Role of cfDNA and ctDNA to improve the risk stratification and the disease follow-up in patients with endometrial cancer: towards the clinical application

Abstract

Blood biomarkers; Endometrial cancer; Liquid Biopsy

Biomarcadors sanguinis; Càncer d'endometri; Biòpsia líquida

Biomarcadors sanguinis; Càncer d'endometri; Biòpsia líquida

Background There has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined. This study was designed to determine the value of cfDNA/ctDNA monitoring in improving the clinical management of patients with localized and recurrent disease. Methods Plasma samples and uterine aspirates (UA) from 198 EC patients were collected at surgery and over time. The genetic landscape of UAs was characterized using targeted sequencing. Total cfDNA was analyzed for ctDNA presence based on the UA mutational profile. Results High cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for DFS (p-value < 0.0001; HR = 9.25) and DSS (p-value < 0.0001; HR = 11.20). This remained clinically significant when stratifying tumors by histopathological risk factors. Of note, cfDNA/ctDNA analyses discriminated patients with early post-surgery relapse and the ctDNA kinetics served to identify patients undergoing relapse before any clinical evidence emerged. Conclusions This is the most comprehensive study on cfDNA/ctDNA characterization in EC, demonstrating its value in improving risk stratification and anticipating disease relapse in patients with localized disease. CtDNA kinetics assessment complements current strategies to monitor the disease evolution and the treatment response. Therefore, implementing cfDNA/ctDNA monitoring in clinical routines offers a unique opportunity to improve EC management. Translational relevance The study demonstrates that high levels of cfDNA and detectable ctDNA at baseline are strong indicators of poor prognosis. This enables more accurate risk stratification beyond traditional histopathological factors, allowing clinicians to identify high-risk patients who may benefit from more aggressive treatment and closer monitoring. Moreover, longitudinal analysis of cfDNA/ctDNA can detect disease recurrence months before clinical symptoms or imaging evidence appear. This early warning system offers a significant advantage in clinical practice, providing a window of opportunity for early intervention and potentially improving patient outcomes.

This work has been supported by the Instituto de Salud Carlos III (ISCIII) (PI20/00969, PI21/00990 and PI20/01566)/Co-fund by the European Union for A.G-M, M.A and L.M-R; the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (PID2022-136854OB-I00) for G.M-B, the CIBERONC CB16/12/00328 for L.M-R, EC, A.G-M and MA) and CB16/12/00295 for G.M-B) and the Fundación científica AECC through grants for research projects to clinical oncology research coordination groups (GCTRA1804MATI) for A.G-M, MA, X.M-G and G.M-B, Proyectos de Excelencia (IN607D2021/05) for L.M-R and ERA PerMed ERA-NET cofunded by the European Union, NextGeneration-EU through ISCIII and FCAECC (AC21_2/00020) for G.M-B and L.M-R. L.M-R and EC are supported by a contract “Miguel Servet” from ISCIII (CP20/00119, CP22/00147, respectively). SO is funded by an FCAECC-postdoctoral grant (PI21/00990). C.C-A is funded by an IDIS-predoctoral grant (2020). J.R-B is supported by a Juan Rodés contract (JR21/00019) from ISCIII.