Molecular subtyping and the 2023 FIGO staging in endometrial cancer: Redefining adjuvant therapy

Abstract

The 2023 update to the FIGO staging system for endometrial cancer has introduced important changes, particularly in classifying early disease, which now more effectively aligns with histological types and molecular profiles to guide treatment strategies. In recent years, molecular classification, including the identification of POLE mutations, mismatch repair deficiency (dMMR), and p53 abnormalities, has become essential in tailoring adjuvant therapies for patients with endometrial cancer. Women with new FIGO stage I non-TP53-mutated tumors, and stage I/II POLE-mutated tumors generally have excellent outcomes, and adjuvant therapy is typically not recommended. In contrast to the established adjuvant treatment of stage IIB disease, controversy surrounds the treatment of stage IIA and IIC patients without POLE mutations. Real-world data suggest that adjuvant radiotherapy or chemotherapy may offer no significant benefit compared to observation in these cases. For stage III POLE-mutated tumors, studies have demonstrated favorable prognoses and high salvage rates upon recurrence, raising important questions about the necessity of adjuvant treatment when complete surgical resection is achieved. For stage III/IV dMMR patients, immune checkpoint inhibitors have demonstrated substantial improvements in both progression-free survival and overall survival when added to chemotherapy, as shown in the RUBY, NRG-GY018, AtTEnd, and ENGOT-en11/GOG-3053/KEYNOTE-B21 trials. These findings have solidified the use of immunotherapy in this molecular subgroup. In the non-specific molecular profile group, hormone receptor status has emerged as a significant prognostic marker. Estrogen receptor-positive tumors in this subgroup have shown favorable responses to progestin therapy, raising the possibility that hormonal therapy could replace chemotherapy in selected patients. Lastly, patients with TP53-mutated tumors, which are associated with poor prognosis, are being evaluated in the RAINBO p53abn-RED trial to assess whether the addition of olaparib to adjuvant chemoradiation can improve outcomes in this high-risk group. In conclusion, integrating molecular subtyping with the 2023 FIGO staging system is reshaping the approach to adjuvant therapy in endometrial cancer, enabling more precise and individualized treatment strategies that improve patient outcomes.