResultsHAS1, HYAL1 and HYAL4 mRNA expression is significantly upregulated, whereas HAS2, HYAL2 and HYAL3 mRNA expression is significantly downregulated in ovarian cancer tissue compared to controls. HAS2 improves cell viability, the capability to form tumour spheroids and has a negative prognostic value regarding overall survival. Lower HAS2 expression and high expression of HYAL2 and HYAL3 favours the survival of ovarian cancer patients. HAS2 knockdown cells and control cells showed a moderate response to combinatorial in vitro chemotherapy with taxol and cisplatin.ConclusionIn conclusion, our study shows that the hyaluronic acid system has a relevant influence on the survival of ovarian cancer patients and could therefore be considered as a possible prognostic factor.

An Integrative Analysis Revealing ZFHX4-AS1 as a Novel Prognostic Biomarker Correlated with Immune Infiltrates in Ovarian Cancer.

Ovarian cancer (OC) is the main cause of deaths worldwide in female reproductive system malignancies. Growing studies have indicated that eRNAs could regulate cellular activities in various tumors. Yet the potential roles of eRNAs in OC progression have not been elucidated. Thus, comprehensive assays were needed to screen the critical eRNAs and to explore their possible function in OC. We used Kaplan–Meier methods to identify survival-associated eRNAs in OC based on TCGA datasets. The levels of ZFHX4-AS1 were examined using TCGA datasets. Further exploration was carried out based on the following assays: clinical and survival assays, GO terms, and KEGG assays. TIMER was applied to delve into the relationships between ZFHX4-AS1 and tumor immune infiltration. In this research, we observed 71 survival-related eRNAs in OC patients. ZFHX4-AS1 was highly expressed in OC specimens and predicted a poor prognosis of OC patients. In addition, high ZFHX4-AS1 expression was positively related to the advanced stages of OC specimens. Multivariate assays revealed that ZFHX4-AS1 was an independent prognostic factor for overall survival of OC patients. KEGG analysis indicated that ZFHX4-AS1 may play a regulatory effect on TGF-beta signaling, PI3K-Akt signaling, and proteoglycans in cancer. The pan-cancer validation indicated that ZFHX4-AS1 was related to survival in eight tumors, namely, UCEC, STAD, SARC, OV, ACC, KICH, KIRC, and BLCA. The expression of ZFHX4-AS1 was correlated with the levels of B cells, T cell CD8+, neutrophil, macrophage, and myeloid dendritic cells. Simultaneously, ZFHX4-AS1 may be a prognostic biomarker and a distinctly immunotherapy-related eRNA in OC.

The Immune Subtype Contributes to Distinct Overall Survival for Ovarian Cancer Patients With Platinum-Based Adjuvant Therapy.

ObjectiveNowadays, platinum-based therapy has been widely used as the first-line therapy of ovarian cancer. However, the effect of the tumor microenvironment on platinum-based therapy remains unclear. In this study, we aim to investigate the relationship between immune microenvironment subtypes and the prognosis of platinum-based therapy in ovarian cancer.MethodsWe integrated 565 ovarian cancer samples from two datasets and obtained the immune subtypes (ISs) by consistent clustering of 1190 immune-related gene expressions. The proportional hazards regression model was used to assess the relationship between ISs and the prognosis of platinum-based adjuvant therapy including progression-free survival (PFS) and overall survival (OS). The prognostic contribution of ISs was validated in three additional cohorts. Non-parametric tests were used to assess genomic characteristics, the proportion of immune cells, and immune-related signature differences among ISs.ResultsWe identified and validated five ISs associated with different clinical outcomes of the platinum-based adjuvant therapy in ovarian cancer patients. These differences were only found in OS rather than PFS. An immune subtype had the worst OS. Those patients mainly derived from the mesenchymal subtype had the lowest tumor purity with a high leukocyte fraction as well as stromal fraction and had the highest TGF-β response signaling. By contrast, an immune subtype characterized by immunoreactive status with the highest CD8+T cell infiltration and elevated IFN-γ response signaling had the best prognosis. Other subtypes with more diverse immunologic features such as lowest macrophage regulation signaling showed intermediate prognoses. Notably, the contribution of ISs to OS was independent of the clinical response to platinum-based drugs.ConclusionOur analysis revealed the association between different immune characteristics and platinum-based adjuvant therapy, indicating the combination of ISs and chemotherapy could optimize the treatment strategy of OC patients.

Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via hsa-miR-542-5p.

Blocking ataxia telangiectasia mutated (ATM), a crucial player in DNA repair responses, has been proposed as a promising strategy in anti-cancer therapy. Most previous studies have focused on DNA damage response-related pathways after administration of ATM inhibitors. However, ATM inhibition could potentially influence a wide range of changes in gene expression, which remain poorly defined. Here, we report that administration of the ATM inhibitor KU60019 led to impaired migration and enhanced apoptosis in the ovarian cancer cell line SKOV3, accompanied by abnormally elevated O-GlcNAc transferase and O-GlcNAcase expression levels. In addition, KU60019 treatment significantly suppressed expression of hsa-miR-542-5p in SKOV3 cells. Up-regulation of hsa-miR-542-5p expression inhibited increases in OGT and OGA level, and reversed the effects of ATM inhibition on apoptosis and migration in SKOV3 cells. Finally, we found aberrant expression of OGT and OGA to be associated with ovarian cancer patient survival. Taken together, our results suggest that ATM inhibition may promote SKOV3 cell apoptosis via suppressing hsa-miR-542-5p and elevating OGT and OGA expression, providing new insights into the application of ATM inhibitors in cancer immunotherapy.

Abstract 3781: Expression of ovarian cancer specific Drp1 splice variants regulate mitochondrial heterogeneity and cell plasticity during tumor progression

Abstract Mitochondrial shape is integral for its proper function and is maintained by a dynamic balance between the events of fission and fusion. Hence, a disruption in the balance is detrimental and has been associated with multiple pathologies including tumorigenesis. We noticed significant heterogeneity in mitochondrial morphology and function in ovarian cancer, which remains the deadliest gynecologic malignancy to date. We discovered that heterogenous mitochondrial dynamics in ovarian cancer cells were associated with specific transcript variant signatures of the fission protein Drp1 (encoded by the gene DNM1L), the primary GTPase responsible for mitochondrial fission. While several Drp1 splice variants have been reported, few studies have linked expression and potential interplay of splice variants of Drp1 on mitochondrial dynamics and function with pathophysiology especially in ovarian cancer. We used 3’RACE, western blotting and LC-MS/MS proteomics analysis to establish the identity of the major Drp1 splice variants expressed in ovarian cancer. We found ovarian cancer cell lines as well as patient-ascites derived cells, predominantly express two Drp1 variants: a transcript including both exons 16 and 17 (16/17) and a transcript lacking exon 16 (-/17). We also validated our findings in TCGA ovarian cancer specimens by analyzing Drp1 splice variant transcripts following annotation of TCGA raw RNAseq data and Salmon expression analysis. Our TCGA analysis of these variants highlighted significant difference in overall survival of ovarian cancer patients. Samples with high Drp1(-/17) expression were associated with poorer overall survival compared to those predominantly expressing Drp1(16/17). Furthermore, carrying out gene set enrichment analysis (GSEA) on TCGA specimens split by high expression of these two variants showed enrichment of distinct gene expression signatures. Overexpression and splice variant specific siRNA knockdown studies demonstrated that Drp1 variants have unique localization and effects on mitochondrial morphology and function. Furthermore, metabolic profiling and 13C metabolic flux analysis highlighted variant specific alterations in mitochondrial metabolic pathways and the TCA cycle. Drp1(-/17) expression enhanced mitochondrial respiratory function and as previously shown, Drp1(-/17) associated with both mitochondria and microtubules, potentially implying a more regulated fission activity as a consequence of controlled subcellular localization. Additionally, Drp1(-/17) was enriched and associated with quiescent phenotype compared to more proliferative phenotype of Drp1(16/17). Hence, expression of distinct Drp1 splice variants may be a novel mechanism to regulate mitochondrial fission, and integral to ovarian cancer cell plasticity under different selection pressures during tumor progression. Citation Format: Zaineb Javed, Dong-Hui Shin, Weihua Pan, Amal Taher Elhaw, Priscilla Tang, Rebecca Phaeton, Mohamed Trebak, Vonn Walter, Nadine Hempel. Expression of ovarian cancer specific Drp1 splice variants regulate mitochondrial heterogeneity and cell plasticity during tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3781.

Abstract 798: Comprehensive genomic profiling of tissue and liquid biopsies reveals the landscape of reversion mutations

Abstract Loss of function mutations in homologous recombination (HR) repair genes predispose individuals to cancer due to the genomic instability brought about by the inability to properly repair DNA. These alterations may also identify patients eligible for treatment with poly (ADP-ribose) polymerase (PARP) inhibitors and platinum drugs that exploit synthetic lethality; however, resistance eventually occurs. This resistance is largely the result of reversion mutations, which restore the DNA repair function of mutated HR genes. We employed a computational approach to identify patients with breast, ovarian, pancreas, or prostate cancer who underwent comprehensive genomic profiling (CGP; Foundation Medicine, Inc.) and had reversion mutations in the BRCA1, BRCA2, PALB2, RAD51C, or RAD51D genes. Reversion mutations were identified in six different categories: 1) missense mutations that occur at the same amino acid position as a deleterious alteration, 2) non-frameshift deletion mutations that encompass a deleterious alteration, 3) frameshift mutations that restore the open reading frame of another frameshift mutation, 4) splice-site mutations that occur at the same exon as a deleterious alteration, 5) copy number losses that remove a deleterious alteration, and 6) intragenic deletions that lead to loss of deleterious mutation. Using our computational approach, we identified 483 patients who 1,112 reversion mutation pairs in both solid tissue- and liquid biopsy-derived samples. The most frequently observed category was a non-frameshift deletion of a deleterious mutation. Overall, a greater number of reversion mutations were found in liquid biopsy samples. BRCA2 was the most frequently reverted gene followed by BRCA1, PALB2, RAD51D, and RAD51C. BRCA1-mutated samples had up to six reversion mutations, and for BRCA2, we observed as many as 228 putative reversion pairs in one sample. PALB2, RAD51C, and RAD51D had no more than two reversion mutations. We further examined co-occurring alterations and found correlations with genes in multiple signaling pathways including the MYC signaling pathway, which contained more mutations in reversion-positive samples. Lastly, we explored real-world longitudinal data from reversion-positive samples and found that the presence of a reversion mutation was significantly associated with lower overall survival for breast, ovarian, and prostate cancer patients. In summary, we characterized the landscape of reversion mutations in patients who underwent tissue or liquid biopsy-based CGP during clinical cancer treatment. Our data provide a better perspective for the identification and treatment of cancers involving a reversion mechanism. Citation Format: Shannon T. Bailey, Meijuan Li, James Thornton, Lei Yang, Chenming Cui, Mark Hartman, Garrett Frampton, Brennan Decker, Christine Vietz. Comprehensive genomic profiling of tissue and liquid biopsies reveals the landscape of reversion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 798.

Abstract 2445: Orchestrated expression of the atypical Rho-GTPase RHOV mediates multicellular aggregate formation in ovarian cancer

Abstract Transcoelomic spread is a major mode of ovarian cancer (OVCA) metastasis, where cells disseminate into the peritoneal ascites fluid, evade anoikis, and form multi-cellular aggregates (MCAs) that mediate anchorage-independent (a-i) survival and invasion of the peritoneal organs. Isolation of MCAs from patient ascites correlates with poor patient survival and resistance to therapy. However, the mechanisms promoting anoikis evasion and OVCA MCA formation in a-i are not fully understood. Our previous data from patient ascites-derived cells, cell lines, and in vivo studies, demonstrate that OVCA cells upregulate the nutrient/stress sensor SIRT3 in response to a-i. We further illustrated that SIRT3 is necessary for the activation of the primary mitochondrial dismutase, SOD2, which in turn promotes the mitochondrial antioxidant defense to maintain optimal survival in a-i. To identify additional key molecular players important for a-i survival downstream of SIRT3, we employed RNA sequencing analysis to compare the transcriptome of SIRT3 knockdown and wildtype cells in both attached and a-i conditions using the serous adenocarcinoma cell line OVCA433. Analysis of early transcriptomic changes, observed within 2 hrs as well as 24 hrs of a-i, revealed that RHOV, a recently identified atypical member of the Rho GTPase family, is the top gene significantly upregulated in a-i. SIRT3 knock-down significantly decreases RHOV expression in 24hr a-i conditions, implicating RHOV as a potential downstream target of SIRT3 signaling in a-i. RHOV was reported to be overexpressed in lung cancer and found to correlate with poor patient outcome and resistance to therapy. RHOV expression also regulates intercellular adhesion dynamics during development. Our data show that genetic silencing of RHOV expression interferes with the ability of OVCA cells to form MCAs in a-i, suggesting that increased expression of RHOV in a-i conditions acts as an adaptive survival advantage mediating cell-cell adhesion and MCA formation. Current work is exploring how RHOV regulates E-cadherin in this context, by focusing on p21-stimulated serine/threonine protein kinase signaling. In addition, the mechanisms of SIRT3 dependent regulation are being explored by determining how changes in mitochondrial protein deacetylation contribute to RHOV transcription. This work highlights an expanding role of SIRT3 in mediating a-i survival of OVCA and explores the novel role of an understudied member of the Rho family of GTPases, RHOV during OVCA metastasis. Finally, given that the formation of MCAs has been correlated with resistance to therapy and increased rates of recurrence, we aim to test how MCA formation and targeting of key players of cell-cell adhesion in a-i, such as a RHOV, can be exploited for novel therapeutic strategies to prolong survival of OVCA patients diagnosed with metastatic disease. Citation Format: Amal T. Elhaw, Yeon Soo Kim, Zaineb Javed, Priscilla Tang, Weihua Pan, Nadine Hempel. Orchestrated expression of the atypical Rho-GTPase RHOV mediates multicellular aggregate formation in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2445.

35P Racial disparities in diagnosis, histological type, treatment and survival in ovarian cancer patients in the US from 1992 to 2018: SEER-based analysis

Ovarian malignancies are the 7th diagnosed malignancy and the 8th cause of death in females worldwide. Ovarian cancer includes a great heterogeneous group of neoplasms that differs in histological type, pathological stage, risk factors, prognosis, and treatment. Racial disparities in incidence, treatment, and mortality in cancers exist globally. With Surveillance, Epidemiology, and End Results (SEER) program in place, detection of these disparities would be feasible. herein racial disparities in ovarian cancer are analyzed.

Long-term survival in newly-diagnosed ovarian cancer patients.

e17543 Background: A proportion of women with ovarian cancer, even those with advanced-stage disease, will experience long-term survival post diagnosis. Mixture cure modeling provides insight into factors related to both short-term recurrence and death as well as long-term survival. The goals of this study were to estimate the long-term survival rate, and to evaluate associations between patient characteristics and the long-term survival rate and landmark 5- and 10- year survival, in a sample of newly-diagnosed ovarian cancer patients. Methods: The Tempus EMR dataset contains patients from academic &amp; community oncology centers in the U.S. This study included adult women with a new primary diagnosis of ovarian, fallopian tube, or peritoneal cancer between 2000 and 2020. Women treated with a poly-ADP ribose polymerase inhibitor (PARPi), pembrolizumab, or nivolumab were excluded (n = 947; final sample size = 6,598). Mixture cure models were used to estimate the long-term survival rate (probability of living as long as an age- and gender-matched person without ovarian cancer), overall and stratified by patient demographic &amp; clinical characteristics. Relative importance of variables associated with long-term survival was evaluated using logistic regression models with 5- and 10-year landmark outcomes. Results: Younger age, earlier stage, lower grade, favorable ECOG score, and platinum sensitivity were associated with better overall survival (OS). The long-term survival rate in our model was 25.0% (95% CI: 21.5-28.9). The long-term survival rate was higher for age &lt; 65 vs. age 75+ [29.0% (24.8-33.6) vs. 10.5% (2.9-31.6)], early vs. advanced stage disease [62.0% (41.4-78.9) vs. 17.8% (14.1-22.2)], grade 1-2 vs. 3-4 [31.4% (12.1-60.3) vs. 20.4% (14.6-27.8)], ECOG 0-2 vs. 3-4 [26.1% (21.4-31.3) vs. 2.6% (0.05- 56.5)], and platinum sensitive vs. platinum resistant patients [47.5% (43.1-51.9) vs. 9.4% (7.0-12.5)]. Analyzing 5- and 10-year landmarks [n = 3,944 (59.8%), n = 3,107 (47.1%), respectively] in multivariable logistic regression models, platinum sensitivity had the strongest association, followed by cancer stage. Conclusions: Understanding differences in long-term survival based on patient characteristics is important for clinical decision-making and personalizing treatment. Overall, one quarter of ovarian cancer patients were long-term survivors; long-term survivors were more likely to be younger and have earlier stage disease, low grade disease, better performance status, or sensitivity to platinum-based therapy. These results also provide a baseline to evaluate long-term survival in patients on newer therapies such as PARPi when sufficient follow-up data are available.

Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer

BackgroundPlatinum based agents—cisplatin and carboplatin in combination with taxanes are used for the treatment of ovarian cancer (OC) patients. However, the majority of OC patients develop recurrent, platinum resistant disease that is uniformly fatal. Platinum treatment enriches for chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSCs), which contribute to tumor recurrence and disease relapse. Acquired platinum resistance also includes metabolic reprograming and switching to oxidative phosphorylation (OXPHOS). Chemosensitive cells rely on glycolysis while chemoresistant cells have the ability to switch between glycolysis and OXPHOS, depending on which pathway drives a selective advantage for growth and chemoresistance. High expression of genes involved in OXPHOS and high production of mitochondrial ROS are characteristics of OCSCs, suggesting that OCSCs favor OXPHOS over glycolysis. Based on connections between OCSCs, chemoresistance and OXPHOS, we hypothesize that platinum treatment induces changes in metabolism that contribute to platinum-induced enrichment of OCSCs.MethodsThe effect of cisplatin on mitochondrial activity was assessed by JC1 staining and expression of OXPHOS genes by RT-qPCR. Cisplatin-induced changes in Sirtuin 1 (SIRT1) levels and activity were assessed by western blot. Small molecule inhibitors of mitochondrial complex I and SIRT1 were used to determine if their enzymatic activity contributes to the platinum-induced enrichment of OCSCs. The percentage of ALDH + OCSCs in OC cells and tumor tissue from xenograft models across different treatment conditions was analyzed using ALDEFLUOR assay and flow cytometry.ResultsWe demonstrate that platinum treatment increases mitochondrial activity. Combined treatment of platinum agents and OXPHOS inhibitors blocks the platinum-induced enrichment of ALDH + OCSCs in vitro and in vivo. Furthermore, platinum treatment increases SIRT1 levels and subsequent deacetylase activity, which likely contributes to the increase in platinum-induced mitochondrial activity.ConclusionsThese findings on metabolic pathways altered by platinum-based chemotherapy have uncovered key targets that can be exploited therapeutically to block the platinum-induced enrichment of OCSCs, ultimately improving the survival of OC patients.

Wnt/β-Catenin Inhibition by CWP232291 as a Novel Therapeutic Strategy in Ovarian Cancer.

The poor prognosis of ovarian cancer patients mainly results from a lack of early diagnosis approaches and a high rate of relapse. Only a very modest improvement has been made in ovarian cancer patient survival with traditional treatments. More targeted therapies precisely matching each patient are strongly needed. The aberrant activation of Wnt/β-catenin signaling pathway plays a fundamental role in cancer development and progression in various types of cancer including ovarian cancer. Recent insight into this pathway has revealed the potential of targeting Wnt/β-catenin in ovarian cancer treatment. This study aims to investigate the effect of CWP232291, a small molecular Wnt/β-catenin inhibitor on ovarian cancer progression. Various in vitro, in vivo and ex vivo models are established for CWP232291 testing. Results show that CWP232291 could significantly attenuate ovarian cancer growth through inhibition of β-catenin. Noticeably, CWP232291 could also s suppress the growth of cisplatin-resistant cell lines and ovarian cancer patient-derived organoids. Overall, this study has firstly demonstrated the anti-tumor effect of CWP232291 in ovarian cancer and proposed Wnt/β-catenin pathway inhibition as a novel therapeutic strategy against ovarian cancer.

A machine learning approach applied to gynecological ultrasound to predict progression-free survival in ovarian cancer patients

In a growing number of social and clinical scenarios, machine learning (ML) is emerging as a promising tool for implementing complex multi-parametric decision-making algorithms. Regarding ovarian cancer (OC), despite the standardization of features that can support the discrimination of ovarian masses into benign and malignant, there is a lack of accurate predictive modeling based on ultrasound (US) examination for progression-free survival (PFS). This retrospective observational study analyzed patients with epithelial ovarian cancer (EOC) who were followed in a tertiary center from 2018 to 2019. Demographic features, clinical characteristics, information about the surgery and post-surgery histopathology were collected. Additionally, we recorded data about US examinations according to the International Ovarian Tumor Analysis (IOTA) classification. Our study aimed to realize a tool to predict 12 month PFS in patients with OC based on a ML algorithm applied to gynecological ultrasound assessment. Proper feature selection was used to determine an attribute core set. Three different machine learning algorithms, namely Logistic Regression (LR), Random Forest (RFF), and K-nearest neighbors (KNN), were then trained and validated with five-fold cross-validation to predict 12 month PFS. Our analysis included n. 64 patients and 12 month PFS was achieved by 46/64 patients (71.9%). The attribute core set used to train machine learning algorithms included age, menopause, CA-125 value, histotype, FIGO stage and US characteristics, such as major lesion diameter, side, echogenicity, color score, major solid component diameter, presence of carcinosis. RFF showed the best performance (accuracy 93.7%, precision 90%, recall 90%, area under receiver operating characteristic curve (AUROC) 0.92). We developed an accurate ML model to predict 12 month PFS.

Mitochondrial transcription factor B2 overexpression increases M2 macrophage infiltration via cytosolic mitochondrial DNA-stimulated Interleukin-6 secretion in ovarian cancer

ABSTRACT Mitochondrial transcription factor B2 (TFB2M) is a protein modulating both mitochondrial DNA (mtDNA) transcription and compacting. In this study, we explored the expression profile of TFB2M in ovarian cancer, its association with infiltration of tumor-associated macrophages (TAMs), and its influence on macrophage polarization. Serial sections of ovarian cancer tissue arrays were stained to detect TFB2M and CD163 expression. Epithelial ovarian cancer cell line OVISE and CAOV4 were used to assess the influence of TFB2M on IL-6 expression. THP-1 cells were utilized as an in vitro model for macrophage migration and polarization. Results showed that higher TFB2M expression is associated with poor survival in ovarian cancer patients. IHC staining confirmed a moderately positive correlation between TFB2M expression and the infiltration of CD163-positive cells in 68 primary ovarian cancer cases. TFB2M overexpression was associated with increased mtDNA outside the mitochondria and elevated IL-6 expression in ovarian cancer cells. When cytosolic mtDNA was selectively inhibited by DNase I, TFB2M-induced IL-6 upregulation was canceled. TFB2M overexpression could activate the nuclear factor kappa-B (NF-κB) signaling pathway via promoting nucleus entry of p65 and p-p65, which was abrogated by inhibiting cytosolic mtDNA, TLR9, or NF-κB signaling pathway. Conditioned medium from OIVSE cells with TFB2M overexpression could induce macrophage migration and M2 polarization. However, these inducing effects were abrogated by DNase I, TLR9 inhibitor, and anti-IL-6 R pretreatment. In conclusion, this study showed a novel role of TFB2M in the immunosuppressive tumor microenvironment. It promotes M2 macrophage infiltration via a cytosolic mtDNA/TLR9/NF-κB/IL-6 pathway in ovarian cancer.