Search Results (89)

Background/Objectives: Tubo-ovarian high-grade serous carcinoma (HGSC) is a highly lethal malignancy, usually diagnosed at an advanced stage due to the lack of early symptoms and biomarkers. Contraceptive hormone use is associated with a reduced risk of HGSC, but the relative contributions of natural versus synthetic progestins, and their interaction with estrogens, are poorly understood. Methods: We evaluated the chemo-preventive efficacy of a synthetic progestin medroxyprogesterone acetate (MPA), progesterone (P4), and combined 17β-estradiol-progesterone (E2 + P4) in a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on the conditional inactivation of one or both alleles of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes (BPRN-het and BPRN-homo mice, respectively). Mice received hormones or placebo via slow-release pellets implanted subcutaneously. After induction of tumor formation, the mice were monitored for tumor development, progression, and survival. Tumor incidence was assessed histologically, and hormone effects were further explored via RNA-seq analysis of oviductal tissues. Results: MPA significantly reduced HGSC incidence and delayed tumor progression compared to the placebo, P4, and P4 + E2 in both BPRN-homo and BPRN-het mice, with up to 78% tumor-free survival in the MPA-treated BPRN-het cohort. P4 monotherapy did not provide significant protection vs. the placebo, but the effects of P4 could have been impacted by a failure to achieve sustained release of the hormone beyond 4–8 weeks. The E2 + P4 combination accelerated tumorigenesis and reduced survival (p < 0.0001 in BPRN-homo and p = 0.0004 in BPRN-het mice). MPA did not affect tumorigenesis in a colon cancer GEMM, or the growth of mouse HGSC-derived cells in vivo, suggesting the role of MPA in the early stages of HGSC development. Gene expression analyses showed that P4 and MPA downregulated cholesterol homeostasis, early and late estrogen response, and epithelial–mesenchymal transition pathways, though only MPA afforded tumor protection. Conclusions: These findings demonstrate that a synthetic progestin, specifically MPA, confers robust protection against HGSC development, while a combination including E2 (E2 + P4) increases risk. This work also illustrates how HGSC GEMMs can be used to compare the chemo-preventive effects of various synthetic progestins on HGSC development in order to prioritize the most effective ones for use in preventing HGSC in both general and high-risk populations. Full article

Background: High-grade serous ovarian cancer (HGSC) is the most common and aggressive subtype of ovarian cancer. Despite initial response to platinum-based chemotherapy, most patients relapse. Cytoreductive surgery at relapse has been shown to improve survival in selected patients, but the biological mechanisms underlying recurrence and resistance remain unclear. This study aimed to investigate whether the mutational profile of HGSC changes from diagnosis to relapse, and to evaluate treatment patterns and survival outcomes in a cohort undergoing cytoreductive surgery. Methods: Sixteen patients with HGSC who underwent cytoreductive surgery at both diagnosis and relapse were included. Matched tumor tissue samples (n = 32) were collected and sequenced using a 501-gene cancer panel. Only pathogenic or likely pathogenic variants were registered. Clinical data, treatment history, and survival outcomes were obtained from medical records, with a median follow-up of 63 months. Results: All patients harbored pathogenic or likely pathogenic mutations, most frequently in TP53 (88%) and BRCA1/2 (38%). The mutational landscape was largely stable, with 15 of 16 patients (94%) showing no mutational changes between diagnosis and relapse. One patient acquired a NOTCH2 mutation at relapse. Complete resection was achieved in 88% of relapse surgeries. Median time to first relapse was 32 months, and overall survival was prolonged, with 87.5% of patients alive at last follow-up. BRCA mutated patients showed longer time to relapse, and overall follow-up compared to BRCA wild-type cases. Conclusions: The somatic mutational profile of HGSC remains remarkably stable from diagnosis to relapse. Clinically, this stability suggests that repeat mutational sequencing at relapse is unlikely to yield new actionable findings and may have limited value in guiding treatment decisions. Instead, resistance mechanisms likely arise from epigenetic or non-genetic changes, underscoring the need for future research in these areas and the continued importance of optimal surgical management in selected patients. Full article

Background/Objectives: Type II ovarian cancer, including high-grade serous carcinoma (HGSC), is genetically unstable and exhibits frequent mutations in the tumor suppressor genes. Mutations of TP53 and BRCA1 genes have been associated with HGSC, which has been suggested as a subtype that arises from the fallopian tube lesion called serous tubal intraepithelial carcinoma (STIC). Although TP53 and BRCA1 genes are well-known tumor suppressor genes, the actual effects of TP53 and BRCA1 mutations in enhancing the development of ovarian cancer initiated from STIC are poorly understood. Methods: In this study, we knocked out Trp53 and Brca-1 in epithelial cell clones derived from mice fallopian tube tissues (known as oviducts) and investigated the potential involvement of these two mutations in inducing cancer stem-like cells as cancer-initiating cells. Results: We have shown that the knockout of Trp53 induced oviduct cells to undergo EMT and acquire stem cell characteristics. Conclusions: Trp53 mutation may induce the early stage of precursor lesions formation at the distal end of the oviducts. Full article

Background: The prognosis for recurrent ovarian cancer is poor, but a small percentage of patients can be cured. The aim of this study was to clarify the criteria for being cured and the characteristics of cured cases. Methods: Ovarian cancer cases at 2 university hospitals and 8 community hospitals were analyzed to identify patients who were considered cured after complete remission (CR) following recurrence. Analyses of the tumors were performed and included BRCA1/2 mutation analysis. Results: Of the 157 cases of recurrence, 21 (13%) showed no evidence of disease (NED). NED cases had a lower rate of ascites at the initial diagnosis, longer disease-free survival, a higher rate of solitary lesions, and a higher rate of secondary debulking surgery. All CR cases except for one showed no further recurrence when DFS reached 4 years, which was considered a criterion for being cured. The case of relapse occurred after long-term treatment with bevacizumab. Furthermore, 19.4% of the CR cases achieved 4-year DFS, which represents 9.3% of the cases of recurrent ovarian cancer and 2.3% of all cases of ovarian cancer. BRCA mutation analysis of the tumor was possible in 17 of the 30 cases of recurrent ovarian cancer that achieved a 4-year DFS. Pathogenic variants of BRCA were found in 5 of the 11 cases of high-grade serous carcinoma. Conclusions: Approximately 10% of patients with recurrent ovarian cancer achieved a 4-year DFS and were mostly cured. The curing of cases not involving high-grade serous carcinoma (HGSC) was unrelated to the presence of pathogenic BRCA variants. Full article

Background/Objectives: High-grade serous carcinoma (HGSC) is the leading cause of ovarian cancer-related mortality. It usually arises from fallopian tube epithelium, with a smaller subset arising in non-tubal sites including the ovary or peritoneum. The origin of HGSCs without evidence of tubal involvement remains unclear. Moreover, in women with genetic predisposition to developing HGSC, the additional protection afforded by prophylactic removal of the ovaries in addition to the fallopian tubes has not yet been established. Methods: We used a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on conditional, somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes (BPRN mice) to compare preventive effects for HGSC via bilateral salpingectomy versus bilateral salpingo-oophorectomy. We also explored the origins of non-tubal HGSCs in ectopic tubal-type epithelium (endosalpingiosis) present in the mouse ovaries and peritoneum. Results: While bilateral salpingectomy significantly reduced the incidence of HGSCs in the GEMM model, bilateral salpingo-oophorectomy completely prevented tumor development. We identified an example of HGSC with apparent origin in endosalpingiosis, implicating endosalpingiosis as a likely precursor for non-tubal HGSC. Conclusions: Our findings confirm the superiority of bilateral salpingo-oophorectomy over salpingectomy alone in reducing HGSC risk and affirm the rationale for surgical strategies to reduce HGSC risk in women carrying pathogenic variants of BRCA1/2 and other genes associated with homologous recombination deficiency. Our findings also illustrate how work with GEMMs can advance new insights into HGSC pathogenesis. Full article

High-grade serous ovarian cancer (HGSC) is a heterogeneous disease. RNA sequencing (RNAseq) of bulk solid tissue is of limited use in these populations due to heterogeneity. Single-cell RNA-seq (scRNA-seq) allows for the identification of diverse genetic compositions of heterogeneous cell populations. New computational methodologies are now available that use scRNAseq results to estimate cell type proportions in bulk RNAseq data. We performed bulk RNA-seq gene expression analysis on 112 HGSC specimens and 12 benign fallopian tube (FT) controls. We identified several publicly available scRNAseq datasets for use as annotation and reference datasets. Deconvolution was performed with MUlti-Subject SIngle Cell Deconvolution (MuSiC) to estimate cell type proportions in the bulk RNA-seq data. Datasets from the Cancer Genome Atlas (TCGA). HGSC repositories were also evaluated. Clinical variables and percentages of cell types were compared for differences in clinical outcomes and treatment results. Pathway enrichment analysis was also performed. Different annotations for referenced scRNA-seq datasets used for deconvolution of bulk RNA-seq data revealed different cellular proportions that were significantly associated with clinical outcomes; for example, higher proportions of macrophages were associated with a better response to primary chemotherapy. Our deconvolution study of bulk RNAseq HGSC samples identified cell populations within the tumor that may be associated with some of the observed clinical outcomes. Full article

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) and inflammation status are emerging prognostic markers in various cancers, but their significance in high-grade serous ovarian carcinoma (HGSC) remains unclear. Our objective was to evaluate different TIL subtypes and inflammation status in relation to progression-free survival (PFS) in primary HGSC. Methods: CD3⁺/CD4⁺/CD8⁺/PD-1+ stromal TILs (sTILs) and intraepithelial TILs (iTILs) were evaluated by manual assessment and digital image analysis (DIA), following TIL Working Group recommendations. Inflammation status was evaluated through the following scores: systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), CA125, and lactate dehydrogenase (LDH). Results: CD8⁺ TILs were the most prevalent subtype in both iTILs and sTILs. However, sTILs were significantly more abundant than iTILs (p < 0.001) among all subsets, except for PD-1+ cells. DIA results of TIL assessments were in agreement with manual assessments. High stromal CD3⁺ and CD8⁺ TILs, PIV, CA125, and LDH, were associated with improved PFS. Potential independent prognostic factors for PFS in manual assessment were PIV (HR = 0.32, CI 95% = 0.12–0.82) and CD8⁺ sTILs (HR = 0.30, CI 95% = 0.12–0.79), whereas in DIA assessment they were CD3⁺ sTILs (HR = 0.31, CI 95% = 0.15–0.67), PIV (HR = 0.35, 95% CI 0.13–0.96), and residual disease (HR = 0.21 95% CI 0.08–0.53). Conclusions: CD3⁺/CD8⁺ sTILs and PIV are promising prognostic indicators in HGSC; however, further research is needed to confirm their clinical utility. Full article

Ovarian cancer is a lethal malignancy, with most patients initially responding to chemotherapy but frequently experiencing recurrence. Previous studies primarily examined tumor characteristics using limited genetic markers or bulk RNA sequencing. Here, we used spatial transcriptomics via the GeoMx^® platform, alongside multispectral immune cell immunofluorescence (IF), to identify biomarkers associated with disease progression following first-line treatment of high-grade serous carcinoma (HGSC). We identified several spatial biomarkers linked to non-recurrence, including elevated NKG7 expression in CD45+ immune cell regions (p = 0.0011) and higher TFPI2 and PIGR expression in tumor areas (p = 2.09 × 10⁻⁶), both associated with improved progression-free survival. Multispectral IF revealed significantly higher regulatory T cell (Treg) to CD8+ T cell ratios in the tumor nests and stroma of recurrent patients (p = 0.016, 0.048). Tregs were also found closer to cancer cells or macrophages than CD8+ T cells in recurrent tumors (p = 0.048), correlating with poor survival. Integrated analysis showed that immune cell density and immune pathway scores in the recurrent group positively correlated with cancer pathway scores, except for NF-κB. This comprehensive analysis revealed clues to interactions between different immune cells and identified biomarkers that may be useful for predicting recurrence of HGSC. Full article

Cancer stem cells (CSCs) significantly contribute to heterogeneity, malignancy, and therapy resistance in ovarian cancer. Recent studies emphasize the role of the vitamin D receptor (VDR) in regulating cell differentiation and stemness in various types of cancer. This study aims to determine the expression levels of CD44, CD133, and VDR in epithelial ovarian tumors (EOTs) and to compare these levels across different tumor types, including benign, atypical proliferative tumors, and five types of malignant phenotypes, in order to evaluate their potential as diagnostic tools for malignancy. Tissue samples from 218 patients diagnosed with EOT were analyzed. Clinical and histopathologic parameters were recorded. Quantitative immunohistochemical tissue microarray analysis was used to assess the expression levels of CD44, CD133, and VDR using two different scoring systems. Comparisons were made between benign tumors (n = 45), atypical proliferative tumors (n = 42), and ovarian carcinomas (n = 131), including high-grade serous (HGSC) and non-HGSC subtypes. Ovarian cancer, especially HGSC, showed a significantly higher expression of CD44 and VDR (p < 0.05) compared to atypical proliferative tumors and benign tumors. The expression of CD133 was highest in atypical proliferative tumors (p < 0.05). A moderate positive correlation was found between CD44, CD133, and VDR in all groups, with significant correlations with tumor grade and FIGO stage in ovarian cancer (p < 0.05). The increased expression of CD44 and VDR in aggressive ovarian cancer, along with elevated CD133 levels in atypical proliferative tumors, highlights the complexity of tumor biology. These markers may serve as valuable targets for the diagnosis of ovarian cancer. Full article

Background: Endocrine therapy is the standard-of-care maintenance treatment for estrogen receptor (ER)-positive breast cancers and is increasingly used in low-grade serous ovarian cancer. However, its therapeutic role in the early maintenance setting for ER-positive high-grade serous ovarian cancer (HGSC) remains undefined. Methods: A retrospective analysis was conducted on clinicopathological data from patients with newly diagnosed ER-positive HGSC following completion of adjuvant chemotherapy. Patients received maintenance therapy either with or without the aromatase inhibitor letrozole, in addition to standard maintenance care. ER expression levels and the administration of letrozole were analyzed, along with outcome measures for the entire cohort, with stratification based on residual disease status. Results: A total of 102 patients with newly diagnosed HGSC were included in the analysis, with 64 (62.7%) receiving letrozole and 38 (37.3%) not receiving letrozole. The median ER expression was 70%, with higher expression observed in the letrozole group compared to the no letrozole group (77.5% vs. 60%). No significant correlation was found between ER expression status and therapy response (p = 0.295 and p = 0.176, respectively). Letrozole therapy was well tolerated with no major adverse effects reported. In the overall cohort, maintenance letrozole therapy did not confer a significant improvement in progression-free survival (median 20.56 months vs. 29.34 months, p = 0.53) or overall survival (OS) (median 79.48 months vs. 46.85 months, p = 0.71) over a median follow-up duration of 23.5 months. However, among patients with no residual disease, maintenance letrozole therapy was associated with a statistically significant improvement in OS compared to those not receiving letrozole (median 114 months vs. 46.9 months, p = 0.006). Conclusions: Maintenance letrozole therapy appears to be a well-tolerated and potentially beneficial intervention in a subset of patients with ER-positive HGSC with no residual disease post-treatment. These findings highlight the need for further validation through prospective randomized trials to comprehensively assess the efficacy of endocrine therapy in this setting and its implications for patient quality of life. Full article

Patient-derived xenograft (PDX) models are powerful tools in cancer research, offering an accurate platform for evaluating cancer treatment efficacy and predicting responsiveness. However, these models necessitate surgical techniques for tumor tissue transplantation and face challenges with non-uniform tumor growth among animals. To address these issues, we attempted to develop a new PDX modeling method using high-grade serous ovarian cancer (HGSC), a fatal disease with a 5-year survival rate of 29%, which requires personalized research due to its morphological, genetic, and molecular heterogeneities. In this study, we developed a new patient-derived cancer cell xenograft (PDCX) model with high engraftment efficiency (64%) that utilizes primary cancer cells instead of patient tissues. Primary cancer cells can be stably cryopreserved for extended periods (up to 485 days), and when transplanted into female NSGA mice, they maintain morphological and molecular characteristics without significant genetic differences compared to their original primary tumors. Furthermore, PDCX models can be easily produced using a syringe, allowing for uniform tumor sizes across multiple animals. Additionally, M2 PDCXs exhibited a significantly faster growth rate compared to M2 PDTXs. Consequently, our PDCX model offers a streamlined approach for evaluating personalized cancer treatments with minimal experimental variability. Full article

In 2025, gynecological cancers are projected to account for approximately 10% of cancer-related deaths in women. High-grade serous ovarian carcinoma (HGSC) and serous endometrial carcinoma (SEC) are the most lethal gynecological cancer subtypes. Both malignancies commonly have TP53 mutations, alterations of the RB1 pathway, and numerous secondary mutations. Both carcinoma types consist of poorly differentiated and highly heterogeneous cell populations at the time of detection. Latent development and rapid progression of HGSC and SEC impede the identification of definitive cells of origin and genetic drivers. Here, we review our current knowledge about cancer-prone cell states and genetic drivers. We also discuss how emerging transcriptomic and genetic tools applied to contemporary model systems may facilitate the identification of novel targets for timely detection and therapeutic intervention. Full article

Women diagnosed with advanced-stage ovarian cancer have a much worse survival rate than women diagnosed with early-stage ovarian cancer, but the early detection of this disease remains a clinical challenge. Some recent reports indicate that genetic variations could be useful for the early detection of several malignancies. In this pilot observational retrospective study, we aimed to assess whether mitochondrial DNA (mtDNA) variations could discriminate the most frequent type of ovarian cancer, high-grade serous carcinoma (HGSC), from normal tissue. We identified mtDNA variations from 20 whole-exome sequenced (WES) HGSC samples and 14 controls (normal tubes) using the best practices of genome sequencing. We built prediction models of cancer with these variants, with good performance measured by the area under the curve (AUC) of 0.88 (CI: 0.74–1.00). The variants included in the best model were correlated with gene expression to assess the potentially affected processes. These analyses were validated with the Cancer Genome Atlas (TCGA) dataset, (including over 420 samples), with a fair performance in AUC terms (0.63–0.71). In summary, we identified a set of mtDNA variations that can discriminate HGSC with good performance. Specifically, variations in the MT-CYB gene increased the risk for HGSC by over 30%, and MT-CYB expression was significantly decreased in HGSC patients. Robust models of ovarian cancer detection with mtDNA variations could be applied to liquid biopsy technology, like those which have been applied to other cancers, with a special focus on the early detection of this lethal disease. Full article

Background/Objectives: All 11 metallothionein protein-coding genes are located on human chromosome 16q13. It is unique among human genetics to have an entire pathway’s genes clustered in a short chromosomal region. Since solid tumors, particularly high-grade serous ovarian cancer (HGSC), exhibit high rates of monoallelic aneuploidy, this region is commonly lost. Studies have not yet been performed to determine what vulnerability may be created in cancer cells with low metallothionein expression. Here, a screen of FDA-approved cancer small molecule drugs for those best targeting low metallothionein ovarian cancer was completed. Methods: Screening methods were tested and compared using vehicle-treated negative controls and cadmium chloride, a positive control for cell loss selective for low metallothionein cells. CAOV3 cells, which are unique in their expression of only two metallothionein isoforms, were used, with or without shRNA knockdown of the predominantly expressed MT2A gene. A library of FDA-approved molecules was then screened. Results: The optimal assay utilized Hoechst 33342 nuclear staining and mechanized fluorescent microscope counting of cell content. Encorafenib, an RAF inhibitor, was identified as the most selective for enhanced cytotoxicity in MT2A knockdown cells compared to scrambled controls. Conclusions: The nuclear stain Hoechst 33342, assessed by fluorescence microscopy, provides a low variance, moderate throughput platform for cancer cell loss screens. Low metallothionein ovarian cancer cells exhibit a vulnerability to the RAF inhibitor encorafenib. Full article

Background: Serous tubal intraepithelial carcinoma (STIC) is an early-stage cancerous lesion found in the fallopian tubes, often at the fimbrial end. It is strongly associated with high-grade serous carcinoma (HGSC), a highly aggressive type of ovarian cancer. STIC is considered a precursor to many HGSC cases, originating in the fallopian tubes. Its development is frequently linked to mutations in the TP53 gene, leading to the formation of a p53 signature, an early abnormality that may progress to HGSC. This signature is more common in BRCA mutation carriers, explaining the higher incidence of STIC in this group. The aim of this review is to evaluate the literature on the incidence of serous tubal intraepithelial carcinoma in patients (both BRCA-positive and BRCA-negative) undergoing preventive salpingo-oophorectomy, analysing the available data and identifying associations between specific characteristics and the onset of STIC. Methods: A comprehensive review of the literature from 2016 to 2023 was conducted using PubMed, focusing on studies analysing the incidence of STIC in BRCA-positive patients undergoing preventive salpingo-oophorectomy. Data on patient characteristics, interventions, outcomes, and incidence of STIC were extracted and analysed. Results: Nine international studies were included in the review, reporting varying incidences of STIC among patients undergoing salpingo-oophorectomy. The overall incidence of STIC in all the women included in the studies was 7.31%, while that in the BRCA-mutated women was approximately 6.08%. Notably, the presence of the TP53 signature was significantly associated with the occurrence of STIC. Conclusions: The etiopathogenesis of STIC involves complex interactions between genetic, environmental, and molecular factors. Further research is needed to fully understand its mechanisms and identify additional risk factors beyond BRCA mutations. Establishing a national database of STIC cases could facilitate future research and improve patient outcomes. Full article