乌鸦传媒

For many years, endometrial cancer has been classified based on the histological morphology and identification of prognostic markers, which are used to guide treatment decisions. However, variations in outcomes are often observed among histologically similar tumors. This has led to a search for new prognostic factors to determine the indications for adjuvant therapy in endometrial cancer patients.¹

Advances in molecular characterization techniques have led to a deeper understanding of the molecular alterations involved in the pathogenesis of endometrial cancer. Analyses from The Cancer Genome Atlas (TCGA) Research Network have identified four subgroups of endometrial carcinomas with distinct clinical, pathological, and molecular features: POLE ultramutated (POLEmut), p53 mutant (p53abn), mismatch repair deficient (MMRd), and no specific molecular profile (NSMP). The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and PORTEC studies integrated similar molecular alterations, providing a prognostic classification system. These subdivisions were introduced into the 2021 European risk stratification system.

Which mutations have the best prognosis?

According to the co-authors of a newly published study, the European Society of Gynecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) clinicopathologic and molecular integrated risk groups are associated with distinct prognoses.² The updated guidelines encourage categorizing tumors according to their molecular classification, especially in high-grade endometrial cancer subgroups. Analyses have confirmed that the molecular subgroup of endometrial carcinomas displaying polymerase-e (POLE) mutations have an excellent prognosis, while the copy-number high tumors have a poor prognosis. Tumors with microsatellite-instability hypermutations and copy-number low tumors have an intermediate prognosis. Based on this knowledge, patients at risk of recurrence who may benefit from adjuvant therapy can be identified, avoiding over- and undertreatment of patients with endometrial cancer.

Loukovaara and colleagues retrospectively implemented the ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups in an unselected cohort of 604 women who underwent surgical treatment for stage I-IV endometrial cancer over a period of six years, between January 1, 2007, and December 31, 2012.² Disease-specific survival outcomes were compared across risk groups in patients with and without molecular knowledge. Using the ProMisE and Leiden molecular classifiers, outcomes were compared for each molecular subgroup within each risk group and assessed to determine the frequency of shift between risk groups.

Using the new knowledge to a greater advantage

The results of the study suggest that clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses (P<.001). Disease-specific outcomes were roughly the same for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, poor outcomes were associated with subgroup p53abn (hazard ratio [HR] 9.1, 95% confidence interval [CI] 2.0 to 41; P=.004) and subgroup MMRd (HR 3.5, 95% CI 1.2 to 10; P=.024) within clinicopathologic low-risk and high-intermediate risk groups, respectively. Using molecular classification, 36 (6.0%) patients by the ProMisE and 38 (7.4%) patients by the Leiden molecular integrated schemas were shifted between risk groups, mostly occurring in the high-intermediate group. In addition, POLE sequencing could be omitted in 60.4% (311/515) of patients without affecting the risk-group assessment.

The investigators concluded that the ESGO-ESTRO-ESP 2021 risk stratification will allow more-precise treatment of endometrial cancer. The clinicopathologic and molecular integrated risk groups are associated with distinct prognoses that may identify patients who would benefit from adjuvant therapy, especially those in the intermediate-risk and high-intermediate risk groups.

鈥淐linicopathologic risk factors may differently modify the prognostic impact of molecular subgroups,鈥� the authors wrote in their report. 鈥淭his emphasizes the need for adjuvant therapy trials in which patients are randomized to treatment arms separately within each molecular subgroup.鈥�²

Published: June 28, 2022