Abstract
The peremptory need to circumvent challenges associated with poorly differentiated epithelial endometrial cancers (PDEECs), also known as Type II endometrial cancers (ECs), has prompted therapeutic interrogation of the prototypically intractable and most prevalent gynecological malignancy. PDEECs account for most endometrial cancer-related mortalities due to their aggressive nature, late-stage detection, and poor response to standard therapies. PDEECs are characterized by heterogeneous histopathological features and distinct molecular profiles, and they pose significant clinical challenges due to their propensity for rapid progression. Regardless of the complexities around PDEECs, they are still being administered inefficiently in the same manner as clinically indolent and readily curable type-I ECs. Currently, there are no targeted therapies for the treatment of PDEECs. The realization of the need for new treatment options has transformed our understanding of PDEECs by enabling more precise classification based on genomic profiling. The transition from a histopathological to a molecular classification has provided critical insights into the underlying genetic and epigenetic alterations in these malignancies. This review explores the genomic landscape of PDEECs, with a focus on identifying key molecular subtypes and associated genetic mutations that are prevalent in aggressive variants. Here, we discuss how molecular classification correlates with clinical outcomes and can refine diagnostic accuracy, predict patient prognosis, and inform therapeutic strategies. Deciphering the molecular underpinnings of PDEECs has led to advances in precision oncology and protracted therapeutic remissions for patients with these untamable malignancies.