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 molecular-morphologic 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.

Fig. 1.. Associations of histological and TCGA classifications in endometrial cancer.

The outer circle shows the histological types of endometrial carcinoma. Seromucinous is a rare histological type and not shown. The inner circle shows the molecular classification of endometrioid and serous tumors based on subgroups identified in TCGA: POLE ultra-mutated group, MSI hypermutated group, copy number (CN) low and high groups. TCGA did not analyze clear cell carcinoma, carcinosarcoma, or poorly differentiated tumors. The outer boxes list various molecular signaling pathways altered in endometrial cancer. CCC, clear cell carcinoma; HG, high grade; LG, low grade; MMMT, malignant mixed Mullerian tumor; N/A, not applicable.

Fig. 2.. Gross and microscopic (H&E staining) appearances of different histological types of endometrial carcinoma.

2A. Endometrioid type tumor usually present with elongated nuclei and some degree of glandular or villoglandular structures. Glandular differentiation and the degree of cellular components are used to differentiate low grade and high grade endometrioid tumors. 2B. Carcinosarcoma has a mixture of malignant epithelial and mesenchymal components. Macroscopically, carcinosarcoma demonstrates necrotic and hemorrhagic neoplasms that occupy the endometrial cavity. Histologically, this biphasic tumor is composed of malignant epithelial glandular features and undifferentiated high-grade sarcoma elements. 2C. Serous type carcinoma is usually characterized by a papillary architecture both histologically and grossly. 2D. Tumor cells of clear cell carcinoma are filled with glycogen and thus have the appearance of being surrounded by a “clear” halo.

Fig. 3.. Gene mutations in serous and endometrioid endometrial cancers.

Distinct molecular genetic alterations in three major cancer genes (ARID1A, TP53, CCNE1) in uterine serous carcinoma and endometrioid carcinoma are shown. The majority of serous cases harbor TP53 mutations and/or CCNE1 locus amplification, while ARID1A mutations are rare. In endometrioid carcinomas, the reverse pattern is observed; these carcinomas are characterized by frequent ARID1A mutations and rare or no TP53 mutations and CCNE1 amplification. Each column represents a case. (red) Genetic alteration present; (green) genetic alteration absent.

Fig. 4.. Common alterations of genes in endometrial carcinomas.

Several mechanisms can lead to carcinogenesis and metastasis, including inhibiting apoptosis, inducing cell proliferation, enhancing TERT transcription, and interfering with DNA repair. ARID1A, PTEN, KRAS, CTNNB1, and MMR molecular pathways exclusively affect endometrioid tumor whereas serous tumors more commonly harbor alterations in TP53, HER2, p16, CCNE1, and FBXW7. ARID1A, AT-rich interaction domain 1A; CCNE1, cyclin E1; CTNNB1, Catenin beta-1; FBXW7, F-box/WD repeat-containing protein 7; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; PI3K, phosphatidylinositol 3- kinase; PTEN, phosphatase and tensin homolog; TERT, Telomerase reverse transcriptase; TP53, cellular tumor antigen 53. This figure is modified from ScienceSlides Online (http://www.scienceslides.com/BH41/common-alterations-in-endometrial-carcinoma-subtypes#).