Endometrial cancer comprises a heterogeneous group of tumors, with distinct risk factors, clinical presentation, histopathological features and molecular characteristics. Currently, treatment of metastatic or recurrent disease is based on conventional chemotherapy combination regimens. Advances in the understanding of the molecular pathology of the two types of endometrial carcinoma—type I (endometrioid) and type II (non-endometrioid)—have underpinned the first steps in the development and testing of targeted therapies. Of the potential therapeutic targets identified to date, clinical trials have only assessed the efficacy of inhibition of the EGFR, VEGFR and PI3K/PTEN/AKT/mTOR signaling pathways; responses to these targeted therapies were modest. Despite the striking molecular differences between type I and type II endometrial cancers, most clinical trials have not taken this diversity into account. The identification of activating mutations of kinases (for example PIK3CA and FGFR2) and loss of function of genes related to DNA repair (for example PTEN) may lead to more biology-driven clinical trials exploiting the concepts of oncogene addiction and synthetic lethality.
Endometrial cancer is a heterogeneous disease with distinct molecular characteristics
The most frequent aberration is the activation of the PI3K/PTEN/AKT/mTOR pathway
Targeted therapies are yet to be introduced in clinical practice
EGFR, mTOR, HER2 and VEGFR inhibitors have been tested in phase II trials as single agents with modest results
The development of more potent inhibitors of the PI3K/PTEN/AKT/mTOR pathway and the identification of new druggable targets has led to the initiation of several biology-driven clinical trials
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The authors of this Review are funded in part by Breakthrough Breast Cancer. K. J. Dedes is funded in part by a Fellowship of the Swiss National Science Foundation (SNF Grant 128,487). The authors acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Center.
A. Ashworth is a patent holder with AstraZeneca and S. B. Kaye is on the advisory board at AstraZeneca. The other authors declare no competing interests.
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Dedes, K., Wetterskog, D., Ashworth, A. et al. Emerging therapeutic targets in endometrial cancer. Nat Rev Clin Oncol 8, 261–271 (2011). https://doi.org/10.1038/nrclinonc.2010.216
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