Clinical utility of plasma ctDNA sequencing monitoring and tumor molecular profile exploration in endometrial carcinoma: A Caribbean prospective cohort from Martinique.
Authors: Marlin Régine , Loger Jean-Samuel , Colomba Emeline , Joachim Clarisse , Vallard Alexis , Bera Odile , Aline-Fardin Aude , Ebring Coralie , Jean-Laurent Mehdi 
Published: June 2023

e17625

Background: A higher incidence of agressive endometrial cancer (EC) has been reported amongst the Martinican population. Indeed, there are respectively 25%, 12% and 3 % of high grade serous carcinoma, carcinosarcoma and clear cell uterine carcinoma, all with poor prognosis. Genomic stratification helps to improve the management of patients with EC. Indeed, localized EC molecular classification discriminated the benefit of adjuvant therapy according to molecular subgroups. However, collecting tissue samples in EC remains challenging. The aim of our study was to assess the clinical utility of ctDNA monitoring in EC and tumor tissue molecular profiling in high grade non endometrioid EC. Methods: We conducted a prospective monocentric study including high grade non endometrioid EC patients enrolled in the EndoNGS trial (NCT04932525). Each patient underwent molecular analysis to define the tumor molecular landscape. A comparative analysis “tumor-germline” including microsatellite instability and panel gene sequencing was then performed. ctDNA was profiled using dPCR and RT PCR. Results: From May 2020 to September 2021, 25 patients with high grade non endometriod EC were included. Median age at diagnosis was 72 years (60-88). FIGO stage at diagnosis was I, II, III and IV in 28%, 4%, 32% and 24% respectively. 10 patients out 25 received radiochemotherapy. Only 6 underwent exclusive radiotherapy and 13 received adjuvant platinum chemotherapy addjuvant to surgery. All tumor had MSS and none harbored a POLE mutation. 19 patients underwent molecular profiling according to a panel of 80 genes. The analysis identified 30 mutations: 22 pathogenic missenses, 3 nonsenses and 5 frameshift mutations. A TP53 mutation was observed in 89.5 % of cases. We identified 26% hotspot mutations. The other mutations are infrequent or not described in TGCA database. TP53 mutation analysis reported 15 missenses, one frameshift and one nonsense mutation. Moreover 88% of TP53 mutated tumors were affected by biallelic inactivation. In this population, variants in PIK3CA represent 26% compared to 42% reported from TGCA database and none PPP2R1A and FBXW7 mutations have been detected compared to 32% and 24% for PPP2R1A and FBXW7 respectively. ctDNA abondance was correlated to the stage. 10 patients had positive ctDNA at diagnosis (9 were stage III and 1 stage IV). In 3 patients, ctDNA became negative during therapy (radiochemotherapy). During course of disease, 15 relapsed, (with a median 12 month relapse free period) amongst which 10 had positive ctDNA. Conclusions: We reported for the first time the molecular profiling of aggressive EC in a homogenous carribbean cohort from Martinique. Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in localized EC is reliable and feasible; ctDNA monitoring was associated to early relapse.