Pierre Laurent-Puig

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.

Identification of a very-high risk subgroup of localized endometrial carcinoma before surgery using circulating tumor DNA: a proof-of-concept study

We aimed to study whether the detection of circulating tumor DNA (ctDNA) may predict the risk of early relapse for patients with localized endometrial carcinoma. Patients who underwent surgical resection at Cochin University Hospital (2021-2023) for International Federation of Gynecology and Obstetrics 2018 stage I to III endometrial carcinoma were prospectively included in a prospective biocollection cohort study. All patients had a plasma sample before surgery (EDTA collection tubes, 4-5 mL). After extraction and bisulfite-conversion of cell-free DNA, ctDNA was evaluated using a droplet-digital polymerase chain reaction assay targeting universally-hypermethylated positions in endometrial carcinoma (OXT, ZSCAN12 genes), and defined as significantly detected above the limit of detection. Patients were classified as high-risk based on 2022 European Society for Medical Oncology/European Society of Gynaecological Oncology/European Society of Pathology guidelines, or preoperative features (non-endometrioid histology, p53-abnormal tumors, or stage III). Events of interest were tumor progression or relapse (event-free survival). Adjusted-HR (aHR) was estimated using Cox regression. Among 128 patients included with median follow-up of 26 months (interquartile range; 15-35), ctDNA was detected in 18 patients (14%). Patients with ctDNA had a 1-year event-free rate of 67% (95% CI [48% to 92%]), vs 91% [82% to 100%] among patients without ctDNA. The ctDNA was detected in 10 (29%) patients among those with preoperative high-risk features (N = 34, 1-year event-free rate = 60% [36%-100%]). ctDNA was associated with event-free survival independently of stage (aHR = 4.26 [1.68-10.8]), 2022 guidelines high-risk (aHR = 3.72 [1.57-8.87]), or preoperative high-risk features (aHR = 3.98 [1.65-9.60]). Elevated ctDNA before surgery identifies a very high-risk subgroup of newly diagnosed endometrial carcinoma, suggestive of occult metastasis. Further studies are warranted to validate this finding and investigate the window of opportunity for neoadjuvant approaches.

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.