new strategies in endometrial cancer: targeting the pi3k...

CCR New Strategies

New Strategies in Endometrial Cancer: Targeting thePI3K/mTOR Pathway—The Devil Is in the Details

Andrea P. Myers1,2

AbstractEndometrial cancer is the most common gynecologic malignancy in the developed world and

affects approximately 40,000 women in the United States each year. The phosphoinositide 3-kinase

(PI3K) signaling pathway regulates key aspects of cancer biology including glucose uptake and

metabolism, cellular growth, and survival. Endometrial cancers harbor the highest rates of PI3K

pathway alterations reported to date. The PI3K pathway is highly druggable and several classes of

agents are in clinical development including rapalogs, pan-PI3K inhibitors, PI3K isoform-specific

inhibitors, dual PI3K/mTOR catalytic inhibitors, mTOR-specific catalytic inhibitors, and AKT

inhibitors. It has been 10 years since the initiation of the first studies of rapalogs as anticancer

agents. There are more than 20 registered clinical trials of PI3K/mTOR inhibitors as single agents or

in therapeutic combinations for the treatment of endometrial cancers. What have we learned from

the completed studies? What can we expect to learn from ongoing studies? What should we anticipate

moving forward? Clin Cancer Res; 19(19); 5264–74. �2013 AACR.

BackgroundEndometrial cancer

Endometrial cancer is the most common gynecolo-gic malignancy in the developed world and affectsapproximately 40,000 women in the United States eachyear (1, 2). Endometrial cancer is increasing in inci-dence, likely due to the growing epidemic of obesity,a strong risk factor for endometrial cancer (2–4).Although the majority of endometrial cancers are diag-nosed when localized to the uterus, up to 25% of casesrecur. Systemic therapies are limited in efficacy forrecurrent and metastatic disease and new therapies arein need (5).

PI3K signalingThe phosphoinositide 3-kinase (PI3K) pathway (Fig. 1)

regulates key aspects of cancer biology including metab-olism, cellular growth, and survival (6). Upon stimula-

tion of receptor tyrosine kinases (RTK), PI3K phosphor-ylates the lipid phosphatidylinositol 4,5- biphosphate(PIP2), creating phosphatidylinositol 3,4,5- triphos-phate (PIP3) (7). PIP3 recruits pleckstrin homologydomain-containing proteins, including the proteinkinase AKT, to the membrane. AKT is phosphorylatedand activated by mTOR complex 2 (mTORC2) and 3-phosphoinositide-dependent protein kinase 1 (PDK1;ref. 8). Among its targets, AKT phosphorylates and inhi-bits tuberous sclerosis complex 2 (TSC2) within themultiprotein TSC complex, which indirectly inhibitsmTOR complex 1 (mTORC1). Hence, PI3K-AKT signal-ing activates mTORC1, a key regulator of metabolismand biosynthetic processes (9, 10). PTEN hydrolyzesPIP3 back to PIP2, deactivating the pathway (11, 12).The PI3K pathway contains numerous negative feedbackloops and is intricately networked with other signalingpathways including the RAS–ERK pathway. Signals fromboth AMP-activated protein kinase (AMPK), a sensor ofenergy stress, and estrogens are also integrated into PI3Ksignaling (13–16).

PI3K in endometrial cancerEndometrial cancers harbor the highest rates of

PI3K pathway alterations reported to date (17). Theimportance of the PI3K pathway in endometrial can-cers was underscored by the identification of germlinemutations in PTEN as the etiology of Cowden syn-drome, an inherited cancer syndrome for which endo-metrial cancer is a diagnostic criterion (18, 19). High

Author's Affiliations: 1Gynecology Oncology Program, Division ofWomen's Cancers, Department of Medical Oncology, Dana-FarberCancer Institute; and 2Division of Signal Transduction, Departmentof Medicine, Beth Israel Deaconess Cancer Center, Boston,Massachusetts

Corresponding Author: Andrea P. Myers, Novartis Institutes for BioMed-ical Research, Inc. Oncology Translational Medicine, 220 MassachusettsAvenue, Cambridge, MA 02139. Phone: 617-871-4991; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-13-0615

�2013 American Association for Cancer Research.

ClinicalCancer

Research

Clin Cancer Res; 19(19) October 1, 20135264

on June 26, 2018. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

http://clincancerres.aacrjournals.org/

rates of somatic PTEN mutations were reported insporadic cases of endometrial cancers shortly thereaf-ter and genetically engineered mouse models con-firmed the role of PTEN loss in endometrial cancerdevelopment (20–24). Candidate gene approachesidentified high rates of PIK3CA (25%–40%) andPIK3RI (15%–25%) mutations, which encode the cat-alytic and regulatory subunits of the PI3K holoenzyme(25–27). Recently completed high-throughput muta-

tion detection as well as whole exome sequencingstudies have confirmed these reports and haveidentified mutations in other key PI3K pathway mem-bers (Fig. 1; refs. 17, 28).

Targeting PI3KThe PI3K pathway is highly druggable and several

classes of agents are in clinical development (Fig. 2).The rapamycin analogs (rapalogs) directly bind and

ERBB2 amplification 15%FGFR2 mutation 13%

RTKInsulin andinsulin-like

growth factor

RAS p85

PIP2 PlP3p110

Pl3K

AKT

PPP2R1A

PDK

mTORC2

AKT1 mutation 2%AKT2 mutation 2.5%AKT3 mutation 5%PPP2R1A mutation 10%

???

PTEN

ERK

AMPK

Metformin

Estrogen

Nutrients

TSCcomplex

Cellsurvivalsignals

TSC1 mutation 4%TSC2 mutation 5%mTOR mutation 11%

NF2

NF2mutations 3%

Biomassgeneration

Proteintranslation

PTEN mutation 65%PIK3CA mutation 53%PIK3R1 mutation 34%PIK3CA amplification 15%

K-RAS mutation 20%

GF

mTORC1

© 2013 American Association for Cancer Research

Figure 1. Environmental signals and molecular alterations that may alter PI3K signals in endometrial cancer. Class Ia PI3Ks are holoenzymescomprised of a catalytic (p110) and regulatory subunit (p85) and can interact with RTKs upon their activation. PI3K phosphorylates PIP2 tocreate PIP3. PTEN hydrolyzes PIP3 to PIP2. With generation of PIP3, AKT is recruited to the membrane, phosphorylated and activated bymTORC2 and PDK. AKT phosphorylates and inactivates the TSC complex, which allows for downstream mTORC1 activation. RTK signaling alsoactivates the RAS pathway; ERK phosphorylates and suppresses TSC. AMPK senses cellular stress and nutrient availability and activatesTSC to suppress further growth signals. The role of PPP2R1A is less well defined but may have inhibitory effects on PI3K/mTOR signals. Rates ofsomatic mutation and amplification are shown in boxes. Reported rates were collected from The Cancer Genome Atlas data from cBIOPortal and may not represent functional mutations. Potential environmental signals common in endometrial cancer are shown in jaggedovals. Dashed lines represent indirect signals. PPP2R1A; Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A a isoform;NF; neurofibromin; PIK3CA; the gene that encodes the p110 a catalytic subunit of PI3K; PIK3R1; the gene that encodes the p85 regulatorysubunit of PI3K.

Targeting the PI3K/mTOR Pathway in Endometrial Cancer

www.aacrjournals.org Clin Cancer Res; 19(19) October 1, 2013 5265



allosterically inhibit mTORC1. Although they targetdownstream of PI3K they are often introduced as the firstclinical PI3K pathway inhibitors. Indeed, nearly 20 yearsof laboratory, translational, and clinical experience withthe rapalogs has offered great insight into basic PI3Ksignaling as well as potential pitfalls and challenges forclinical developing of these inhibitors as anticanceragents (29). Newer classes of PI3K pathway inhibitorsin clinical development include pan-PI3K inhibitors,

PI3K isoform-specific inhibitors, dual PI3K/mTOR cata-lytic inhibitors, mTOR-specific catalytic inhibitors, andAkt inhibitors (30, 31).

On the HorizonGiven the high rate of PI3K pathway alteration,

endometrial cancer seems to be an optimal diseasefor the development of PI3K pathway inhibitors.

© 2013 American Association for Cancer Research

PIP2

AKT

mTORC2

mTORC1

TSCcomplex

PIP3

αα

PI3KPI3Kβ

βδ

PI3Kβ

PI3K

Pan-PI3Kinhibitor

PI3K

PIP2

AKT

mTORC2

mTORC1

TSCcomplex

PIP3

AKTinhibitor

PI3K

PIP2

AKT

mTORC2

mTORC1

TSCcomplex

PIP3

PI3K

PIP2

AKT

mTORC2

mTORC1

TSCcomplex

PIP3 PI3K

PIP2

AKT

mTORC2

mTORC1

TSCcomplex

PIP3

PI3K/dualmTORC inhibitor

mTORCcatalytic inhibitor

PI3Kβinhibitor

α-PI3Kinhibitor

PI3K

PIP2

AKT

mTORC2

mTORC1

TSCcomplex

PIP3

Rapalog

α

Figure 2. Classes of PI3K/mTORpathway inhibitors. Themolecular targets of classes ofPI3K/mTOR pathway inhibitorsare shown in each panel.Rapalogs indirectly inhibitmTORC1. The Pan-PI3Kinhibitors target the three classIA PI3Ks (a, b, and d), which aredesignated by their p110catalytic subunits (a, b, and d).Dual PI3K/mTORC inhibitorstarget the Class Ia PI3Kisoforms, mTORC1, andmTORC2. mTORC catalyticinhibitors target mTORC1 andmTORC2. AKT inhibitors targetAKT. Isoform-specific inhibitorsinclude PI3Ka, PI3Kb, andPI3Kd and target theirrespective PI3K isoforms.

Myers

Clin Cancer Res; 19(19) October 1, 2013 Clinical Cancer Research5266



It has been 15 years since the initiation of thefirst studies of rapalogs as anticancer agents. Thereare numerous registered clinical trials of PI3K/mTOR inhibitors as single agents or in combina-tions for the treatment of endometrial cancers(Tables 1 and 2). What have we learned from thecompleted studies? What can we expect to learnfrom ongoing studies? What should we anticipatemoving forward?

The rapalogsRapalogs as single agents. Frommore than a half dozen

clinical trials of the rapalogs as single agents, it can beconcluded that rapalogs have a modest, but reproducibleantitumor activity in endometrial cancer (Table 1).Objective response rates range from 0%–30% dependingupon the clinical population; clinical response ratesare higher in populations that have not received priorchemotherapy and response occurs across histologicsubtypes including endometroid, high-grade papillaryserous, and clear cell cancers. Importantly, there is a sub-set, albeit small, of patients with complete and/or durableresponses (32–37).Predictive biomarkers for rapalogs. A molecular bio-

marker that predicts the clinical benefit of rapalogs hasyet to be identified for endometrial cancer. Several studieshave explored the association of molecular biomarkersand response (33, 38–40). The largest, most comprehen-sive study to date has been a combined analysis of threeNational Cancer Institute of Canada Clinical Trials Group(NCIC CTG) studies, each of which evaluated a rapalog assingle-agent therapy in advanced endometrial cancer(40). Seventy to eighty tumor samples were evaluatedfor common mutations in a set of 17 related cancer genesas well as for protein expression of PTEN and stathmin(STMN), a cytoskeletal protein with expression thatis associated with PI3K pathway activation (41). Thesestudies reported no association between clinical responserates and PTEN mutation, PIK3CA mutation, PTEN orSTMN protein expression.The strength of these studies is the large sample size.

Although the studies were exploratory in nature, giventhe rates of the PTEN mutations and protein loss,PIK3CA mutation and STMN expression in endometrialcancer, there was adequate power to detect clinicallymeaningful differences in outcomes of the definedmolecular subgroups. There were also weaknesses inthis study. First, the study population is clinically het-erogeneous and includes untreated and pretreatedpatients and patients who were treated with differentrapalogs. Second, although technologically advanced forthe time, the mutation analysis was limited to "hot-spots" and thus misclassification may have been intro-duced (26). Finally, associative analyses were limited toobjective response rates and did not include time toevent studies.Associative studies from the Group d’Investigateurs

Nationaux pour l’Etude des Cancers Ovariens (GINECO)

led study of everolimus were recently reported (38). Ina study of 34 patients, there was no identified asso-ciation of PTEN or PI3KCA mutation and clinical ben-efit. However, K-Ras mutation was associated with adecreased progression-free and overall survival in thispopulation.

Although imperfect and validation from other largerstudies is needed, these data suggest that PTEN andPIK3CA alterations are not reliable biomarkers for pre-dicting clinical benefit to the rapalogs and that K-Rasmutation may predict a group unlikely to benefit fromrapalogs. Indeed, these results are consistent with pre-clinical and translational data which highlight potentialclinical pitfalls of the rapalogs as single agents. Rapalogexposure relieves mTORC1-dependent negative feed-back loops affecting RTK signaling resulting in upregula-tion of both RAS-ERK and PI3K pathways (13). Tumorscan thus circumvent rapalog inhibition by relying onRAS-ERK signaling or PI3K signals that are independentof mTORC1.

Other candidate biomarkers. Although not yet molecu-larly defined, there remains a subset of patients who greatlybenefit from rapalog monotherapy. The clinical use ofprospectively classifying these patients mandates that wecontinue the search for a predictive biomarker. Recentclinical data on rapalogs in other cancers as well as labo-ratory studies of mTOR signaling suggest additional ave-nues to explore.

In bladder cancer, TSC1 mutation is associated withclinical response to a rapalog (42). Iyer and colleaguesconducted whole genome sequencing on archivedtumor from a patient who had a complete and durableresponse to everolimus. Analysis revealed mutations inTSC1 and neurofibromin 2 (NF2), genes whose proteinproducts regulate mTORC1 signaling. Targeted sequenc-ing of the tumors from the other trial participants iden-tified an association with TSC1 mutation and best tumorresponse. These data suggest that TSC1 and NF2 beevaluated as biomarkers for rapalogs in endometrialcancer and also highlight the benefit of deep sequencingexploration of tumors from patients with an unexpectedlevel and duration of benefit to molecularly targeteddrugs.

The perspective that mTORC1 functions only torelay proliferative signals from PI3K is a limited view ofmTORC1 regulation and function. Recent laboratory-based studies highlight that our understanding ofmTORC1 is incomplete. In addition to signals from theTSC complex, mTORC1 is directly regulated by othernutrient-sensing proteins including the recently de-scribed ragulator complex (43). In addition, two researchgroups have identified the importance of mTORC1 inregulating de novo pyrimidine synthesis by its phosphory-lation and activation of the enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, anddihydroorotase; refs. 44, 45). Tumors with microsatelliteinstability have been reported to have CAD amplifica-tion, perhaps suggesting a heavy reliance on de novo





Tab

le1.

Com

pletedan

don

goingpha

seIIclinical

trials

ofsing

leag

entPI3K/m

TORpathw

ayinhibito

rsin

endom

etria

lcan

cera

Inve

stigationa

lag

ent

Target

Treatmen

tpopulation

NCT#

(dateregistered)

Clin

ical

resu

lts

(n)

Toxicities

Referen

ce

Temsirolim

usmTO

RC1

Che

mo-na

ïve

NCT0

0072

176

(11/20

03)

CR(0/33)

bMos

tco

mmon

�grad

e3

AEs:

fatig

ue,d

iarrhe

a,pne

umon

itis

33PR(4/33)

b

SD�

8wee

ksc(20/33

)

Temsirolim

usmTO

RC1

1prio

rline

NCT0

0072

176

(11/20

03)

CR(0/27)

Mos

tco

mmon

�grad

e3

AEs:

fatig

ue,d

iarrhe

a,pne

umon

itis,

dys

pne

a,hy

pok

alem

ia

33PR(1/27)

SD�

8wee

ksc(12/27

)

Eve

rolim

usmTO

RC1

1-2prio

rlines

dNCT0

0087

685

(7/200

4)CR(0/35)

PR(0/35)

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Mos

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Ridaforolim

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AEs:

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emia,m

outh

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nemia

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Tab

le1.

Com

pletedan

don

goingpha

seIIclinical

trials

ofsing

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entPI3K/m

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ayinhibito

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endom

etria

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(Con

t'd)

Inve

stigationa

lag

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Target

Treatmen

tpopulation

NCT#

(dateregistered)

Clin

ical

resu

lts

(n)

Toxicities

Referen

ce

MK-220

6AKT

1-2prio

rlines

NCT0

1312

753

(12/20

10)

CR(0/36)

Mos

tco

mmon

�grad

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AEs:

rash

,hyp

erglyc

emia,

52PR(2/36)

SD�

8wee

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�6mon

ths(4/36)

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KM12

0Pan

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1prio

rlines

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2890

41(1/201

1)Not

yetrepo

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Not

yetreported

Not

recruitin

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treported

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0Dua

lmTO

RC/PI3K

1–2prio

rlines

NCT0

1455

493

(10/20

11)

Not

yetrepo

rted

Not

yetreported

Not

recruitin

g,no

treported

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2123

84Dua

lmTO

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1–2prio

rlines

NCT0

1420

081

(8/201

1)Not

yetrepo

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yetreported

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6915

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Adjuva

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lyNCT0

1397

877

(7/201

1)Not

yetrepo

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Tab

le2.

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pletedan

don

goingpha

seIIclinical

trials

ofPI3K/m

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combinationwith

othe

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cytotoxic

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ïve

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pyrimidine synthesis and potential sensitivity to rapalogtreatment (46).Rapalogs in combination. The rapalogs continue to

be studied in combination with other cytotoxic andbiologic agents. Phase II studies of rapalogs with hor-monal agents as well as antiangiogenic agents have beencompleted (refs. 47–49; Table 2). Toxicity of these classcombinations may be limiting. The combination armof GOG 248, a randomized study of temsirolimuswith or without hormonal therapy was terminatedbecause of thromboembolic events (48). Combinationsof rapalogs and antiangiogenic agents also report highrates of vascular events (49; Susan Campos; personalcommunication).GOG 86P is a "pick-the-winner" randomized phase II

study evaluating 3 different agents, including temsirolimus,in combination with carboplatin and paclitaxel. Thisstudy has embedded translational studies that could beinformative. Should a predictive biomarker for single-agentrapalog response be identified, it will be important toknow whether it can be generalized to rapalogs in thera-peutic combinations.

PI3K pathway inhibitorsRapalogs are incomplete inhibitors of mTORC1 tar-

gets and, due to feedback loops, can result in activationof upstream PI3K signals (50, 51). It has been hypoth-esized that newer PI3K pathway agents, which targetfurther upstream in the pathway, will be more clinicallyeffective. Numerous phase Ib/II clinical trials areunderway including pan-PI3K, dual PI3K/mTOR, AKT,and catalytic mTOR inhibitors (www.clinicaltrials.gov; Table 1). Although clinical reports are expectedsoon, the results for the majority of these studies haveyet to be reported.Results from a phase II study of MK-2206, an allosteric

AKT inhibitor were recently reported (52). This study wasprospectively stratified for PIK3CA mutations and wasdesigned to explore the hypothesis that patients withtumors that harbor PIK3CA mutation would be morelikely to derive benefit from MK-2206. Of the 36 patientsenrolled, 9 were classified as PIK3CA mutant and 27 werePIK3CA wild-type. There was 1 event of clinical benefit inthe PIK3CA-mutant group and 4 events of clinical benefitin the PIK3CA wild-type group suggesting that there islimited clinical use for prospective PIK3CA mutationtesting predict response to AKT inhibitors. All 4 partici-pants who were on treatment for more than 6months hadtumors of serous histology, a histology that represents adisproportionate number of deaths from endometrialcancer.PI3K pathway inhibitors are also being evaluated

in combination studies. On the basis of the tight net-working with the RAS-ERK pathway combination ofMEK and other RTK inhibitors are of great interest. PhaseI studies of combination have identified notable re-sponses in endometrial cancer though exploration ofdosing to minimizing toxicity continues (53). PI3K

pathway inhibitors are also being studied in combina-tion with cytotoxics (Table 2 and www.clinicaltrials.gov)though efficacy results in endometrial cancer have yetto be reported.

The future: contextualizing PI3K signalingResults from many PI3K pathway inhibitors trials

are anticipated. (Tables 1 and 2). However, these firstreports suggest that PI3K/mTOR pathway inhibitors assingle agents are not as efficacious as hoped. In recog-nition that clinical trials should generate as well as testhypotheses, there are some avenues that warrant furtherexploration.

Of drugs and targets. Preclinical and translationaldata strongly support that PI3K signaling underpinsendometrial cancer biology and this prior knowledgeneeds to be accounted for in the interpretation ofPI3K/mTOR pathway inhibitor trial results. At this earlyjuncture, negative studies in this disease should steerfocus to the investigational agents as much as challengethe validity of PI3K as a target. Pharmacodynamic stud-ies to verify pathway inhibition at achievable exposuresshould remain an integral part of these early-phasestudies as the maximal tolerated may not equate tothe biologically optimal dose. The enhanced specificityand potency of newer classes of agents such as themTORC1/2 catalytic and PI3K isoform-specific inhibi-tors hold promise and should also be evaluated inendometrial cancer.

Metabolic context. Obesity is an established risk fac-tor for developing endometrial cancer with a nearly 3-fold increase in risk (4). The biology underlying theassociations between obesity, endometrial cancer risk,and outcomes remains incompletely understood. How-ever, chronic overexposure to hormones elevated in theobese state such as insulin, insulin-like growth factors,and estrogens, likely contribute (54). The PI3K pathwayis the key-regulating pathway of glucose uptake andmetabolism (6) perhaps suggesting that PI3K pathwayalteration may need to be explored in the context of apatient’s metabolic state. Recent studies evaluating theassociation of PI3K pathway alterations show an inter-action between PTEN protein loss, obesity, and prog-nosis. Patients with obesity with PTEN loss haveimproved outcomes as compared with those with PTENretained. In contrast, in the nonobese population,patients with PTEN loss have worse outcomes (55). Inaddition, retrospective analysis of the combinationstudy of everolimus and letrozole show a clinical ben-efit rate that is twice as high in patients taking theantidiabetic agent metformin as compared with thosewho are not (56). Whether metformin is merely asso-ciated with a subpopulation of patients whose endo-metrial cancer is more like to response to rapalogs orwhether there is a causal effect (direct or indirect)remains unclear.

Histologic context. Unlike breast cancers, treatmentrecommendations for endometrial cancers are not based





on upfront molecular classifications. The most commonendometrial cancer histologies (endometroid, papillaryserous, clear cell, mixed) are treated with the same che-motherapeutic regimens. Results from the MK-2206 trial,in which all patients with 6 months of progression-freesurvival had tumors of serous histology suggest that amore nuanced approach may be warranted. Isolatedmolecular differences between these histologies havebeen described (27). Recent studies of whole-exomesequencing of uterine papillary serous cancers furtherdetail the differences and have identified candidate mole-cular changes to explore as potential molecular biomar-kers for AKT inhibitor response (57–59). In addition,these studies may be useful for the classification of endo-metrial cancers that are challenging to classify by histo-logy alone (60).

Mutational context. Comprehensive genome studiesincluding the The Cancer Genome Atlas highlightssome interesting features of the PI3K pathway that seemto be particular to endometrial cancer (17, 28). Unlikeother cancers, comutations within the PI3K pathwayare common. There is a strong association of PIK3CAand PTEN as well as PIK3R1 and PTEN mutations.PIK3R1 and PIK3CA comutation are uncommon(17, 28). PIK3CA mutations are distributed differentlyin endometrial cancers than other cancers in whichPIK3CA mutations are common such as breast cancer(26). Functional studies suggest that not all mutations inPIK3CA and PIK3RI have the same cellular impact (28).How these very specific mutational features impactendometrial cancer biology and clinical outcomes areunder investigation.

In conclusion, the PI3K pathway underlies endo-metrial cancer development and remains a key targetfor new therapeutics. Ongoing and future clinical inves-tigation should recognize the intricacies of this path-way as highlighted above. Translational studies shouldbe comprehensive including complete sequencingand copy number analysis and pharmacodynamic stud-ies; tumors from patients with robust responsesshould be studied in detail metabolic data such as bodymass index, presence of diabetes, and use of antidia-betic agents should be collected. Together with emerg-ing clinical reports these data can help guide the opti-mal development of PI3K pathway inhibitors in endo-metrial cancer.

Disclosure of Potential Conflicts of InterestA.P. Myers is employed as a clinical program leader for

Novartis and is a consultant/advisory board member of EISAI andSanofi.

AcknowledgmentsThe authors thank C. Dibble and B. Emerling for thought-

ful input and L. Cantley, G. Mills, and U. Matulonis for mentor-ship. The author would like to apologize in advance to investi-gators whose work could not be primarily cited due to spacelimitation.

Grant SupportThis work was supported by a Stand Up To Cancer Dream Team Trans-

lational Cancer Research Grant, a Program of the Entertainment IndustryFoundation (SU2C-AACR-DT 0209).

Received April 29, 2013; revised July 17, 2013; accepted July 28, 2013;published online October 2, 2013.

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2013;19:5264-5274. Clin Cancer Res Andrea P. Myers

The Devil Is in the Details−−Pathway New Strategies in Endometrial Cancer: Targeting the PI3K/mTOR

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