REVIEW

CURRENT
OPINION Treatment strategies for endometrial cancer:
current practice and perspective
Yeh C. Lee, Stephanie Lheureux, and Amit M. Oza

Purpose of review
Endometrial cancer incidence is increasing in North America and is a major cause of morbidity and
mortality in women. We review recent literature published on treatment of endometrial cancer and
highlight areas of active interest.

Recent findings
There has been movement toward minimal invasive surgery at diagnosis; lymph node staging remains
controversial and continues to be investigated. Progress has been made to establish consensus on
endometrial cancer risk classification to promote consistency for future trial design. Molecular
characterization of endometrial cancer and its integration into clinicopathological profiling to develop
predictive biomarkers for treatment selection are active areas of research. Optimal adjuvant treatment
strategy in high-risk endometrial cancer remains to be defined with recognition of treatment-related toxicity.
Despite encouraging results in drug development for treatment of advanced/recurrent endometrial cancer,
no targeted therapies beyond hormonal therapy are approved. There is an urgent need for scientifically
validated therapy with predictive biomarkers.

Summary
Our understanding of endometrial cancer has evolved through improvements in molecular biology,
allowing improved definition of target-specific therapies. The precise role and sequence of conventional
and targeted therapies, including immunotherapy, will require careful attention to the design of clinical
trials with translational emphasis to allow the discovery, validation, and implementation of predictive
biomarkers into clinical care.

Keywords
drug therapy, endometrial cancer, treatment

INTRODUCTION radiation-related toxicity [7] and potentially

&

Endometrial cancer is the most common gyneco- under-dosing of chemotherapy [8 ].

logical cancer in the developed countries with fur-
ther increase in incidence expected in the next 10
years. The prognosis for stage I disease is generally
good with majority considered cured with surgery;
however, prognosis for advanced disease (stage III or
IV) is poor, with 5-year overall survival (OS) rates
The incidence of hereditary endometrial cancer,
Lynch syndrome, in unselected populations is
approximately 1.8–2.3% [9,10], and up to 9% in
patients under age 50 [11,12]. Women with Lynch
syndrome have a 20–60% chance of presenting with
endometrial cancer as the first clinical manifes-
&

ranging from 47 to 69 and 15 to 17%, respectively
[1,2], and therapeutic options beyond first-line che-
motherapy are limited.
Many women with endometrial cancer have
& Drug Development Program, Division of Medical Oncology and Hema-
comorbidities, such as diabetes and obesity [3 ],
which are known risk factors for the development
of endometrial cancer, and important in consider-
ing treatment strategy to improve outcome. Mor-
&
bid obesity poses challenges to surgery [4 ] and
delivery of radiation and chemotherapy, with elev-
& &
ated perioperative morbidity [5 ,6 ], higher risk of
tation [13 ]; confirming that a patient with endo-
metrial cancer is Lynch syndrome-related has the
tology, Princess Margaret Cancer Centre, University of Toronto, Toronto,
Ontario, Canada
Correspondence to Dr Amit M. Oza, Princess Margaret Cancer Centre,
610 University Ave., Toronto, ON M5G 2M9, Canada.
Tel: +1 416 946 2818; e-mail: amit.oza@uhn.ca
Curr Opin Obstet Gynecol 2017, 29:47–58
DOI:10.1097/GCO.0000000000000338

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Gynecologic cancer
KEY POINTS
 Progress in defining risk classification and establishing
consensus recommendation will promote consistency for
future clinical trial design.
 Molecular characterization of endometrial cancer and
integration of this information into clinicopathological
profiling to develop predictive biomarkers for treatment
selection are active areas of research.
 There is a demand to investigate target-specific
treatment with predictive biomarkers as there is still yet
an approved targeted agent beyond hormonal
treatment in endometrial cancer.
 The design of clinical trials should incorporate
translational research to allow discovery, validation,
and implementation of predictive biomarkers into
clinical care.
potential to influence early detection, screening,
and prevention of other Lynch syndrome-associated
cancers (i.e., colorectal cancer screening). Impor-
tantly, potentially unaffected family members
would gain the opportunity to undergo genetic
counseling and testing, and reduce their risks of
endometrial cancer and colorectal cancers.
There is an urgent need for improvement in all
aspects of management of this disease. In this
review, we focus on the recent progress and inno-
vations reported in the literature over the past 18
months and highlight areas of interest to build new
treatment strategies for endometrial cancer moving
forward.
INTEGRATION OF MOLECULAR
CLASSIFICATION AND HISTOPATHOLOGY
FOR ENDOMETRIAL CANCER
Traditionally, endometrial cancers are classified
into two main categories. Type I endometrial can-
cer, with endometrioid histology represents up to
80% of the cases, potentially expresses estrogen
receptors and/or progesterone receptors that may
be targetable using hormonal therapy. Type II endo-
metrial cancer, consisting of serous, clear cell, or
undifferentiated carcinoma histology, is less com-
mon (10–20%) but carries higher risk of recurrence
&&
[14 ,15]. Type I endometrial cancer is generally
associated with genetic alterations in KRAS, PTEN,
PIK3CA, CTNNB1, and MLH1 promoter hyperme-
thylation [16,17]. Type II endometrial cancer is
mainly characterized by increased levels of mTOR
or TP53 mutations in serous carcinomas [15,17,18].
Despite the molecular differences, a pooled analysis
48 www.co-obgyn.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
suggested that both types share many common
etiologic factors [17,19].
The Cancer Genome Atlas (TCGA) genomic
profiling has been used to create molecular classifi-
cation of four subgroups that more accurately reflect
underlying tumor biology and clinical outcome:
Polymerase episilone (POLE) ultramutated, microsa-
tellite instability (MSI) hypermutated, copy-number
low and copy-number high [17]. POLE-ultramutated
endometrial cancer exhibits a striking mutation
burden and an enhanced antitumor T-cell response
which may explain the favorable outcome of these
&
tumors [20 ].
MOVEMENT TOWARD MINIMAL INVASIVE
SURGERY AND ONGOING DEBATE ON
LYMPH NODE STAGING
The cornerstone of treatment in early stage endo-
metrial cancer is surgery, which typically involves
total hysterectomy and removal of both fallopian
tubes and ovaries. Surgery also provides valuable
information for staging purposes and tissue for mol-
ecular characterization to tailor appropriate adju-
vant treatment modalities that benefit patients at
increased risk of disease relapse.
Conventional oncologic surgery for endo-
metrial cancer is performed by laparotomy but there
is now movement toward minimally invasive tech-
niques such as laparoscopic approach or robot-
assisted laparoscopic surgery (RALS). A recent retro-
spective cohort study has shown superior surgical
outcomes in women with stage I–II endometrial
cancer who had minimally invasive surgery (laparo-
scopy and robotics) compared with abdominal
surgery and the RALS arm had the best outcome
in this study in terms of shortest operative time,
minimal blood loss and transfusion, and low peri-
&
operative complication rate [21 ]. A phase III study,
ROBOGYN, comparing clinical benefit of RALS and
laparoscopic surgery in women with gynecological
cancers is underway (NCT01247779, Table 1).
The findings from the Adjuvant External Beam
Radiotherapy in Treatment of Endometrial Cancers
Trial (ASTEC) trials showed no evidence of benefit in
OS or recurrence-free survival (RFS) for pelvic lym-
phadenectomy or adjuvant external beam radiation
in early stage endometrial cancer [22,23]. Indeed,
studies demonstrated that significant risk factors
associated with endometrial cancer mortality
included age, grade, depth of myometrial invasion,
and cervical stromal involvement [24], whereas
nodal status was not independently associated
[23]. However, controversy remains as the lympha-
denectomy specified in these studies was not com-
prehensive. Furthermore, even if lymphadenectomy
Volume 29  Number 1  February 2017
 Treatment strategies for endometrial cancer Lee et al.

Table 1. Overview of current clinical trials in endometrial cancer [cut off date November 1st, 2016]

NCT Phase Study title Intervention

Surgery
NCT02762214 III Role of uterine manipulator in hysterectomy (RoManHy) Clermont-Ferrand uterine
manipulator
NCT01247779 III Perioperative morbidity in gyneco-oncology according to the Robot-assisted coelioscopy
procedure: coelioscopy versus robot-assisted coelioscopy
(ROBO-GYN)
NCT02566811 III Selective targeting of adjuvant therapy for endometrial cancer Abdominal surgery þ/
(STATEC) lymphadenectomy
NCT02564276 III Indocyanine green versus blue dye for detection of sentinel Sentinel lymph node biopsy
lymph node in endometrial cancer
NCT02598219 III Evaluation of sentinel node policy in early stage endometrial Sentinel lymph node biopsy
carcinomas at intermediate and high risk of recurrence
(SENTIRAD)
NCT02658565 II Selective surgical staging for the treatment of endometrial Lymphadenectomy
cancer based on intraoperative consultation
NCT02560571 II Preoperative studies for prediction of lymph nodes Ultrasound
involvement in endometrial cancer patients
Chemotherapy þ/ radiation
NCT00411138 III Randomized trial of radiation therapy with or without Radiation þ/ chemotherapy
chemotherapy for endometrial cancer (PORTEC-3)
NCT00942357 III Carboplatin and paclitaxel with or without cisplatin and Chemoradiation þ/
radiation therapy in treating patients with stage I, stage II, chemotherapy
stage III, or stage IVA endometrial cancer (GOG-258)
NCT00807768 III Pelvic radiation therapy or vaginal implant radiation therapy, Pelvic radiation vs. brachytherapy
paclitaxel, and carboplatin in treating patients with high-
risk stage I or stage II endometrial cancer (GOG-249)
NCT02501954 III Trial of cisplatin plus radiation followed by carbo and taxol Sequential vs. sandwich therapy
vs. sandwich therapy of carbo and taxol followed by
radiation then further carbo and taxol
NCT01244789 III Chemotherapy or observation in stage I–II intermediate or Carboplatin–paclitaxel vs.
high-risk endometrial cancer observation
NCT01041027 II A pilot phase II trial of radiation therapy ‘sandwiched’ Carboplatin–paclitaxel radiation
between paclitaxel and carboplatin in patients with high-
risk endometrial cancer after standard surgical staging
NCT02112552 II A pilot phase II trial of intravenous paclitaxel and Paclitaxel þ IP carboplatin
intraperitoneal carboplatin followed by radiation in patients
with advanced stage uterine serous carcinoma
NCT02744898 II A phase 2 feasibility study of abraxane and carboplatin in Carboplatin þ abraxane
epithelial neoplasms of the uterus
NCT00492778 II Radiation therapy with or without cisplatin in treating patients Pelvic radiation þ/ cisplatin
with recurrent endometrial cancer
Antiangiogenics therapy
NCT01770171 II Carboplatin–paclitaxel  bevacizumab in advanced (stage Carboplatin–paclitaxel þ/
III–IV) or recurrent endometrial cancer bevacizumab
NCT02866370 II Study of nintedanib compared to chemotherapy in patients Nintedanib vs. chemotherapy
with recurrent clear cell carcinoma of the ovary or
endometrium
NCT02730416 II Combination chemotherapy with nintedanib/placebo in Carboplatin–paclitaxel þ/
endometrial cancer nintedanib
NCT01935934 II Cabozantinib-S-malate in treating patients with recurrent or Cabozantinib-S-malate
metastatic endometrial cancer
Molecular target therapy
NCT02549989 II Study of LY3023414 for the treatment of recurrent or LY3023414 (dual PI3K/mTOR
persistent endometrial cancer inhibitor)
NCT02728258 II Copanlisib in treating patients with persistent or recurrent Copanlisib (PI3KCA inhibitor)
endometrial cancer

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Gynecologic cancer

Table 1 (Continued)

NCT Phase Study title Intervention

NCT01367002 II Evaluation of carboplatin/paclitaxel with and without Carboplatin-paclitaxel þ/

trastuzumab (Herceptin) in uterine serous cancer trastuzumab (Her2 inbihitor)
Hormonal therapy
NCT02684227 II Enzalutamide in combination with carboplatin and paclitaxel Enzalutamide þ carboplatin–
in endometrial cancer paclitaxel
NCT02397083 II Phase II study of intrauterine device (IUD) alone or in Intrauterine device þ/ everolimus
combination with everolimus in endometrial cancer
NCT02188550 II Single arm trial with combination of everolimus and letrozole Everolimus þ letrozole
in treatment of platinum resistant relapse or refractory or
persistent ovarian cancer/endometrial cancer
NCT02228681 II Everolimus and letrozole or hormonal therapy to treat Everolimus þ letroxole vs.
endometrial cancer
tamoxifen þ medroxyprogesterone acetate
NCT02730429 II Trial of letrozole þ/ palbociclib in metastatic endometrial Letrozole þ/ palbociclib
cancer
NCT02657928 II Ribociclib and letrozole in treating patients with relapsed ER Letrozole þ ribociclib
positive ovarian, fallopian tube, primary peritoneal or
endometrial cancer
NCT02064725 II Virexxa (sodium cridanimod) w/progestin therapy in pts w/ Sodium cridanimob þ/
progesterone receptor neg recurrent/persistent endometrial Medroxyprogesterone acetate
CA
NCT02730923 I/II Hormone receptor positive endometrial carcinoma treated by AZD2014 (dual mTORC1/2
dual mTORC1/mTORC2 inhibitor and anastrozole inhibitor) þ/ anastrozole
(VICTORIA)
Metformin
NCT02874430 II Metformin hydrochloride and doxycycline in treating patients Metformin þ doxycycline
with localized breast or uterine cancer
NCT01877564 II A randomized pilot study to evaluate the effects of a short Metformin
course of metformin versus no therapy in the period prior to
hysterectomy for grade 1–2 adenocarcinoma of the
endometrium in obese non-diabetic women
Combination therapy
NCT02755844 I/II Safety and efficacy of metronomic cyclophosphamide,
metformin and olaparib in endometrial cancer patients
Metformin þ olaparib þ metronomic cyclophosphamide
NCT01686126 II Improving the treatment for women with early stage cancer of Metformin þ/ levonorgestrel
the uterus (feMME)
NCT02035787 II Metformin with the levonorgestrel-releasing intrauterine device Metformin þ LR-IUD
(LR-IUD) for the treatment of complex atypical hyperplasia
(CAH) and endometrial cancer (EC) in nonsurgical patients
NCT02725268 II Phase 2 study of MLN0128, combination of MLN0128 with Paclitaxel MLN0128 (dual
MLN1117, paclitaxel and combination of MLN0128 with TORC1/2 inhibitor) MLN1117
paclitaxel in women with endometrial cancer (PI3Ka inhibitor)
NCT02208375 I/II mTORC1/2 inhibitor AZD2014 or the oral AKT inhibitor AZD2014 (mTORC1/2 inhibitor);
AZD5363 for recurrent endometrial and ovarian cancer AZD5363 (AKT inhibitor)
Immunotherapy
NCT02912572 II Study of avelumab in patients with MSS, MSI-H and POLE- Avelumab
mutated recurrent or persistent endometrial cancer
NCT02899793 II Pembrolizumab in ultramutated and hypermutated Pembrolizumab
endometrial cancer
NCT02549209 II Pembro/carbo/taxol in endometrial cancer Carboplatin–
paclitaxel þ pembrolizumab
NCT02628067 II Study of pembrolizumab (MK-3475) in participants with Pembrolizumab
advanced solid tumors (MK-3475-158/KEYNOTE-158)

IP, intraperitoneal; POLE, polymerase episilone.

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is not therapeutic in its own right, it may provide
useful staging information to guide choice of adju-
vant treatment. For instance, a subset of patients, up
to 9% [24] with only one (or none) of the risk factors,
have positive nodes only identifiable with lympha-
denectomy, and without this knowledge would not
be considered for adjuvant treatment.
Long-term data from a prospective study on
sentinel lymph node (SLN) biopsy have shown no
significant difference in 50-month RFS in patients
&
with or without detected SLN [25 ]. This study was
not powered for RFS analysis and a significantly
larger proportion of patients with positive SLN
had received adjuvant therapy which may have
influenced the study outcome.
DECISION FOR ADJUVANT TREATMENT
FOR STAGE I DISEASE
The majority of patients with early stage disease have
favorable clinical outcome, and, therefore, the
dilemma in clinical practice is how to best distinguish
the small subset of patients who will unfortunately
experience disease relapse. Traditionally, risk assess-
ment has been based on clinicopathological features,
such as age, histological subtype, tumor grade, and
presence of lymphovascular space invasion (LVSI).
Emerging data also suggested that being an African-
American plays an adverse prognostic role for endo-
metrial cancer, independent of comorbidities [26 ].
Notably, definition and utility for these risk
categories varies between studies. The updated inter-
national consensus has addressed the risk classifi-
cation and will provide better clarity for treatment
recommendations and clinical trial design moving
&&
forward [14 ].
Correlative studies performed on the pooled
biobank from the PORTEC studies have improved
the ability to identify biomarkers of response. There
is growing evidence showing that immune-histo-
chemical demonstration of L1 cell adhesion mol-
ecule (L1CAM) is associated with high-risk features,
& &
such as high tumor grade [27 ,28 ], LVSI [28 ,29 ],
& &
deep myometrial invasion [27 ,29 ], and nodal
& &
spread [27 ,29 ], and thus a predictor of poor clinical
outcome. Although L1CAM expression is more com-
monly found in Type II endometrial cancer
& & &
[27 ,29 ,30 ], a small proportion (up to 17%) of
patients with Type I endometrial cancer (endome-
&
trioid subtype) also express L1CAM [29 ,31,32] and
this marker has been validated to be a strong and
independent predictor of poor outcome, even in
&
stage I disease [29 ]. This finding carries great poten-
tial to change clinical practice. Once immunohis-
tochemical L1CAM expression is validated, it would
be possible to identify high-risk patients in need of
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Treatment strategies for endometrial cancer Lee et al.
more aggressive surveillance or consideration of
adjuvant treatment. L1CAM testing may also be
possible from curettage material (preoperative biop-
sies), and this may direct decisions for more radical
surgical plan, such as lymphadenectomies.
Recent advancements to integrate prognostic
molecular alterations with these clinicopathological
factors have achieved a better risk assessment model
&&
[33 ]. The majority (97%) of the tumors can be
classified into the four molecular categories: POLE-
mutant, MSI, p53-mutant, and no specific molecular
profile (NSMP). On the basis of this model, approxi-
mately 15% of patients with early stage (majority
stage I disease) had concerning risk features, such
as p53-mutant, and/or more than 10% L1CAM and
LVSI, warranting consideration for adjuvant treat-
ment. On the contrary, about 50% of patients had
favorable features, such as POLE-mutant, microsatel-
lite-stable, and CTNNB1 wild-type tumors, thus may
ovoid adjuvant treatment. This integrated risk model
will be incorporated into prospective studies for fur-
ther validation. The PORTEC-4A trial (NTR5841) has
been developed to select patients with early stage
endometrial cancer based on their molecular profile
for adjuvant radiation.
DECISION FOR ADJUVANT TREATMENT IN
STAGE II–III DISEASE
&
Despite complete surgical resection, patients with
stage II–III disease are at increased risk of recurrence
and the estimated 5-year OS was 75–85 and 40–
65%, respectively [34]. Adjuvant treatment options
include chemotherapy and radiation; however, the
optimal scheduling is yet to be established. There is a
debate on whether sequential delivery vs. the sand-
wich approach of radiation and chemotherapy
would provide better therapeutic outcome.
Recent reports from multicenter retrospective
analysis of stage IIIa patients seem to favor com-
bined chemoradiation instead of radiation alone in
&
high-risk group [35 ]. In another study of patients
& &
with stage IIIC1 endometrial cancer, adjuvant che-
motherapy significantly reduced the para-aortic
recurrence but did not influence 5-year survival
&
[36 ]. Results of PORTEC-3, investigating postoper-
ative pelvic radiation vs. concurrent chemoradia-
tion followed by chemotherapy, and GOG-258,
investigating chemotherapy alone vs. weekly cispla-
tin combined with pelvic radiation followed by
adjuvant chemotherapy, are eagerly awaited.
In general, there is a lack of toxicity or quality-
of-life data for chemoradiation alone, or followed by
chemotherapy (in sequence or ‘sandwich’ strategy)
in endometrial cancer. Currently, there are multiple
small retrospective studies that reported that most
www.co-obgyn.com 51
Gynecologic cancer
of the patients treated with adjuvant chemoradia-
tion followed by chemotherapy tolerated and com-
&
pleted treatment without major toxicities [37 ] apart
from hematological side-effects. There was no sig-
nificant difference in toxicity observed in patients
undergoing sequential chemotherapy followed by
&
radiation or ‘sandwich’ fashion [38 ] apart from
hematological toxicities.
Recently, the toxicity and the 2-year health-
related quality-of-life data from the PORTEC-3 trial
showed significantly higher toxicity in patients
undergoing chemoradiation (cisplatin weeks 1
and 4) followed by adjuvant chemotherapy com-
&&
pared with radiation alone [39 ]. The majority of
toxicity experienced had improved within 6–12
months, apart from sensory neuropathy (25%)
which remained significantly worse in the combi-
nation arm after 24 months. In addition, lower
physical functioning scores have been reported by
patients in the combination arm after 24 months.
Therefore, if the benefit of combination is deter-
mined in the final analysis, patient selection and
dose schedule may need to be fine-tuned according
to toxicity.
TREATMENT DECISION FOR METASTATIC
OR RECURRENT ENDOMETRIAL CANCER
In patients with localized recurrent disease, radi-
ation can be considered. Improvement in radiation
techniques with application of intensity-modulated
radiation therapy (IMRT) has resulted in better
toxicity profile and patient tolerability. One large
retrospective study examined the use of IMRT for
patients with isolated nodal recurrence and found
that patients who received concurrent chemoradia-
tion (given as weekly cisplatin) had significantly
longer median survival as compared with IMRT
alone, 61.9 and 28.7 months, respectively
(P ¼ 0.034) [40 ]. Prospective studies are warranted
&
and data from a phase 2 is pending (NCT00492778,
in Table 1).
Hormonal therapy is a treatment option in
endometrial cancer, particularly for patients with
recurrent low-grade endometrioid histology, and
can be considered as the first target-specific therapy
in this disease; however, the predictive value of
estrogen receptor/progesterone receptor status
remains a little controversial. Preliminary report
from the PARAGON study (ANZGOG 0903) enroll-
ing recurrent gynecological cancers with estrogen
receptor/progesterone receptor positive tumor
expression demonstrated that patients with endo-
metrial cancer derived clinical benefit (44% at 3
months) from anastrozole with significant improve-
& &
ment in quality of life [41 ].
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Chemotherapy is the main modality of treatment
for metastatic or recurrent endometrial cancer. The
most common regimen consists of doublet of carbo-
platin and paclitaxel, with variable overall response
rate (ORR) at 30–60% and median OS of around 1 year
[42–45]. There is, however, no defined or accepted
standard second-line therapy. Single agent doxoru-
bicin or potentially weekly paclitaxel have been
used in this setting, with modest activity. Decision
of second-line chemotherapy often lies between
rechallenging the same regimen or switch to mono-
therapy. Patients with good performance status
should be considered for clinical trials.
Novel agents being investigated include non-
&
pegylated liposomal doxorubicin [46 ]; AEZS-108,
an LHRH-agonist coupled to doxorubicin [47];
and Selinexor (KPT-330), an oral selective inhibitor
of nuclear export [48]. Ixabepilone failed to show
significant improvement in OS, when compared
with current standard agents (doxorubicin or pacli-
taxel) [49].
By analogy to ovarian cancer, platinum-free
interval has been used in practice but question
remains whether the same principle would apply
to endometrial cancer to guide treatment strategy.
A retrospective analysis from SGSG012/GOTIC004/
Intergroup study has shown that rechallenge with
platinum-based chemotherapy at the time of disease
&
recurrence can induce further response [50 ].
DISEASE CHARACTERIZATION TO DRIVE
TARGETED THERAPY
Recent years have seen efforts to refine molecular
characterization to customize therapeutic strategies
and thereby improve therapeutic outcomes of endo-
metrial cancer. However, simply identifying and
targeting mutations does not necessarily equate to
treatment response because of tumor heterogeneity
and complex feedback loops that may lead to
‘escape’ pathways. Patient-derived tumor xenograft
models may provide opportunities to better under-
stand the molecular and microenvironment charac-
&
teristics [51 ].
There is an unmet need for effective treatment for
endometrial cancer but as yet there is no approved
targeted therapy in this cancer beyond hormonal
therapy [52]. Among many targeted agents investi-
gated, antiangiogenic and mTOR/PI3K pathway
inhibitor agents have demonstrated clinical activity
and remain under further investigation. Managing
toxicities in this patient population remains chal-
lenging and often limits therapeutic options. Over
the past year, several phase II trials have been con-
ducted and are summarized below and shown in
& &
Table 2 [41 ,53 –65 ].
Volume 29  Number 1  February 2017
 Table 2. Targeted agents evaluated in phase II clinical setting published after January 2015

Agents Targets Number of patients Regimen Study outcome Reference

Studies that have met prespecified efficacy in phase II setting

&
Bevacizumab VEGF 15 no prior platinum/taxane Carboplatin–paclitaxel þ bevacizumab, ORR 73%; mPFS 18 months; mOS 58 [53 ]
followed by bevacizumab as months
maintenance therapy
&
Cediranib (AZD2171) VEGFR1–3, PDGFRa/b; 53 prior 1–2 lines of Cediranib mPFS 3.65 months; mOS 12.5 months [54 ]
FGFR1 chemotherapy
&
Ridaforolimus mTOR 130 prior 1–2 lines of Ridaforolimus vs. control arm (progestin mPFS 3.6 vs. 1.9 months (P ¼ 0.008) [55 ]
chemotherapy or investigator’s choice chemo)
&
Letrozole þ everolimus Estrogen receptor, 38 prior 0–2 lines of Everolimus þ letrozole CBR 40%; ORR 32% [56 ]
progesterone receptor; chemotherapy
mTOR
Studies that failed to meet prespecified efficacy in phase II setting (insufficient activity)
&
Trebananib (AMG386) Angiopoietin1/2 32 prior 1–2 lines of Trebananib CBR 28%; mPFS 1.97 months; mOS 6.6 [57 ]
chemotherapy months
&
Dalantercept ALK1 28 prior 1–2 lines of Dalantercep mPFS 2.1 months; mOS 14.5 months [58 ]
chemotherapy
&
Selumetinib (AZD6244, MEK1/2 54 prior 1–2 lines of Selumetinib mPFS 2.3 months [59 ]
ARRY142886) chemotherapy
&
Pilaralisib PI3K 67 prior 1–2 lines of Pilaralisib CBR 13.4%; 6-month PFS 11.9% [60 ]
(SAR245408; XL147) chemotherapy
&

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Dovitinib (TKI258) FGFR1–3; VEGFR1–3; 53 prior 1 line of chemotherapy Dovitinib in FGFR2-mutant and non- CBR 64%, mPFS 4 months; mOS 20 [61 ]
PDGFR-b, c-KIT FGFR2-mutant months
&
Temsirolimus mTOR 44 (22 with endometrial cancer); Temsirolimus Insufficient activity [62 ]
prior 1–2 lines of
chemotherapy
Ongoing study with published preliminary results
&
Bevacizumab GOG- VEGF 349 chemotherapy-naı̈ve Carboplatin–paclitaxel þ bevacizumab PFS not significantly increased but OS is [63 ]
86P vs. carboplatin– significantly increased (P < 0.04) in
paclitaxel þ temsirolimus vs. carboplatin–paclitaxel þ bevacizumab
carboplain– arm
ixabepilone þ bevacizumab
&
Cabozantinib (XL184) VEGFR2 RET, MET, AXL, 79 prior 1 line of chemotherapy Cabozantinib Met predefined activity; data ongoing [64 ]
KIT
&
Anastrozole Estrogen receptor, 84 prior 0–3 lines of Anastrozole CBR 44%; mPFS 3.2 months; significant [41 ]
progesterone receptor chemotherapy improvement in quality of life
&

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Letrozole þ everolimus Estrogen receptor, 62 prior 1–2 lines of Everolimus þ letrozole þ metformin Data from 49 pts, CBR 60%; ORR 29% [65 ]
þ metformin progesterone receptor; chemotherapy
mTOR AMPK, mTOR

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CBR, clinical benefit rate; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate.
Treatment strategies for endometrial cancer Lee et al.

53
Gynecologic cancer
Targeting the angiogenesis pathway
Preliminary data from study GOG86P investigating
bevacizumab, combined with chemotherapy, in
advanced or recurrent endometrial cancer chemo-
therapy naı̈ve population, showed high ORR of
59.5% with significant OS improvement (P < 0.04)
but not progression-free survival (PFS) improvement
(P ¼ 0.40) in comparison to the historic reference for
carboplatin/paclitaxel or the other arms (carbopla-
tin/paclitaxel/temsirolimus or carboplatin/ixabepi-
&
lone/bevacizumab) [63 ]. Recently, sunitinib and
cediranib were reported in a phase II setting showing
&
activity with tolerable toxicities [54 ,66]. Interest-
ingly, high-microvessel density appears to correlate
with longer PFS, and deserves further evaluation
&
[54 ]. Cabozantinib is also of interest, showing
activity and tolerability in all histology types and
&
warrants further investigation [64 ].
Targeting the PI3K/Akt/mTOR pathway
Overexpression or mutation in the PI3K/Akt/mTOR
pathway in endometrial cancer is common [67].
mTOR inhibitors that have shown encouraging
activity in recurrent endometrial cancer include
temsirolimus [68], everolimus [69], and more
&
recently ridaforolimus [55 ]. A phase II randomized
study comparing ridaforolimus to standard therapy
(progestin or physicians’ choice chemotherapy)
demonstrated a significant PFS improvement (3.6
vs. 1.9 months, P ¼ 0.008) but with a considerable
&
toxicity profile [55 ]. Another phase II study inves-
tigating temsirolimus in heavily pretreated patients
with ovarian cancer and endometrial cancer did not
demonstrate clinical benefit, in contrary to prior
&
studies [62 ,68].
Targeting glucose metabolism
Preclinical studies have shown a growth inhibitory
effect of metformin in endometrial cancer cell lines,
via the inhibition of AMPK, which leads to stabiliz-
ation of TSC2 and inhibition of mTORC1 signaling
pathway and alterations in glucose metabolism
[70,71]. Similarly, metformin appears to display
potent apoptotic and antimitogenic actions in serous
endometrial cancer cell line [72]. A recent window of
opportunity study assessing metformin prior to
surgery was associated with a significant decrease
&
in Ki-67 expression in endometrial cancer [73 ].
Retrospective analysis from patients diagnosed
with endometrial cancer and on metformin for dia-
betes have suggested statistically longer survival
(45.6 vs. 12.5 months, P ¼ 0.006) compared with
those on other treatment for diabetes [74] but these
retrospective studies have important limitations
54 www.co-obgyn.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
and should be interpreted cautiously. These find-
ings, however, supporting a linkage between endo-
metrial cancer and metabolism pathway warrant
further investigation to identify a potential target
for treatment and prevention.
Combination of targeted therapies
Prior study investigating combination of mTOR
inhibitor and hormonal therapy did not show
enhanced activity [75]; however, more recent study
investigating the combination (using different agent
within the same class, everolimus, and letrozole)
demonstrated clinical benefit rate of 40% at 4 months
with acceptable toxicity. Women with endometrioid
and CTNNB1 mutation seem to benefit from this
combination. Another study investigating combi-
nation of everolimus, letrozole, and metformin
showed a higher clinical benefit of 60% at 4 months
&
and manageable toxicity [65 ]. Other combination
strategies are underway (Table 1). Preclinical data
exploring combination therapy such as dual PI3K/
mTOR inihibitor (SAR245409) and MEK inhibitor
(pimasertib) showed evidence of synergistic antitu-
&
mor effect in endometrial cancer cell lines [76 ].
RECENT TREATMENT CONCEPTS UNDER
INVESTIGATION
Microsatellite mismatch repair status and
immunotherapy
Recent data seem to show a significant association
between microsatellite mismatch repair (MMR)
status and outcome in endometrial cancer, con-
trary to a previous meta-analysis [77]. Correlation
between MMR-related protein expression and
clinicopathologic features in endometrial cancer
using immunohistochemical (IHC) found a signi-
ficant improvement in 5-year OS, 94 vs. 78%
(P ¼ 0.009), in MMR-deficient patients compared
&
with MMR proficient patients [78 ]. However,
inter-study heterogeneity in histology subtypes and
adjuvant treatment received in the meta-analysis
[77] may have influenced the study outcome. The
&
significantly improved OS reported [78 ] may be
attributable to the majority of patients with inter-
mediate-to-high-risk disease receiving postoperative
chemotherapy as adjuvant treatment.
There is heightened interest exploring the thera-
peutic potential for immunotherapy in endometrial
cancer. The immune microenvironment in endo-
metrial cancer tumor with MSI exhibits elevated
&
CD8 and granzyme B cells [79 ], which may allow
these patients to respond favorably to immunother-
apy. In addition, patients with POLE-ultramutated
Volume 29  Number 1  February 2017

endometrial cancer may be suitable for this treat-
ment strategy as this tumor type exhibits a striking
mutational burden and an enhanced antitumor
&
T-cell response [20 ]. Preliminary results from
KEYNOTE-028 study showed an ORR of 13% with
6-month PFS at 19% in patients who had failed prior
&
systemic chemotherapy [80 ]. There are currently
multiple studies underway (Table 1) and would
provide insight to the complex immune landscapes
of these tumors.
Homologous recombination deficiency in
endometrial cancer
On the basis of the recent advances in endometrial
cancer characterization, the genes implicated in
DNA repair are of interest in serous endometrial
&
cancer [81 ]. In a retrospective analysis, high
homologous recombination deficiency (HRD)
score appears to correlate adverse outcome in
& && of outstanding interest
endometrial cancer [82 ]. In endometrial cell lines
and an orthotopic mouse model with high-HRD
score, olaparib treatment decreased tumor growth
&
and may be a potential therapeutic target [82 ,83].
Phosphatase and tensin homolog (PTEN) loss of
function, common in endometrioid endometrial
cancer, may contribute to genomic instability
via the RAD51-mediated DNA repair pathway
(homologous recombination) and, therefore,
renders tumor sensitive to poly (ADP-ribose) poly-
merase inhibition [84].
CONCLUSION
The majority of the women with early stage endo-
metrial cancer have favorable outcome and treat-
ment strategies, therefore, focus on patient selection
in order to avoid overtreatment in patients who
will not relapse and propose adjuvant treatment
to the subset of patients who will recur. The updated
international consensus has provided guidelines
regarding the risk stratification and evidence-based
&&
treatment [14 ]. There is, however, persistent
debate about the lymph node staging and the
optimal schedule of adjuvant treatment (chemo-
therapy and/or radiation). The upcoming results
from the large randomized trials completed would
help to address these issues.
The OS in advanced stage or recurrent endo-
metrial cancer has not changed over the past
decades. Although different targeted therapies have
been investigated in endometrial cancer, none has
resulted in a change in clinical practice to date.
Efforts are ongoing to best identify the subset of
patients who will most likely respond to these treat-
ment approaches, the biomarkers that are likely
1040-872X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Treatment strategies for endometrial cancer Lee et al.
predictive of response, and the combinations of
therapies that are effective with tolerable toxicity.
Future trial design should incorporate current
knowledge of tumor molecular classification and a
robust biomarker testing.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 29  Number 1  February 2017