Molecular Classification and Emerging Targeted Therapy in Endometrial Cancer

Abstract

Recent advances in molecular studies, especially genome-wide analyses, have revealed the landscape of genomic alterations present in endometrial carcinomas, and have provided valuable insight into the pathogenesis of this disease. The current challenges are in developing a molecularmorphological classification system to enhance traditional pathologic diagnosis and in determining the optimal approach to using this new information to guide clinical management. Molecular assays may be particularly beneficial in allowing the earlier detection of endometrial cancer or precursor lesions and in guiding personalized treatment approaches. In this review, we describe the current molecular landscape of endometrial cancers, efforts underway to incorporate molecular alterations into the current classification systems, and the development of diagnostic tools for the early detection of endometrial cancer. Finally, we present opportunities for using these data to tailor therapeutic strategies. A comprehensive understanding of the molecular alterations responsible for the origination, relapse, and resistance patterns of this disease will ultimately improve outcomes for patients with endometrial cancer.

Metabolomic Biomarkers for Detection, Prognosis and Identifying Recurrence in Endometrial Cancer

“…Prognostic factors currently used in clinical practice include histological subtype, tumour grade and stage, depth of myometrial invasion and presence or absence of lymphovascular space invasion (LVSI) [10,104]. Women with high-grade, advanced-stage, non-endometrioid EC generally have poor outcomes [21]. Currently, characterisation of tumour grade and histological type is performed by histopathologists, a subjective process with only moderate inter-observer reproducibility.…”

“…Four novel EC categories have recently been proposed by The Cancer Genome Atlas Research Network (TCGA): polymerase epsilon (POLE) ultra-mutated, microsatellite unstable (MSI), copy number low and copy-number high [18], and have been validated in multiple studies [19,20]. It has been postulated that these molecular subtypes could be used to better define prognosis and recurrence risk than traditional risk prediction models based on clinical predictors [20,21]. Treatment of EC is usually surgical (hysterectomy and bilateral salpingo-oophorectomy), although a significant minority are offered conservative management in the form of hormonal manipulations, especially women of childbearing age who wish to preserve their fertility [9].…”

Betaglycan Gene (TGFBR3) Polymorphism Is Associated with Increased Risk of Endometrial Cancer

“…The MSI subgroup is related to deficiencies in a DNA mismatch repair system leading to common mutations of ARID 5 B , PTEN , PIK 3 CA and PIK 3 R 1 genes. The copy-number low subgroup is described also as microsatellite stable and corresponds to more than half of low-grade endometrioid tumors, whereas copy-number high subgroup reflects to serous histopathology [ 6 , 7 , 8 ]. Moreover, up to 5% of ECs are described as familial ones, due to the loss-of-function or expression alterations of DNA mismatch repair genes, i.e., ( MLH 1, MSH 2, MSH 6 or PMS 2).…”

Laminin Receptor 1: Can It Have a Role in Molecular Classification and Targeted Therapy of Endometrial Cancer?

“…Thanks to the recent molecular studies, genomic alterations leading to the pathogenesis of these types of cancers have been revealed extensively. Nowadays, conventional pathologic diagnoses of them do not seem to be able to sufficiently guide the optimal clinical managements and therefore, efforts to develop a new classification system based on their molecularmorphologic features is highly encouraged (1). Publication of the Cancer Genome Atlas (TCGA) report on a genomic analysis of 373 endometrial carcinomas (2) forced the efforts to incorporate molecular testing into routine histologic evaluation (3).…”

“…Publication of the Cancer Genome Atlas (TCGA) report on a genomic analysis of 373 endometrial carcinomas (2) forced the efforts to incorporate molecular testing into routine histologic evaluation (3). Although DNA polymerase epsilon, catalytic subunit (POLE), mismatch repair (MMR), and human epidermal growth factor receptor 2 (HER2) are highly evaluated molecular tests due to potential efficacy of immune checkpoint inhibitors and other targeted therapies, the data is not sufficient to attain a clear consensus on which tests to perform (1). Laminin receptor 1 (LAMR) which is a multifunctional protein with important roles not only in tumorcell migration and invasion but also in tumor-cell proliferation, survival, and protein translation, has been shown to be overexpressed in many malignant tumors including endometrial cancer (4-7).…”