Guillaume Beinse

Platinum free interval and clinical benefit of the second-line chemotherapy in recurrent uterine and ovarian carcinosarcoma: a retrospective cohort analysis

Uterine and ovarian carcinosarcomas (OCSs) are rare and aggressive neoplasms. We assessed whether progression free survival after initial treatment (PFS1) was associated with the clinical benefit of chemotherapy after progression, estimated as overall survival (OS) after progression/relapse. All consecutive patients treated with chemotherapy for stage I-IV uterine/OCS in Cochin University Hospital between 2010 and 2022 were included in this retrospective cohort. Association between PFS1 and OS after progressive disease (PD) was determined by Cox regression. Optimal PFS1 threshold for OS after PD prediction was determined by a time-dependent receiver operating characteristic-curve analysis. Forty patients treated for endometrial (n=32) or OCS (n=8) were included. Median PFS1 and OS after PD were 16 months 95% confidence interval (95% CI=11-not available [NA]) and 6 months (95% CI=2-15). In patients who relapsed/progressed (n=20), OS after PD was anticipated by PFS1 (Pearson r=0.61; area under the curve=0.79; 95% CI=0.6-1). At the threshold of PFS1 ≤/>9 months (n=6/n=7), median OS post PD were 2 months (0.1-NA) and 15 months (6-NA), for patients treated with platinum/anthracycline based chemotherapy in second line. Patients receiving best supportive care alone (n=7) had a median OS post PD of 8 months (1.3-NA). Our results highlight that a subgroup of carcinosarcomas patients exhibits a durable benefit from chemotherapy in the relapse settings, and suggest the use of PFS1, as a proxy of platinum-sensitivity, to select patients who might derive higher clinical benefit of a 2nd line of chemotherapy.

Association between molecular classification and overall survival in patients with metastatic endometrial carcinoma: ancillary results of the UTOLA phase II GINECO trial

We aimed to describe the association between molecular sub-groups and outcomes in patients with advanced/metastatic endometrial carcinoma amenable to maintenance/active surveillance after carboplatin-based chemotherapy. Patients treated in the GINECO trial UTOLA (NCT03745950, randomly allocating patients 2:1 to olaparib/placebo after tumor control under carboplatin-based chemotherapy), with prospective centralized targeted next-generation sequencing, and mismatch repair and p53 immunostainings were included. Next-generation sequencing (667.5 kb) included POLE (exo-nuclease domain), TP53, PIK3CA, PIK3R1, PTEN, KRAS, and CTNNB1. Tumors were categorized following the 2022 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines as POLE-mutated, mismatch repair-deficient, p53-abnormal (immunostaining or TP53 mutation), and with no specific molecular profile. Exploratory analyses categorized non-p53-abnormal tumors based on literature (mismatch repair-deficient: mutational burden; no specificity: PIK3R1/PTEN wild-type tumors, CTNNB1/KRAS-mutated tumors, others). Among 145 patients in the intention to treat population (median follow-up 31 months), 1, 21 (15%), 76 (53%), and 45 (32%) had POLE, mismatch repair-deficient, p53-abnormal, and non-specific tumors (2 missing mismatch repair), respectively. Molecular characterization was associated with progression-free (log-rank, p = .017) and overall survival (p < .001). Patients with p53abn tumors had a hazard ratio for death of 2.43, 95% confidence interval 1.50 to 3.93 (adjusted on age, stage IV, measurable lesions after chemotherapy). Exploratory analyses showed high mutational burden mismatch repair-deficient tumors with prognostic similar to p53abn tumors, whereas tumors with lower mutational burden had better progression-free survival. PIK3R1/PTEN wild-type and CTNNB1/KRAS-mutated non-specific tumors had better outcomes than p53abn tumors. Other non-specific tumors have survival similar to p53abn tumors. Integration of molecular sub-group as a stratification parameter might be considered for randomized trials in advanced/metastatic endometrial carcinoma after carboplatin-based chemotherapy. Deeper characterization of mismatch repair-proficient tumors might enhance prognostication.

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.

ESR1 Mutation in Endocrine Treatment-Naïve Endometrial Cancer: Prevalence, Characteristics, and Prognostic Implications, Results from the UTOLA Phase II GINECO Trial

Abstract Purpose: Aromatase inhibitors (AI) are used to treat estrogen receptor (ER)–positive low-grade endometrioid endometrial cancer. In breast cancer, ESR1 mutations are rare at diagnosis (&amp;lt;5%) but are frequently acquired in AI-resistant cases and are considered one of the major resistance mechanisms to endocrine therapy. This study aimed to assess the prevalence of ESR1 mutations in hormonotherapy-naïve endometrial cancer samples and correlate them with molecular profiles, ER expression, and clinical outcomes. Experimental Design: A total of 147 patients with advanced endometrial cancer who had responded to first-line chemotherapy were recruited into the UTOLA trial. Archival endometrial cancer tumor tissues underwent sequencing of 127 genes, including ESR1. Only hotspot mutations in the ligand-binding domain were evaluated. ESR1 mutation prevalence was validated in the Genomics England dataset. In UTOLA, tumors were classified as POLE, MMR deficient, TP53abn, or no specific molecular profiles (NSMP) based on the Proactive Molecular Risk Classifier for Endometrial Cancer (PROMISE) classification. Results: Of 147 patients, 137 had sufficient tumor material for sequencing. ESR1 mutations were identified in eight tumors (6%), including Y537S/C/N (n = 4), L536H/P (n = 2), and E380Q (n = 2). A similar prevalence (3.5%) was found among 1,311 tumors in the Genomics England dataset. All ESR1 mutation cases were low-grade endometrioid endometrial cancer, ER-positive, and PR-positive, and classified as NSMP. Among patients with metastatic NSMP low-grade endometrioid endometrial cancer, 22% (8/37) harbored ESR1 mutations. Survival outcomes after platinum chemotherapy were similar between patients with ESR1 mutation endometrial cancer and ESR1 wild type (median, not reached vs. 25.3 months; P = 0.114). Conclusions: ESR1 mutations, while rare overall in treatment-naïve endometrial cancer, are more prevalent in patients with NSMP low-grade endometrioid endometrial cancer, potentially affecting AI efficacy. ESR1 status should be considered in selecting hormonotherapy and as a stratification factor in AI trials.

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.