Dataset Information

First-Line Management of Advanced High-Grade Serous Ovarian Cancer.

ABSTRACT: Purpose of review: Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.

Recent findings: Recent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.

SUBMITTER: Mahmood RD

PROVIDER: S-EPMC7270049 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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First-Line Management of Advanced High-Grade Serous Ovarian Cancer.

Mahmood Reem D RD Morgan Robert D RD Edmondson Richard J RJ Clamp Andrew R AR Jayson Gordon C GC

Current oncology reports 20200604 6

<h4>Purpose of review</h4>Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vas ...[more]

PMID: 32494876

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Project description:High-grade serous ovarian carcinoma (HGSOC) is the most frequent histological type of ovarian cancer and the one with worst prognosis. Unfortunately, the majority of established ovarian cancer cell lines which are used in the research have unclear histological origin and probably do not represent HGSOC. Thus, new and reliable models of HGSOC are needed. Ascitic fluid from a patient with recurrent HGSOC was used to establish a stable cancer cell line. Cells were characterized by cytogenetic karyotyping and short tandem repeat (STR) profiling. New generation sequencing was applied to test for hot-spot mutations in 50 cancer-associated genes and fluorescence in situ hybridization (FISH) analysis was used to check for TP53 status. Cells were analyzed for expression of several marker genes/proteins by reverse-transcription polymerase chain reaction (RT-PCR), fluorescence-activated cell sorting (FACS), and immunocytochemistry (ICC). Functional tests were performed to compare OVPA8 cells with five commercially available and frequently used ovarian cancer cell lines: SKOV3, A2780, OVCAR3, ES2, and OAW42. Our newly-established OVPA8 cell line shows morphologic and genetic features consistent with HGSOC, such as epithelial morphology, multiple chromosomal aberrations, TP53 mutation, BRCA1 mutation, and loss of one copy of BRCA2. The OVPA8 line has a stable STR profile. Cells are positive for EpCAM, CK19, and CD44; they have relatively low plating efficiency/ability to form spheroids, a low migration rate, and intermediate invasiveness in matrigel, as compared to other ovarian cancer lines. OVPA8 is sensitive to paclitaxel and resistant to cisplatin. We also tested two FGFR inhibitors; OVPA8 cells were resistant to AZD4547 (AstraZeneca, London, UK), but sensitive to the new inhibitor CPL304-110-01 (Celon Pharma, ?omianki/Kie?pin, Poland). We have established and characterized a novel cell line, OVPA8, which can be a valuable preclinical model for studies on high-grade serous ovarian cancer.

Project description:BackgroundPrimary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients.MethodsIn this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan-Meier.ResultsIn advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60-97.00%, 46.40-89.30% and 0.774-0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression.ConclusionsAs a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy.

Project description:BackgroundHigh-grade serous ovarian cancer (HGSOC) has poor survival rates due to a combination of diagnosis at advanced stage and disease recurrence as a result of chemotherapy resistance. In BRCA1 (Breast Cancer gene 1) - or BRCA2-wild type (BRCAwt) HGSOC patients, resistance and progressive disease occur earlier and more often than in mutated BRCA. Identification of biomarkers helpful in predicting response to first-line chemotherapy is a challenge to improve BRCAwt HGSOC management.MethodsTo identify a gene signature that can predict response to first-line chemotherapy, pre-treatment tumor biopsies from a restricted cohort of BRCAwt HGSOC patients were profiled by RNA sequencing (RNA-Seq) technology. Patients were sub-grouped according to platinum-free interval (PFI), into sensitive (PFI > 12 months) and resistant (PFI < 6 months). The gene panel identified by RNA-seq analysis was then tested by high-throughput quantitative real-time PCR (HT RT-qPCR) in a validation cohort, and statistical/bioinformatic methods were used to identify eligible markers and to explore the relevant pathway/gene network enrichments of the identified gene set. Finally, a panel of primary HGSOC cell lines was exploited to uncover cell-autonomous mechanisms of resistance.ResultsRNA-seq identified a 42-gene panel discriminating sensitive and resistant BRCAwt HGSOC patients and pathway analysis pointed to the immune system as a possible driver of chemotherapy response. From the extended cohort analysis of the 42 DEGs (differentially expressed genes), a statistical approach combined with the random forest classifier model generated a ten-gene signature predictive of response to first-line chemotherapy. The ten-gene signature included: CKB (Creatine kinase B), CTNNBL1 (Catenin, beta like 1), GNG11 (G protein subunit gamma 11), IGFBP7 (Insulin-like growth factor-binding protein 7), PLCG2 (Phospholipase C, gamma 2), RNF24 (Ring finger protein 24), SLC15A3 (Solute carrier family 15 member 3), TSPAN31 (Tetraspanin 31), TTI1 (TELO2 interacting protein 1) and UQCC1 (Ubiquinol-cytochrome c reductase complex assembly factor). Cytotoxicity assays, combined with gene-expression analysis in primary HGSOC cell lines, allowed to define CTNNBL1, RNF24, and TTI1 as cell-autonomous contributors to tumor resistance.ConclusionsUsing machine-learning techniques we have identified a gene signature that could predict response to first-line chemotherapy in BRCAwt HGSOC patients, providing a useful tool towards personalized treatment modalities.

Dataset Information

First-Line Management of Advanced High-Grade Serous Ovarian Cancer.

Publications

First-Line Management of Advanced High-Grade Serous Ovarian Cancer.

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