Ovarian Serous Adenocarcinoma Research Articles

PATH-51. CENTRAL NERVOUS SYSTEM METASTASES ARE GENOMICALLY DIVERGENT FROM THEIR RESPECTIVE EXTRACRANIAL SITES

Abstract INTRODUCTION Next-generation sequencing (NGS) has become standard of care in establishing the diagnosis and guiding treatment of cancers. Our understanding of genomic evolution of brain metastases (BM) and leptomeningeal disease (LMD) from solid tumor malignancies remains limited. Here we present updated data from our pilot study. METHODS We prospectively collected clinical data and NGS of seventeen patients undergoing craniotomy for symptomatic BM from solid tumor malignancies or cerebrospinal fluid (CSF) sampling for LMD. Matched systemic and CNS analyses were performed using a research-based NGS assay. When extracranial disease tissue was unavailable, liquid NGS served as a surrogate. RESULTS CNS metastases were present at initial diagnosis in 10/17 and 11/17 patients had not received systemic therapy prior to CNS tissue sampling. The predominant cancer type was NSCLC (n=11), followed by breast cancer (n=3), ovarian high grade serous carcinoma (n=1), GEJ adenocarcinoma (n=1), and basosquamous carcinoma of skin (n=1). The mean tumor mutational burden in extracranial samples was 3.65 (SD 3.34; SEM 0.97), in contrast to CNS samples 21.63 (SD 26.47; SEM 7.64). Concordant mutations in matched sampling had an increase in CNS variant allele frequency (VAF) (27.8% vs 17.3%; arithmetic difference = 10.5, p=0.054) and CNS gene copy number alterations (CNA) (2.4 copies vs 0.8 copies; arithmetic difference = 1.6, p=0.171). Known driver alterations in EGFR, KRAS and PIK3CA were retained. LMD was present in 4/17 patients, with two present at enrollment and two developing during the study. CONCLUSIONS Matched sequencing reveals CNS metastases to harbor a significantly higher TMB, retention of primary driver alterations with a trend towards higher VAF and CNA of concordant mutations. While limited by small sample size, these data indicate genetic evolution in CNS metastases regardless of prior treatment status.

The relationship between serum interleukin-1β and circulating CD16+ neutrophils for assessing progression-free time in advanced ovarian cancer

BACKGROUND: Ovarian cancer is the most aggressive gynecological tumor with high mortality. The ambivalent, both helper and suppressive effects of neutrophils on the cells of innate and adaptive immunity determines their important immunoregulatory role in the development of malignant tumors. AIM: Evaluation of the effect of serum interleukin-1β and circulating neutrophils CD16+ on progression-free time in advanced ovarian cancer. MATERIAL AND METHODS: In 42 primary patients with serous ovarian adenocarcinoma (median age 54 years) with ascites and 15 patients with benign ovarian tumors (median age 60 years) admitted for examination and treatment to the Regional Clinical Oncology Dispensary before receiving neoadjuvant antitumor treatment (2015–2020), the level of interleukin-1β in the blood serum was determined using enzyme immunoassay, and the number of CD16+ neutrophils was determined by fluorescence microscopy using monoclonal antibodies. Statistical processing was performed using Statistica 13 and Jamovi 2.4.14 programs. Progression-free time analysis of patients was performed using the Cox and Kaplan–Meier regression methods. RESULTS: It was found that the number of circulating CD16+ neutrophils in advanced ovarian cancer with ascites was lower than in benign ovarian tumors [48.0; 95% confidence interval (CI) 46.59–48.12 versus 50.0; 95% CI 48.51–49.76; p=0.017]. At the same time, the level of interleukin-1β in the blood serum in advanced ovarian cancer with ascites was higher than in benign ovarian tumors [2.52 (95% CI 2.50–3.37) versus 1.26 (95% CI 0.97–1.55) (p=0.0001)]. In multivariate Cox analysis in patients with ascites (odds ratio 4.334; 95% CI 1.83–10.23; p=0.001), both the CD16+ neutrophil count (odds ratio 0.73; 95% CI 0.62–0.86; p=0.0001) and serum interleukin-1β levels (odds ratio 1.90; 95% CI 1.41–2.57; p=0.0001) had prognostic significance for assessing progression-free time. CONCLUSION: The number of circulating CD16+ neutrophils and serum interleukin-1β levels simultaneously affect progression-free time in advanced ovarian cancer.

The minimally invasive resection of port-site metastasis of ovarian cancer after laparoscopy with cutaneous integrity: a case report and literature review

BackgroundPostoperative wound recovery following laparotomy for port-site metastasis (PSM) resection is a concern. Reports indicate that wound healing disorders occur in patients with PSM. The challenges associated with PSM resection include the complete removal of the lesion, ensuring rapid wound healing, and maintaining the integrity of the abdominal wall. To date, there have been no reports on a minimally invasive approach for PSM resection following ovarian cancer through the inner side of the abdominal wall.Case presentationA 66-year-old G2P1 patient with a history of high-grade serous ovarian adenocarcinoma IIA presented with two abdominal wall masses, suspected to be PSM. She underwent laparoscopic resection of the lesions under general anesthesia. The excised masses measured approximately 10 cm and 5 cm, and margins were negative. The surgery lasted 1 hour and 33 minutes, with minimal intraoperative bleeding and no complications. The postoperative recovery was smooth. No recurrence was observed during the 12-month follow-up.ConclusionsIn our view, laparoscopy may be used as a minimally invasive technique that allows for PSM in the abdominal wall.

Value analysis of preoperative peripheral blood LMR in predicting prognosis of serous papillary ovarian adenocarcinoma

ObjectiveTo analyze the predictive effect of preoperative peripheral blood leukocyte related inflammatory indicators on the prognosis of patients with serous papillary ovarian adenocarcinoma.MethodsA retrospective analysis was conducted on the case data of 83 patients with ovarian cancer undergoing tumor cell reduction surgery admitted to our hospital from January 2017 to December 2020. Pathological findings confirmed serous papillary ovarian adenocarcinoma. Kaplan–Meier method was used to analyze the relationship between lymphocyte to monocyte ratio (LMR) and the patients survival prognosis. Analyzing factors affecting patient prognosis which using a multivariable Cox risk.ResultsThe overall survival (OS) of the patients with serous papillary ovarian adenocarcinoma in high LMR group was higher than that in the low LMR group preoperative. The disease free survival (DFS) of ovarian adenocarcinoma patients in the high LMR group was higher than that in the low LMR group preoperative. That was the low LMR indicating a poor prognosis. Single factor analysis showed that age of onset was correlated with OS and DFS, and the body mass index (BMI) was only correlated with OS. Multivariable analysis showed that the age of onset (HR = 2.571, 95% CI 1.199–5.512, P = 0.015) and BMI (HR = 0.337, 95% CI 0.158–0.718, P = 0.005) were independent risk factors for OS.ConclusionsAlthough the serous papillary ovarian adenocarcinoma patients with preoperative peripheral blood LMR reduction have poor prognosis, the correlation between LMR values and prognosis is not significant. Therefore, it is not recommended to use preoperative peripheral leukocyte related inflammatory indicators as prognostic markers for serous papillary ovarian adenocarcinoma.

Amplified Cell Cycle Genes Identified in High-Grade Serous Ovarian Cancer.

The objective of this study was to identify differentially expressed genes and their potential influence on the carcinogenesis of serous-type ovarian cancer tumors. Serous cancer is an epithelial ovarian cancer subtype and is the most common type of ovarian cancer. Transcriptomic profiles of serous cancer and non-cancerous datasets were obtained from the Gene Expression Omnibus (GEO-NCBI). Differentially expressed genes were then derived from those profiles; the identified genes were consistently upregulated in three or more transcriptomic profiles. These genes were considered as the serous ovarian cancer gene set for further study. The serous gene set derived from the transcriptomic profiles was then evaluated for ontological functional analysis using the Molecular Signatures Database. Next, we examined the mutational impact of this serous gene set on the transcriptomic profile of high-grade serous ovarian (HGSO) adenocarcinoma using the cBioPortal database. Results from OncoPrint revealed that 26 genes were amplified in more than 5% of HGSO cancer patients. Interestingly, several of these genes are involved in cell cycle processes, including genes ATPase family AAA domain containing 2 (ATAD2), recQ-like helicase 4 (RECQL4), cyclin E1 (CCNE1), anti-silencing function 1B histone chaperone (ASF1B), ribonuclease H2 subunit A (RNASEH2A), structural maintenance of chromosome 4 (SMC4), cell division cycle associated 20 (CDC20), and cell division cycle associated 8 (CDCA8). The receiver operating characteristic (ROC) curve results also revealed higher specificity and sensitivity for this subtype of tumors. Furthermore, these genes may affect the recurrence of serous ovarian carcinogenesis. Overall, our analytical study identifies cell cycle-related genes that can potentially be targeted as diagnostic and prognostic markers for serous ovarian cancer.

Effect of ubiquitin-specific proteinase 43 on ovarian serous adenocarcinoma and its clinical significance

Background Ovarian cancer stands as a highly aggressive malignancy. The core aim of this investigation is to uncover genes pivotal to the progression and prognosis of ovarian cancer, while delving deep into the intricate mechanisms that govern their impact. Methods The study entailed the retrieval of RNA-seq data and survival data from the XENA database. Outliers were meticulously excluded in accordance with TCGA guidelines and through principal components analysis. The R package ‘deseq2’ was harnessed to extract differentially expressed genes. WGCNA was employed to prioritise these genes, and Cox regression analysis and survival analysis based on disease-specific time were conducted to identify significant genes. Immunohistochemistry validation was undertaken to confirm the distinct expression of USP43. Furthermore, the influence of USP43 on the biological functions of ovarian cancer cells was explored using techniques such as RNA interference, western blotting, scratch assays, and matrigel invasion assays. The examination of immune infiltration was facilitated via CIBERSORT. Results The study unearthed 5195 differentially expressed genes between ovarian cancer and normal tissue, comprising 3416 up-regulated and 1779 down-regulated genes. WGCNA pinpointed 204 genes most intimately tied to tumorigenesis. The previously undisclosed gene USP43 exhibited heightened expression in tumour tissues and exhibited associations with overall survival and disease-specific survival. USP43 emerged as a driver of cell migration (43.27 ± 3.91% vs 19.69 ± 1.94%) and invasion ability (314 ± 32 vs 131 ± 12) through the mechanism of epithelial mesenchymal transition, potentially mediated by the KRAS pathway. USP43 was also identified as a booster of CD4+ T memory resting cell infiltration, while concurrently reducing M1 macrophages within cancer, thereby fostering a milieu with relatively immune suppressive traits. Interestingly, USP43 demonstrated connections with epigenetically regulated-mRNAsi, although not with mRNAsi. Conclusion This study underscores the role of USP43 in facilitating tumour migration and invasion. It postulates USP43 as a novel therapeutic target for ovarian cancer treatment.

Tc-99m-MDP Uptake in Extraosseous Metastases from Ovarian Papillary Serous Adenocarcinoma.

The uptake of Tc-99m-uptake of Tc-99m-methylene diphosphonate (MDP) on bone scintigraphy can be seen at sites other than bone in a varying number of benign and malignant conditions. Extraosseous metastatic calcifications can occur in ovarian papillary serous adenocarcinoma (PSAC). These extraosseous calcifications show Tc-99m-MDP uptake. We report a case of a female in her sixties who had a previous history of PSAC of the ovary. The patient had undergone neoadjuvant chemotherapy (NACT) followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy. She also received adjuvant chemotherapy. Tc-99m-MDP bone scan was performed post chemotherapy because the patient complained of lower backache. The scan showed increased uptake in the lower thoracic and lumbar vertebral regions. However, single-photon emission computed tomography/computed tomography (CT) localizes the uptake to metastatic calcified peritoneal deposits. Further 18F-fluorodeoxyglucose positron emission tomography/CT confirmed widespread peritoneal and omental metastatic disease with increased uptake.

Amplification of Hippo Signaling Pathway Genes Is Governed and Implicated in the Serous Subtype-Specific Ovarian Carcino-Genesis.

Among women, ovarian cancer ranks as the fifth most common cause of cancer-related deaths. This study examined the impact of Hippo signaling pathway on ovarian carcinogenesis. Therefore, the signatures related to Hippo signaling pathway were derived from the molecular signatures database (MSigDB) and were used for further analysis. The Z score-based pathway activation scoring method was employed to investigate the expression patterns of these signatures in the mRNA expression profiles of ovarian cancer cohorts. Compared to other subtype tumors, the results of this study show that the Hippo signaling pathway signatures are dysregulated prominently in serous subtype-specific ovarian carcinogenesis. A receiver operating characteristic (ROC) curve-based results of the Hippo gene set, yes-associated protein 1 (YAP1), and mammalian sterile 20-like kinases 1 (MST1) genes can predict the serous subtype tumors by higher specificity and sensitivity with significant areas under the curve values also further reconfirmed these signaling dysregulations. Moreover, these gene sets were studied further for mutation analysis in the profile of high-grade serous ovarian adenocarcinoma in the cBioPortal database. The OncoPrint results reveal that these Hippo signaling pathway genes are amplified highly during the grade three and stage third or fourth of serous type ovarian tumors. In addition, the results of the Dependency Map (DepMap) plot also clearly show that these genes are amplified significantly across the ovarian cancer cell lines. Finally, overall survival (OS) curve plot investigations also revealed that these gene expressions show poor survival patterns linked to highly expressed conditions in serous subtypes of ovarian cancer patients with significant p-values (p < 0.05). Thus, the current finding would help to develop the targeted therapies treatment for serous subtype ovarian carcinogenesis.

Unraveling the molecular mechanisms of lymph node metastasis in ovarian cancer: focus on MEOX1

BackgroundLymph node metastasis (LNM) is a major factor contributing to the high mortality rate of ovarian cancer, making the treatment of this disease challenging. However, the molecular mechanism underlying LNM in ovarian cancer is still not well understood, posing a significant obstacle to overcome.ResultsThrough data mining from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we have identified MEOX1 as a specific gene associated with LNM in ovarian cancer. The expression of MEOX1 was found to be relatively high in serous ovarian adenocarcinoma, and its higher expression were associated with increased tumor grade and poorer clinical prognosis for ovarian cancer patients. Bioinformatics analysis revealed that MEOX1 exhibited the highest mRNA levels among all cancer types in ovarian cancer tissues and cell lines. Furthermore, gene set enrichment analysis (GSEA) and pathway analysis demonstrated that MEOX1 was involved in various LNM-related biological activities, such as lymphangiogenesis, lymphatic vessel formation during metastasis, epithelial-mesenchymal transition (EMT), G2/M checkpoint, degradation of extracellular matrix, and collagen formation. Additionally, the expression of MEOX1 was positively correlated with the expression of numerous prolymphangiogenic factors in ovarian cancer. To validate our findings, we conducted experiments using clinical tissue specimens and cell lines, which confirmed that MEOX1 was highly expressed in high-grade serous ovarian cancer (HGSOC) tissues and various ovarian cancer cell lines (A2780, SKOV3, HO8910, and OVCAR5) compared to normal ovarian tissues and normal ovarian epithelial cell line IOSE-80, respectively. Notably, we observed a higher protein level of MEOX1 in tumor tissues of LNM-positive HGSOC compared to LNM-negative HGSOC. Moreover, our fundamental experiments demonstrated that suppression of MEOX1 led to inhibitory effects on ovarian cancer cell proliferation and EMT, while overexpression of MEOX1 enhanced the proliferation and EMT capacities of ovarian cancer cells.ConclusionsThe results of our study indicate that MEOX1 plays a role in the lymph node metastasis of ovarian cancer by regulating multiple biological activities, including the proliferation and EMT of ovarian cancer, lymphangiogenesis, and ECM remodeling. Our findings suggest that MEOX1 could serve as a potential biomarker for the diagnosis and treatment of ovarian cancer with LNM.

An algorithm for the pre-operative differentiation of benign ovarian tumours based on magnetic resonance imaging interpretation in a regional core hospital: a retrospective study

ObjectiveFor selecting minimally invasive surgery (i.e. laparoscopic ovarian cystectomy) for treating ovarian tumours (OTs) in premenopausal patients, the pre-operative differentiation of benign ovarian tumours (Be-OTs) based on magnetic resonance imaging (MRI) interpretation is important. This paper describes the authors’ 8-year experience of approximately 1000 OT cases, and provides information about a diagnostic algorithm to help other hospitals. Study designThe medical records of 901 patients aged < 50 years with OTs from 1 January 2015–31 March 31 2023 were reviewed. First, the accuracy of pre-operative differentiation between Be-OTs and borderline/malignant ovarian tumours (Bo/Ma-OTs) was compared in each type of OT. Second, to identify the factors influencing differentiation between Be-OTs and Bo/Ma-OTs in 164 serous/mucinous ovarian tumours (SM-OTs), a multi-variate logistic regression analysis was performed to assess the effect of 13 factors, including MRI findings, OT size and tumour markers. ResultsIn the comparison of diagnostic accuracy of pre-operative MRI for each OT type, accuracy was found to be notably high for ovarian endometrial cyst (OEC) (n = 409), ovarian mature cystic teratoma (OMCT) (n = 308), ovarian endometrioid adenocarcinoma (OEA) (n = 6) and ovarian clear cell adenocarcinoma (OCCA) (n = 14). On the other hand, discrepancies between MRI and pathological findings often occurred in SM-OTs, including ovarian serous cystadenoma (n = 86), ovarian mucinous adenocarcinoma (n = 61), ovarian serous adenocarcinoma (n = 12) and ovarian mucinous adenocarcinoma (n = 5). In the multi-variate logistic regression analysis of the latter 164 patients, in addition to MRI findings, OT size and carbohydrate antigen 125 also had an effect to some extent. The combination of MRI interpretation and OT size may enhance differentiation of Be-OTs and Bo/Ma-OTs. ConclusionsAmong four types of OTs (OEC, OMCT, OEA and OCCA), MRI interpretation was able to differentiate between Be-OTs and Bo/Ma-OTs almost perfectly. Additionally, to mitigate the difficulty in differentiating SM-OTs, OT size may be useful in combination with MRI findings, although further accumulation and analysis of OT cases is needed.

Changes in urine metabolite concentration as a minimally invasive marker of ovarian serous adenocarcinoma

Introduction. Detection of ovarian cancer (OC) at the earliest possible stages is a priority for gynecological oncology, since 5-year survival rates decrease significantly with the progression of the disease. Currently, there is a huge need for more effective diagnostic methods and approaches. In recent years, fluid biopsy has received increasing attention in precision medicine because it is minimally invasive and can be repeated many times, allowing for realtime disease monitoring.Aim. Study of the urine metabolomic profile of patients with ovarian carcinoma.Materials and methods. To perform metabolomic analysis, 50 urine samples from patients with a diagnosis of serous ovarian carcinoma and 20 samples from apparently healthy individuals were selected. For protein precipitation, 300 mkl of urine was mixed with 600 mkl of a solution of acetonitrile LC-MS (Merck, Germany) and methanol LC-MS (Merck, Germany) (3:1 ratio). Chromatographic separation of metabolites was performed on a Vanquish Flex UHPLC System chromatograph (Thermo Scientific, Germany). The chromatograph was coupled to an Orbitrap Exploris 480 mass spectrometer (Thermo Scientific, Germany) equipped with an electrospray ionization source. Chromatographic separation was carried out on a Hypersil GOLD™ C18 column (1.9mkm, 10 x 2.1 mm) using the following eluents: A, 0.1 % formic acid; B, acetonitrile containing 0.1 % formic acid.Results. A total of 417 metabolites of various classes were identified by HPLC-MS. It was shown that in the urine of patients with OC 14 metabolites (kynurenine, phenylalanyl-valine, lysophosphatidylcholine (18:3), lysophosphatidylcholine (18:2), alanyl-leucine, lysophosphatidylcholine (20:4), L-phenylalanine, phosphatidylinositol (34:1), 5-methoxytryptophan, 2-hydroxymyristic acid, 3-oxocholic acid, lysophosphatidylcholine (14:0), indoleacrylic acid, lysophosphatidylserine (20:4)) had a significantly higher concentration compared to apparently healthy individuals. The content of 12 compounds, on the contrary, was reduced (L-beta-aspartyl-L-phenylalanine, myristic acid, decanoylcarnitine, aspartyl-glycine, malonylcarnitine, 3-hydroxybutyrylcarnitine, 3-methylxanthine, 2,6-dimethylheptanoylcarnitine, 3-oxododecanoic acid, N-acetylproline, L-octanoylcarnitine, capryloylglycine). This indicates a significant metabolomic imbalance in patients with OC.Conclusion. The metabolomic profile study of urine by UHPLC-MS showed that in patients with serous ovarian carcinoma there is an imbalance in the content of certain fatty acids and their derivatives, acylcarnitines, phospholipids, amino acids and their derivatives, as well as some derivatives of nitrogenous bases. At the same time, 26 metabolites with abnormal concentrations in urine may have some potential as non-invasive biomarkers of OC in women belonging to high-risk groups.

Unveiling a Rare Complication: Gemcitabine-Induced Cardiomyopathy in Ovarian Serous Adenocarcinoma

Gemcitabine is a nucleoside analogue and pyrimidine antimetabolite authorized for the treatment of ovarian cancer. It is generally considered safe and well-tolerated, with only a few reported cases of cardiac adverse effects. However, we present a case of gemcitabine-induced dilated cardiomyopathy in a 33-year-old female receiving gemcitabine as second-line therapy for ovarian serous adenocarcinoma. The patient had no history of hypertension or significant cardiac issues. She presented with clinical symptoms, laboratory abnormalities, and imaging findings consistent with congestive cardiac failure, along with a Left Ventricular Ejection Fraction (LVEF) of 25-30%. Gemcitabine administration was immediately discontinued, and treatment with Furosemide, ACE inhibitors, and Beta-blocker agents was initiated. Subsequently, the patient’s condition improved, with the resolution of symptoms and normalization of cardiac findings upon discontinuation of gemcitabine. This is the first reported case demonstrating objective evidence of gemcitabine-induced dilated cardiomyopathy in a patient with ovarian serous adenocarcinoma without a significant cardiac history. Although rare, it is crucial to promptly diagnose gemcitabine-induced cardiomyopathy to initiate appropriate management protocols.

Development of prediction model to estimate future risk of ovarian lesions: A multi-center retrospective study

BackgroundTo develop the preoperative prediction of ovarian lesions using regression-based statistics analyses and machine learning methods based on multiple serological biomarkers in China. Methods1137 patients with ovarian lesions in Zhujiang Hospital and 518 patients in others hospital in China were randomly assigned to training, test and external validation cohorts. Five machine learning classifiers, including Random Forest (RF), Extreme Gradient Boosting (XGB), Support Vector Classifier (SVC), K-nearest Neighbor (KN), Multi-Layer Perceptron (MLP) and the Lasso-Logistics prediction model (LLRM) were used to derive diagnostic information from 23 predictors. ResultsThe RF model had a high diagnostic value (AUC = 0.968) in predicting benign and malignant ovarian disease. Age and MLR were also potential diagnostic indicators for predicting ovarian disease except tumor indicators. The RF model well distinguished borderline ovarian tumors (AUC = 0.742). The RFM had a high predictive power to identify ovarian serous adenocarcinoma (AUC = 0.943) and ovarian endometriosis cysts (AUC = 0.914). ConclusionsThe RF models can effectively predict adnexal lesions, promising to be adjuncts to the preoperative prediction of ovarian cancer.

An artificial intelligence prediction model based on extracellular matrix proteins for the prognostic prediction and immunotherapeutic evaluation of ovarian serous adenocarcinoma.

Background: Ovarian Serous Adenocarcinoma is a malignant tumor originating from epithelial cells and one of the most common causes of death from gynecological cancers. The objective of this study was to develop a prediction model based on extracellular matrix proteins, using artificial intelligence techniques. The model aimed to aid healthcare professionals to predict the overall survival of patients with ovarian cancer (OC) and determine the efficacy of immunotherapy. Methods: The Cancer Genome Atlas Ovarian Cancer (TCGA-OV) data collection was used as the study dataset, whereas the TCGA-Pancancer dataset was used for validation. The prognostic importance of 1068 known extracellular matrix proteins for OC were determined by the Random Forest algorithm and the Lasso algorithm establishing the ECM risk score. Based on the gene expression data, the differences in mRNA abundance, tumour mutation burden (TMB) and tumour microenvironment (TME) between the high- and low-risk groups were assessed. Results: Combining multiple artificial intelligence algorithms we were able to identify 15 key extracellular matrix genes, namely, AMBN, CXCL11, PI3, CSPG5, TGFBI, TLL1, HMCN2, ESM1, IL12A, MMP17, CLEC5A, FREM2, ANGPTL4, PRSS1, FGF23, and confirm the validity of this ECM risk score for overall survival prediction. Several other parameters were identified as independent prognostic factors for OC by multivariate COX analysis. The analysis showed that thyroglobulin (TG) targeted immunotherapy was more effective in the high ECM risk score group, while the low ECM risk score group was more sensitive to the RYR2 gene-related immunotherapy. Additionally, the patients with low ECM risk scores had higher immune checkpoint gene expression and immunophenoscore levels and responded better to immunotherapy. Conclusion: The ECM risk score is an accurate tool to assess the patient's sensitivity to immunotherapy and forecast OC prognosis.

Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers.

Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array. Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model. We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317.

Preclinical testing of farletuzumab ecteribulin (FZEC [MORAb-202]) and MORAb-109, folate receptor α and mesothelin targeting antibody-drug conjugates (ADCs), in rare gynecologic cancers.

e17634 Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA), have limited treatment options and molecular alterations that drive cell proliferation and drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used in first-line treatment of most gynecologic cancers; however, the AMA eribulin is known to have additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho et al. Cancer Res 82:4457, 2022). Eribulin ADCs have been developed for targeted delivery to limit toxicity and maximize response. FZEC is an anti-folate receptor α (FRA)-eribulin ADC (Shimizu et al. Clin Cancer Res 27:3905, 2021) and MORAb-109 targets eribulin to mesothelin (MSLN; Albone et al. Annals Oncol 31:S491, 2020). Here we provide preclinical data to support clinical trials of FZEC and MORAb-109 in rare gynecologic cancers. Methods: Fresh tumor tissue from patients consented to the WEHI Stafford Fox Rare Cancer Program was used to establish a cohort of patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), OCS, USC and OCCA. PDX models were screened for FRA and MSLN expression by IHC and quantified by HALO software, and 15 models were selected for in vivo testing. Tumor-bearing mice were treated with eribulin (1 mg/kg TIW 3 wks), FZEC (12.5 mg/kg Q14Dx3) or MORAb-109 (25 mg/kg Q14Dx3) and compared to standard of care treatments. Results: About 80% of HGSOC PDX models were FRA positive with no difference between models from chemonaïve samples vs multiple lines of prior treatment. FRA expression was frequent in USC and OCCA models, with MSLN seen in a smaller subset. Despite most (80%) models being cisplatin refractory, 11/15 responded to eribulin with the 4 non-responders having high MDR1 expression and being from previously treated patients. Overall, responses to FZEC and MORAb-109 appeared to correlate with FRA and MSLN expression; importantly, some models with moderate to high target antigen expression showed deeper and more durable responses to FZEC and MORAb-109 compared to eribulin. Conclusions: Responses to FZEC and MORAb-109 correlated with FRA and MSLN expression, with equivalent or better activity compared to eribulin in target-positive PDX models of HGSOC, USC and OCCA. [Table: see text]

E030 Rheumatologists beware! Digital ischaemia as a presenting feature in metastatic ovarian cancer

Abstract Background/Aims Digital ischaemia is an umbrella term to describe the spectrum of acral vascular phenomena irrespective of aetiology, ranging from temporary (as in Raynaud’s phenomenon) to permanent (necrosis). It can be the presenting feature in multiple cancer types, and can be present with or without other features of connective tissue disease. Methods A 54-year-old woman was referred to Rheumatology with a four-day history of acute pain and ischaemic discolouration of all her fingertips bilaterally. There was no history of Raynaud’s phenomenon and no other clinical features of connective tissue disease. She had never smoked. There was a family history of breast cancer in her maternal aunt. She was admitted under vascular surgery for urgent review. All ten fingertips were ischaemic, with a capillary refill time of greater than five seconds. The history was otherwise significant for abdominal bloating, altered bowel habit and fatigue. Examination revealed normal peripheral pulses with no bruits, normal heart sounds and chest sounds. Her abdomen was soft with a mildly enlarged liver. Results FBC, U&amp;E, and LFTs showed no abnormalities. CRP, ESR, ANA, serum protein electrophoresis and complement levels were all normal. Blood tests for ANCA, rheumatoid factor and anti-CCP were also negative. Lupus anticoagulant, anti-cardiolipin and anti-B2-glycoprotein were all negative. The tumour marker CA125 was markedly elevated at 837kU/L (0.0-35.0kU/L). A CT abdomen &amp; pelvis showed a large right-sided adnexal mass with multiple enhancing peritoneal and omental nodules and moderate ascites. Biopsy of a metastatic deposit in the omentum revealed high grade serous ovarian adenocarcinoma. Partial improvement in digital ischaemia was achieved with iloprost and maintenance apixaban and sildenafil. Four cycles of carboplatin and paclitaxel chemotherapy produced near-complete resolution of digital ischaemia symptoms, corresponding to a fall in her CA125 level and reduction in the size of the ovarian mass and intra-abdominal metastases on CT. Ten cases of digital ischaemia associated with ovarian cancer have been described prior to this. The age of onset ranged from 45 to 71, with a median age of 56. Most patients had digital ischaemia without features of connective tissue disease. Four had no blood test abnormalities other than a raised tumour marker CA125. The time from onset of digital ischaemia to diagnosis of ovarian cancer ranged from less than one week to 2 years, with a median time of four months. Conclusion This case study supports previous findings that patients with digital ischaemia associated with ovarian cancer may have normal markers of inflammatory or rheumatological disease. Marked therapeutic responses can be achieved with systemic anti-cancer therapies. Therefore, underlying cancer should be suspected in patients with new-onset or worsening digital ischaemia over the age of 45. A high index of suspicion is required - rheumatologists beware! Disclosure J.H. Miller: None. P. Merry: None.

OPTIMISING THE TREATMENT OF PATIENTS WITH ADVANCED OVARIAN CANCER: AN ANALYSIS OF PRELIMINARY RESULTS

Summary. Aim: to evaluate surgical complications, side effects of chemotherapy, 1- and 3-year survival in patients with advanced ovarian cancer against the background of the introduction of optimized personalized treatment. Object and methods: for this purpose, a comparative analysis of the results of clinical examination and treatment of 74 patients with primary serous ovarian adenocarcinoma of stages III–IV (FIGO 2015) who were treated at the University Clinic of Odesa National Medical University was conducted. Patients were divided into 2 groups: Group IA — patients with primary ovarian cancer who were treated with primary cytoreductive surgery (PDS) + adjuvant chemotherapy (ACT) — 43 patients; IB group — patients with primary ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) + interval cytoreductive surgery (ICS) + adjuvant chemotherapy — 16 patients. Results: the absence of statistical difference in the median overall survival in groups IA (PDS + ACT) and IB (NACT + ICS + ACT) was shown to be explained by the complete volume of cytoreduction performed. There was a change in 3-year survival from 56.3 to 70.7% (χ2 = 0.951; p = 0.329) and an increase in 5-year survival from 12.5 to 60.9% (φ = 0.0012; p &lt; 0.05). In group IB, the percentage of postoperative complications in patients and the average length of hospital stay after cytoreductive surgery were lower than in group IA, but the difference was statistically insignificant. When comparing the frequency of side effects of paclitaxel/carboplatin chemotherapy treatment in groups IA and IB, the values of χ2 = 36.441; p = 0.0195 were obtained. Thus, it was proved that in the IB group, the toxic effects of chemotherapy of 3–4 degrees of severity were significantly more common. Conclusions: there was no statistical difference when comparing the median overall survival and progression-free survival in the study groups. It has also been shown that primary cytoreductive surgery with macroscopically visible residual masses, especially in suboptimal and suboptimal volume (CC 2-3), leads to a significant decrease in survival rates in patients with ovarian cancer.

Gene co-expression network analysis revealed novel biomarkers for ovarian cancer.

Ovarian cancer is the second most common gynecologic cancer and remains the leading cause of death of all gynecologic oncologic disease. Therefore, understanding the molecular mechanisms underlying the disease, and the identification of effective and predictive biomarkers are invaluable for the development of diagnostic and treatment strategies. In the present study, a differential co-expression network analysis was performed via meta-analysis of three transcriptome datasets of serous ovarian adenocarcinoma to identify novel candidate biomarker signatures, i.e. genes and miRNAs. We identified 439 common differentially expressed genes (DEGs), and reconstructed differential co-expression networks using common DEGs and considering two conditions, i.e. healthy ovarian surface epithelia samples and serous ovarian adenocarcinoma epithelia samples. The modular analyses of the constructed networks indicated a co-expressed gene module consisting of 17 genes. A total of 11 biomarker candidates were determined through receiver operating characteristic (ROC) curves of gene expression of module genes, and miRNAs targeting these genes were identified. As a result, six genes (CDT1, CNIH4, CRLS1, LIMCH1, POC1A, and SNX13), and two miRNAs (mir-147a, and mir-103a-3p) were suggested as novel candidate prognostic biomarkers for ovarian cancer. Further experimental and clinical validation of the proposed biomarkers could help future development of potential diagnostic and therapeutic innovations in ovarian cancer.

Abstract 4262: Immunotherapy of ovarian cancer targeting FSHR by innate and adaptive immunity

Abstract Ovarian cancer (OC) represents the deadliest gynecologic malignancy. Despite important advances in the field of OC therapy, recurrent OC still has very poor prognosis with a median survival of 1 year. Due to the close interaction between the ovarian cancer cells and tumor microenvironment, development of treatment strategies which not only target the tumor cells but also the components of the tumor microenvironment hold significance. Notably, a prime obstacle in the development of therapies is to identify targets with specific expression limited to the tumor surface and not the healthy tissues. The follicle-stimulating hormone receptor (FSHR) is one such target with selective expression in ovarian granulosa cells and thus, a potentially important therapeutic target in OC. Therefore, we developed monoclonal antibodies against FSHR and focused on studies of the most potent of these reagents. Anti-FSHR antibody bound to diverse FSHR expressing ovarian serous and clear cell adenocarcinoma cells suggesting these antibodies could be used to specifically target OC. We then designed a novel DNA encoded bispecific T cell engager targeting FSHR (FSHRxCD3) and evaluated this bispecific in therapeutic models for the treatment of OC. FSHRxCD3 bispecific in the presence of human PBMCs was highly specific in killing FSHR positive ovarian tumor lines. However, T cell approaches alone may not be fully effective in treating OC, referred as Immunologically “Cold” Tumors. Hence, we hypothesized that engaging the other components of immune system, would provide better tumor control. Increasing lines of evidence suggest that OC is receptive to Natural killer (NK) cell attack. We designed antibodies against human Siglec-7, an inhibitory receptor present on human NK cells and showed they could bind to NK cells. We then used these to create a novel class of bispecific NK engager (NKE) that simultaneously targets both Siglec-7 and FSHR (Siglec-7xFSHR). This NKE was potent at killing FSHR positive OC targets in both in vitro and in vivo assays. Multiple Ovarian tumors including BRCA mutated and PARPi resistant ovarian cancer cells could be targeted by this immune therapy. Our data demonstrate the therapeutic potential of these two novel bispecific molecules and initial studies suggest that their combination may be valuable in patients with OC. Citation Format: Devivasha Bordoloi, Pratik Bhojnagarwala, Abhijeet J. Kulkarni, Opeyemi S. Adeniji, Alfredo Perales-Puchalt, Ryan P. O’Connell, Xizhou Zhu, Elizabeth M. Parzych, Rugang Zhang, Mohamed Abdel-Mohsen, David B. Weiner. Immunotherapy of ovarian cancer targeting FSHR by innate and adaptive immunity [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 4262.