Translating biological insights into improved management of endometrial cancer

Abstract

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to help to address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians (FIGO) staging model. Furthermore, we provide an overview of disease management in the first-line and recurrent disease settings. With increasing use of molecular profiling and updates in treatment paradigms, we also summarize new developments in this rapidly changing treatment landscape.

Figure 1.. Incidence and mortality of cancers of the corpus uteri.

a. Age-standardized global incidence of cancers of the corpus uteri. b. Global mortality of cancers of the corpus uteri. Adapted with permission from ref 2.

Figure 1.. Incidence and mortality of cancers of the corpus uteri.

a. Age-standardized global incidence of cancers of the corpus uteri. b. Global mortality of cancers of the corpus uteri. Adapted with permission from ref 2.

Figure 2.. Suggested molecular profiling workflow in patients with endometrial cancer.

This decision matrix provides a general overview of the molecular profiling workflows required to identify distinct molecular subtypes of endometrial cancer. Specific details will differ based on the clinical situation and resource availability and/or prioritization for each institution. ER, oestrogen receptor;FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MMR, mismatch repair; MMRd, mismatch repair deficient; MMRp, mismatch repair proficient; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NSMP, no specific molecular profile; POLE, DNA polymerase epsilon; PR, progesterone receptor.

Figure 3.. Endometrial cancer staging criteria.

Endometrial cancer is staged according to the International Federation of Gynecology and Obstetrics (FIGO) criteria (2009), including an update published in 2023, stipulating that molecular testing for relevant pathological characteristics (such as POLE mutations, mismatch repair deficiency (MMRd), and/or p53 status) should be performed when feasible. a, Stage I disease (limited to the corpus uteri). b, Stage II disease (tumours invading the cervical stroma but remaining confined to the uterus). Stage I–II disease with POLE mutations or p53 aberrations should undergo modifications for the final FIGO stage (e.g. stage IA for POLE mutated tumours and stage IIC for p53 aberrant tumours), despite initial stage based on anatomopathologic features. c, Stage III (with local and/or regional tumour spread) and d, Stage IV (with tumour invasion of the bladder and/or bowel mucosa and/or distant metastases). Stage III–IV disease is not modifiable by molecular classification; however, the molecular classification should be recorded if known. Aggressive histological types include high-grade endometrioid endometrial carcinomas (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas. DMI, deep myometrial invasion; LVSI, lymphovascular space invasion. Adapted from ref. , Springer Nature Limited.

Figure 3.. Endometrial cancer staging criteria.

Endometrial cancer is staged according to the International Federation of Gynecology and Obstetrics (FIGO) criteria (2009), including an update published in 2023, stipulating that molecular testing for relevant pathological characteristics (such as POLE mutations, mismatch repair deficiency (MMRd), and/or p53 status) should be performed when feasible. a, Stage I disease (limited to the corpus uteri). b, Stage II disease (tumours invading the cervical stroma but remaining confined to the uterus). Stage I–II disease with POLE mutations or p53 aberrations should undergo modifications for the final FIGO stage (e.g. stage IA for POLE mutated tumours and stage IIC for p53 aberrant tumours), despite initial stage based on anatomopathologic features. c, Stage III (with local and/or regional tumour spread) and d, Stage IV (with tumour invasion of the bladder and/or bowel mucosa and/or distant metastases). Stage III–IV disease is not modifiable by molecular classification; however, the molecular classification should be recorded if known. Aggressive histological types include high-grade endometrioid endometrial carcinomas (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas. DMI, deep myometrial invasion; LVSI, lymphovascular space invasion. Adapted from ref. , Springer Nature Limited.