Management of Advanced Endometrial Cancer and Inhibitors of the PI3K/AKT/mTOR Pathway

Abstract

Endometrial cancer is the most common gynaecological malignancy in industrialised countries and is increasing in incidence and prevalence (Colombo et al., Ann Oncol 22:vi35–9, 2011; Jemal et al., CA Cancer J Clin 61:69–90, 2011; Bray et al., Cancer Epidemiol Biomark Prev 14:1132–42, 2005; Evans et al., Br J Cancer 104:1505–10, 2011; National Cancer Institute: Surveillance Epidemiology and End Results. SEER cancer statistics review 1975–2009 (Vintage 2009 populations) 2012 Apr (updated 20 Aug 2012; cited 2 Dec 2012). Available from: http://seer.cancer.gov/csr/1975_2009_pops09/). Most patients with endometrial cancer are diagnosed with early stage disease that can be surgically resected (Jemal et al., CA Cancer J Clin 61:69–90, 2011; National Cancer Institute: Surveillance Epidemiology and End Results. SEER cancer statistics review 1975–2009 (Vintage 2009 populations) 2012 Apr (updated 20 Aug 2012; cited 2 Dec 2012). Available from: http://seer.cancer.gov/csr/1975_2009_pops09/). However, a significant proportion of patients relapse following surgery or present de novo with inoperable advanced or metastatic disease (Colombo et al., Ann Oncol 22:vi35–9, 2011; Jemal et al., CA Cancer J Clin 61:69–90, 2011; National Cancer Institute: Surveillance Epidemiology and End Results. SEER cancer statistics review 1975–2009 (Vintage 2009 populations) 2012 Apr (updated 20 Aug 2012; cited 2 Dec 2012). Available from: http://seer.cancer.gov/csr/1975_2009_pops09/; Lindahl et al., Anticancer Res 32:3391–5, 2012; Greer et al., J Natl Compr Canc Netw 7:498–531, 2009). There is no standard management for advanced endometrial cancer although chemotherapy or endocrine therapy is frequently used despite limited efficacy or overall survival (OS) benefit (Vale et al., Cochrane Database Syst Rev (15):CD003915, 2012; Kokka et al., Cochrane Database Syst Rev (8):CD007926, 2010; Pectasides et al., Cancer Treat Rev 33:177–90, 2007). Chemotherapeutic regimens for advanced disease most commonly include taxanes, platinums, anthracyclines as monotherapy or in combination with response rates (RR) ranging from 25 to 60 % (Vale et al., Cochrane Database Syst Rev 15:CD003915, 2012; Pectasides et al., Cancer Treat Rev 33:177–90, 2007; Dizon Gynecol Oncol 2:373–81, 2010; Dellinger et al., Expert Rev Anticancer Ther 9:905–16, 2009; Ray and Fleming, Semin Oncol 36:145–54, 2009; Hill and Dizon, Drugs 72:705–13, 2012; Tsoref and Oza, Curr Opin Oncol 23:494–500, 2011). Survival rates have failed to improve over the last 25 years (Jemal et al., CA Cancer J Clin 58:71–96, 2008). There are no novel targeted therapies licensed for the treatment of endometrial cancer despite investigation of several different classes of molecule in clinical trials. The rapid advances in biotechnology platforms and initiatives such as The Cancer Genome Project (National Cancer Institute: The Cancer Genome Atlas. Uterine corpus endometrial cancer. [Internet] 2012 (updated 14 May 2012; cited 2 Dec 2012). Available from: http://cancergenome.nih.gov/cancersselected/endometrial), to identify and characterize aberrant molecular pathways (Liang et al., Genome Res 22:2120–9, 2012), is enabling a more patient-selective approach for the development of novel agents and an opportunity to improve treatment efficacy. One such example is PTEN-PI3K-AKT-mTor signalling which is commonly disrupted in endometrial malignancy (Slomovitz and Coleman, Clin Cancer Res 18:5856–64, 2012; Oda et al., Cancer Res 65:10669–73, 2005). Several molecular lesions have been identified in this pathway that can be targeted with novel therapeutics. A number of these agents have been and continue to be explored in the management of advanced endometrial cancer (Dedes et al., Nat Rev Clin Oncol 8:261–71, 2011). The rationale, classes of novel therapeutics, clinical experience, limitations and future considerations of targeting the PTEN-PI3K-AKT-mTor pathway in endometrial cancer will be discussed.