Molecular Classification of Endometrial Cancer and Its Impact on Therapy Selection

Abstract

Endometrial cancer (EC) accounts for 90% of uterine cancer cases. It is considered not only one of the most common gynecological malignancies but also one of the most frequent cancers among women overall. Nowadays, the differentiation of EC subtypes is based on immunohistochemistry and molecular techniques. It is considered that patients' prognosis and the implementation of the appropriate treatment depend on the cancer subtype. Patients with pathogenic variants in POLE have the most favorable outcome, while those with abnormal p53 protein have the poorest. Therefore, in patients with POLE mutation, the de-escalation of postoperative treatment may be considered, and patients with abnormal p53 protein should be subjected to intensive adjuvant therapy. Patients with a DNA mismatch repair (dMMR) deficiency are classified in the intermediate prognosis group as EC patients without a specific molecular profile. Immunotherapy has been recognized as an effective treatment method in patients with advanced or recurrent EC with a mismatch deficiency. Thus, different adjuvant therapy approaches, including targeted therapy and immunotherapy, are being proposed depending on the EC subtype, and international guidelines, such as those published by ESMO and ESGO/ESTRO/ESP, include recommendations for performing the molecular classification of all EC cases. The decision about adjuvant therapy selection has to be based not only on clinical data and histological type and stage of cancer, but, following international recommendations, has to include EC molecular subtyping. This review describes how molecular classification could support more optimal therapeutic management in endometrial cancer patients.

Keywords: endometrial cancer; molecular subtypes; personalized treatment.

Figure 1

Summary of information regarding endometrial cancer molecular subtypes. The diagnosis of the molecular subtype is hierarchical according to the PROMISE diagram, with POLE mutation as the dominant determinant even if p53abn status is found. Based on [16,17,21,22,23,24,25]. * NSMP is sometimes considered a subtype associated with poor prognosis [26,27]. DDR—DNA damage response; IHC—immunohistochemistry; MMR—mismatch repair; dMMR—deficiency of mismatch repair; MSI—microsatellite instability; NGS—next-generation sequencing; POLE—DNA Polymerase Epsilon, Catalytic Subunit; NSMP—no specific molecular profile; PD-1—programmed death receptor 1; PD-L1—programmed death-ligand 1.

Figure 2

Proposed approach to therapy decision-making in multiple classifiers. Based on [97,98,99].