Investigator
Erasmus Mc
Epigenetic and Genomic Hallmarks of PARP-Inhibitor Resistance in Ovarian Cancer Patients
Background: Patients with advanced-stage epithelial ovarian cancer (EOC) receive treatment with a poly-ADP ribose-polymerase (PARP) inhibitor (PARPi) as maintenance therapy after surgery and chemotherapy. Unfortunately, many patients experience disease progression because of acquired therapy resistance. This study aims to characterize epigenetic and genomic changes in cell-free DNA (cfDNA) associated with PARPi resistance. Materials and Methods: Blood was taken from 31 EOC patients receiving PARPi therapy before treatment and at disease progression during/after treatment. Resistance was defined as disease progression within 6 months after starting PARPi and was seen in fifteen patients, while sixteen patients responded for 6 to 42 months. Blood cfDNA was evaluated via Modified Fast Aneuploidy Screening Test-Sequencing System (mFast-SeqS to detect aneuploidy, via Methylated DNA Sequencing (MeD-seq) to find differentially methylated regions (DMRs), and via shallow whole-genome and -exome sequencing (shWGS, exome-seq) to define tumor fractions and mutational signatures. Results: Aneuploid cfDNA was undetectable pre-treatment but observed in six patients post-treatment, in five resistant and one responding patient. Post-treatment ichorCNA analyses demonstrated in shWGS and exome-seq higher median tumor fractions in resistant (7% and 9%) than in sensitive patients (7% and 5%). SigMiner analyses detected predominantly mutational signatures linked to mismatch repair and chemotherapy. DeSeq2 analyses of MeD-seq data revealed three methylation signatures and more tumor-specific DMRs in resistant than in responding patients in both pre- and post-treatment samples (274 vs. 30 DMRs, 190 vs. 57 DMRs, Χ2-test p < 0.001). Conclusion: Our genome-wide Next-Generation Sequencing (NGS) analyses in PARPi-resistant patients identified epigenetic differences in blood before treatment, whereas genomic alterations were more frequently observed after progression. The epigenetic differences at baseline are especially interesting for further exploration as putative predictive biomarkers for PARPi resistance.
Genome-wide cell-free DNA methylation profiling in advanced stage ovarian cancer. Are we looking at the tumor or the patient's immune response to the tumor?
The aim of this study was to identify differentially methylated regions in cell-free DNA (cfDNA) between healthy persons and patients with advanced stage ovarian cancer (ASOC) and to identify differences in cfDNA methylation before and after cytoreductive surgery. Plasma-derived cfDNA was analyzed by a high-throughput genome wide DNA methylation sequencing technique: MeD-seq. A training set of therapy naïve cfDNA samples of patients with ASOC (≥FIGO stage IIIB, n=10) was compared with cfDNA of healthy controls (n=10) to define a ASOC specific cfDNA methylation signature. A cumulative hypermethylation score was constructed and a validation set of pre- and postoperative samples of 39 patients were compared using this score. MeD-seq results of tumor tissue samples were correlated with cfDNA results. Patients with ASOC showed a clear distinct cfDNA methylation signature from healthy controls (p<0.0001). This cfDNA-methylation signature resulted in preoperative hypermethylation scores (135; interquartile range 110-163) that were significantly higher than postoperative hypermethylation scores (91; interquartile range 76-101) (p<0.001). The cfDNA methylation signature at baseline differed from tumor tissue and was more closely related to DNA methylation of immune-related cells (T-lymphocytes, neutrophil granulocytes, monocytes, and B-lymphocytes) than to ASOC tissue. MeD-seq provides a promising method for genome wide methylation profiling of cfDNA. Patients with ASOC could clearly be distinguished from healthy controls and differed pre- and postoperatively.
Cost Study of the PlasmaJet Surgical Device Versus Conventional Cytoreductive Surgery in Patients With Advanced-Stage Ovarian Cancer
PURPOSEAdjuvant use of Neutral Argon Plasma (PlasmaJet Surgical Device) during cytoreductive surgery (CRS) for advanced-stage epithelial ovarian cancer improves surgical outcomes. The aim of this study is to examine the costs of adjuvant use of the PlasmaJet during surgery compared with conventional CRS in advanced-stage epithelial ovarian cancer.MATERIALS AND METHODSThe patients were randomly assigned to surgery with or without the PlasmaJet. Analysis of the intra- and extramural health care costs was performed. Costs were divided into three categories: costs of the diagnostic phase (T1), inpatient care up to discharge including costs of surgery (T2), and outpatient care including chemotherapy until 6 weeks after the last cycle of chemotherapy (T3).RESULTSOverall, 327 patients underwent CRS (surgery with PlasmaJet: n = 157; conventional surgery: n = 170). The mean total health costs were significantly higher for CRS with adjuvant use of PlasmaJet compared with conventional CRS (€19,414 v €18,165, P = .017). Costs are divided into costs of the diagnostic phase (€2,034 v €1,974, P = .890), costs of inpatient care (€10,956 v €9,556, P = .003), and costs of outpatient care (€6,417 v €6,628, P = .147).CONCLUSIONMean total health care costs of the use of PlasmaJet in CRS were significantly higher than those for conventional CRS. This difference is fully explained by the additional surgery costs of the use of PlasmaJet. However, surgery with the use of the PlasmaJet leads to a significantly higher percentage of complete CRS and a halving of stomas. A cost-effectiveness analysis will be performed once survival data are available (funded by ZonMw, Trial Register NL62035.078.17).
Factors predicting postoperative morbidity after cytoreductive surgery for ovarian cancer: a systematic review and meta-analysis
Advances in ovarian cancer cytoreductive surgery have enabled more extensive procedures to achieve maximal cytoreduction but with a consequent increase in postoperative morbidity and mortality. The aim of this study was to evaluate factors for postoperative morbidity after extensive cytoreductive surgery for primary epithelial ovarian cancer (EOC), particularly those which may be modifiable. Electronic databases were searched. Meta-analysis was conducted using random-effects models. Fifteen relevant studies, involving 15,325 ovarian cancer patients, were included in this review. Severe 30-day postoperative complications occurred in 2,357 (15.4%) patients. The postoperative mortality rate was 1.92%. Meta-analysis demonstrated that patient with following risk factors; age (p0 (p=0.001), albumin level <3.5 g/dL (p<0.001), presence of ascites on CT scan (p=0.013), stage IV disease (p<0.001) and extensive surgical procedure (p<0.001) has a significantly increase risk of developing postoperative complications. Surgical procedures including peritonectomy (p=0.012), splenectomy (p<0.001) and colon surgery (p<0.001) were significant predictors for postoperative complications. Moreover, we found that patients who received neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) had a lower risk of developing severe complications compared to those who underwent primary debulking surgery (PDS) (p<0.001). Our study demonstrated that patient performance status and hypoalbuminemia were the only significant adjustable preoperative risk factors associated with postoperative complications. Patients who underwent NACT-IDS had a lower risk of developing severe complications compared to PDS. International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42021282770.
Substantial discordance between structured pre-operative computed tomography (CT) reports and intraoperative findings in advanced ovarian cancer cytoreductive surgery, affecting treatment decisions
The aim of this study was to assess the agreement and diagnostic accuracy of structured preoperative computed tomography (CT) findings compared to intraoperative findings in advanced ovarian cancer patients undergoing primary or interval cytoreductive surgery. Patients with CT scans suggesting advanced ovarian cancer were enrolled in the study. Agreement between CT reports, reviewed using European Society of Urogenital Radiology (ESUR) criteria, and surgical findings were evaluated with the kappa coefficient. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each radiologic feature. From February 2018 to September 2020, 258 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIIB-IV epithelial ovarian cancer were enrolled. Agreement between ESUR-reviewed CT reports and surgical findings was slight to fair (kappa = 0.115-0.352). The most common CT findings were peritoneal carcinomatosis, omental metastases, and bowel involvement. Sensitivity and specificity of peritoneal carcinomatosis were 0.91 (95% confidence interval [CI]: 0.86-0.94) and 0.19 (95% CI: 0.10-0.31), with an area under the receiver operating characteristic curve (AUC) of 0.55 (95% CI: 0.46-0.64). Omental metastases had a sensitivity of 0.91 (95% CI: 0.87-0.95) and specificity of 0.27 (95% CI: 0.16-0.40) with an AUC of 0.59 (95% CI: 0.52-0.65). Bowel involvement showed a sensitivity of 0.61 (95% CI: 0.54-0.67), specificity of 0.71 (95% CI: 0.58-0.83), and AUC of 0.66 (95% CI: 0.58-0.74). This study demonstrates limited concordance between ESUR-reviewed CT reports and intraoperative findings in advanced ovarian cancer. Even when interpreted by expert radiologists, CT imaging alone may inadequately reflect disease burden. These findings emphasise the ongoing challenges of imaging-based surgical planning and support the need for further development and validation of more accurate preoperative assessment tools.
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