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Abstract

Keywords

Among female-specific cancers worldwide, endometrial cancer is the third most common after breast cancer and cervical cancer. In addition, it is the most common gynecological cancer in the USA and Europe. The incidence of this disease appears to be increasing. The cause of this increase is multifactorial, but a few possible factors involved are increasing obesity, an aging population leading to more postmenopausal women and greater tamoxifen use. Surgery is generally the primary treatment of this disease and postoperative radiation therapy in some patients with high or intermediate risk may prevent locoregional recurrences. Adjuvant chemotherapy improves progression-free survival in advanced or recurrent cancer. However, overall survival in patients with advanced disease is poor. Hence, better therapy is needed and targeted molecular therapies are emerging as possible treatment candidates. These include molecules that target VEGF, mTOR, tyrosine kinases, human EGF receptors and FGF receptors. Therapies targeting specific molecular features should be evaluated in future strategies in the treatment of endometrial cancer.

The numbers of menopausal women in the world are increasing, and the proportion of those 60 years and older will increase from 11.2% of the total population in the year 2011 to an estimated 22% in the year 2050 [201]. Women over 60 years of age make up 63% of patients diagnosed with endometrial cancer [202]. Hence, this is a disease of postmenopausal women and this feature must be considered when the pathogenesis and its impact is studied [1]. In addition, the incidence of endometrial cancer has grown when compared with that in the year 2000 [2]. Risks of this cancer increase in women who are obese and in those who use tamoxifen [3]. Diabetes and hypertension are also associated risk factors and as a result metformin is under evaluation as a potential targeted therapeutic approach [4,5]. The strategic treatment plans for this disease must concentrate more on prevention and more effective targeted specific cancer abnormalities that minimize unfavorable adverse effects.

The world report by Globocan shows that there were 288,387 new cases of endometrial cancer in 2008 making this the second most common gynecologic cancer after cervical cancer [6]. Accordingly, the world age-specific incidence rate was 8.2 per 100,000 women-years [6]. There were 73,854 deaths from this cancer in 2008 and this number is increasing. In the USA, more than 47,000 estimated new endometrial cancer cases are expected to be diagnosed with 8010 deaths in 2012 [7]. In addition to being the most common cancer among gynecologic cancers in the USA, it is the third ranked cancer following cervical and ovarian cancer in women living in developing countries such as Thailand [8]. Fortunately, most cases are diagnosed at an early stage with good prognoses. However, almost 30% of cases already have regional or distant diseases [202], and many are resistant to traditional therapy. The 5-year survival rate at all stages in the USA (81.8%) [202] is higher than in developing countries (67%) [9].

Current endometrial cancer treatment strategies

A total of 70% of patients have disease localized to the uterus, the rest have some regional or distant spread [202]. Surgery remains the mainstay of primary treatment. Surgical staging should be performed in all apparent early cases, while cytoreductive surgery can be utilized in the patients with advanced diseases. Radical hysterectomy is an option in patients with cervical involvement. New International Federation of Gynecology and Obstetrics staging 2009 has been included in management strategies in Thailand and other countries.

Since one-fifth of patients are premenopausal, conservation of hormone production by retention of the ovaries, in patients with early stage and low-grade tumor, have been reported. No worse overall survival (OS) rates have been observed in these patients whose ovaries have been conserved [10,11]. However, there are two reported cases of ovarian cancer in patients who had their ovaries conserved [12]. Furthermore there is risk of occult ovarian metastases and the risk of hormonal stimulation [13]. Hence, ovarian conservation is a nonstandard strategy, so conservation is still controversial. However, it should be considered that hormonal therapy is the first form of ‘targeted’ therapy and dates back to the 1950s. It should always be considered in this disease as should ovarian preservation.

Postoperative radiation therapy decreases the locoregional recurrence rate for the patients with high–intermediate risk [14,15]. Adjuvant chemotherapy improves progression-free survival (PFS) in advanced or recurrent cancer [16]. Platinum-based regimens are effective alternatives when added to radiation therapy for patients with high-risk, advanced or recurrent diseases and may offer a survival advantage. Combination of cisplatin and doxorubicin significantly improved PFS and OS compared with whole abdominal irradiation in patients with advanced endometrial carcinoma [17]. Concurrent chemoradiation therapies are ongoing in the PORTEC 3 trial and GOG 258 trial. These two trials should help determine the benefit of radiation therapy in high-risk patients who have also received chemotherapy. The future of molecular targeted therapies is potentially useful in early stages in patients with poor prognostic features who are at high risk for recurrence.

The majority of endometrial cancers are diagnosed at an early stage, with approximately 72% stage I, 12% stage II, 13% stage III and 3% stage IV. Most patients with early stage (stage I/II) are potentially cured by surgery with or without adjuvant radiotherapy resulting in a 5-year survival rate of 74–91% [18]. However, mortality rates increase with advancing stage of disease despite advances in radiotherapy, surgery, and chemotherapeutic efforts and the median OS in these patients is approximately 1 year [19,20]. With recent advances in molecular genetic studies, there is evidence to suggest that the morphological and clinical characteristic differences between endometrioid (type I) and nonendometrioid (type II) cancers harbor genetic alterations of various genes that affect signaling pathways and hence may lead to targetable therapies ( Table 1 ) [21,22].

Table 1.

Clinicopathological characteristics classified by types of endometrial cancers.

Clinicopathological characteristics	Type I	Type II
Histologic type	Endometrioid	Nonendometrioid (e.g., serous or clear cell)
Grade	1, 2	2, 3
Precursor	Endometrial hyperplasia	None or carcinoma in situ
Etiology	Unopposed estrogen, obesity	Sporadic
Stage	I, II	III, IV
Survival	Favorable	Poor

Molecular targeted therapy

Potential therapeutic advances in the treatment of women's cancers are molecular therapies. In theory, these can be directed at cancer cells, while eliminating, or at least reducing, adverse side effects. Currently over 10% of gynecologic cancer patients die annually, despite use of the most effective cytotoxic, surgical and radiation strategies [23]. There is also significant toxicity related to these traditional therapies. Drugs targeting molecular pathways directed at cancer cells' survival are potential attractive treatment options.

Understanding the biology of cancer can lead to the development of novel and more effective treatment strategies [24]. Preclinical studies have identified many molecular features that define the transformation to cancer [25]. Some proteins have been discovered, which effectively block the cancerous cascades. These lead to pharmaceutical design and development of novel drugs. Currently, Phase I and II trials have shown promise as viable treatment options. The two types of endometrial cancer are delineated based on their histologic and molecular features which form the basis for targeted therapies [26]. The most common is type I (65%), of which most have PTEN mutations. Type I cancer arises in women with obesity, hyperlipidemia and signs of hyperestrogenism: anovulatory uterine bleeding, infertility, late onset of the menopause and hyperplasia of the stroma of the ovaries and endometrium. It is associated with cancers that are well and moderately differentiated tumors (82.3% grade 1 [well differentiated] and grade 2 [moderately well differentiated]), have superficial invasion of the myometrium (69.4%), then to be highly sensitive to progestogens (80.2%) and have a favorable prognosis (85.6% 5-year survival rate).

Type II endometrial cancer arises in women who tend to be thin and have few of the phenotypic features of patients with type I. This type is found in 35% of endometrial cancers. In patients with the type II endometrial cancer, there are typically no endocrine or metabolic disturbances, and they are often occult, poorly differentiated tumors (62.5% grade 3 [poorly differentiated]) with a tendency for deep invasion of tumor into the myometrium (65.7%); high frequency of metastatic spread into the pelvic lymph nodes (27.8%); decreased sensitivity to progestogens (42.5%); and doubtful prognosis (58.8% 5-year survival rate) [26].

PI3K/AKT/mTOR inhibitors

PIK3CA mutations are very common (36%) in endometrial cancer and were first reported in 2005 [27]. PI3K/AKT/mTOR inhibitors are also promising targets for endometrial cancer because this pathway is often activated.

The PI3K/AKT/mTOR pathway plays an important role in many cellular activities, such as growth, proliferation, survival, motility, autophagy, apoptosis and angiogenesis. It is one of the most commonly activated signaling pathways in human cancers [28,29]. New anticancer agents can be classified as PI3K inhibitors, dual PI3K/mTOR inhibitors, or specific mTOR inhibitors, and AKT inhibitors [30,31]. PTEN is a tumor suppressor gene, and loss of its function by mutation is a common mechanism, and PTEN mutation appears to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated PI3K/Akt/mTOR signaling.

Temsirolimus (CCI-779), an ester of the macrocyclic immunosuppressive agent sirolimus (rapamycin [Rapamune®], Wyeth, NJ, USA), is a cytostatic cell cycle inhibitor with anti-tumor properties. Temsirolimus inhibits the mammalian target of mTOR, a serine–threonine kinase involved in the initiation of mRNA translation [32], and has been shown to inhibit the growth of a wide range of histologically diverse tumor cells. An open-label, multicenter, Phase II study (n = 62) has recently been reported evaluating the therapeutic effects of temsirolimus as a single agent in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer [33]. Temsirolimus, 25 mg intravenously, was administered in 4-week cycles. The results showed 14 versus 4% of partial response, and 69 versus 48% of stable disease in the chemotherapy-naive group versus chemotherapy-treated group, respectively. The adverse events in patients using temsirolimus were not severe and included fatigue, rash, mucositis and asymptomatic pneumonitis (42%). Hematologic adverse events were generally mild, and the most common was lymphopenia. The single-agent activity of temsirolimus was independent of PTEN status. Other agents with differential activities and toxicities have been studied such as everolimus, ridaforolimus and deforolimus [34].

An oral mTOR inhibitor, everolimus, was studied in a single-institution, open-label, Phase II study in patients with measurable recurrent, endometrioid histology, endometrial cancer who had failed at least one and no more than two prior chemotherapeutic regimens [35]. It was administered at a dose of 10 mg daily for 4-week cycles until disease progression or toxicity. A total of 28 patients were evaluated. Twelve out of 28 (43%) patients had not developed disease progression at the time of the first objective evaluation (8 weeks). All these patients had stable disease (SD; median: 4.5 cycles; range: two to ten cycles). Of these patients, 12 discontinued treatment because of toxicity (6 patients), disease progression (5 patients) and noncompliance (1 patient). The common toxicities were fatigue, anemia, pain, lymphopenia and nausea.

A preclinical study in endometrial cancer cell lines using a dual PI3K/mTOR inhibitor, NVP-BEZ235, was recently reported [36]. There were anti-tumor effects of NVP-BEZ235 and RAD001 (an mTOR inhibitor) in 13 endometrial cancer cell lines. PTEN mutant cell lines without KRAS alterations (n = 9) were more sensitive to both inhibitors than were cell lines with KRAS alterations (n = 4). Dose-dependent growth suppression was more commonly induced by NVP-BEZ235 than by RAD001. It is suggested that a dual PI3K/mTOR inhibitor, which induced cancer cell growth suppression, could be a promising therapeutic approach for endometrial carcinomas.

Antiangiogenesis strategies

It has been recognized, since the 1970s, that there is an association with viable growing tumor and blood vessel growth stimulating factors [37 –39]. Therefore, VEGF is a major stimulus for endothelial cell proliferation in endometrial carcinoma [40].

Bevacizumab is a recombinant human monoclonal IgG1 antibody that selectively binds to and neutralizes all isoforms of VEGF [41]. The mechanism of action is to bind and inactivate VEGF, thereby inhibiting endothelial and, possibly, tumor cell activation and proliferation [42]. It is approved by the US FDA for metastatic colorectal, non-small-cell lung, renal cell and breast cancers. In gynecological cancers, its use should be considered in the patients with recurrent ovarian cancer and may be useful in patients with endometrial cancers. The most common side effect is hypertension. However, other adverse effects include intractable headaches, bowel perforation and even stroke. However, generally bevacizumab is well tolerated and active based on PFS at 6 months observed in recurrent or persistent endometrial cancer and warrants further investigation. A Phase II, GOG 229 trial recruited 52 patients with persistent or recurrent endometrial cancer previously receiving one to two prior cytotoxic regimens with measurable disease [43]. Bevacizumab dosing 15 mg/kg intravenously every 3 weeks without dose modification except for at least a 10% change in bodyweight were given until progression or prohibitive toxicity. No gastrointestinal perforations or fistulae occurred. Seven patients (13.5%, 90% CI for the true response rate: 6.5–27%), with median response duration of 6 months, experienced clinical responses (one complete response and six partial responses). The median response duration was 6 months. 21 patients (40.4%) survived with tumor-free progression for at least 6 months. Median PFS and OS times were 4.2 and 10.5 months, respectively. A study group of 11 women with multisite recurrent endometrial cancer and leiomyosarcoma treated with single agent bevacizumab, as well as those treated with bevacizumab in combination with cytotoxic chemotherapy showed some partial responses (two out of 11) and stable disease (three out of 11) [44].

Another targeted therapy is VEGF trap (aflibercept), which is a fusion protein containing VEGF binding regions of VEGF receptor, which reacts to VEGF-A ligand ( Figure 1 ). Aflibercept targets VEGF and PGF. It may have activity in ovarian cancer [45]. The Phase II trial by a Gynecologic Oncology Group study evaluated aflibercept in the treatment of recurrent or persistent endometrial cancer [46]. A total of 44 patients were included, 18 patients (41%) had two prior regimens; 27 (61%) had prior radiation. Aflibercept, 4 mg/kg intravenously every 14 days (4-week cycles), was administered until disease progression or prohibitive toxicity. The 6-month PFS rate was 41%; three patients (7%; 90% CI: 2–17) had partial response. Of note, 10 patients (23%) met the PFS at 6 months end point without starting a subsequent therapy; and the remaining eight patients discontinued therapy for toxicity and started another therapy before the 6 months elapsed. Median PFS and OS were 2.9 and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23; 5%), constitutional (seven; 0%), hemorrhage (two; 5%), metabolic (seven; 2%) and pain (seven; 0%). Two treatment-related deaths were recorded: gastrointestinal perforation and arterial rupture. FGF1 expression was associated with response. In conclusion, aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population.

Figure 1.

Pathways of recent molecular targeted drugs in endometrial cancer cells and tumor-associated endothelial cells.

FGF receptor inhibition

Molecularly targeted therapies of this variety have been effective in some cancer types, although no targeted FGF receptor (FGFR) therapy is approved for use in endometrial cancer. The recent identification of activating mutations in FGFR2 in endometrial cancer has generated a novel target for the development of therapeutic agents. The somatic mutations of the FGFR2 tyrosine kinase (TK) gene are present in 12% of endometrial carcinomas, with additional instances found in cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in fibroblast (NIH 3T3) cells in vitro [47]. The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that are associated with craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation.

FGFR2 gene encodes FGFR2b in epithelial cells, and FGFR2c in mesenchymal cells. FGFR2b is a high affinity receptor for FGF1, FGF3, FGF7, FGF10 and FGF22, while FGFR2c for FGF1, FGF2, FGF4, FGF6, FGF9, FGF16 and FGF20. Gene amplification or missense mutation of FGFR2 occurs in endometrial cancer and also ovarian cancer. Genetic alterations of FGFR2 induce aberrant autoinhibition of FGFR2 signaling activation by over releasing FGFR2, or creation of a FGF signaling autocrine loop. Switching of FGFR2b to FGFR2c is associated with a more malignant phenotype [48].

Mutations that predominantly occur in the endometrioid carcinoma, type I endometrial cancer, are mutually exclusive with KRAS mutation, but occur in the presence of PTEN abrogation ( Table 2 ). In vitro studies have shown that the endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074. Investigation of these agents in endometrial cancer patients with activating FGFR2 mutations is warranted [49]. Among PD173074, SU5402 and AZD2171 functioning as FGFR inhibitors, AZD2171 seems to be the most promising anticancer drug. Cancer genomics and genetics show a cancer-driving pathway towards therapeutic optimization. FGFR2ome is defined as a complete data set of single nucleotide polymorphisms, copy number variation, missense mutation, gene amplification and predominant isoform of FGFR2. FGFR2ome analyses in several tumor types should be carried out to establish integrative database of FGFR2 for the rational clinical application of targeted therapy [48]. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such as FGFR2 mutation inhibits transformation and survival of cancer cells, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma [47].

Table 2.

Molecular characteristics classified by types of endometrial cancers.

Molecular genetic characteristics	Mechanism	Type I approximate frequency (%)	Type II approximate frequency (%)	Ref.
HER2/neu	Amplification/overexpression	0–3	30–40	[53,66,74–77]
KRAS	Mutation	10–40	0–10	[78,79]
β-catenin	Mutation	10–45	0–3	[80–82]
E-cadherin	Reduced/nonexpression	10–60	40–90	[80,83–85]
FGFR2	Mutation	16	2	[47,86,87]
EGFR	Overexpression	40–45	35–60	[75,88,89]
PIK3CA	Amplification	2–15	45	[90–92]
TP53	Mutation/overexpression	5–20	80–90	[93,94]
PTEN	Mutation/deletion	50–80	Up to 10	[95,96]
MLH1	Promoter methylation	20	Rare	[97,98]
CDC4	Mutation/deletion	Rare	15	[99]
MSI	MMR gene defects	20–45	0–15	[100–103]

The FGF family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including breast and ovarian carcinomas. The identification of activating mutations in the FGFR2 gene in endometrial tumors, such agents with activity against FGFRs, are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Effects of FGFR inhibition on the in vitro efficacy of contemporary chemotherapy in endometrial cancer cell lines were evaluated. Human endometrial cancer cell lines with wild-type or activating FGFR2 mutations were used to determine any synergism with concurrent use of the pan-FGFR inhibitor, PD173074, and the chemotherapeutics, doxorubicin and paclitaxel, on cell proliferation and apoptosis. As a result, FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with doxorubicin or paclitaxel showed synergistic activity in the FGFR2 mutant cell lines evaluated. Even though the nonmutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the cytostatic effect of doxorubicin and paclitaxel in a subset of FGFR2 wild-type endometrial cancer cell lines. A potential therapeutic benefit from combination of an FGFR inhibitor with standard chemotherapeutic agents in endometrial cancer therapy particularly in patients with FGFR2 mutation positive tumors has been suggested [50]. FGFR is one of the most interesting targets and requires further clinical evaluations in patients with advanced or recurrent endometrial cancers.

HER2/neu & EGFR inhibitors

The membrane TK receptors of the human EGF receptor (HER) family play a significant role in cancer development. Binding of a growth factor to the extracellular domain results in aggregation and conformational shifts in the receptor and activation of the inner TK leading to activation of secondary signals by downstream phosphorylation [51]. The EGF receptor (EGFR) family consists of four groups of TK receptors: ErbB-1 or EGFR, ErbB-2 or HER2/neu, ErbB-3 or HER3, and ErbB-4 or HER4 [52]. Cancer growth can be driven by overexpression of these receptors. Recently, HER2/neu overexpression and gene amplification were found to be more prevalent in patients with papillary serous endometrial cancer, whereas, grade 1 endometrioid adenocarcinoma showed a lower level [53 –55]. These observations provide a role in the targeted therapy of uterine papillary serous carcinoma for the use of trastuzumab (anti-HER2/neu antibody). Inhibition of EGFR signaling is accomplished by using either monoclonal antibodies (e.g., trastuzumab) against the extracellular domain or small molecule inhibitors (e.g., erlotinib, gefitinib, lapatinib and imatinib) against the intracellular kinase domain of the receptors. A Phase II GOG study evaluating the use of trastuzumab as a single agent did not demonstrate any activity in women with advanced or recurrent HER2/neu-positive endometrial carcinoma [56]. However, such results have recently been challenged, due to the many shortcomings in the design of the GOG181b study [57]. Evidence of trastuzumab activity in uterine papillary serous carcinoma has been reported in vitro, as well as in case reports of advanced and recurrent cases [58 –60]. Promising results were obtained in these heavily pretreated patients either with trastuzumab alone or in combination with chemotherapy. This supports the hypothesis that trastuzumab may be an attractive treatment option for advanced stage papillary serous tumors that overexpress the erbB2, and is worthy of further study [61].

It was revealed that HER2 is overexpressed in endometrial cancer tissue, with high-grade nonendometrioid type of cancer tissue [62]. Monoclonal anti-HER2 antibody (trastuzumab) was used to treat these patients with measurable, HER2 overexpression or HER2 amplification tumors, International Federation of Gynecology and Obstetrics stage III, IV, or recurrence [56]. It was administered intravenously at a dose of 4 mg/kg in the first week, then 2 mg/kg weekly until disease progression. A total of 33 of the 286 tumors (11.5%) were HER2 amplified. Three out of eight (38%) clear cell carcinomas and seven out of 25 serous carcinomas (28%) had more HER2 amplification compared with 7% (two out of 29) of endometrioid adenocarcinomas. This study revealed no major tumor responses. Twelve patients experienced stable disease, 18 had progressive disease and three were indeterminate. Neither HER2 overexpression nor HER2 amplification appeared to be associated with survival. As a single agent, trastuzumab did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification in Phase II trials. As there were controversial and debated evidences, trastuzumab in combination should undergo further study.

EGFR inhibitors are agents that react to inhibit EGFR on cancer cells ( Figure 1 ). Erlotinib is a small molecule and a potent reversible inhibitor of EGFR TK that blocks receptor autophosphorylation. A Phase II study of erlotinib (NCIC IND-148) was performed to evaluate the single-agent activity of erlotinib in patients with advanced, recurrent or metastatic disease who were chemotherapy naive and had received up to one line of prior hormonal therapy [63]. It was administered at a daily dose of 150 mg. A total of 32 patients were evaluated. Drug-related severe toxicities were infrequent, with grade 4 elevation of transaminases (AST). There were four partial responses (12.5%; 95% CI: 3.5–29%) lasting 2–36 months. Fifteen patients had SD, with a median duration of 3.7 months (range: 2–12 months). EGFR expression was positive in 19 patients. Three patients had partial response (16%), seven (37%) had SD, eight had progressive disease and one was not assessable. Erlotinib was tolerated with a 12.5% overall objective response rate. Molecular analysis did not identify EGFR mutations in responders or correlation of response with gene amplification [63].

Gefitinib is a direct inhibitor of the EGFR TK by binding to the ATP-binding site of the enzyme. Thus the function of the EGFR TK in activating the Ras signal transduction cascade is inhibited; malignant cells are also inhibited. Gefitinib is the first selective inhibitor of the EGFR TK, which is also referred to as HER1 or ErbB-1 [64]. An in vitro study on type I Ishikawa H and type II Hec50co endometrial carcinoma cells showed potential therapeutic effects of gefitinib with different sensitivities [65].

Lapatinib is a dual EGFR/HER2 kinase inhibitor. The therapeutic implication in endometrial carcinoma is supported mainly by studies in human cancer cell lines and it is being investigated currently in clinical trials [66]. A Phase II trial was performed to evaluate the efficacy and safety [67]. Patients with persistent/recurrent endometrial cancer following one or two prior regimens were treated with 1500 mg oral lapatinib daily until progression or severe toxicity. Three patients out of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. It was implied that lapatinib may be beneficial in some cases.

Multitargeted pathway inhibition

Imatinib mesylate is a TK inhibitor which specifically targets the c-Kit, Abl and PDGF receptor. The majority of primary and recurrent endometrioid adenocarcinoma, as well as primary and recurrent uterine papillary serous carcinomas express Abl and PDGF receptor. This preclinical data suggests that imatinib mesylate may be useful in the treatment of patients with endometrial carcinoma [68].

The group of TK inhibitors is composed of anti-TK receptors, intracellular TK and multi-TK inhibitors. They are successful in inhibiting various cancers. TK receptor inhibitor (sorafenib) has been used in the treatment of endometrial cancer. The nonrandomized Phase II trial recruited 40 patients with uterine carcinoma who had measurable diseases and zero to one prior chemotherapy regimen [69]. Sorafenib (400 mg) was administered orally twice daily, in a 4-week cycle. Two (5%) patients had a partial response and 17 (42.5%) achieved SD. Five out of 17 patients had SD lasting at least 4 months. The 6-month PFS rate was 29%, and the median OS was 11.4 months. Grade 3/4 drug-related toxicities included hypertension (13%), hand–foot syndrome (13%), hypophosphatemia (7%), anemia (5%), rash (5%), diarrhea (5%), thrombosis (5%), fatigue (5%) and bleeding (5%). Sorafenib had some activities in patients with uterine carcinoma. Continuing studies will move to reveal whether these are beneficial.

More targets other than VEGF are in ongoing studies. Focal adhesion kinase [70,71], EZH2 and Dll4 are active molecules for angiogenesis and cancer growth ( Figure 1 ) [24]. A number of preclinical studies will be conducted.

Conclusion

Currently, surgery is the main treatment, with postoperative radiation therapy used in high–intermediate risk patients to decrease their locoregional recurrences. Adjuvant chemotherapy has improved PFS in advanced or recurrent cancers. Molecular targeted therapies are in focus including anti-VEGF, mTOR inhibitors, TK inhibitors, human EGFR and FGFR inhibitors. They could become future strategies among patients with endometrial cancer in developing countries and the world.

Future perspective

It is important to continue to identify and study molecularly targeted therapies, such as antiangiogenesis therapies. In addition to current standard chemotherapy regimens [72], these molecular targeted therapies may further improve tumor responses. Neoadjuvant molecular therapy, concurrent with radiation therapy or sequential adjuvant postoperative chemotherapy in advanced and recurrent cancer should be the focus of further studies. Synergistic effects from combined antiangiogenesis and other molecular targeted therapies have been revealed in preclinical studies and require evaluation [73]. Hence, clinical studies including combinations of these drugs such as bevacizumab and temsirolimus should be considered as in (GOG229G) and other ongoing studies (GOG229L and GOG229K).

Executive summary

World incidences of endometrial cancer are increasing in high-risk women, including the elderly, those with obesity and tamoxifen users.

Women over 60 years of age make up 63% of women diagnosed with endometrial cancer.

Patients with early-stage disease have a good prognosis with the current surgical, radiation therapy and chemotherapeutic treatment strategies.

However, further investigations of modern molecular therapies are needed to improve prognosis in women with advanced and recurrent cancers.

Molecular targeted therapies are potentially useful in early stages, given promising results with patients at more advanced stages.

The main categories of targeted therapy are: PI3K/AKT/mTOR inhibition; angiogenesis and FGF receptor inhibition; HER2 and EGF receptor inhibition; and multitargeted pathway inhibition.

Other targets include: aflibercept, focal adhesion kinase inhibitor, enhancer of zeste homolog 2 inhibitor and delta-like ligand 4 inhibitor.

Combination treatments show promise for the future.

Footnotes

Acknowledgements

The authors thank P Nartthanarung and T Nartthanarung, Kasetsart University Laboratory School, International Program, Bangkok, Thailand, for assisting in manuscript preparation and figure creation.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Targeted Endometrial Cancer Therapy as a Future Prospect

Abstract

Keywords

Current endometrial cancer treatment strategies

Molecular targeted therapy

PI3K/AKT/mTOR inhibitors

Antiangiogenesis strategies

FGF receptor inhibition

HER2/neu & EGFR inhibitors

Multitargeted pathway inhibition

Conclusion

Future perspective

Footnotes

Acknowledgements

References