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Endometrial cancer (EC) is the fourth most common malignancy among women. The majority of ECs (72%) are detected in early stages (stage I-II), whereas 20% have regional metastasis (stage III) and 8% distant metastasis (stage IV) [1].
There is an increasing body of evidence based on clinicopathologic and molecular data to suggest that EC can be divided into two distinct types [2]. The endometrioid histology of EC, the most common histological subtype, comprises the type I cancers. Type I cancers are characterized by preceding premalignant disease and high rates of estrogen receptor (ER) and progesterone receptor (PR) expression. Type I ECs are usually low grade and often do not spread beyond the uterus. The prognosis of early-stage type I cancers is favorable, with a 5-year survival of >97% in stage I and >80% in stage II.
Type II endometrial carcinomas comprise all the nonendometrioid histologies including serous or clear-cell cancers, arise in the background of atrophic endometrium and are not related to the ER pathway. In spite of the higher prevalence of type I cancers, type II tumors account for a high proportion of EC-related deaths (44%) due to their aggressive behavior.
Patients with metastatic or recurrent EC have a poor prognosis, despite the availability of systemic treatments, including endocrine therapy and combination chemotherapy. Compared with other gynecological malignancies such as breast and ovarian cancer, objective response rates of metastatic EC to systemic treatments are poor and are associated with median survival of 8-16 months [3]. Until recently, endocrine therapy, typically using progestagens or tamoxifen, has been the only targeted treatment available for women with EC. However, response rates are at best modest, and endocrine treatment is usually offered to frail patients with comorbidities or those with low proliferating, nonaggressive metastatic cancers.
In view of the limited efficacy of current systemic therapies for EC, novel targeted treatments have been investigated [2]. With increasing knowledge of molecular aberrations of ECs, it has been apparent that PI3K/PTEN/AKT/mTOR signaling is one of the most commonly activated pathways in both EC types and is associated with aggressive phenotype [4]. It has therefore been reasoned that targeting this pathway could lead to an efficient and selective cancer cell killing in EC.
The aim of this review is to discuss...