The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

Abstract

Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing (POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

Keywords: chemotherapy; endometrial cancer; molecular oncology; molecular testing; targeted therapy.

Figure 1.

The planned treatment arms for the TransPORTEC RAINBO program of clinical trials. DDR, DNA damage response; PD-L1, programmed death-ligand 1; POLE, polymerase epsilon; MMRd, mismatch repair deficient; NSMP, no specific molecular profile; RAINBO, refining adjuvant treatment in endometrial cancer based on molecular profile.

Figure 2.

POLEmut endometrial cancer. (a) H&E staining (low power) showing endometrioid features with a prominent host inflammatory infiltrate. (b) H&E staining (higher power) showing an area with serous-like features, including nuclear pleomorphism. The variable morphology, host lymphocytic infiltrate and nuclear atypia are all features associated with POLEmut tumours. In this case there is also subclonal mutant pattern expression of p53 (c), with overexpression on the left and wild-type expression on the right. H&E, haematoxylin and eosin; POLE, polymerase epsilon.