Recent and current Phase II clinical trials in ...

Review

Recent and current Phase II clinical trials in endometrial cancer: review of the state of art 1.

Introduction

2.

Early-stage disease

3.

Advanced, metastatic and

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of Toronto on 06/20/14 For personal use only.

recurrent disease 4.

Conclusion

5.

Expert opinion

Stephanie Lheureux, Michelle Wilson & Helen J Mackay† Princess Margaret Hospital, Division of Medical Oncology and Hematology, Ontario, Canada

Introduction: Endometrial cancer (EC) is the most common gynecological cancer in the developed world. For women with advanced or high-risk disease, survival has remained unchanged over the last 20 years highlighting the need for better therapies. Phase II trials are critical to ascertain an estimate of benefit and determine which new agents undergo further development. Areas covered: Based on a literature search of MEDLINE and ASCO over the last 5 years, the authors present Phase II clinical trial data in the context of EC management. They highlight ongoing clinical trials from the National Cancer Institute website and suggest future directions to address ongoing questions. Expert opinion: A better understanding of EC biology and high-quality preclinical studies will inform the future design of EC Phase II studies. Inclusion of correlative studies and continued longitudinal profiling in future trials is essential to elucidate mechanisms of drug resistance and response. Targeting the phosphoinisotol-3-kinase, angiogenesis, DNA repair and metabolic pathways appear promising strategies for subsets of patients with recurrent or advanced disease. Further, investigation of maintenance strategies and radio-sensitizing agents in the frontline setting should be explored. Given the patient demographic, and frequency of co-morbidities, tolerability and quality of life are key be considerations when designing future studies. Keywords: clinical trial, endometrial cancer, Phase II, treatment Expert Opin. Investig. Drugs (2014) 23(6):773-792

1.

Introduction

Endometrial cancer (EC) is the most common gynecological cancer in Western countries with 49,560 new cases and 8190 deaths estimated in 2013 in the USA [1]. More than 90% of cases occur in women older than 50 years of age, with a median age of 63. Furthermore, with an aging population the incidence of EC is likely to continue to rise. Standard chemotherapy has remained unchanged for many years with no molecularly targeted therapies approved in this disease site. Consequently, EC lags behind other caner types and is in desperate need for effective therapies. Phase II trials are critical to determine which novel agents deserve further investigation in EC. Well-established risk factors for EC have been identified, which in some cases, may inform and be relevant for future development of therapeutic interventions. Long-lasting endogenous or exogenous hyperestrogenism including polycystic ovarian syndrome and tamoxifen therapy is associated with development of EC [2-5]. Type 2 diabetes and obesity (body mass index > 30) increase the risk of EC three- to fourfold. Age and histological grade have been associated with a worse prognosis [6].

10.1517/13543784.2014.907272 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

773

S. Lheureux et al.

Article highlights. . . .

.

.


. .

Endometrial cancer (EC) survival has not changed. Classification by histology and molecular aberrations are likely to stratify future trials. Standard therapy has remained similar over the past 20 years highlighting the need for novel therapeutics strategies. Targeting the PIK3CA pathways needs further investigation and further clarification of relevant biomarkers. Antiangiogenesis agents seem to be an useful strategy. Metformin is an interesting drug, which is likely to be the subject to a number of upcoming trials. EC patient characteristics need to be considered particularly with respect to toxicities and elderly population.

This box summarizes key points contained in the article.

Histopathological features Two main clinicopathological types of EC have been recognized (Figure 1): estrogen-dependent endometrioid (type I) representing 80% of EC and estrogen-independent non-endometrioid carcinoma (type II), including serous, clear cell carcinoma, carcinosarcoma, mucinous adenocarcinoma, squamous cell carcinoma and mixed adenocarcinoma [5]. Despite molecular differences, a pooled analysis suggests both types share many common etiologic factors [7]. To date, the implications of the different subtypes remain not well defined. 1.1

Molecular characteristics EC is associated with a number of inheritable germline mutations including loss of DNA mismatch repair in Lynch syndrome [8]. For women with the Lynch syndrome (LS), EC will be the first cancer-related diagnosis in 40 -- 60% of patients [8,9]. A rare autosomal dominant condition associated with mutation in phosphatase and tensin homolog (PTEN), Cowden syndrome carries a 5 -- 19% risk of EC [8]. The recent integrated genomic characterization of EC has identified four categories (Figure 1): i) POLE ultramutated (catalytic subunit of DNA polymerase epsilon involved in nuclear DNA replication and repair); ii) microsatellite instability (MSI) hypermutated; iii) low copy number; and iv) high copy number [10]. Uterine serous tumors and approximately 25% of high-grade endometrioid tumors have extensive copy-number alterations, few DNA methylation changes, low estrogen/ progesterone receptor (PrR) levels and frequent TP53 mutations [10]. MSI in tumor samples occurs approximately 25% of sporadic cases of EC [11]. An alteration of phosphatidylinositide 3-kinases (PI3K)/ protein serine-threonine kinase AKT pathway was described in 92 and 60% of type I and II tumors, respectively [10]. EC has more frequent mutations in the PI3K/AKT pathway 1.2

774

than any other tumor type studied by the Cancer Genome Atlas. The PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates key aspects of cancer biology including metabolism, cellular growth and survival (Figure 2) [12,13]. Activation of the PI3K/AKT pathway occurs frequently in type I EC through a variety of mechanisms: loss of PTEN up to 70% of cases and or PI3K mutations occurring in up to 36% of cases [14,15]. A recent large series confirmed that type I tumors are characterized by PTEN loss and also showed that type II tumors are characterized by increased levels of mTOR and lower rates of PTEN [16]. This observation showed that PTEN has a main role in the pathogenesis of type I, and mTOR is mainly involved in type II EC. In addition to its role in regulating the PI3K/ AKT/mTOR pathway, PTEN loss of function causes genetic instability, a phenotype attributed to defects in homologous recombination DNA repair [17,18]. This may make EC susceptible to synthetic lethality. Globally, the role and interaction of the microenvironment are not well understood. In current practice, patients are not treated on molecular characterization. 2.

Early-stage disease

The majority of patients present with operable early-stage disease with 5-year survival approximately 80% [19,20]. Extent of surgery at diagnosis with the inclusion or not of lymphadenectomy is controversial and beyond the scope of this review. Optimizing adjuvant therapy, particularly in high- and intermediate-risk patients, is currently an active area of research. Adjuvant radiotherapy is currently the standard of care for International Federation of Gynecology and Obstetrics stage IB to II with intermediate risk of relapse. Risk factors identified that predict risk of recurrence include: histological subtype, histological grade, myometrial invasion ‡ 50%, lymphovascular space invasion, lymph node metastases and tumor diameter > 2 cm [21]. Many advocate chemotherapy for those with stage III disease or poor prognostic histology based on GOG 122 [22] and confirmed in other studies [23]. The role of chemotherapy in addition to radiotherapy for high-risk, higher stage and poor prognostic histology is being further investigated in Phases III studies PORTEC3, GOG 249 and GOG 258. Phase II studies of adjuvant chemoradiotherapy Current Phase II trials of chemotherapy in combination with radiotherapy are seeking to optimize both the regimen and the sequence of delivery of these therapeutic modalities. Based on the curative intent of treatment, and recognizing the comorbidities and biological age of many EC patients, tolerability is a key priority in these trials. Timing of radiotherapy in relation to chemotherapy before, after and mid- (so called sandwich) treatment and concurrent schedules are under investigation (Table 1). 2.1

Expert Opin. Investig. Drugs (2014) 23(6)

Recent and current Phase II clinical trials in EC

Endometrial cancer


Type I Oestrogen dependant endometrioid

Type II Non-estrogen dependant Non-endometrioid

MSI (20 – 40%)

Serous: TP53 mutation (90%)

KRAS mutation (11 – 26%) β-catenin accumulation (18 – 47%)

HER2 alteration (40%) Clear cell: HG nuclei-glycogen-rich

HER2 alteration (10%)

Carcinosarcoma: aggressive behaviour

PI3KAKT/mTOR-PTEN pathway highly dysregulated in both type mechanisms leading to pathway activation different in both type

POLE ultramutated

MSI

CN low

CN high

Figure 1. Endometrial cancer is a heterogeneous disease with distinct molecular characteristics. CN: Copy number; HG: High grade; MSI: Microsatellite instability.

Three Phase II trials have investigated ‘sandwich’ schedules [24-26]. Reported 3-year progression-free survival (PFS) ranging from 50 to 71% and 3-year overall survival (OS) between 68 and 90% [24-26]. Radiation was completed in 86 -- 95% of women with 80 -- 85% receiving all chemotherapy treatment cycles [24-26]. The chemotherapy combinations used in these studies were docetaxel/carboplatin and paclitaxel/carboplatin, with lower rates of grade 3 -- 4 neurotoxicities seen with the former regimen. One of these trials by Einstein et al. limited inclusion criteria to women with serous EC [26]. In contrast to the other studies, 78% had stage I disease [26]. In early stage (I/II) disease, they demonstrated PFS and OS of 65.5 and 76.5 months and with PFS and OS of 25.8 and 35.9 months in stage III/IV patients, respectively. By contrast, other studies have given the entire chemotherapy course prior to radiotherapy based on the rationale that the deliverable dose intensity of chemotherapy postradiation may be reduced and that infield chemosensitivity may be lower than in un-irradiated tissue; both factors translating into high rates of progression and recurrence. Scribner et al. gave six cycles of carboplatin/docetaxel to patients with stage III disease at initial diagnosis; 84.4% were endometrioid histology [27]. PFS and OS at 3 years were 54.4 and 65.8%, respectively [27]. Completion rates for chemotherapy were 73.3% [27]. Twenty percent did not receive radiation with the most common reason being noncompliance, small bowel obstruction, enteritis and neutropenia [27]. Concurrent chemoradiation was explored in women with serous EC. Patients received six doses of weekly paclitaxel

combined with radiation followed by four cycles of adjuvant paclitaxel [28]. The full radiation dose was delivered in 90% of patients with 60% of patients completing all cycles of chemotherapy. Only one (3.3%) patient had grade 3 neuropathy [28]. PFS at 5 years was 83% and OS 85%. Similar to the Einstein study, the majority (60%) of patients had stage I disease [28]. Concurrent treatment with weekly carboplatin (AUC 2) with radiation followed by four cycles of carboplatin/paclitaxel has also been investigated. Completion rates of chemotherapy were only 68% with 10% developed hypersensitivity reactions to platinum, a higher than expected rate in a chemo-naive population [29]. In patients with high-intermediate risk disease, vaginal cuff brachytherapy followed by three cycles of doublet therapy with carboplatin/paclitaxel has been investigated with 83% completing all chemotherapy [30]. At 3 years, 87% were disease free [30]. The effect of adjuvant therapy on quality of life has been investigated in a small study involving four cycles of carboplatin/paclitaxel followed by radiation and brachytherapy [31]. There was no overall change in health score with therapy with < 3% experiencing non-hematological grade 3 -- 4 toxicities. Current Phase II trials (Table 2) continue to investigate the sequence and the components of therapy. Chemotherapy regimens under scrutiny are variations of a platinum/taxanebased doublet. Only one trial currently limits the histology to endometrioid (NCT0037362). With Phase II studies, cross-trial comparisons are complex and subject to bias. Optimal sequence and regimen have yet


775

S. Lheureux et al.

VEGFR

ER/PR


Megesterol acetate Tamoxifen Anastrazole Letrozole Mifeprestine Fulvestrant

EGFR/HER2

Trastuzumab Aflibercept Bevacizumab Thalidomide

Brivanib E7080 Sunitinib Cabozantinib

Erlotonib Gefitinib Lapatanib

PTEN PIP2 p85 PI3K PIP3

PDK

AKT

mTORC2

mTORC

mTORC1 mRNA translation

BKM 120 XL147

MK 2206

GDC-0980 PF-05212384 PF-04691502 XL147 GDC-0980 Everolimus Ridaforolimus Temsirolimus PF-05212384

Transcription factors

Angiogenesis

Apoptosis Cell cycle arrest

Cell growth Cell proliferation

Figure 2. Current and recent targeted agents in Phase II trials. Upon stimulation of receptor tyrosine kinases, PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate 2 (PIP2) into PIP3 resulting in the activation of AKT. Among its targets, AKT controls the activation of the downstream effector of the pathway, the mammalian target of rapamycin (mTOR) which activates two key substrates 4EBP1 and p70S6K resulting in increased translation of target genes involved in angiogenesis (VEGF) and cell cycle progression (cyclin D1, c-Myc) [12]. Tumor suppressor PTEN can dephosphorylate PIP3, reversing AKT activation and inhibiting further downstream signaling. However, in the absence of PTEN inhibition, AKT phosphorylates, leading to mTOR activation. ER: Estrogen receptor; HER2: Human EGFR 2; PI3K: Phosphatidylinositide 3-kinase; PIP: Phosphatidylinositol-4,5-bisphosphate; PrR: Progesterone receptor; PTEN: Phosphatase and tensin homolog; VEGFR: Vascular EGFR.

to be identified in EC. Toxicity is a problem that can compromise delivery of the recommended combined therapy with myelosuppresion, a common occurrence. Despite the belief that clear cell and serous cancers require chemotherapy as they have a high risk of progression, data from GOG 776

122 and NSGO trials did not support a benefit in patients with serous histology [22,23]. Trials exploring this issue are required together with further exploration of the impact of adjuvant treatment on the emerging molecular subgroups of EC and the interest of biologic targeted agents.



Table 1. Published and presented trials on adjuvant therapy in endometrial cancer in last 5 years. Study Lupe et al. (2009) [25]

N 43


41 Narayan et al. (ASCO 2010) [29]

Geller et al. (2011) [24]

41

Koensgen et al. 35 (ASCO 2011) [31]

Einstein et al. (2012)[26]

Scribner (2012) [27]

Jhingran et al. (2013) [28]

Landrum et al. (2013) [30]

78

Treatment

Indication

Drug activity

External beam radiation (45 -- 50.4 Gy) ± HDR (3# 5 -- 7.5 Gy) brachytherapy sandwiched’ in 6 cycles Paclitaxel 175 m/m2 Carboplatin (350 mg/m2) every 21 days (4 cycles pre and 2 postradiation) External beam radiation (54 Gy) with carboplatin (AUC2) weekly 6 during radiation, followed by four cycles Paclitaxel 175 m/m2 Carboplatin (AUC 5 -- 6) every 21 days

Stage III and IV ECs with minimum TAH/BSO Endometrioid histology 37%

Chemotherapy completed 81% Radiation completed 100% HDR brachytherapy completed 95% Med DFS = 50 months Med OS = not reached 3-year DFS = 53% 3-year OS = 68%

High-risk EC following a minimum of TAH/BSO Clear cell/serous histology excluded

External beam radiation (45 Gy) ± HDR (1 -- 3#) brachytherapy ‘sandwiched’ in 6 cycles Docetaxel 75 m/m2 Carboplatin (AUC6) every 21 days (3 cycles pre- and postradiation) Paclitaxel 175 m/m2 Carboplatin (AUC5) every 21 days for 4 cycles followed by external beam radiation (45 Gy) and brachytherapy (15 Gy) External beam radiation (45 Gy) ± HDR brachytherapy (3# 5 Gy) ‘sandwiched’ in 6 cycles Paclitaxel 175 m/m2 Carboplatin (AUC 6 -- 7.5) every 21 days (3 cycles pre- and postradiation) Docetaxel 75 m/m2 Carboplatin (AUC6) every 21 days for 6 cycles followed by external beam radiation (50.4 Gy) ± brachytherapy (low or high dose)

Stage III and IVb ECs with minimum TAH and surgical staging Endometrioid histology 78%

Concurrent chemotherapy completed 78% Adjuvant chemotherapy (four cycles) completed 78% All chemotherapy completed 68% Radiation completed 100% 3-year FFS 73% 3-year OS 93% Chemotherapy completed 85% Radiation completed 39/41 pts 95% HDR brachytherapy completed 25 pts Estimated 3-year PFS 71% Estimated 3-year OS 90%

High-risk EC following TAH/BSO/ Chemotherapy completed 100% lymphadenectomy Radiation completed 100% Endometrioid histology 86% 2-year PFS 77.1% No overall change in quality of life Stages I--IV uterine papillary serous carcinoma with no residual disease postsurgery Serous histology 100%

Chemotherapy completed 83.3% Radiation completed 85.9% Brachytherapy in 63 patients PFS (stage I/II) = 65.5 months OS (stage I/II) = 76.5 months PFS (stage III/IV) = 25.8 months OS (stage III/IV) = 35.9 months 45 Stage III and IV ECs (confined to Chemotherapy completed 73.3% pelvis) with minimum TAH/BSO Radiation completed 77.8% (20% Endometrioid histology 84% refused any radiation) HDR brachytherapy completed 11 pts Med PFS 36.9 months Med OS 74.5 months Estimated 3-year PFS 54.4% Estimated 3-year OS 65.8% 31/32 External beam radiation (45 Gy) Stage I--IIIA uterine papillary Concurrent chemotherapy completed with Paclitaxel (50 mg/m2) serous carcinoma with no 60% weekly 5 during residual disease postsurgery Adjuvant chemotherapy (4 cycles) radiation, + HDR brachytherapy Serous histology 100% completed 77% (3# 5 Gy) followed by 4 cycles Radiation completed 90% Paclitaxel 135 m/m2 every 2-year local control rate 87% 21 days 2-year PFS 87% 2-year OS 93% 5-year local control rate 87% 5-year PFS 83% 5-year OS 85% 23 Vaginal cuff brachytherapy High-intermediate risk EC or Chemotherapy completed 83% 3 fractions (700 cGy) stage I--IIB serous or clear cell Radiation completed 100% Paclitaxel 175 m/m2 Carboplatin Endometrioid histology 65% 3-year PFS 91% (AUC6) every 21 days for 3 cycles

DFS: Disease-free survival; EC: Endometrial cancer; FFS: Failure-free survival; Gy: Gray; HDR: High-dose rate; i.v.: Intravenous; mths: Months; OS: Overall survival; PFS: Progression-free survival; pts: Patients. Expert Opin. Investig. Drugs (2014) 23(6)

777

S. Lheureux et al.

Table 2. Current NCI Phase II trials in adjuvant setting.


Trial

Treatment

Patient selection

NCT01461746

Docetaxel plus cisplatin followed by radiation after surgery in high-risk EC

NCT01041027

Radiation sandwiched between chemotherapy with carboplatin and paclitaxel (three cycles pre- and postradiation). The fourth cycle overlaps with internal high-dose radiation

NCT00373620

Concurrent chemotherapy and radiation with weekly paclitaxel after surgery Paclitaxel and carboplatin

NCT00584909

NCT00258362

NCT01943058

Carboplatin. Docetaxel and radiation therapy (induction chemotherapy) followed by consolidation chemotherapy Carboplatin and paclitaxel with or without herceptin Medroxyprogesterone acetate plus levonorgestrel-releasing intrauterine system (LNG-IUS) Megestrol acetate or LNG-IUS

NCT00483327

Megestrol acetate

NCT00788671

Levonorgestrel intrauterine device

NCT01877564

Preoperative metformin (randomized)

NCT01367002 NCT01594879

High-risk disease defined as stage III, stage II and stage I with two of the following: grade 3, LVI myometrium involvement greater than ½, stage Ib-II clear cell or serous carcinoma High-risk EC defined as: Stage I with < 50 myometrial invasion and grade 3 with LVI Stage I with > 50% myometrial invasion and grade 2 or 3 tumor Stage II or III Stage IV with no residual macroscopic disease Endometrioid carcinoma stage III/IV

Primary end point PFS

Location of recurrence Toxicity

2-year PFS

High-risk stage II and Ic grade 2 and 3 ECs Terminated Stage III and IV ECs Closed awaiting results

DFS

Advanced (stage III/IV) or recurrent uterine serous papillary carcinoma. Grade 1 endometrial carcinoma confined to endometrium based on MRI Atypical endometrial hyperplasia or grade 1 endometrioid adenocarcinoma < 50% myometrial involvement Atypical endometrial hyperplasia or grade 1 or 2 EC Complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma Grade 1 or 2 adenocarcinoma of the endometrium Must be obese and non-diabetic

PFS Markers of response RR

Percentage of patients progression free and alive

RR

Best pathological response RR

IHC-based tissue markers of proliferation: ki67, phosphorylated histone H3, estrogen receptor (ER), PrR and telomerase (hTERT) Tolerability

DFS: Disease-free survival; EC: Endometrial cancer; IHC: Immunohistochemical; LVI: Lymphovascular invasion; NCI: National Cancer Institute; PFS: Progression-free survival; PrR: Progesterone receptor; RR: Response rate.

Adjuvant hormonal therapy This class is traditionally used in the recurrent setting with relatively disappointing evidence supporting the use of hormonal therapy in the adjuvant setting [32-34] However, recently hormonal therapy postchemotherapy has been revisited by Bevis et al. [35]. In 28 patients (71% primary stage III or IV disease), megestrol was continued for 5 years after completing doublet chemotherapy with paclitaxel/carboplatin. Results are encouraging with a median OS of 36.3 months and with a median PFS of 31.9 months. In patients desiring fertility preservation, there may be a role for progestin-based therapy in early-stage disease [36]. It has been 2.2

778

postulated that in a carefully selected small subset of patients with well-differentiated EC and no evidence or myometrial invasion or poor prognostic factors, there may be a role for conservative management. The biggest concern is risk of disease progression while on therapy or after initial response [36]. Most of the data, to date, is encouraging with favorable pregnancy outcomes but is based on small patient numbers. A meta-analysis identified only 12 published studies addressing the efficacy of oral or intrauterine progestin in a total of 230 patients with atypical endometrial hyperplasia (AEH) or early endometrial adenocarcinoma [37]. Only one involved the use of intrauterine progestin [38]. Of the



Table 3. Chemotherapy Phase II trials published in recurrent endometrial cancer.


Study

N

Treatment

Dizon et al. (2009) [49]

52

2

Indication

Ixabepilone 40 mg/m every 3 weeks

Second-line treatment in advanced EC

McMeekin et al. (2009) [48]

50

Trabectedin 1.3 mg/m2 every 3 weeks


Miller et al. (2009) [47]

27

Pemetrexed 900 mg/m2 every 3 weeks


Brown et al. (2010) [51]

21

Primarily advanced or recurrent EC

Emons et al. (EORTC-NCI-AACR 2010) [50]

43

Gemcitabine 1000 mg/m2 and cisplatin 30 mg/m2 D1 and D8 each 21-day cycle Due to myelosuppression, dose reduced to: Gemcitabine 900 mg/m2 and cisplatin 30 mg/m2 D1 and D8 each 21-day cycle Zoptarelin doxorubicin (AEZS-108) 267 mg/m2 i.v. every 3 weeks

Legge et al. (2011) [46]

18

Nonpegylated doxorubicin (Myocet) 60 mg/m2 every 4 weeks


Tait et al. (2011) [45]

24

Gemcitabine 800 mg/m2 days 1 and 8 every 3 weeks


Vandenput et al. (2012) [52]

29

Paclitaxel 60 mg/m2 and Carboplatin 2.7 AUC weekly

Primarily advanced or recurrent EC

LHRH-positive advanced or recurrent EC Majority of pts included were chemo naı¨ve

Drug activity RR = 12% SD ‡ 8 weeks = 60% Median PFS = 2.9 mths 6 months PFS = 20% RR = 2.2% Median PFS = 1.8 mths Median OS = 6.7 mths RR = 4% Median PFS = 2.7 mths Median OS = 9.4 mths CR: 2 pts (10%) PR: 8 pts (40%) SD: 6 pts (30%) Median PFS = 7.2 mths Median OS = 18.2 mths

CR = 5.1% (2 pts) PR = 25.6% (10 pts) SD = 43.6% (17 pts) Median TTP = 7 mths Median OS = 14.3 mths No CR or PR SD = 27.5% Median PFS = 9 weeks Median OS = 2 weeks PR = 4% SD = 39% Median PFS = 1.7 mths Overall RR = 39% Chemo naive: Median PFS = 9 mths Median OS = 12 mths Previous line of chemo: Median PFS = 8 mths Median OS = 9 mths

Chemo: Chemotherapy; CR: Complete response; D: Day; EC: Endometrial cancer; i.v.: Intravenous; LHRH: Luteinizing hormone-releasing hormone; mths: Months; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; RR: Response rate; SD: Stable disease; TTP: Time to progression.

remaining trials examining oral progestin, only 2 were prospective with only 60 patients between them. This highlights the paucity and need for high-quality data evaluating the efficacy and role in this patient population. They found only 2.7% progressed while on therapy but 20.1% relapsed after an initial complete response. All current studies are concentrating on AEH and grade EC with only one allowing grade 2 lesions (Table 2).

therapy are used to improve therapeutic options. Surgery and radiation may be appropriate depending on the location of the recurrent disease and initial treatment. Newer agents are under investigation. As more is learnt about the signaling pathways integral to this disease, clinical trials are being instigated to explore specific targeted therapies in an attempt to improve patient outcomes (Figure 2) [40]. Chemotherapy The most active agents in chemotherapy-naive EC patients are platinum, taxanes and anthracyclines with RRs of 20 -- 30% [41-43]. Prior radiation potentially complicates delivery by compromising penetrance and impacting on bone marrow reserve [43]. Triplet regimens have demonstrated superior RRs at the cost of increasing toxicity [43,44]. Results are expected from the GOG209 shortly, but preliminary data suggest that doublet therapy (carboplatin/paclitaxel) is similar 3.1

Advanced, metastatic and recurrent disease

3.

For patients inoperable at presentation or diagnosed with metastatic or recurrent disease, treatment options are limited. Historically, recurrent EC was managed with hormonal therapy with response rates (RRs) in the order of 20% [39]. Today, both conventional chemotherapy regimens and antihormonal


779


S. Lheureux et al.

to triplet. RRs after first-line chemotherapy are disappointing, with taxanes currently the most effective [41,43]. Various agents have been tested in a number of small Phase II trials (Table 3) [45-49]. The majority of monotherapy trials have shown minimal activity with RR varying from 0 to 12% [45-49]. However, zoptarelin doxorubicin (AEZS-108), a LHRH-cytotoxic hybrid molecule doxorubicin, demonstrating promising results with 31% objective RR [50]. Only 25% of these patients had received prior chemotherapy in contrast to the majority of patients included in the other monotherapy Phase II trials. Zoptarelin doxorubicin is under investigation as second-line therapy in a Phase III trial (NCT01767155). With respect to doublet therapy gemcitabine/cisplatin and weekly carboplatin/paclitaxel have shown evidence of efficacy with promising RRs but at the cost of toxicity particularly hematological toxicities [51,52]. To our knowledge, there are no current on-going Phase II trials investigating chemotherapy alone. Hormonal therapy A significant proportion of EC, particularly the type 1 subtype express estrogen (ER) or progesterone receptors (PrR), makes hormonal therapies an attractive therapeutic option. Agents investigated include progestogens, selective estrogen receptor modulators (SERM), aromatase inhibitors (AIs) and gonadotropin-releasing hormone inhibitors. Studies have demonstrated palliation of symptoms and disease control with RRs ranging from 9 to 55% with an average PFS of 4 months and OS of 7 -- 11 months, with treatments [41,53]. Progestogens, to date, demonstrate the most favorable tolerability and efficacy with RRs of 22% overall [41,53]. Positive receptor status in particular PrR has been shown to correlate with response [54]. Low-grade histology is also predictive of response [39]. A small number of receptor-negative patients may still benefit emphasizing the need to explore the multiple mechanisms involved [39,41,55]. A recent Cochrane review, however, showed no improvement in survival in advanced EC with hormonal therapy [56]. To detect a benefit, large randomized trials would be required, and to date, most trials have had small sample sizes potentially masking benefit [56]. The ability to demonstrate improvement in quality of life and symptom control was also insufficiently assessed in these studies [56]. Results with other commonly used hormonal therapies have been discouraging. AI and tamoxifen (an SERM) have demonstrated overall RR of approximately 10% [57-59]. On subgroup analysis, tamoxifen showed higher RRs of 23 and 14% in grade 1 and 2 patients, respectively [57]. In a recent Phase II trial, mifepristone, a selective PrR modulator was studied in PrR-positive advanced or recurrent EC achieving only stable disease (SD) as a single agent [60]. The combination of tamoxifen and megestrol has been proposed to be more efficacious due to upregulation of the PrR by tamoxifen, but in practice, no clear benefit has been seen [61,62]. 3.2

780

Novel hormonal agents are under investigation (Table 4). Fulvestrant is a pure estrogen antagonist with a high affinity for ER but in contrast to tamoxifen has no agonist activity [63]. Based on the efficacy and tolerability in breast cancer and successful inhibition of tamoxifen-stimulated EC in xenograft models [64], fulvestrant has been studied in two Phase II trials [55,65]. Contrary to expectations, the first trial found a higher RR in PrR-positive than ER-positive patients (20 and 16%, respectively) [55]. An additional study including only ER- or PrR-positive patients demonstrated a partial response (PR) of 11.4% in the intention to treat population and 15.4% in the per protocol arm [65]. Only 40% of patient had received prior chemotherapy [65]. Although this did not reach the planned target for efficacy, three patients achieved remissions lasting > 32 months [60]. Identification of differential immunohistochemical steroid sulfatase expression in normal and cancerous endometrium (86 and 0%) has led to heightened interest in this pathway as a target [66]. This pathway is involved in hydrolysis of estrone and dehydroepiandrosterone sulfates to their active form. In view of promising results in xenograft models [67], a Phase II trial was launched in EC with BN83495, a firstin-class SPS inhibitor (NCT00910091). The results of this study comparing efficacy of BN83495 to megestrol acetate in chemotherapy-naive patients are pending. Further work to clarify the role of hormonal therapy is essential (Table 5). Currently, the PARAGON Phase II study is investigating anastrozole (AI) in women with potentially hormone-responsive recurrent gynecologic neoplasms (ANZGOG 0903). It aims to establish RR, clinical benefit, quality of life and predictors of response across a range of gynecological malignancies with correlative studies integral to the trial design. The PI3K/AKT/mTOR signaling pathway Based on the rationale to target this pathway in EC, six Phase II trials have investigated the use of rapalogs as a single agent in recurrent EC (Table 4). They have demonstrated modest but reproducible antitumor activity across histology subtypes, predominantly SD and an objective RR from 0 to 25% [13,68-73]. RR is higher in chemotherapy-naive patients. This class of agents has shown an acceptable toxicity profile including asthenia, diarrhea, rash, thrombocytopenia, anemia and metabolic abnormalities including hyperglycemia and hyperlipidemia. One of the class-specific toxicities encountered in Phase II studies was interstitial pneumonitis. Hormonal therapy has been studied in comparison with mTOR inhibitors. Progestin has an inferior PFS but no difference in OS when compared directly to an mTOR inhibitor ridaforolimus (PFS 1.9 vs 3.6 months, p = 0.008; OS 8.9 vs 10 months, p = 0.4) [64]. Combination therapy with mTOR and an AI has been trialed based on preclinical evidence that mTOR inhibition overcomes hormonal resistance. The combination of letrozole 2.5 mg with everolimus 10 mg demonstrated a clinical benefit rate (CBR) of 42% in 19 evaluable patients (trial accrual 28 patients) but SD only needed to 3.3



Table 4. Published and presented targeted therapy Phase II trials in endometrial cancer in the past 5 years. Study


Hormonal therapy Ramondetta et al. (2009) [60]

N

Treatment

Indication

12

Mifepristone

Bevis et al. (ASCO 2010) [35]

28

Covens et al. (2011) [55]

53/67*

Carboplatin (AUC6) Paclitaxel (175 mg/m2) every 21 days for 6 cycles with megestrol acetate 40 mg OD for 5 years Fulvestrant 250 mg i.m. 4 weekly

Stomovitz et al. (ASCO 2011) [74]

28

Everolimus (mTOR) 10 mg OD Letrozole (AI) 2.5 mg OD

Recurrent EC 1 -- 2 lines of previous chemotherapy

Emons et al. (2013) [65]

35

Fulvestrant 250 mg i.m. monthly

Advanced or recurrent EC ER or PR positive

Everolimus (mTOR i) 10 mg orally OD

Recurrent or persistent EC £ 2 prior chemo regimen

Advanced, persistent or recurrent EC, and no prior chemotherapy for metastatic disease unless patient achieved CR and was PFS > 6 months after completion of therapy Metastatic and/or locally advanced recurrent EC

PI3K/mTOR/PTEN pathway 35 Slomovitz et al. (2010) [68]

Fleming et al. (ASCO 2011) [75]

21

Temsirolimus 25 mg weekly plus megestrol acetate 80 mg b.i.d. for 3 weeks alternating with tamoxifen 20 mg b.i.d. for 3 weeks

Mackay et al. (ASCO 2011) [72]

35

Ridaforolimus (mTOR i) 40 mg orally for 5 days/ week

Oza et al. (2011) [73]

60

Temsirolimus (mTOR i) 25 mg i.v. weekly

PR-positive advanced or recurrent endometrioid adenocarcinoma (n = 10) or low-grade endometrial stromal sarcoma (n = 2) Stage III-IV or recurrent disease

Recurrent, persistent, metastatic EC One line of chemotherapy

Recurrent or metastatic EC 2 groups chemo-naive (CN: 33 pts) chemo treated (CT: 27 pts)

Drug activity SD = 25% Med PFS = 48 days Med OS = 10 mths

Med PFS = 31.9 mths Med OS = 36.3 mths

RR: ER ±: 16%/0% PR ±: 20%/0% Med PFS (mths): ER ±: 10/2 Med OS (mths): ER ±: 3/26 CBR 42% OR 21% SD defined as ‡ 8 weeks (10/42) PR = 11.4% (ITT) 15.4% (PP) SD = 22.8% Med TTP = 2.3 mths Med OS = 13.2 mths No PR response SD = 43% Med duration of SD = 4.5 mths CBR at 20 weeks: 20% Excess venous thromboses (7 events): DVT (n = 5) and nonfatal PE (n = 2). 1 sudden death 1 myocardial infarction PR: 3 patients PR: 2 pts (CN) Duration = 7.9 and 8.3 mths SD: 58% Median duration = 6.6 mths PD: 35% Response: CN: PR =24%, SD ‡ 8 weeks = 69% CT: PR = 4%, SD ‡ 8 weeks = 46% PFS (mths): CN: 7.33 CT: 3.25

*Only 53 included in analysis as 14 excluded prior to therapy. z Limit based on previous doxorubicin dose -- maximum 320 mg/m2. § Study reports PFS6 of 41% but includes 8 patients who started new therapy due to toxicity. b.i.d.: Twice a day; CN: Chemotherapy naive; CR: Complete response; D: Day; EC: Endometrial cancer; FISH: Fluorescence in situ hybridization; i: Inhibitors; i.m.:intramuscular; i.v.: Intravenous; mths: Months; mTOR: Mammalian target of rapamycin; OD: Once daily; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PFS6: Progression-free survival at 6 months; PR: Partial response; SD: Stable disease; TTP: Time to progression. Expert Opin. Investig. Drugs (2014) 23(6)

781

S. Lheureux et al.

Table 4. Published and presented targeted therapy Phase II trials in endometrial cancer in the past 5 years (continued).


Study

N

Treatment

Indication

Oza et al. (ASCO 2011) [73]

130

Randomization ridaforolimus (mTOR i) 40 mg orally for 5 days/week - progestin or chemo

Unresectable stage III or IVA or metastatic EC treated with 1 or 2 prior lines of chemo

Colombo et al. (2013) [71]

45

Recurrent EC £ 2 prior chemo regimen

Myers et al. (ASCO 2013) [78]

37

Ridaforolimus (mTOR i) 12.5 mg i.v. OD for 5 days every 2 weeks 2 doses of MK-2206 (Akti) -- 200 mg stopped due to skin toxicity -- 135 mg

Ray-Coquard et al. (2013) [70]

44

Everolimus (mTOR i) 10 mg orally OD

Recurrent or persistent EC £ 2 prior chemo regimen

34

Suntinib 50 mg daily 4 weeks then 2 week break

Aghajanian et al. (2011) [82]

52/56

Bevacizumab 15 mg/kg every 3 weeks

Recurrent or metastatic EC £ 1 line of previous chemotherapy Persistent or recurrent EC 1 -- 2 prior regimens

Einstein et al. (ASCO 2012) [77]

26

First recurrence of EC Only chemotherapy in adjuvant setting allowed

Coleman et al. (2012) [84]

49

Temsirolimus 25 mg i.v. weekly Bevacizumab 10 mg/kg i.v. days 1, 15 of 28 days cycle Aflibercept 4 mg/kg i.v. q14 days

Alvarez et al. (2013) [76]

49/53

Persistent or recurrent EC 1 -- 2 prior regimens

Vergote et al. (ASCO 2013) [86]

133

Temsirolimus 25 mg i.v. weekly Bevacizumab 10 mg/kg i.v. days 1, 15 of 28 days cycle Lenvatinib 24 mg daily

Angiogenic agents Correa et al. (ASCO 2010) [85]

Recurrent EC, all histologies except carcinosarcoma


Metastatic/unresectable EC 1 -- 2 prior regimens

Drug activity Experimental arm: PR/SD = 0/35% Med PFS = 3.6 mths Med OS = 10 mths Control arm: PR/SD = 4.3/17% Med PFS = 1.9 mths Med OS = 8.9 mths PR = 11% (5/45 pts) SD ‡ 16 weeks: 8/45 pts 6 mths PFS = 18% 9 pts PIK3CA mutated: 1 pt with both PR and 6 mths PFS 27 pts PIK3CA WT: 1 pt with PR -- 3 pts with 6 mths PFS No difference in activity between the 2 doses SD ‡ 8 weeks = 12/36 pts At 6 mths: PR = 9% SD = 27% Median PFS = 2.8 mths Median OS = 8.1 mths ORR = 15% Med TTP = 2.53 mths Med OS = 19 mths *In 20 evaluable pts ORR = 13.5% PFS 6 mths = 40.4% Med PFS = 4.2 mths Med OS = 10.5 mths PR 20% PFS at 6 mths -- 48% CBR 40%

ORR 7% PFS6 = 23%§ Med PFS = 2.9 mths Med OS = 14.6 mths ORR 24.5% PFS6 = 46.9%§ Med PFS = 5.6 mths Med OS = 16.9 mths ORR = 14.3% Med PFS = 5.4 mths Med OS = 10.6 mths High- vs Low-baseline Ang-2:

*Only 53 included in analysis as 14 excluded prior to therapy. z Limit based on previous doxorubicin dose -- maximum 320 mg/m2. § Study reports PFS6 of 41% but includes 8 patients who started new therapy due to toxicity. b.i.d.: Twice a day; CN: Chemotherapy naive; CR: Complete response; D: Day; EC: Endometrial cancer; FISH: Fluorescence in situ hybridization; i: Inhibitors; i.m.:intramuscular; i.v.: Intravenous; mths: Months; mTOR: Mammalian target of rapamycin; OD: Once daily; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PFS6: Progression-free survival at 6 months; PR: Partial response; SD: Stable disease; TTP: Time to progression.

782



Table 4. Published and presented targeted therapy Phase II trials in endometrial cancer in the past 5 years (continued). Study

N

Treatment

Indication

Drug activity ORR = 61% vs 18% Med PFS = 9.5 vs 3.7 mths Med OS = 23 vs 8.9 mths


EGFR pathway Fleming et al. (2010) [91]

33/34

Trastuzumab 4 mg/kg in wk1

Stage III/IV or recurrent EC Unlimited number of chemotherapy regimensz

Leslie et al. (2012) [94]

30

Lapatinib 1500 mg daily

Persistent or recurrent EC £ 2 prior regimens

Leslie et al. (2013) [89]

29

Gefitinib 500 mg daily


ORR 0% SD 12 IHC-positive tumors: Med PFS = 1.84 mths Med OS = 7.85 mths FISH-positive tumors: Med PFS = 1.81 mths Med OS = 6.8 mths PR 3.3% PFS6 = 10% Med PFS = 1.82 mths Med OS = 7.33 mths PFS ‡ 6 mths = 4 pts ORR 3.8% *Of 26 evaluable pts

*Only 53 included in analysis as 14 excluded prior to therapy. z Limit based on previous doxorubicin dose -- maximum 320 mg/m2. § Study reports PFS6 of 41% but includes 8 patients who started new therapy due to toxicity. b.i.d.: Twice a day; CN: Chemotherapy naive; CR: Complete response; D: Day; EC: Endometrial cancer; FISH: Fluorescence in situ hybridization; i: Inhibitors; i.m.:intramuscular; i.v.: Intravenous; mths: Months; mTOR: Mammalian target of rapamycin; OD: Once daily; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PFS6: Progression-free survival at 6 months; PR: Partial response; SD: Stable disease; TTP: Time to progression.

persist 8 weeks [74]. The duration of response was not reported but 11 stopped prior to 2 cycles due to progression. The most common drug-related toxicities were fatigue, nausea, stomatitis, hypertriglyceridemia and hyperglycemia. Currently, letrozole (AI) is also being studied in combination with everolimus and metformin (NCT01797523) with the primary end point of CBR at 8 weeks. The combination of temsirolimus with megestrol acetate/tamoxifen was investigated but closed prematurely due to an unacceptable rate of venous thrombosis and insufficient activity to offset this risk [75]. The combination of an mTOR inhibitor and an angiogenic agent has been investigated. The combination of temsirolimus (25 mg weekly) with bevacizumab (10 mg/kg every 2 weeks) demonstrated a promising ORR of 24.5% and PFS at 6 months of 46.9% [76]. Median OS was 16.9 months [76]. The combination had significant toxicity with 38.8% (19/49) discontinuing treatment because of this [76]. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment and independent to the number of previous treatment lines or history of radiation. Two gastrointestinal--vaginal fistulas, two intestinal perforations and one grade 4 thrombosis were seen. Three patient deaths were possibly treatment-related [76]. A similar study at ASCO showed a PR rate of 20 and 48% were progression free at 6 months of 48% [77]. Based on the knowledge that the mTOR complex is actually composed of two components, the mTORC1-Raptor

complex primary coordinator of translational control via 4EBP1 and p70S6K; and the mTORC2-Rictor complex whose function is less well described but likely regulates cell proliferation and survival in part by AKT activation, newer classes of PI3K pathway inhibitors are in Phases II (Table 5). Indeed, mTORC1 is sensitive to inhibition by rapamycin and its analogs, whereas mTORC2 is not. In the presence of selective mTORC1 inhibition, mTORC2 can exert a positive feedback on AKT. Results from a Phase II study of MK-2206, an allosteric AKT inhibitor, showed that four patients from the 36 enrolled were on treatment for > 6 months [78]. Interestingly, these patients had tumors of serous histology, a histology subtype associated with worse OS. This study found that stratification by PI3KCA mutations did not predict drug response. Similarly, a retrospective assessment of a large cohort of EC patients treated with single-agent rapalogs in three separate trials showed no correlation between clinical response and PTEN or PI3KCA mutation, PTEN or STMN protein expression [79]. A molecular biomarker that predicts the clinical benefit of rapalogs has yet to be identified for EC.

Angiogenesis Angiogenesis is one of the cardinal processes leading to invasion and metastasis in solid tumors [80]. In EC, elevated VEGF plasma levels have been correlated with poor prognosis [81]. 3.4


783

S. Lheureux et al.

Table 5. Current Phase II trials in recurrent endometrial cancer. Trial

Treatment

Patient selection


Hormonal therapy NCT01797523 Everolimus, letrozole and metformin

ANZGOG0903

Anastrozole

NCT00910091

BN83495 versus Megestrol Acetate

PI3K/mTOR/PTEN pathway NCT00729586

Histologically confirmed recurrent EC (endometrioid and mixed tumors, any grade) that is refractory to curative therapy No more than two prior chemotherapy regimens Potentially hormone responsive recurrent/ metastatic gynecologic neoplasms ER-positive advanced or recurrent EC

Temsirolimus with or without megestrol and tamoxifen

NCT01455493

GDC-0980 (inhibitor of class 1 PI3K and mTOR)

NCT01420081

NCT01289041

PF-04691502 And PF-05212384 (Two Dual PI3K/ mTOR Inhibitors) PI3K inhibitor BKM120

NCT01550380

PI3K inhibitor BKM120

NCT01396408

Sunitinib or temsirolimus

NCT01013324

XL147 (PI3K inhibitor)

NCT01307631

MK2206 (AKT inhibitor)

NCT00977574

Paclitaxel, carboplatin and bevacizumab or paclitaxel, carboplatin and temsirolimus or ixabepilone, carboplatin and bevacizumab

Angiogenic agents NCT01935934 XL184 (cabozantinib)

NCT01111461

E7080

Primary end point CBR at 8 weeks

CBR PFS

Advanced, persistent or recurrent EC This study is ongoing but not recruiting participants Recurrent or persistent EC. This study is ongoing but not recruiting participants Recurrent EC - disease progression following one or two lines of prior treatment with platinum

RR Survival time PFS RR PFS at 6 months

Advanced EC - one prior line of antineoplastic treatment with a cytotoxic agent This study is ongoing but not recruiting participants Advanced, metastatic or refractory endometrial or ovarian, fallopian tube or primary peritoneal cancer with PI3 kinase pathway activation This study is not yet open for participant recruitment Rare malignancies including clear cell endometrium Any number of previous lines Advanced or recurrent after one platinum-based chemotherapy regimen for EC Recurrent or persistent high-grade EC with a serous component Stage III, stage IV or recurrent EC This study is ongoing but not recruiting participants

RR in all patients and patients with an activated PI3K pathway status RR

Metastatic EC with one of the following histologies: endometrioid, serous, carcinosarcoma, clear cell, adenosquamous or mixed histology May have received adjuvant therapy (chemo- and/or radiation) and must have received one prior line of cytotoxic therapy for recurrent or metastatic disease. Patients who progress within 6 -- 12 months of adjuvant treatment completion are eligible without additional lines of treatment Recurrent or primarily unresectable EC -- 1 prior systemic, platinum-based chemotherapy regimen This study is ongoing but not recruiting participants

RR 12 weeks PFS 12 weeks

CBR at 16 weeks

RR

RR PFS at 6 months PFS at 6 mths RR PFS

RR

CBR: Clinical benefit rate; EC: Endometrial cancer; i: Inhibitors; mTOR: Mammalian target of rapamycin; PFS: Progression-free survival; RR: Response rate.

784



Table 5. Current Phase II trials in recurrent endometrial cancer (continued).


Trial

Treatment

NCT00888173

Brivanib

NCT01770171

Carboplatin-paclitaxel ± bevacizumab

NCT00513786

Carboplatin-paclitaxel ± bevacizumab

NCT01379534

TKI258 (Dovitinib)

EGFR pathway NCT01367002 Other NCT01011933

Patient selection Recurrent or persistent EC Must have received 1 prior chemotherapeutic regimen This study is ongoing but not recruiting participants Advanced stage III or IV, or recurrent EC. Include all carcinomas, including endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma One previous chemotherapy lines is allowed if platinum-free interval is > 6 months Advanced stage III or IV, Include all carcinomas, including endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma No previous chemotherapy This study is ongoing but not recruiting participants Advanced and/or metastatic EC One line of treatment for advanced or metastatic disease

Primary end point RR PFS 6 mths

PFS 3 months

PFS 24 months Toxicity

18-week PFS

Carboplatin and paclitaxel with or without herceptin

Advanced (stage III/IV) or recurrent uterine serous papillary carcinoma.

PFS Markers of response

AZD6244, Selumetinib (MEKi)

Recurrent endometrial epithelial carcinoma This study is ongoing but not recruiting participants

PFS RR

CBR: Clinical benefit rate; EC: Endometrial cancer; i: Inhibitors; mTOR: Mammalian target of rapamycin; PFS: Progression-free survival; RR: Response rate.

Thalidomide was the first angiogenic agent assessed demonstrating a RR on 12.5% with only 8.3% surviving 6 months [81]. Bevacizumab, a recombinant humanized monoclonal antibody against VEGF-A, is the most commonly studied anti-angiogenic agent. A 13.5% RR and a 6-month PFS rate of 40.4% with single-agent bevacizumab was demonstrated in GOG 229-E [82]. Median OS was 10.5 months [61]. There were no gastrointestinal fistula or perforations seen and only three grade 4 toxicities (metabolic and one gastric bleed) [82]. They detected a striking association between elevated VEGRA and poor outcome, but interestingly, this did not correlate with the levels in archival tissue [82]. By contrast, higher levels in the tumor were associated with reduced risk of death. Based on the benefit seen in other solid malignancies such as colorectal cancer in conjunction with a small retrospective review in EC cancer [83], a randomized Phase II study (NCT01770171) is investigating carboplatin/paclitaxel with or without bevacizumab in stage III-IV or recurrent disease. The primary outcome is PFS. A further study is comparing the combination of carboplatin, paclitaxel and bevacizumab with carboplatin, ixabepilone, temsirolimus and bevacizumab (NCT00977574). The toxicity with this combination will need to be watched with caution. Aflibercept, a VEGR ligand-binding fusion protein that serves as a ‘decoy receptor’ for VEGR, is another angiogenic

agent that has been studied in EC. It targets VEGF and placental growth factor. In GOG 229-F, aflibercept demonstrated a PFS at 6 months of 23% with only a 7% PR rate in 44 patients [84]. Tolerability was an issue with 32% stopping due to toxicity, and two cases of reverse posterior leukoencephalopathy were described [84]. Fibroblast growth factor 1 (FGF1) expression was associated with outcome [84]. Sunitinib an oral tyrosine kinase inhibitor has also been investigated with promising results. In 34 patients, the RR was 15% with a median time to progression of 2.5 months and a median OS of 19 months [85]. However, 60% of patients had a dose reduction with the most common side effects seen hypertension and fatigue. This drug is currently being compared with temsirolimus in an ongoing National Cancer Institute (NCI) trial (NCT01396408). Newer angiogenic agents under investigation include lenvatinib, cabozantinib and dovitinib (Tables 4 and 5). Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGF1-4, RET, KIT and PDGFR-b. A RR of 14.3% by independent review with a median PFS of 5.4 months and a median OS of 10.6 months was seen in 133 patients [86,87]. In correlative studies, they identified seven cytokine and angiogenic factors where baseline levels correlated with survival -- Ang-2, Il-8, HGR, VEGFA, PIGF, Tie-2 and TNF-a. Only Ag-2 correlated with maximum


785


S. Lheureux et al.

tumor shrinkage [86]. Based on low- and high-baseline levels of Ag-2 (> 2082), they found an ORR of 61 and 18%, median PFS of 9.5 and 3.7 months, median OS of 23 and 8.9 months, respectively. Patients with mutations in PIK3CA showed a trend to worse outcomes. The integration of correlative studies is highlighted in recent Phase II trial design. As illustrated above by identifying more specific target populations, RR and hopefully subsequent long-term outcome will improve. Cabozantinib, a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, is being investigated in patients with metastatic EC (NCT01935934). While the primary objective is PFS at 12 weeks, correlative studies are aiming to assess clinical response in conjunction with baseline molecular status of archival tumor in particular hepatocyte growth factor receptor amplification and mutation status. By contrast, dovitinib (TKI258) a potent receptor tyrosine kinase inhibitor of VEGFR, platelet-derived growth factor receptor and FGFR is documenting the FGFR mutational status in correlation with RR (NCT01379534) to determine if this is a potential therapeutic target.

EGFR pathway The EGFR is a family of four tyrosine kinase receptors that are overexpressed in both types of EC and is important in growth and metastases [88]. Despite the success in other malignancies, to date, results with agents targeting this pathway have been relatively disappointing [41]. Gefitinib and erlotonib are orally active inhibitors of EGFR tyrosine kinase activity. Gefitinib was found to be tolerable but did not demonstrate sufficient results to pursue further with a RR of only 3.8% and a PFS at 6 months of 15.3% [89]. Interestingly, they did demonstrate that a high serum EGFR pre-cycle 1 was associated with better OS but the significance of this remains uncertain [89]. Erlotonib demonstrated a higher RR of 12.5% lasting 2 -- 36 months in 32 patients [90]. They found no correlation with EGFR amplification and found that only 16% of EGFR-positive patients had a response [90]. Trastuzumab is a monoclonal antibody that interferes with the human EGFR 2 (HER2) receptor, overexpressed in 10 -30% of type I and 40 -- 80% of type II [10,88,91,92]. In a small single-agent study, no activity was detected [91]. HER2 positivity was defined by either immunohistochemistry or fluorescence in situ hybridization (FISH) amplification, but 45.5% had no gene amplification questioning the relevance of the results in this small population [88,93]. Lapatinib is the first dual inhibitor in clinical use acting as a tyrosine kinase inhibitor of EGFR and HER2. In a small unselected population, lapatinib demonstrated a PFS at 6 months of only 10% with an RR of only 3.3% [94]. HER2 expression was only seen in 8% of patients [94]. A patient with a PR was found on correlative studies to have a specific mutation (E690K), which is thought provoking [94]. 3.5

786

However, in general, lapatinib has insufficient activity as a single agent in an unselected population. Metformin Although there is no current Phase II evidence, metformin is an old drug with renewed interest as a new strategy in EC. Metformin is an oral biguanide classically known for its role in the management of diabetes. It suppresses hepatic gluconeogenesis causing decreased serum levels of glucose and insulin. The anticancer effects of metformin are associated with both direct insulin-independent and indirect insulindependent actions of the drug [95,96]. Metformin has demonstrated inhibition of proliferation and induction of apoptosis of EC cell lines [97]. The insulin-lowering effects of metformin may contribute to its anticancer efficacy given that insulin has mitogenic and prosurvival effects. In addition to its effect on glucose uptake and glycolysis, metformin activates AMPactivated protein kinase (AMPK) leading to phosphorylation of acetyl CoA carboxylase resulting in increased fatty acid oxidation [95,96]. It affects cell growth by inducing p53-dependent autophagy and inhibiting mTOR and protein synthesis [95,96]. Metformin use has been suggested to reduce the risk and improve the survival in obesity-related cancers, but these correlations have varied between studies [98-100]. Preclinical data have suggested that the link may be related to higher levels of circulating insulin and estradiol in obese women [101,102]. A retrospective review examined 985 patients in which 114 (12%) had diabetes treated with metformin and a further 136 (14%) had diabetes not treated with metformin. They demonstrated an improvement in survival in diabetic patients with non-endometrioid adenocarcinoma treated with metformin than diabetics not using metformin and non-endometrioid cases who were non-diabetic [102]. This remained significant on multivariate analysis [102]. No benefit was observed in those with endometrioid histology. In a further retrospective analysis, metformin was associated with improved recurrence free and OS in EC but not time to recurrence [103]. The effect of metformin on disease-specific survival is uncertain, but given the fact that 25% of patients with EC have diabetes and > 80% are obese; further investigation is warranted [103]. Metformin was shown to reduce proliferation in a preoperative study in obese patients with EC with a mean reduction in ki67 of 19.5% [104]. Currently, Burnett et al. are investigating the role of metformin in a randomized neoadjuvant trial in 40 grade I/II EC patients. The aim is to evaluate immunohistochemistry-based tissue markers of proliferation: ki67, phosphorylated histone H3, ER, PrR and telomerase (hTERT). To be eligible, patients must be obese with no history of diabetes (NCT01877564). The clinical safety, known pharmacodynamic properties, preclinical and retrospective data make metformin a promising therapeutic option. This therapeutic option will be explored with future research particularly in the recurrent setting. 3.6




4.

Conclusion

Although the majority of EC are diagnosed when disease is localized to the uterus, up to 25% of cases will recur. Adjuvant therapy in high-intermediate risk needs to include a combination of chemotherapy and radiation to improve both distant and local controls -- the exact sequence remains controversial. The role of molecularly targeted agents in the adjuvant setting remains largely unexplored. Systemic options have shown limited efficacy for recurrent metastatic disease, and new therapies are needed. Inhibition of the PI3K/AKT/ mTOR, hormone and angiogenic pathways allows clinical benefit to a subset of patient. A better understanding of pathway interactions is necessary to provide personalized medicine in EC and optimize patient outcomes. 5.

Expert opinion

EC has lagged behind other tumor types with respect to molecular characterization and targeted therapeutics. Historically, studies have mostly included all women with all subtypes of EC collectively. However, given even our knowledge of the behaviour and characteristics of type 1 and 2 cancers ‘one size’ clearly will not fit all in terms of a therapeutic approach. A move has been made to manage patients with serous histology more aggressively due to the similarities that they share with high-grade serous ovarian cancer in comparison to other histological subtypes. In the adjuvant setting, a combination approach is likely to yield the best control rates for the patient. The optimal treatment regimen and sequence remain uncertain, but sandwiching therapy seems to be a strategy that optimizes delivery of chemotherapy without compromising radiation to potentially achieve better local and distant control. Cross-trial comparisons in this Phase II setting are fraught and ultimately randomized Phase III studies need to address this. Maintenance therapy should be revisited. Recent evidence with megestrol offers promise but needs larger numbers and longer follow-up. Investigation of radio-sensitizers and molecularly targeted agents that prevent repopulation are needed in this disease. As we learn more about the biology of this disease, investigation of molecularly targeted agents in the maintenance phase is an attractive option. Our current level of knowledge makes it difficult for us to predict which patient populations might benefit from this approach at this time. As the molecular characteristics of EC are better defined, customized therapeutic strategies need to evolve. However, caution is necessary as ‘what we think we know is not always what there is to know’ emphasizing the important of highquality correlative trials in any EC study design. Based on this model, we believe basket trials based on histology or molecular subtype is a way to address resource constraints while addressing important questions for the patient.

Simply identifying and targeting a mutation does not always equate to a response. Alterations in the PIK3CA pathway are common in EC, but response to targeted agents, to date, has been less than anticipated. It remains unclear whether the results reflect the class of agent, the dose, or an escape pathway established within the cells. Incorporation of pharmacodynamic studies with paired biopsies in Phase II studies is essential to allow assessment of the extent of inhibition in the specific tumor subtype and allow interpretation of confounding factors such as the microenvironment, which are unique to EC. The feasibility of such an approach can be challenging in practice particularly with interpreting results of biopsies from radiated fields. The PIK3/AKT/mTOR pathway has been the focus of much interest with promising early results. It remains unclear whether single-agent activity is sufficient, but tolerability with combination therapy is questionable. New pan-PI3K, dual PI3K/mTOR and AKT inhibitors have been developed to counteract the positive feedback loop with potentially important implications regarding the emergence of resistance to first-generation mTOR inhibitors (rapalogs) that exclusively target mTORC1, with no effect on mTORC2. To date, the studies with PI3K or AKT or dual PI3K/mTOR inhibitor are relatively immature and cannot provide definitive information about activity in EC patients. The potential side-effect profile of these drugs targeting upstream of the pathway needs to be interpreted with caution particularly as toxicities are likely to be worse in elderly patients with co-morbidities such as obesity and diabetes. The intricate relationship between the PI3K pathway with numerous negative feedback loops and other signaling pathways, including RAS-ERK, AMPK and estrogens, may help explaining the lower long-term benefit or objective RR than expected [105]. Given metformin behaves to some degree as an mTOR inhibitor, in conjunction with its wider mechanisms of action, treatment both alone and in combination with other therapies needs to be explored. Given metformin’s low-toxicity profile, cost and known pharmacodynamic properties, we expect further studies are on the horizon. RRs to hormonal agents are lower than anticipated despite selection based on receptor expression, particularly in comparison to those achieved in breast cancer. Further studies assessing pharmacokinetic interactions are necessary in the trials investigating hormone therapy in EC. Extrapolating from breast cancer data with fulvestrant, higher dosing with an additional loading dose has demonstrated improved efficacy [106]. In addition, evidence suggests that AIs are less effective than tamoxifen in obese breast cancer patients [107]. Whether these factors also contribute to the limited benefit seen in EC needs to be determined. The influence of the microenvironment and immunological characteristics of EC remains elusive but has implications for future research. Orthotopic primary xenograft models in ovarian and cervical cancer have been helpful in studying molecular and microenvironment characteristics, but to


787


S. Lheureux et al.

date, the authors are not aware that this has not been achieved in EC. With respect to immunotherapy, there is no current clinical data in EC. However, tumor infiltrating lymphocyte (TIL) counts and peritumoral lymphocytes have been described as independent predictors for MSI high-status group in EC [108]. Moreover, the presence of TILs appears to be an independent prognostic factor in EC [109]. These observations identify a further unmet need. Trials need to define the timing and role of angiogenic agents in EC -- currently, this is unclear. Extrapolating from other disease sites, the use postchemotherapy at recurrence may be beneficial. Newer multitargeted agents such as cabozantinib and lenvatinib may offer more benefit by acting on multiple pathways particularly if a marker of response such as Ag-2 levels can be validated. Toxicity, to date, with respect to fistula formation given the majority of patients have had prior surgery and radiation has been surprisingly low. Although combination regimens seem to be synergistic, the toxicities may be limiting. Small benefits in highly selected patients in trials may disappear when applied to those with co-morbidities in the community at the expense of increased toxicity [110]. Poly adenosine diphosphate ribose (PARP) inhibitors are agents that may hold further promise particularly in both serous and endometrioid histology [111]. While similar hallmarks of DNA repair deficiencies are seen in serous EC as serous ovarian cancer, there is also evidence that loss of PTEN function as seen in endometrioid histology predicts sensitivity to PARP inhibition particularly in a low-estrogenic hormonal setting [112,113]. Olaparib (PARP inhibitor) is being studied with carboplatin in the Phase I setting in recurrent or refractory ‘women’s cancers’ (NCT01237067). If PARP inhibition is more effective with estrogen depletion, combination with a hormonal agent may be beneficial if Phase I results meet expectations. Trials with PARP inhibitors are necessary in EC. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63(1):11-30

2.

Lindemann K, Vatten LJ, Ellstrom-Engh M, Eskild A. Body mass, diabetes and smoking, and endometrial cancer risk: a follow-up study. Br J Cancer 2008;98(9):1582-5

3.

4.

788

Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 2002;11(12):1531-43 Cook LS, Nelson HE, Stidley CA, et al. Endometrial cancer and a family history

Research to address this faces many challenges. Resource constraints with respect to time and patient numbers are a constant dilemma particularly as biomarkers become integral to trial design. Emerging data on the molecular characteristics of EC makes this a very exciting and challenging time for those designing Phase II studies in EC. As EC becomes a collection of rare diseases international collaborations, such as with the Gynecologic Cancer Intergroup, will become increasingly important to ensure that we maximize what is learnt from each trial. Optimizing trial design is vital. We advocate the use of basket trials to address some of these restraints, but randomized controlled trials are essential if we are to challenge current care paradigms. Consideration of pharmacokinetics, tolerability and most importantly quality of life in these patients is the key if we are to improve the outcome for women with EC in the future. We have to challenge our current standard of care, integrate the disease biology with the treatment, in conjunction with innovatively designed trials to meet this unmet need -- it is time to move forward in EC.

Acknowledgement S Lheureux, M Wilson contributed equally to this work -- co primary first author.

Declaration of interest 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. screening and treatment. Histopathology 2013;62(1):2-30

of cancer. Gynecol Oncol 2013;130(2):334-9 5.

Colombo N, Preti E, Landoni F, et al. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi33-8

9.

Lu KH, Dinh M, Kohlmann W, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 2005;105(3):569-74

6.

Marchetti C, Pisano C, Mangili G, et al. Use of adjuvant therapy in patients with FIGO stage III endometrial carcinoma: a multicenter retrospective study. Oncology 2011;81(2):104-12

10.

7.

Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol 2013;31(20):2607-18

Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497(7447):67-73 First wide genomic profiling in endometrial cancer.

8.

Folkins AK, Longacre TA. Hereditary gynaecological malignancies: advances in


..

11.

Mackay HJ, Gallinger S, Tsao MS, et al. Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: results from studies of the NCIC Clinical


Trials Group (NCIC CTG). Eur J Cancer 2010;46(8):1365-73 12.

13.


.

14.

15.

16.

17.

18.

19.

20.

Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7(8):606-19 Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 2010;7(4):209-19 Complete review of the mTOR pathway in cancer. Kong D, Suzuki A, Zou TT, et al. PTEN1 is frequently mutated in primary endometrial carcinomas. Nat Genet 1997;17(2):143-4 Minaguchi T, Yoshikawa H, Oda K, et al. PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas. Clin Cancer Res 2001;7(9):2636-42 Peiro G, Peiro FM, Ortiz-Martinez F, et al. Association of mammalian target of rapamycin with aggressive type II endometrial carcinomas and poor outcome: a potential target treatment. Hum Pathol 2013;44(2):218-25

..

23.

Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer–results from two randomised studies. Eur J Cancer 2010;46(13):2422-31

24.

Geller MA, Ivy JJ, Ghebre R, et al. A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a "Sandwich" method for stage III, IV, and recurrent endometrial cancer. Gynecol Oncol 2011;121(1):112-17 Pilot trials for sandwich therapy as strategy in adjuvant endometrial cancer setting.

.

25.

.

26.

Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 2007;128(1):157-70 Gupta A, Yang Q, Pandita RK, et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle 2009;8(14):2198-210 Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006;95(Suppl 1):S105-43 Tangjitgamol S, Manusirivithaya S, Lertbutsayanukul C. Adjuvant therapy for early-stage endometrial cancer: a review. Int J Gynecol Cancer 2007;17(5):949-56

21.

Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105(2):103-4

22.

Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of wholeabdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic

Oncology Group Study. J Clin Oncol 2006;24(1):36-44 Benefit of chemotherapy in adjuvant therapy of endometrial cancer.

27.

28.

Lupe K, D’Souza DP, Kwon JS, et al. Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer. Gynecol Oncol 2009;114(1):94-8 Pilot trials for sandwich therapy as strategy in adjuvant endometrial cancer setting. Einstein MH, Frimer M, Kuo DY, et al. Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma. Gynecol Oncol 2012;124(1):21-5 Scribner DR Jr, Puls LE, Gold MA. A phase II evaluation of docetaxel and carboplatin followed by tumor volume directed pelvic plus or minus paraaortic irradiation for stage III endometrial cancer. Gynecol Oncol 2012;125(2):388-93 Jhingran A, Ramondetta LM, Bodurka DC, et al. A prospective phase II study of chemoradiation followed by adjuvant chemotherapy for FIGO stage I-IIIA (1988) uterine papillary serous carcinoma of the endometrium. Gynecol Oncol 2013;129(2):304-9

29.

Narayan K, Rischin D, Quinn M, et al. Adjuvant chemotherapy and chemoradiation following surgery for high-risk endometrial cancer. J Clin Oncol 2010;28(Suppl): abstract 5028

30.

Landrum LM, Nugent EK, Zuna RE, et al. Phase II trial of vaginal cuff brachytherapy followed by chemotherapy in early stage endometrial cancer patients


with high-intermediate risk factors. Gynecol Oncol 2014;132(1):50-4 31.

Koensgen D, Belau A, Sehouli J, et al. N-E SGOG. Adjuvant sequential chemo-radiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase II study of the NOGGO. J Clin Oncol 2011;29(Suppl):abstract 5109

32.

Lewis GC Jr, Slack NH, Mortel R, Bross ID. Adjuvant progestogen therapy in the primary definitive treatment of endometrial cancer. Gynecol Oncol 1974;2(2-3):368-76

33.

Macdonald RR, Thorogood J, Mason MK. A randomized trial of progestogens in the primary treatment of endometrial carcinoma. Br J Obstet Gynaecol 1988;95(2):166-74

34.

Vergote I, Kjorstad K, Abeler V, Kolstad P. A randomized trial of adjuvant progestagen in early endometrial cancer. Cancer 1989;64(5):1011-16

35.

Bevis K, Kilgore L, Alvarez R, et al. Combination therapy with paclitaxel, carboplatin, and megesterol acetate for advanced-stage and recurrent endometrial carcinoma: a phase II study. J Clin Oncol 2010;28(Suppl): abstract 5093

36.

Bovicelli A, D’Andrilli G, Giordano A, De Iaco P. Conservative treatment of early endometrial cancer. J Cell Physiol 2013;228(6):1154-8

37.

Baker J, Obermair A, Gebski V, Janda M. Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature. Gynecol Oncol 2012;125(1):263-70

38.

Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186(4):651-7

39.

Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol 1999;17(6):1736-44 Key study supporting hormonal therapy in advanced endometrial cancer.

..

789

S. Lheureux et al.

40.

Dedes KJ, Wetterskog D, Ashworth A, et al. Emerging therapeutic targets in endometrial cancer. Nat Rev Clin Oncol 2011;8(5):261-71

41.

Tsoref D, Oza AM. Recent advances in systemic therapy for advanced endometrial cancer. Curr Opin Oncol 2011;23(5):494-500 Therapeutic options review in endometrial cancer.

.


42.

Hoskins PJ, Swenerton KD, Pike JA, et al. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a Phase II study. J Clin Oncol 2001;19(20):4048-53

43.

Fleming GF. Systemic chemotherapy for uterine carcinoma: metastatic and adjuvant. J Clin Oncol 2007;25(20):2983-90

44.

Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2004;22(11):2159-66

45.

46.

47.

48.

49.

790

Tait DL, Blessing JA, Hoffman JS, et al. A phase II study of gemcitabine (gemzar, LY188011) in the treatment of recurrent or persistent endometrial carcinoma: a gynecologic oncology group study. Gynecol Oncol 2011;121(1):118-21 Di Legge A, Trivellizzi IN, Moruzzi MC, et al. Phase 2 trial of nonpegylated doxorubicin (Myocet) as second-line treatment in advanced or recurrent endometrial cancer. Int J Gynecol Cancer 2011;21(8):1446-51 Miller DS, Blessing JA, Drake RD, et al. A phase II evaluation of pemetrexed (Alimta, LY231514, IND #40061) in the treatment of recurrent or persistent endometrial carcinoma: a phase II study of the Gynecologic Oncology. Gynecol Oncol 2009;115(3):443-6 McMeekin DS, Lisyanskaya A, Crispens M, et al. Single-agent trabectedin as second-line therapy of persistent or recurrent endometrial cancer: results of a multicenter phase II study. Gynecol Oncol 2009;114(2):288-92 Dizon DS, Blessing JA, McMeekin DS, et al. Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic oncology group trial 129-P. J Clin Oncol 2009;27(19):3104-8

60.

Ramondetta LM, Johnson AJ, Sun CC, et al. Phase 2 trial of mifepristone (RU-486) in advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma. Cancer 2009;115(9):1867-74

61.

Whitney CW, Brunetto VL, Zaino RJ, et al. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92(1):4-9

Vandenput I, Vergote I, Neven P, Amant F. Weekly paclitaxel-carboplatin regimen in patients with primary advanced or recurrent endometrial carcinoma. Int J Gynecol Cancer 2012;22(4):617-22

62.

Fiorica JV, Brunetto VL, Hanjani P, et al. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92(1):10-14

53.

Wright JD, Barrena Medel NI, Sehouli J, et al. Contemporary management of endometrial cancer. Lancet 2012;379(9823):1352-60

63.

Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51(15):3867-73

54.

Decruze SB, Green JA. Hormone therapy in advanced and recurrent endometrial cancer: a systematic review. Int J Gynecol Cancer 2007;17(5):964-78

64.

55.

Covens AL, Filiaci V, Gersell D, et al. Phase II study of fulvestrant in recurrent/ metastatic endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2011;120(2):185-8

O’Regan RM, Cisneros A, England GM, et al. Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth. J Natl Cancer Inst 1998;90(20):1552-8

65.

Emons G, Gunthert A, Thiel FC, et al. Phase II study of fulvestrant 250 mg/month in patients with recurrent or metastatic endometrial cancer: a study of the Arbeitsgemeinschaft Gynakologische Onkologie. Gynecol Oncol 2013;129(3):495-9

66.

Utsunomiya H, Ito K, Suzuki T, et al. Steroid sulfatase and estrogen sulfotransferase in human endometrial carcinoma. Clin Cancer Res 2004;10(17):5850-6

67.

Foster PA, Woo LW, Potter BV, et al. The use of steroid sulfatase inhibitors as a novel therapeutic strategy against hormone-dependent endometrial cancer. Endocrinology 2008;149(8):4035-42

68.

Slomovitz BM, Lu KH, Johnston T, et al. A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 2010;116(23):5415-19 First clinical Phase II trial evaluating the interest of mTOR inhibitor.

50.

Emons G, Sehouli J, Gorchev G, et al. Phase II study of AEZS-108 (AN-152), a targeted cytotoxic LHRH analog, in patients with LHRH receptor positive endometrial cancer. Protocol AGO-GYN 5, AGO study group, Germany. Eur J Cancer Suppl 2010;8(7):120

51.

Brown J, Smith JA, Ramondetta LM, et al. Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: results of a prospective phase 2 trial. Cancer 2010;116(21):4973-9

52.

56.

57.

58.

59.

Kokka F, Brockbank E, Oram D, et al. Hormonal therapy in advanced or recurrent endometrial cancer. Cochrane Database Syst Rev 2010;(12):CD007926 Thigpen T, Brady MF, Homesley HD, et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2001;19(2):364-7 Ma BB, Oza A, Eisenhauer E, et al. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers–a study of the National Cancer Institute of Canada Clinical Trials Group. Int J Gynecol Cancer 2004;14(4):650-8 Rose PG, Brunetto VL, VanLe L, et al. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2000;78(2):212-16


.

69.

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical


Trials Group. J Clin Oncol 2011;29(24):3278-85 70.


71.

72.

73.

74.

Ray-Coquard I, Favier L, Weber B, et al. Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. Br J Cancer 2013;108(9):1771-7 Colombo N, McMeekin DS, Schwartz PE, et al. Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 2013;108(5):1021-6 Mackay H, Welch S, Tsao M, et al. Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192. J Clin Oncol 2011;29(Suppl):abstract 5013 Oza A, Poveda A, Clamp A, et al. A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotheraphy (C) in female adult patients with advanced endometrial carcinoma. J Clin Oncol 2011;29(Suppl):abstract 5009 Stomovitz BM, Brown J, Johnston TA, et al. A phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 2011;29(Suppl):abstract 5012

75.

Fleming GF, Filiaci VL, Hanjani P, Gynecologic Oncology Group. Hormone therapy plus temsirolimus for endometrial carcinoma (EC): Gynecologic Oncology Group trial #248. J Clin Oncol 2011;29(Suppl):abstract 5014

76.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2013;129(1):22-7

77.

Einstein MH, Wenham RM, Morgan R, et al. Phase II trial of temsirolimus and bevacizumab for initial recurrence of endometrial cancer. J Clin Oncol 2012;30(Suppl):abstract 5025

78.

Myers AP, Broaddus R, Makker V, SU2C Dream Team: PI3K in Women’s Cancers. Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC). J Clin Oncol 2013;31(Suppl):abstract 5524

79.

.

Mackay HJ, Eisenhauer EA, Kamel-Reid S, et al. Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer 2014;120(4):603-10 No correlation was observed between biomarkers and response or progression.

80.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74

81.

McMeekin DS, Sill MW, Benbrook D, et al. A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: a Gynecologic Oncology Group study. Gynecol Oncol 2007;105(2):508-16

82.

.

83.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 2011;29(16):2259-65 First Phase II trial evaluating the interest of bevacizumab in advanced endometrial cancer. Wright JD, Powell MA, Rader JS, et al. Bevacizumab therapy in patients with recurrent uterine neoplasms. Anticancer Res 2007;27(5B):3525-8

84.

Coleman RL, Sill MW, Lankes HA, et al. A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2012;127(3):538-43

85.

Correa R, Mackay H, Hirte HW, et al. A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: a trial of the Princess Margaret Hospital, The University of Chicago, and California Cancer Phase II Consortia. J Clin Oncol 2010;28(Suppl):abstract 5038

86.

Funahashi Y, Penson RT, Powell MA, et al. Analysis of plasma biomarker and tumor genetic alterations from a phase II trial of lenvatinib in patients with advanced endometrial cancer. J Clin Oncol 2013;31(Suppl):abstract 5591

87.

Vergote I, Teneriello M, Powell MA, et al. A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: angiopoietin-2 as a predictive marker for clinical outcomes.


J Clin Oncol 2013;31(Suppl):abstract 5520 88.

Bansal N, Yendluri V, Wenham RM. The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control 2009;16(1):8-13

89.

Leslie KK, Sill MW, Fischer E, et al. A phase II evaluation of gefitinib in the treatment of persistent or recurrent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2013;129(3):486-94

90.

Oza AM, Eisenhauer EA, Elit L, et al. Phase II study of erlotinib in recurrent or metastatic endometrial cancer: NCIC IND-148. J Clin Oncol 2008;26(26):4319-25

91.

Fleming GF, Sill MW, Darcy KM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2010;116(1):15-20

92.

Samarnthai N, Hall K, Yeh IT. Molecular profiling of endometrial malignancies. Obstet Gynecol Int 2010;2010:162363

93.

Santin AD. Letter to the Editor referring to the manuscript entitled: “Phase II trial of trastuzumab in women with advanced or recurrent HER-positive endometrial carcinoma: a Gynecologic Oncology Group study” recently reported by Fleming et al., (Gynecol Oncol., 116; 15-20;2010). Gynecol Oncol 2010;118(1):95-6; author reply 96-7

94.

Leslie KK, Sill MW, Lankes HA, et al. Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. Gynecol Oncol 2012;127(2):345-50

95.

Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med 2011;9:33 Evidence supporting potential interest in the role of metformin in cancer.

.

96.

Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther 2010;9(5):1092-9

791

S. Lheureux et al.

97.

98.


99.

Cantrell LA, Zhou C, Mendivil A, et al. Metformin is a potent inhibitor of endometrial cancer cell proliferation– implications for a novel treatment strategy. Gynecol Oncol 2010;116(1):92-8 Bodmer M, Becker C, Meier C, et al. Use of metformin and the risk of ovarian cancer: a case-control analysis. Gynecol Oncol 2011;123(2):200-4 Sadeghi N, Abbruzzese JL, Yeung SC, et al. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 2012;18(10):2905-12

100. Chlebowski RT, McTiernan A, Wactawski-Wende J, et al. Diabetes, metformin, and breast cancer in postmenopausal women. J Clin Oncol 2012;30(23):2844-52 101. Gunter MJ, Hoover DR, Yu H, et al. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008;17(4):921-9 102. Nevadunsky NS, Van Arsdale A, Strickler HD, et al. Metformin use and endometrial cancer survival. Gynecol Oncol 2014;132(1):236-40 103. Ko EM, Walter P, Jackson A, et al. Metformin is associated with improved

792

survival in endometrial cancer. Gynecol Oncol 2014;132(2):438-42

endometrial cancer. Gynecol Oncol 2009;114(1):105-10

104. Schuler KM, Rambally BS, DiFurio MJ, et al. A preoperative window study of metformin for the treatment of endometrial cancer. J Clin Oncol 2013;31(Suppl):abstract 5519

110. Booth CM, Tannock IF. Evaluation of treatment benefit: randomized controlled trials and population-based observational research. J Clin Oncol 2013;31(26):3298-9

105. Myers AP. New strategies in endometrial cancer: targeting the PI3K/mTOR pathway–the devil is in the details. Clin Cancer Res 2013;19(19):5264-74

111. Reinbolt RE, Hays JL. The role of PARP inhibitors in the treatment of gynecologic malignancies. Front Oncol 2013;3:237

106. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 2010;28(30):4594-600 107. Goodwin PJ, Pritchard KI. Obesity and hormone therapy in breast cancer: an unfinished puzzle. J Clin Oncol 2010;28(21):3405-7 108. Shia J, Black D, Hummer AJ, et al. Routinely assessed morphological features correlate with microsatellite instability status in endometrial cancer. Hum Pathol 2008;39(1):116-25 109. de Jong RA, Leffers N, Boezen HM, et al. Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II


112. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med 2010;2(53):53ra75 113. Janzen DM, Paik DY, Rosales MA, et al. Low levels of circulating estrogen sensitize PTEN-null endometrial tumors to PARP inhibition in vivo. Mol Cancer Ther 2013;12(12):2917-28

Affiliation Stephanie Lheureux, Michelle Wilson & Helen J Mackay† † Author for correspondence Princess Margaret Hospital, Division of Medical Oncology and Hematology, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada E-mail: [email protected]