**6.2. Human Epidermal Growth Factor Receptor (EGFR) Inhibitors**

Epidermal Growth Factor Receptor (EGFR) is frequently expressed in normal endometrial tissues; however, its overexpression is correlated with advanced endometrial cancer and poor prognosis [110]. Examples of EGFR inhibtors include erlotinib and gefitinib, both of which are low-molecular weight tyrosine kinase inhibitors.

In a phase II clinical trial of erlotinib in 23 patients with recurrent endometrial cancer, only one patient (4.3%) experienced partial response [115]. In a phase II clinical trial of gefitinib in 29 patients with recurrent endometrial cancer, only one patient (3.4%) experienced complete response [116].

Cetuximab is a monoclonal antibody targeted against EGFR. A phase II clinical trial of cetuximab in management of recurrent endometrial cancer is still ongoing [110].

Trastuzumab belongs to human EGFR type 2 (HER-2)-related inhibitors [110]. HER-2 overex‐ pression is implicated in the development of advanced endometrial cancer and poor prognosis [117, 118], and specifically found in up to 20-30% of patients with serous endometrial cancer [119]. A phase II clinical trial of trastuzumab in 33 patients with HER-2 amplified recurrent/ advanced endometrial cancer did not result in any clinical beneficial response [120]

Lapatinib is an inhibitor targeting EGFR and HER-2 receptors. A phase II clinical trial of lapatinib in management of recurrent endometrial cancer is still ongoing [110].

#### **6.3. Angiogenesis Inhibitors**

rate was 9% and progression-free interval ranged from 1 to 6 months. Despite the drug-related adverse events were well-tolerated, it was concluded that anastrozole does not offer any

Another multi-center phase II clinical trial by Ma and colleagues [108] studied the effect of letrozole in 28 patients with metastatic or recurrent endometrial cancer who previously received progestin-based and/or chemotherapy regimens. One patient (3.6%), two patients (7.1%) and eleven patients (39%) experienced a complete response, a partial response and a median 6.7-month stable disease, respectively. The median time to progression and overall survival were approximately 4 and 9 months, respectively. The most frequently encountered drug-related adverse events in a descending order were: hot flashes, grade I and II (28%),

In short, it can be concluded that AIs greatly failed to offer survival benefits in management

**6. The role of molecular-target therapy in management of endometrial**

As opposed to conventional cytotoxic drugs, molecular-targeted cytotoxic drugs are able to differentiate between normal cells and cancerous cells, and therefore specifically damage only the cancerous cells by inhibiting the cellular molecules/pathways associated with neoplastic

PTEN genetic mutations are associated with reduced apoptosis and are implicated in more than 80% of endometrioid cancer of the uterus [109]. The effects of PTEN genetic muta‐ tions can be decreased by utilizing mammalian target of rapamycin (mTOR) inhibitors (for example, temsirolimus, ridaforolimus, everolimus, and AP2357) by interrupting phosphoi‐ nositide 3-kinase̸AKT̸mTOR pathway [109, 110]. In a phase II clinical trial of temsiroli‐ mus in previously chemotherapy-untreated patients with recurrent endometrial cancer, 26% and 63% of patients experienced partial response and stable disease, respectively [111]. In a phase II clinical trial of temsirolimus in previously chemotherapy-treated patients with recurrent endometrial cancer, 7% and 44% of patients experienced partial response and

In a phase II clinical trial of ridaforolimus as a single agent in patients with advanced endo‐ metrial cancer, a total 29% of patients experienced clinical beneficial response in the form of complete response, partial response or prolonged stable disease for more than 16 weeks [113]. In a phase II clinical trial of everolimus as a single agent in patients with recurrent endometrial cancer, 21% of patients experienced confirmed clinical beneficial response in the form of complete response, partial response or prolonged stable disease at 20 weeks after therapy [114]. There is an ongoing randomized controlled trial single-agent temsirolimus versus a combina‐

survival advantages.

168 Contemporary Gynecologic Practice

followed by fatigue and anemia

of patients with endometrial cancer

proliferation and metastasis [109].

stable disease, respectively [112].

tion of temsirolimus and hormonal therapy [109]

**6.1. Mammalian target of rapamycin (mTOR) inhibitors**

Vascular Endothelial Growth Factor (VEGF) plays central roles in angiogenesis and overexpression is a feature in advanced endometrial cancer and correlated with poor prognosis [110, 121].

In a phase II clinical trial of single agent bevacizumab (a recombinant humanized immuno‐ globulin monoclonal antibody targeted against VEGF) in 52 patients with recurrent endome‐ trial cancer, only 7 patients (around 14%) showed complete/partial response at 6 months following treatment. The median progression-free survival and overall survival were roughly 4 and 11 months, respectively. The adverse side effects were tolerated [122]. Wright and colleagues [123] studied the role of bevacizumab in 10 patients with recurrent endometrial cancer. Only two (20%) and three (30%) patients responded to treatment and experienced stable disease, respectively. A GOG 229-E phase II clinical trial of single-agent bevacizumab, and GOG 229-G phase II clinical trial of a combination of bevacizumab and temsirolimus in management of patients with metastatic endometrial cancer are still ongoing [109, 110].

Aflibercept is a fusion protein with high-affinity against VEGF receptors [110]. In a phase II clinical trial of single agent Aflibercept in 44 patients with recurrent endometrial cancer, only 3 patients (around 8%) experienced partial response. Moreover, 18 patients (41%) experienced progression-free survival of 6 months; however, of these, 8 patients had to withdraw afliber‐ cept secondary to drug-related adverse events. The median progression-free survival and overall survival were roughly 3 and 15 months, respectively [124].

Thalidomide possesses anti-angiogenetic action [110]. In a phase II clinical trial in 24 patients with chemotherapy-unresponsive recurrent endometrial cancer, 3 patients (12.5%) experi‐ enced partial response and 2 patients (8.3%) had a progression-free survival of more than 6 months. The median progression-free survival and overall survival were roughly 1.7 and 6.3 months, respectively [125].

Sunitinib is a multi-kinase inhibitor with an anti-angiogenetic action. It is currently under investigation in clinical trials to assess its effectiveness in management of patients with recurrent endometrial cancer [109, 110].

The existing response rates to molecular-targeted regimen as single-agent treatment are largely insignificant and additional randomized clinical trials are necessary, probably with a combi‐ nation of currently available treatments and an exploration for elements influencing molecular targeted drug sensitivity.
