BACKGROUND: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result.
METHODS: GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record.
RESULTS: Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result.
CONCLUSIONS: Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

BACKGROUND: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear.
METHODS: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk.
RESULTS: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations.
CONCLUSIONS: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

UNASSIGNED: Ovarian cancer (OC) is the most lethal gynecological cancer in the United States. Among the different types of OC, serous ovarian cancer (SOC) stands out as the most prevalent. Transcriptomics techniques generate extensive gene expression data, yet only a few of these genes are relevant to clinical diagnosis.
UNASSIGNED: Methods for feature selection (FS) address the challenges of high dimensionality in extensive datasets. This study proposes a computational framework that applies FS techniques to identify genes highly associated with platinum-based chemotherapy response on SOC patients. Using SOC datasets from the Gene Expression Omnibus (GEO) database, LASSO and varSelRF FS methods were employed. Machine learning classification algorithms such as random forest (RF) and support vector machine (SVM) were also used to evaluate the performance of the models.
UNASSIGNED: The proposed framework has identified biomarkers panels with 9 and 10 genes that are highly correlated with platinum-paclitaxel and platinum-only response in SOC patients, respectively. The predictive models have been trained using the identified gene signatures and accuracy of above 90% was achieved.
UNASSIGNED: In this study, we propose that applying multiple feature selection methods not only effectively reduces the number of identified biomarkers, enhancing their biological relevance, but also corroborates the efficacy of drug response prediction models in cancer treatment.

Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132-/- mice to obtain mechanistic insights. In vivo experiments established an immune-competent tumour-bearing mouse model, and CD8 T cell, Treg, and macrophage infiltration post-Myc overexpression were evaluated via flow cytometry. Additionally, adoptive transfer of OTI CD8 T cells was conducted to investigate antigen-specific immune response variations after Myc overexpression. The findings revealed a noteworthy delay in HIF1a degradation, enhancing its functionality and promoting the classical Warburg effect upon Myc overexpression. Lactic acid secretion by Myc-overexpressing tumour cells promoted Gpr132-dependent M2 macrophage polarization, leading to the induction of macrophages capable of significantly suppressing CD8 T cell function. Remarkably, heightened macrophage infiltration in tumour microenvironments post-Myc overexpression was observed alongside impaired CD8 T cell infiltration and function. Interestingly, CD4 T-cell infiltration remained unaltered, and immune-suppressive effects were alleviated when Myc-overexpressing tumour cells were administered to Gpr132-/- mice, shedding light on potential therapeutic avenues for ovarian cancer management.

OBJECTIVE: To evaluate if exercise and sitting time during chemotherapy were associated with chemotherapy side-effects, completion of planned chemotherapy and survival.
METHODS: We used data from the Ovarian cancer Prognosis And Lifestyle (OPAL) Study, a national prospective cohort of adults with newly-diagnosed epithelial ovarian cancer. At 3-monthly questionnaires we asked about exercise and sitting time in the past week, and treatment-related side-effects. Details about treatment, toxicities, progression and death were abstracted from medical records. We used linear, logistic and Cox regression, respectively, to assess associations between both exercise and sitting time, and chemotherapy side-effects and completion (≥85% relative dose intensity) and survival.
RESULTS: 503 eligible participants were included in one or more analyses. Patients participating in higher-intensity exercise (≥30 min of moderate-vigorous exercise/week; 24%) reported significantly better Functional Assessment of Chronic Illness/Cancer Therapy (FACIT)-Fatigue (32.2 vs. 26.7) and FACT-Trial Outcome Index (69.4 vs. 61.7) scores, and were less likely to have clinician-reported moderate-severe neurotoxicity (odds ratio [OR]:0.50; 95% confidence interval [95%CI]:0.29-0.88), than minimal exercisers (<30 min moderate-vigorous exercise/week & <120 min walking/week; 52%). Participating in higher-intensity exercise was also possibly associated with greater chemotherapy completion (OR:1.70; 95%CI:0.90-3.20), particularly for paclitaxel. Sitting time was not associated with chemotherapy completion. For patients with advanced disease who underwent cytoreduction and received first-line carboplatin and paclitaxel, there was a suggestion higher-intensity exercise during chemotherapy may improve survival (HR:0.68; 95%CI:0.47-1.01).
CONCLUSIONS: Patients with ovarian cancer who carry out moderate-vigorous exercise during chemotherapy have fewer side-effects and potentially better completion of planned chemotherapy and overall survival.

Ovarian cancer represents a major public health concern worldwide. High-grade serous ovarian cancer (HGSOC) is a primary epithelial ovarian cancer. Cisplatin resistance poses a substantial obstacle in the management of HGSOC, leading to unfavourable patient outcomes. The primary objective of this study was to investigate the mechanisms underlying cisplatin resistance in patients with HGSOC. TCGA data, GSE65819 dataset, and multiMiR package were used to identify 35 differentially expressed miRNAs (DE-miRNAs). Differentially expressed mRNAs (DE-mRNAs) are indicated using TCGA data. Further, weighted gene co-expression network analysis (WGCNA) was used to determine the correlation coefficients between the DE-mRNAs and DE-miRNAs. A network of miR-486-3p and TMIGD2 was constructed. Molecular biology experiments also indicated that low miR-486-3p or high TMIGD2 expression significantly increased the migratory rate and cisplatin resistance of both SK-OV3 and A2780 cells. In contrast, overexpression of miR-486-3p or downregulation of TMIGD2 decreased the migration rate and enhanced the sensitivity to cisplatin treatment, which provides insights for the development of novel therapeutic approaches. Moreover, RNA-binding protein immunoprecipitation experiment was used to determine the relationship between miR-486-3p and TMIGD2. Cell rescue assays were performed to further investigate these regulatory relationships. In TCGA and GSE65819 datasets, Benjamini and Hochberg false discovery rates (FDR) were selected for P-values. In the molecular biology experiments, one-way analysis of variance was employed to compare different groups, supplemented by Bonferroni post-hoc testing. Statistical significance was set at p < 0.05.

Ovarian cancer (OC) is the deadliest malignancy of the female reproductive system. The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Despite these treatments, there remains a high rate of tumor recurrence and resistance to platinum. Recent studies have highlighted the potential anti-tumor properties of metformin (met), a traditional diabetes drug. In our study, we investigated the impact of met on the anticancer activities of cisplatin (cDDP) both in vitro and in vivo. Our findings revealed that combining met with cisplatin significantly reduced apoptosis in OC cells, decreased DNA damage, and induced resistance to cDDP. Furthermore, our mechanistic study indicated that the resistance induced by met is primarily driven by the inhibition of the ATM/CHK2 pathway and the upregulation of the Rad51 protein. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP.

UNASSIGNED: Ovarian cancer (OC) is a major gynecological malignancy with varying prognosis. The Neutrophil-toLymphocyte Ratio (NLR) has been proposed as a potential prognostic biomarker. This study aimed to evaluate the prognostic and clinical value of NLR in OC.
UNASSIGNED: A systematic review and meta-analysis were performed following PRISMA guidelines, including studies that evaluated the association between NLR and survival outcomes in OC patients. Search was performed in PubMed, Embase, Web of Science, and Cochrane Library databases. Quality assessment was done using Newcastle-Ottawa Scale (NOS). Heterogeneity was assessed, and pooled hazard ratios (HRs) were calculated using fixed or random-effects models as appropriate.
UNASSIGNED: Sistematski pregled i meta-analiza su obavljeni u skladu sa smernicama PRISMA, uključujući studije koje su procenile povezanost između NLR i ishoda preživljavanja kod pacijenata sa OC. Pretraga je obavljena u bazama podataka PubMed, Embase, Web of Science i Cochrane Library. Procena kvaliteta je urađena korišćenjem Njukasl-Otava skale (NOS). Heterogenost je procenjena, a udruženi odnosi opasnosti (HRs) su izračunati korišćenjem modela fiksnih ili slučajnih efekata prema potrebi.
UNASSIGNED: Analizirano je dvadeset studija koje su uključivale različite etničke pripadnosti, uzraste i veličinu uzorka. Utvrđeno je da je visok NLR u obrnutoj korelaciji sa ukupnim preživljavanjem (OS) (HR=1,21, 95% CI 1,09-1,34, P<0,001) i preživljavanjem bez progresije (PFS) (HR=1,20, 95% CI 1,03-1,38, P<0,001). Stratifikovane analize su pokazale jaču povezanost kod azijskih pacijenata, studije sa manjim veličinama uzoraka, mlađim pacijentima i višim graničnim vrednostima NLR.
UNASSIGNED: Meta-analiza sugeriše značajnu inverznu povezanost između NLR i ishoda preživljavanja kod pacijenata sa OC, naglašavajući potencijal NLR-a kao jednostavnog, isplativog prognostičkog biomarkera. Međutim, značajna heterogenost i uticaj zbunjujućih faktora naglašavaju potrebu za daljim istraživanjem.

Amphiregulin (AREG) stimulates human epithelial ovarian cancer (EOC) cell invasion by downregulating E-cadherin expression. YAP is a transcriptional cofactor that has been shown to regulate tumorigenesis. This study aimed to examine whether AREG activates YAP in EOC cells and explore the roles of YAP in AREG-induced downregulation of E-cadherin and cell invasion. Analysis of the Cancer Genome Atlas (TCGA) showed that upregulation of AREG and EGFR were associated with poor survival in human EOC. Treatment of SKOV3 human EOC cells with AREG induced the activation of YAP. In addition, AREG downregulated E-cadherin, upregulated Egr-1 and Slug, and stimulated cell invasion. Using gain- and loss-of-function approaches, we showed that YAP was required for the AREG-upregulated Egr-1 and Slug expression. Furthermore, YAP was also involved in AREG-induced downregulation of E-cadherin and cell invasion. This study provides evidence that AREG stimulates human EOC cell invasion by downregulating E-cadherin expression through the YAP/Egr-1/Slug signaling.

BACKGROUND: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis.
METHODS: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma.
RESULTS: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy.
CONCLUSIONS: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.