Valérie Taly

Clinical value of circulating tumor DNA for patients with epithelial ovarian cancer

Despite progress in recent years, epithelial ovarian cancer remains a pathology with a poor prognosis, primarily because of late and invasive diagnosis. Conventional follow-up relies on imaging, CA125, and predictive tools such as KELIM-CA125 and the chemotherapy response score. However, these methods are non-specific and result in delays before obtaining results. Recently, many research teams have focused on liquid biopsies, which provide direct access to tumor material in biological fluids. This review examines the clinical potential of circulating tumor DNA (ctDNA) in epithelial ovarian cancer. A systematic search of the PubMed database was conducted. Inclusion criteria were studies published in English, original research articles, reviews, or meta-analyses focused on ctDNA and ovarian cancer. Exclusion criteria included non-peer-reviewed sources, articles with insufficient data, and studies not directly related to the topic. In epithelial ovarian cancer, ctDNA allows quantitative evaluation of tumor burden and qualitative analysis by detecting specific tumor DNA variations, such as epigenetic modifications or genetic mutations. Furthermore, its half-life is less than 2 hours, enabling dynamic monitoring of tumor evolution. This capability could facilitate earlier diagnosis, better screening, and more effective therapeutic follow-up. The qualitative approach also has the potential to predict chemoresistance. Technologies used to detect ctDNA in blood include quantitative polymerase chain reaction, digital polymerase chain reaction, and next-generation sequencing, which allow quantification and identification of DNA molecule modifications. CtDNA is a promising biomarker for epithelial ovarian cancer and could address several challenges in its management. However, further research is needed to establish its role in routine clinical practice, particularly, to identify a detection method that is highly sensitive, specific, and generalizable to a wide patient population.

Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers

Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD. Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan-Meier curves and Cox models. In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4-0.7, Pearson correlation = 0.64-0.86, all P < 10 UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.

ctDNA for Prognostication and Monitoring in Patients with Metastatic Endometrial Carcinoma Treated with Olaparib: Validation in the GINECO-UTOLA Trial

Abstract Purpose: ctDNA may offer a noninvasive means to evaluate tumor response and anticipate disease dynamics before radiologic changes in advanced endometrial carcinoma. Experimental Design: This ancillary analysis included patients from the multicenter, randomized, phase II GINECO-UTerin OLAparib (UTOLA) trial (NCT03745950) evaluating olaparib/placebo as maintenance after first-line platinum-based chemotherapy. Plasma samples were collected at screening after chemotherapy (baseline), 3 months (M3), and progression. ctDNA detection was assessed by a validated methylation-based Droplet Digital PCR (MethddPCR) assay targeting DNA positions universally methylated in endometrial carcinoma. Results: Among 130 evaluable patients, ctDNA was detected in 25 of 129 (19%, 1 technical fail) at baseline, 15 of 80 (19%) at M3, and 33 of 52 (63%) at progression. Baseline ctDNA positivity was independently associated with poorer progression-free survival (PFS) [median 1.81 vs. 7.39 months; adjusted HR = 5.33 (3.17–8.97)] and overall survival (OS) [10.3 vs. 24.7 months; adjusted HR = 3.98 (2.28–6.91); adjusted for age, stage IV at diagnosis, p53abn subgroup, and residual measurable lesions after chemotherapy]. Patients with baseline ctDNA had median OS of 9.36 months under olaparib versus 19.6 months under placebo (log-rank P = 0.05). Patients with increasing ctDNA at M3 had median PFS of 1.67 months, versus 9.64 months without, and median OS of 18.8 versus 25.8 months. ctDNA rising was predictive of poor postprogression OS under olaparib but not under placebo (interaction test, P &amp;lt; 0.001). Conclusions: MethddPCR-ctDNA is an independent prognostic biomarker for OS in advanced/metastatic endometrial carcinoma. MethddPCR-ctDNA may identify patients unlikely to benefit from PARP inhibition, guide therapeutic decisions, and should be further evaluated as a new stratification parameter in future endometrial carcinoma trials.