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CANCER PREVENTION RESEARCH | RESEARCH ARTICLE
PROgesterone Therapy for Endometrial CancerPrevention in Obese
Women (PROTEC) Trial:A Feasibility Study A CAbigail E. Derbyshire1,
Jennifer L. Allen2, Matthew Gittins3, Bhavna Lakhiani2, James
Bolton4,Joseph Shaw4, Philip W. Pemberton5, Michelle Needham6,
Michelle L. MacKintosh1,Richard J. Edmondson1,2, Henry C.
Kitchener2, and Emma J. Crosbie1,2
ABSTRACT◥
Obesity is the major etiologic driver for endometrial cancer.The
levonorgestrel intrauterine system (LNG-IUS) reduces therisk of
endometrial cancer and its precursor, atypical hyper-plasia. We
assessed feasibility and uptake of the LNG-IUS forprimary
prevention of endometrial cancer in high-risk womenand its impact
on endometrial tissue biomarkers.Womenwithclass-III obesity [body
mass index (BMI) > 40 kg/m2] andhistologically normal
endometriumwere invited to participatein a clinical trial of the
LNG-IUS for endometrial protection.Recruitment, successful LNG-IUS
insertion, and adherence totrial procedures were recorded. We
measured impact of theLNG-IUS on circulating biomarkers of
endometrial cancerrisk, endometrial proliferation (Ki-67, pAKT,
PTEN), endo-metrial hormone receptor status [estrogen receptor and
pro-gesterone receptor (PR)], mental wellbeing, and
menstrualfunction.At 6months,women chose to keep their
LNG-IUSorhave it removed. In total, 103 women were approached,
54were offered a participant information sheet, 35 agreed
toparticipate, and 25 received a LNG-IUS. Their median age and
BMI were 54 years [interquartile range (IQR) 52–57] and47 kg/m2
(IQR 44–51), respectively. Three women (3/35, 9%)were ineligible
due to atypical hyperplasia/endometrial canceron their baseline
biopsy. The LNG-IUS was well tolerated andhad a positive overall
effect on bleeding patterns and mentalwellbeing. The LNG-IUS was
associated with endometrialmorphologic change, reduced Ki-67, and
PR expression, butcirculating biomarkers of endometrial cancer risk
wereunchanged. All but one woman (96%) kept her LNG-IUS.The LNG-IUS
appears to be acceptable to some women withclass-III obesity for
primary prevention of endometrial cancer,which could provide a
strategy for a prevention trial.
Prevention Relevance: Novel strategies are urgently need-ed to
prevent the rise in endometrial cancer diagnoses pre-dicted by
escalating obesity rates. Here, we show that womenwith class III
obesity arewilling to engage in risk reductionwitha levonorgestrel
intrauterine system, which could provide astrategy for an
endometrial cancer prevention trial.
IntroductionEndometrial cancer is the sixth most common cancer
in
women, with more than 382,000 new diagnoses and 89,900
deaths recorded globally in 2018 (1). The incidence of
endo-metrial cancer is rising sharply in parallel with
escalatingobesity rates (2). Obesity is the strongest risk factor
for themost common histologic subtype, endometrioid (type I)
endo-metrial cancer, and its precursor lesion, atypical hyperplasia
(3).Such is the strength of the association that approximately
40%of endometrial cancers are thought to be directly attributable
toobesity (4), and a marked dose–response relationship
bestowshigher risk as body mass index (BMI) rises (5). It has
beenestimated that women with obesity class III (BMI > 40
kg/m2)have a 7-fold increased risk of endometrial cancer
comparedwith normal weight women (BMI 18.5–25 kg/m2; ref. 3).
Thebiological mechanism responsible for this association relates
tothe endometrial stimulatory effect of adipose-derived
estrogen,which is unopposed by progesterone in an ovulatory
andpostmenopausal women, and augmented by the negative
con-sequences of insulin resistance and chronic inflammation
(6).Weight loss achieved and sustained through bariatric
surgeryreduces endometrial cancer risk (7, 8) with measurable
impacton circulating biomarkers of adiposity, reproductive
hor-mones, and insulin status, accompanied by downregulationof
pro-oncogenic signaling pathways in the endometrium (9).
1Division of Gynaecology, Manchester University NHS Foundation
Trust,Manchester Academic Health Science Centre, Manchester, United
Kingdom.2Division of Cancer Sciences, Faculty of Biology, Medicine
and Health, Universityof Manchester, St Mary’s Hospital,
Manchester, United Kingdom. 3Centre forBiostatistics, School of
Health Sciences, University of Manchester, ManchesterAcademic
Health Science Centre, Manchester, United Kingdom. 4Department
ofHistopathology, Manchester University NHS Foundation Trust,
ManchesterAcademic Health Science Centre, Manchester, United
Kingdom. 5Department ofClinical Biochemistry, Manchester University
NHS Foundation Trust, ManchesterAcademic Health Science Centre,
Manchester, United Kingdom. 6Sleep ApnoeaService, Salford Royal
Hospitals NHS Foundation Trust, Salford, United Kingdom.
Note: Supplementary data for this article are available at
Cancer PreventionResearch Online
(http://cancerprevres.aacrjournals.org/).
Corresponding Author: Emma J. Crosbie, University of Manchester,
5th FloorResearch, St Mary’s Hospital, Oxford Road, Manchester M13
9WL, UnitedKingdom. Phone: 44-161-701-6942; Fax: 44-161-701-6919;
E-mail:[email protected]
Cancer Prev Res 2021;14:263–74
doi: 10.1158/1940-6207.CAPR-20-0248
�2020 American Association for Cancer Research.
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Bariatric surgery is neither available, appropriate, nor
accept-able to everyone with an elevated BMI, however, and cannot
berecommended solely for the purpose of primary prevention
ofendometrial cancer (10). Dietary caloric restriction can
facil-itate weight loss, particularly if accompanied by increased
levelsof physical activity, but the amount of weight lost and
durationof benefit is considerably lower than following bariatric
sur-gery (11). Alternative strategies are therefore urgently
neededto provide protection to women at greatest risk of
endometrialcancer in order to thwart the explosion in incidence
ratespredicted by modeling studies (12, 13).The levonorgestrel
intrauterine system (LNG-IUS) delivers
progestin directly to the endometrium, counteracting the
stim-ulatory effect of estrogen through stromal decidualization,
down-regulation of proliferative signaling pathways, and
glandularatrophy (14). Epidemiologic studies have shown ever-users
ofthe LNG-IUS have a reduced risk of endometrial cancer (15,
16),and severalmeta-analyses havedemonstrated its effectiveness as
atherapeutic agent for women with atypical hyperplasia and
low-grade cancers confined to the endometrium (17–19).
Despitestrong evidence for its anticancer activity, no previous
studieshave investigateduse of the LNG-IUSas a chemopreventive
agentfor the primary prevention of obesity-driven endometrial
cancer.It is not known whether women with a raised BMI are aware
oftheir increased risk of endometrial cancer or whether they
wouldbe prepared to engage in risk reduction with a LNG-IUS.
Inpreparation for a clinical efficacy study, we measured
feasibility,participation rate, and compliance with the LNG-IUS for
endo-metrial protection inwomenwith class-III obesity.We studied
itsshort-term effects on endometrial morphology, proliferation,and
hormone receptor status and on circulating biomarkers ofendometrial
cancer risk. Further, we explored the impact of theLNG-IUS on
menstrual bleeding patterns, as well as mentalwellbeing, through
validated questionnaires.
Materials and MethodsStudy governanceThe study was sponsored by
Manchester University NHS
Foundation Trust (MFT) and approved by the Cambridge
EastResearch Ethics Committee—(15/EE/0063), Medicine andHealthcare
Products Regulatory Authority (MHRA, reference21387/0234/001–0001),
and local Research and Developmentdepartments. The trial was
prospectively registered on theEuropean (EudraCT number
2014–005610–37) and UK(ISRCTN40940943) clinical trial databases and
conducted inaccordance with Good Clinical Practice guidelines and
theDeclaration of Helsinki.
Study designThis was a single-arm feasibility study of the
LNG-IUS for
endometrial protection in women with class III obesity. Wom-en
attended clinic at baseline (screening visit, T0),
2�1months(LNG-IUS inserted in clinic, T1), and 8 �3 months
(finalassessment, T2; Fig. 1). Serial assessment of
anthropometricmeasures (weight, BMI, andwaist:hip ratio),
serumbiomarkers
(hormone status, insulin resistance, and adiposity),
endome-trial biomarkers (endometrial morphology, hormone
receptorstatus, Ki-67 proliferation index, and pro-proliferation
signal-ing molecules), menstrual bleeding patterns, and mental
well-being was performed at all time points.
Feasibility, willingness to receive, and compliance withthe
LNG-IUSWillingness to receive the LNG-IUS for endometrial pro-
tection was determined as the proportion of eligible womenwho
agreed to its insertion. The feasibility of using the LNG-IUS in
women with class-III obesity was calculated as theproportion of
successful LNG-IUS insertions. Complicationsof insertion, side
effects, and adverse events were recorded.At T2 final visit, women
chose whether to keep theirLNG-IUS for ongoing endometrial
protection or have itremoved. Adherence with repeated endometrial
samplingand other trial procedures was recorded. Compliance withthe
LNG-IUS was calculated as the proportion of womenwho chose to keep
their LNG-IUS.
ParticipantsEligible women were ≥18 years of age with a BMI ≥40
kg/m2
and histologically normal endometrium at baseline. All
parti-cipants gave written, informed consent. We advertised
thestudy on the University of Manchester and MFT websites,Cancer
Research UK and UK ISRCTN clinical trials databases,on socialmedia
platforms, and byword ofmouth.We recruitedwomen who approached the
research team for participationdirectly and those attending
gynecology and sleep apneaoutpatient clinics at MFT and Salford
Royal Hospitals NHSFoundation Trust, respectively. Exclusion
criteria includedprevious hysterectomy; LNG-IUS or other
intrauterine devicewithin the past 6 months; planning pregnancy,
pregnant, orbreastfeeding; previous endometrial ablation;
congenital oracquired uterine anomaly; history of pelvic
inflammatorydisease or genital actinomyces; breast cancer; overdue
cervicalscreening or last screen abnormal; immunodeficiency;
activelytrying to lose weight; contraindications to LNG-IUS,
includingcoagulopathy, liver disease, migraine, raised blood
pressure,arterial disease, postpartum endometritis, infected
abortionduring the past 3 months or recent trophoblastic disease
withpersistently elevated hCG levels; and inability to tolerate
endo-metrial sampling/ LNG-IUS insertion as an outpatient.
Medical history and baseline safety checkAt baseline, we
recorded last menstrual period (LMP),
menstrual bleeding pattern, and contraceptive use.
Postmen-opausal status was defined as LMP occurring >1 year
before iffollicle-stimulating hormone (FSH), luteinizing
hormone(LH), and estradiol levels were confirmatory; the
remainingparticipants were considered premenopausal. A urinary
preg-nancy test was performed if indicated. Cervical screening
wasoffered in accordancewith theNationalHealth Service
CervicalScreening program. High vaginal and endocervical swabs
weretaken to exclude active lower genital tract infection.
Medical
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historywas documented. Screening bloods, including full
bloodcount, urea, and electrolytes and liver function tests were
takento confirm medical fitness for participation in the trial.
LNG-IUS insertionTheMirena LNG-IUS (Bayer plc)was inserted in
clinic at T1;
women were advised to take paracetamol and NSAIDs 1 hourbefore
insertion, if not contraindicated. The procedure wascarried out on
a colposcopy couch using aWinterton speculumunder aseptic
conditions, according to the manufacturer’sinstructions. Safety
monitoring was by telephone call at 6,
12, and 18 weeks following LNG-IUS insertion. Side
effects,adverse events, and complications were recorded.
Participantswere advised to attend their General Practitioner for a
coilthread check 4 weeks after LNG-IUS insertion.
Anthropometric measurementsHeight was measured using a
stadiometer with shoes
removed. Weight was measured using electronic scales follow-ing
removal of bulky clothing and BMI derived using theformula kg/m2.
Waist to hip ratio was calculated from waist(midpoint between lower
margin of last palpable rib and top of
Figure 1.
Study flow chart showing accrual and retention
ofparticipants.
PROgesterone Therapy for Endometrial Cancer Prevention
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the iliac crest measured with a tape measure) and hip
circum-ference (widest portion of the buttocks).
Blood biomarkersSerum obtained by venepuncture following a
6-hour fast was
used to measure (i) reproductive function (LH; FSH; sexhormone
binding globulin, SHBG; testosterone; free androgenindex, FAI;
estradiol; progesterone), (ii) insulin resistance[glucose and
insulin to derive Homeostasis Model Assessment:Insulin Resistance,
HOMA-IR (20); glycosylated hemoglobinA1c, HbA1c), (iii) adiposity
(adiponectin, leptin), and (iv)inflammation (C-reactive protein,
CRP). With the exceptionof adiponectin and leptin, all analytes
were measured usingautomated routine clinical service protocols in
the MFT Clin-ical Biochemistry Laboratory. Adiponectin and leptin
weremeasured with a DuoSet ELISA development kit
(R&DSystems).
Endometrial histopathology and tissue biomarkersEndometrial
sampling was performed using a Pipelle
(Carefusion) or MedGyn Endosampler (MedGyn). Premeno-pausal
participants were sampled on day 12 �2 of the men-strual cycle,
where possible. Endometrial tissue was formalin-fixed,
paraffin-embedded, sectioned, and stained with hema-toxylin and
eosin. Endometrial morphology was assessed by aconsultant
gynecological pathologist. In premenopausal parti-cipants,
endometrial morphology and reproductive hormoneprofile was used
alongside LMP to determine menstrual cyclephase. Abnormalities were
confirmed by a second consultantgynecological pathologist and
classified according to WorldHealth Organization guidelines (21,
22).Tissue sections (4 mm) were baked for 30 minutes at 70�C.
The automated Ventana BenchMark Ultra IHC Staining Mod-ule
(Ventana Co.) was used with the Ultraview 3, 30 diamino-benzidine
(DAB) v3 detection system (Ventana Co.). Tissuesections were
deparaffinized and incubated in EZPrep VolumeAdjust (Ventana Co.).
A heat-induced antigen retrieval proto-col was carried out using a
TRIS–ethylenediamine tetraceticacid–boric acid pH 8 buffer, Cell
Conditioner 1 (CC1). Thesections were incubated with ultraviolet
inhibitor blocking solu-tion for 4 minutes, followed by an
optimized concentration ofantibody (Supplementary Table S1).
Sections were then incu-bated with horseradish peroxidase–linked
secondary antibody,DAB chromogen, and copper. Counterstain
(Hematoxylin II)was applied for 12 minutes before a 4-minute
incubation withbluing reagent. Slides were dehydrated through three
steps of99% industrial methylated spirits (IMS) and two changes
ofXylene. Sections were coverslipped using ClearVue MountXYL
(Thermo Scientific). Negative (isotype control) and posi-tive
tissue controls were used for quality assurance.The Ki-67 score was
the proportion of glandular cells with
positive nuclear staining. TheKi-67 scorewas determined
from>1,000 nuclei scored in 3 representative high-powered
fields(x20), chosen by the study pathologists; scanty samples
werescored in their entirety (23). Estrogen (ER) and
progesteronereceptor (PR) staining was assessed by modified H-score
(0–
18), the product of area score (proportion of positively
stainedtissue, scored 0–6), and intensity of staining score (0 ¼
none,1 ¼ mild, 2 ¼ moderate, and 3 ¼ strong). Phosphorylated (p)AKT
staining was scored using the percentage of positivelystained
tissue [H¼ (3�% strong staining)þ (2�%moderatestaining) þ (% weak
staining)] to account for within tissueheterogeneity (0–300). PTEN
status was scored “PTEN null” ifthere were endometrial glands
negative for PTEN adjacent topositive stroma. Slides were scored as
“PTEN positive” if allendometrial glands expressed PTEN (24).
Scoring was per-formed manually by two independent scorers who
wereblinded to time point. Discrepant scores (>10% or
disagree-ment as to PTEN status) were reviewed and resolved
byconsensus agreement.
Menstrual blood loss and mental wellbeing assessmentTwo
validated questionnaires, the Hospital Anxiety and
Depression Scale (HADS; refs. 25, 26) and Warwick–Edinburgh
Mental Wellbeing Scale (WEMWBS; refs. 27, 28),were completed at
baseline and follow-up to determine wheth-er the LNG-IUS had an
impact on mental wellbeing. For theHADS, different cutoffs are
indicative of a mental healthdisorder, depending on clinical
context (26), but lower scoresindicate absent or lower severity of
symptoms. For theWEMWBS, the mean score in the general population
is 51,with higher scores reflecting improved mental wellbeing
(27).Premenopausal participants completed theMenstrual
BleedingQuestionnaire (29) at baseline and follow-up.
Sample size considerationsThis was a preliminary study designed
to inform recruitment
rates, feasibility of and likely adherence to a clinical
efficacy trialof the LNG-IUS for endometrial protection in women
withclass-III obesity. We considered that a clinical efficacy
trialcould be successfully conducted if >50% of eligible
womenagreed to participation, >50% of those eligible had a
LNG-IUSsuccessfully fitted, and >75% of women kept their LNG-IUS
for>6 months. We also measured LNG-IUS–induced change
incirculating and tissue biomarkers to inform intermediarybiomarker
endpoints for our definitive study. We did notperform a formal
sample size calculation and planned thepragmatic recruitment of 30
to 40 women over a 6- to 12-month recruitment period.
Statistical analysisStatistical analyses were performed using
GraphPad Prism
5.0b forMac (GraphPad Software) and SPSS 23.0 forMac (IBMCorp.).
Descriptive statistics included mean and SD for nor-mally
distributed, and median and interquartile range (IQR)for
nonnormally distributed, data. Within-individual changesover time
were compared using paired t test and Wilcoxonsigned-rank test for
normally distributed and nonnormallydistributed data, respectively.
To assess the short-term impactof the LNG-IUS on endometrial
proliferation, a mixed effectsregression model was fitted, with
Ki-67 score set as the depen-dent variable, time point (baseline
set as reference category) as
Derbyshire et al.
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the predictor of interest and the covariates baseline Ki-67
score,age, menopausal status (pre/post), smoking (never, ever,
cur-rent), type II diabetes mellitus (yes/no) baseline BMI,
andbaseline waist:hip ratio. A further analysis was performed
thatincluded weight at follow-up, to determine if change in
weightwas responsible for change in Ki-67 at outcome. To account
forrepeated measures within participants, a random effect
inter-cept was included to account for the within subject
versusbetween subject variation. To account for possible
departuresin normality, a cluster bootstrapping procedure was
employedwith 1,000 replications. In an effort to emphasize
clinicallyover statistically important effects, data are reported
in termsof mean difference effect estimates and 95% confidence
inter-vals (CI).
ResultsStudy populationBetween October 2015 and September 2016,
103 women
were approached, 54 were offered a participant informationsheet,
35 agreed to participate, and 25 received a LNG-IUS(Fig. 1).
Forty-nine women (48%) were ineligible to receive theparticipant
information sheet for the following reasons: LNG-IUS in situ (n¼
13); previous hysterectomy (n¼ 12); pendingbariatric surgery (n ¼
10); social/capacity reasons (n ¼ 7);LNG-IUS contraindicated (n¼
4), or BMI < 40 kg/m2 (n¼ 3).Nineteen women (35%) declined
participation for the follow-ing reasons: none given (n ¼ 8);
declined device (n ¼ 3);declined “hassle” (n¼ 3); declined
procedures (n¼ 3), or otherreasons (n¼ 2). Thus 35 of 54 (65%)
eligible women consentedto the baseline screening assessment, 10 of
35 (29%) eitherfailed screening or withdrew their consent, and 25
of 35 (71%)proceeded to LNG-IUS insertion. Three of the six
screenfailures (3/35, 9%) had occult atypical hyperplasia or
endome-trial cancer on their baseline biopsy. All four withdrawals
(4/35,11%) found baseline endometrial sampling too painful
toconsider further procedures. Our final study population
com-prised 25 women with a median age and BMI of 54 years
(IQR52–57) and 47 kg/m2 (IQR 44–51), respectively (Table 1).There
were no significant differences between women whoconsented to
participate and women who declined in terms ofage (54 vs. 52
years), BMI (47 vs. 46 kg/m2), or ethnicity/race(all except three
were White British). Nine (36%) were pre-menopausal but just 4 had
regular menstrual cycles; most wereeither amenorrheic (2/12) or
experienced irregular menstrualbleeding (3/12). Four (16%) were
using hormone replacementtherapy (3/25, 12%) or oral contraceptives
(1/25, 4%) atbaseline, which they continued throughout the trial.
All hadat least one comorbidity, most commonly type II diabetes
(10/25, 40%), hypertension (15/25, 60%), or asthma (8/25, 32%),and
48% had more than three comorbidities.
Compliance with intervention and study proceduresAll 25 women
received the LNG-IUS in clinic without
complication. There were no insertion failures, expulsions,
uterine perforations, or lost devices. One woman (4%) devel-oped
mild symptoms of endometritis following LNG-IUSinsertion, which was
treated with oral antibiotics. One patientcomplained of pelvic
discomfort/mild pain following LNG-IUSinsertion that settled with
oral analgesia. Other adverse andserious adverse events,
specifically urinary tract infection (1/25,4%), vasculitis (1/25,
4%), sciatica (1/25, 4%), and attemptedsuicide (1/25, 4%), were not
thought to be related to the LNG-IUS.Allwomenkept their
LNG-IUSuntil theirfinal assessmentwhen one woman (4%) chose to have
it removed (“easier nowthan later”); the remaining 24 women (96%)
kept their LNG-IUS for ongoing endometrial protection. All 25 women
werecompliant with study procedures, including sequential
endo-metrial biopsies (all 3 biopsies taken, 25/25).
Endometrial morphology and biomarkersThree of 35 participants
(9%) had an incidental finding of
atypical hyperplasia or endometrial cancer on a
pre–LNG-IUSbiopsy andwere excluded from the study. All other women
hadhistologically normal endometrium at T0 (baseline) and T1(time
of LNG-IUS insertion). Many of the samples were scanty.Morphology
was consistent with menopausal status and/orreported phase
ofmenstrual cycle, as appropriate. At follow-up(T2), all
endometrial biopsies showed stromal decidualizationand glandular
atrophy, consistent with the progesterone effectassociated with
LNG-IUS treatment.
Table 1. Baseline characteristics of the study population.
Median age (IQR), years 54 (52–57)White British, n (%) 24
(96)Median weight (IQR), kg 124 (111–143)Median BMI (IQR), kg/m2 47
(44–51)Median waist:hip ratio (IQR) 0.87 (0.83–0.93)Menopausal
status, n (%)
Premenopausal 9 (36)Postmenopausal 16 (64)
Menstrual cycle, n (%)Amenorrheic 2 (8)Regular 4 (16)Irregular 3
(12)
Parity, n (%)0 1 (4)1 6 (24)2 10 (40)3þ 8 (32)
Exogenous hormones, n (%) 4 (16)Polycystic ovary syndrome
(PCOS), n (%) 6 (24)Comorbidities, n (%)
Hypertension 15 (60)Type II diabetes mellitus 10
(40)Hypercholesterolemia 5 (20)Gallbladder/liver disease 5
(20)Thromboembolic disease 3 (12)Asthma/COPD 8 (32)Sleep apnea 9
(36)Osteoarthritis 15 (60)Depression/anxiety 8 (32)
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The LNG-IUS was associated with a significant decrease
inendometrial proliferation as assessed by Ki-67 score.
ThemeanKi-67 score was 27.1% (SD 23.4) at baseline, 21.8% (SD 14.8)
atthe time of LNG-IUS insertion, and 12.7% (SD 10.9) at follow-up.
A mixed effects regression model adjusting for withinparticipant
clustering, potential confounders, and weightchange between time
points is shown in Table 2. Betweenbaseline (T0) and time of
LNG-IUS insertion (T1) and betweenbaseline (T0) and follow-up (T2),
the change inKi-67 scorewas�5.4% (95%CI,�17.1%, 6.3%) and�14.6%
(�25.3%,�3.9%),respectively. These results were consistent across
all threemodels, indicating that potential sources of
confounding,including change in weight during follow-up, had little
effecton Ki-67 score. PR expression decreased with LNG-IUS
treat-ment (Table 3). There was no significant change in
expressionof the other endometrial biomarkers, estrogen receptor,
PTEN,or pAKT. Interestingly, all three women excluded because
ofoccult endometrial abnormalities had PTEN-null glands, and
afurther 2 of 25 participants in the study had PTEN-null
glandsbefore but not after LNG-IUS insertion.
Anthropometric and circulating biomarkers ofendometrial cancer
riskOverall, women lost weight during the trial, although this
was not clinically significant [median weight 124.4 kg
(IQR111–143), 123.9 kg (IQR 111–142), and 123 kg (IQR 111–144)at
T0, T1, and T2, respectively]. There were no clinicallysignificant
changes in circulating biomarkers of reproductivefunction, insulin
resistance, adiposity, or inflammation acrossthe three time points
(Table 3), with the notable exception of
altered serum FSH, LH, and progesterone levels over time,which
likely reflect natural reproductive aging in our perimen-opausal
cohort.
Menstrual bleeding and mental wellbeingOf the 9 premenopausal
participants, 2 (22%) were amen-
orrheic, 4 (44%) had regular, and 3 (33%) irregular
menstrualbleeding at baseline. As expected, the 7 women who
experi-enced menstrual bleeding reported a significant reduction
inblood loss with the LNG-IUS; all but two became
amenorrheicaccording to the Menstrual Bleeding Questionnaire.
Mentalwellbeing improved with the LNG-IUS according to both
theWEMWBS andHADS scales (Table 4). A change in score of 2–3 points
is clinically significant, but did not reach
statisticalsignificance, most likely because of small numbers.
DiscussionThe PROTEC trial was undertaken to assess the
feasibility of
a future clinical efficacy trial of the LNG-IUS for
endometrialprotection in women with class-III obesity. In a
12-monthrecruitment period, we approached 103 women, 54 (52%)
ofwhommet the inclusion criteria, 35 (65%) agreed to
participate,and 25 (71%) proceeded to LNG-IUS insertion. There were
noinsertion failures, and all women were fully compliant with
allstudy procedures, including an endometrial biopsy at the
finalvisit. There were no related serious adverse events but one
caseeach of endometritis and postinsertion pain, both
recognizedcomplications of LNG-IUS treatment. We observed no
detri-mental impact of the LNG-IUS on mental wellbeing and
self-
Table 2. Mixed effects regression model reporting change in
Ki-67 score over time.
Ki-67 score (number of observations ¼ 71)Factor Category Coef
(95% CI)a Coef (95% CI)b Coef (95% CI)c
Time point T0—Baseline (Ref) - - -T1—LNG-IUS �5.27 (�16.9, 6.39)
�5.37 (�17.1, 6.33) �5.76 (�17.5, 5.99)T2—Follow-up �14.4 (�25.1,
-3.62) �14.6 (�25.3, -3.91) �15.3 (�25.9, �4.58)
Baseline age - 0.69 (�0.50, 1.85) 0.77 (�0.49, 2.04)Baseline
weight - �0.26 (�0.90, 0.38) �0.32 (�0.98, 0.33)Baseline BMI - 0.94
(�1.00, 2.82) 1.09 (�0.84, 3.03)Smoker Never (Ref.) - -
Ever - 3.54 (�7.70, 14.8) 3.21 (�8.02, 14.4)Yes - 7.34 (�4.80,
19.5) 7.92 (�4.28, 20.1)
Type II diabetes mellitus No (Ref.) - -Yes - �2.73 (�10.9, 5.49)
�2.23 (�10.8, 6.30)
Menopause status Post (Ref.) - -Pre - 5.56 (�3.80, 14.9) 5.42
(�4.16, 15.0)
Change in weight - - �0.41 (�1.50, 0.68)Constant 27.1 (17.8,
36.4) �23.82 (�107, 58.9) �28.5 (�117, 560.0)Random effects
(Bootstrapped)Variance constant 7.17E-12 2.38E-11 2.69E-11Variance
residuals 285.4 290.3 290.8Intraclass correlation 1.47E-13 8.20E-14
9.25E-14
aMixed model with time of assessment only adjusted for within
participant clustering.bMixed model with time of assessment
adjusted for within participant clustering and baseline screening
characteristics.cMixed model with time of assessment adjusted for
within participant clustering, baseline screening characteristics,
and change in weight from baseline.
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reported menstrual bleeding profiles improved for our
pre-menopausal participants. These data suggest that women
atgreatest risk of obesity-driven endometrial cancer are willing
toengage in risk reduction with a LNG-IUS and that a
clinicalefficacy trial could be feasible. Roughly a quarter of
womenapproached for the trial had a LNG-IUS inserted, indicating
arelatively high proportion of screen failures and noncontinua-tion
rate. These findings must be factored in to the design of aclinical
efficacy trial.To determine the short-term impact of the LNG-IUS
on
biomarkers of endometrial cancer risk, we measured change
inanthropometric variables, reproductive hormones,
insulinresistance, endometrial morphology, and glandular
prolifera-tion status between baseline, 2 months, and 8 months.
Aspredicted, we observed stability in these biomarkers prior
toLNG-IUS insertion. Short-term treatment with the LNG-IUSwas
associated with changes in endometrial morphology,
reduced proliferation, and PR expression; there were no
asso-ciated changes to circulating hormone levels, measures
ofinsulin resistance, or adiposity. An unexpected finding wasthat
women lost an average 2.5 kg in weight during the study;however,
this was neither clinically nor statistically significant.Given our
conviction that women with class-III obesity are atsufficiently
high risk of endometrial cancer that they wouldbenefit from
risk-reducing measures, it is striking that 3 of 35(9%) of our
participants had an incidental finding of atypicalendometrial
hyperplasia or endometrioid endometrial cancerat baseline,
requiring hysterectomy. This is consistent with ourprevious study
that found 10 of 72 (14%) women with class-IIIobesity referred for
weight loss management had occult under-lying endometrial neoplasia
(9).Endometrial glands are clonal cell populations that
frequent-
ly harbor driver mutations in cancer genes (30). PTEN-nullglands
confer a proliferative advantage, predisposing to
Table 3. Changes in anthropometric, blood, and endometrial
tissue biomarkers over time.
T0—baseline n ¼ 25 T1—LNG-IUS n ¼ 25 T2—follow-up n ¼
25Anthropometric measures, mean (SD)
Weight, kg 129.1 (19.2) 128.3 (19.4) 126.7 (19.2)BMI, kg/m2 48.3
(6.3) 48.0 (6.4) 47.5 (6.7)Waist:hip ratio 0.9 (0.07) 0.88 (0.07)
0.87 (0.07)
Blood biomarkers of reproductive function, mean (SD)Estradiol,
pmol/L 11.8 (6.6) 9.7 (5.5) 10.1 (6.0)Progesterone, ng/mL 3.1 (2.8)
3.8 (3.8) 1.4 (1.0)Testosterone, nmol/L 7.1 (3.6) 6.3 (3.4) 6.8
(3.7)SHBG, nmol/L 43.6 (28.8) 44.6 (24.7) 41.6 (21.9)FAI 3.1 (2.7)
2.5 (2.2) 2.6 (1.8)LH, IU/L 18.5 (13.1) 17.1 (12.8) 23.3 (16.1)FSH,
IU/L 28.8 (23.0) 27.9 (21.7) 35.1 (23.8)
Blood biomarkers of insulin resistance, mean (SD)Glucose, mmol/L
5.5 (0.8) 5.5 (1.0) 5.5 (0.9)Insulin, mU/L 139.0 (122.6) 123.1
(78.8) 124.9 (110.8)HOMA 12.5 (7.1) 28.0 (24.3) 33.8 (34.9)HbA1c,
mmol/mol 41.9 (8.2) 41.7 (9.3) 42.2 (9.5)
Blood biomarkers of adiposity, mean (SD)Adiponectin, mg/L 5.6
(13.4) 3.6 (3.7) 3.2 (4.1)Leptin, ng/mL 77.3 (35.2) 82.9 (46.0)
83.4 (41.4)
Blood biomarkers of inflammation, mean (SD)CRP, mg/L 9.0 (4.1)
6.2 (3.3) 7.3 (4.0)
Tissue biomarkers, mean (SD)Ki-67 score (%) 27.1 (23.4) 21.8
(14.8) 12.7 (10.9)pAKT H-score 105.5 (49.9) 89.4 (38.3) 93.1
(40.6)Estrogen receptor (ER) H-score 0.8 (0.1) 0.9 (0.1) 0.8
(0.1)PR H-score 0.8 (0.2) 0.9 (0.1) 0.4 (0.2)Any PTEN-null glands
(n, % participants) 2 (8%) 2 (8%) 0 (0%)
Table 4. Changes in mental wellbeing and quality of life over
time.
WEMWBS HADS
All participants n ¼ 25 Subset of participantsa n ¼ 17 All
participants n ¼ 25 Subset of participantsa n ¼ 17Baseline (T0)
Mean score (SD) 45.4 (10.6) 47.3 (10.9) 17.1 (10.4) 12.3
(9.3)Follow-up (T2) Mean score (SD) 47.9 (9.1) 52 (10.9) 14.9 (9.5)
11.4 (8.8)
aAfter excluding women with known depression/anxiety
disorder.
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endometrial carcinogenesis, and have been shown to
persistbetween menstrual cycles, but only a small proportion
pro-gresses to endometrial cancer (31). We found PTEN-nullglands in
all three women with occult endometrial abnormal-ities and in two
participants with histologically normalendometrium before, but not
after, LNG-IUS insertion. Thisis consistent with the hypothesis
that PTEN-null glandsin morphologically normal endometrium
represent latentendometrial cancer precursors that regress with
LNG-IUStreatment (24).Although the endometrial impact of the
LNG-IUS is well
studied (32, 33), this is the first trial to offer the LNG-IUS
towomen with class-III obesity for the primary prevention
ofendometrial cancer. Confirmation that the expected endome-trial
effects of the LNG-IUS are observed in this population isimportant
given their defining characteristics, specifically theirclass-III
obesity and amenorrhea or irregular menstrual bleed-ing, which
distinguish them from regular users of the device. Itis known that
Ki-67 score is higher in endometrium harvestedfrom women with
obesity compared with that collected fromnormal weight women (34).
We considered that the expectedchange in endometrial morphology, a
reduction in glandularproliferation as assessed by Ki-67 score, and
downregulation ofendometrial progesterone receptors would confirm
the utilityof the LNG-IUS at standard doses in this population. We
alsoquantified theKi-67 drop at 6months post–LNG-IUS insertionfor
the purposes of developing an intermediary molecularendpoint for a
definitive trial of the LNG-IUS for endometrialprotection uponwhich
a sample size calculation could be based.It is interesting that the
15%Ki-67 drop observed after 6-monthtreatment with the LNG-IUS was
similar to that observed afteran average bariatric surgery–induced
weight loss of 22 kg at2 months in women with class-III obesity
(9). Bariatric surgeryis known to reduce endometrial cancer risk
(7, 8, 35), andalthough the mechanisms underlying risk reduction
are notfully understood, it is thought that downregulation of
endo-metrial pro-proliferative signaling pathways could be
impor-tant (9, 36). Ki-67 is only expressed by proliferating cells,
ahallmark of cancer; indeed, Ki-67 is known to differentiatebenign
from malignant endometrium, with higher Ki-67scores observed in
high-grade, advanced stage cancer andcorrelating with poor survival
outcomes in this group (37).We considered that a reduction in
glandular proliferationin benign peri- and postmenopausal
endometrium couldreduce the risk of mutational events that trigger
malignanttransformation (10).We have demonstrated proof of
principle that some women
at high risk of obesity-driven endometrial cancer are preparedto
engage in risk reduction with a LNG-IUS, paving the way fora
clinical efficacy trial in this population. Despite concerns
thatLNG-IUS insertion would be challenging in the outpatientsetting
in postmenopausal women with class-III obesity, wehad no insertion
failures, consistent with previous studies (38).Concerns that
uterine instrumentation would be unacceptableto women who did not
have a gynecological complaint were
also unsubstantiated, with 32 of 35 (91%) participants
con-senting to and undergoing three sequential biopsies,
withoutcomplication. Further, we found the LNG-IUS was not
asso-ciatedwith a detrimental impact onmental wellbeing using
twovalidated questionnaires, with even some suggestion that men-tal
wellbeing improved during the trial, possibly due toimproved
menstrual bleeding profiles and peace of mindregarding endometrial
health; indeed 24 of 25 (96%) partici-pants chose to keep their
LNG-IUS at the end of the trial forongoing endometrial protection.
A short-term study of thiskind cannot confirm that women will be
compliant with theLNG-IUS in the medium to long-term, however. Nor
can ithelp define the optimal duration of a clinical efficacy
trial. Wedid not deliberately target perimenopausal women for
trialparticipation, although long-term use of the LNG-IUS in
aclinical efficacy trial would ideally avoid women whose
com-pliance could be compromised by future pregnancy plans.
Thesingle-center nature of this research is a limitation of the
study,because we cannot necessarily extrapolate feasibility of
ourapproach to other centers, countries, or healthcare settings.
Thelack of racial and ethnic diversity in our study
populationprecludes any insight into the acceptability and uptake
of theLNG-IUS for uterine protection in non-White British women.We
do not know whether women would consent to random-ization to a no
intervention arm, which would be the idealclinical efficacy trial
design, and would certainly affect feasi-bility of the definitive
study. Furthermore, our biomarkerfindings should be interpreted
with caution given the smallsample size and marked heterogeneity of
participating womenwith respect to age, menopausal status, and use
of exogenoushormones at baseline.Although invasive, the advantage
of the LNG-IUS is that it
releases a continuous supply of levonorgestrel directly to
theendometrium, avoiding the peaks and troughs observed withoral
administration and eliminating compliance issues (39).Apart from
insertion problems, there are few contraindicationsto its use, at
least partly because systemic concentrations of thedrug are much
lower than those achieved with oral adminis-tration (40). Serum
levonorgestrel levels are 20-fold lower inLNG-IUS users than
levonorgestrel-containing combined oralcontraceptive pill users,
for example (41). There is an inversecorrelation between serum
levonorgestrel concentrationsand BMI (42), suggesting even lower
systemic levels in ourpopulation. A further advantage of the
LNG-IUS for thisindication is that it would be expected to
eradicate or treatlatent endometrial cancer precursors, atypical
hyperplasia,and occult obesity-driven endometrial cancer, as
previouslydemonstrated (24, 17–19). Regression of established
endome-trial abnormalities takes 6 to 12 months or longer and is
morelikely in the case of atypical hyperplasia (approximately
90%complete response rate) than early stage endometrial cancer(67%
complete response rate; ref. 43). There are currently novalidated
biomarkers that predict LNG-IUS response to estab-lished disease
(44), although some show promise (45, 46),mandating careful
assessment of any new bleeding that
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develops following device-induced amenorrhea (47) in
anendometrial cancer prevention trial.Overall, we found the LNG-IUS
to be safe and well-
tolerated, with no unacceptable side effects in our
studypopulation. This is particularly important if the LNG-IUS
isbeing used for endometrial protection rather than an estab-lished
clinical indication, and should be a focus of futurework. There is
no evidence that the LNG-IUS increases therisk of cardiometabolic
disorders in obese women (48), but arecent systematic review found
LNG-IUS users have a mod-estly increased breast cancer risk [OR ¼
1.16 (95% CI, 1.06–1.28), I2 ¼ 78%, P < 0.01], although most of
the includedstudies failed to adjust for BMI (49). Clearly this is
animportant area for further research. The LNG-IUS mayprevent the
endometrial consequences of excess adiposity,but it does not
address the cardiovascular or metabolicsequelae of obesity and
competing risks for death.In summary, identifying women at greatest
risk of endome-
trial cancer and developing evidence-based prevention
strat-egies are important given the escalating rates of obesity
andassociated emerging epidemic of endometrial cancer across
theworld (50). The LNG-IUSmay be an effective deterrent
againstobesity-driven endometrial cancer and offer endometrial
pro-tection for those at highest risk. It reduces risk in the
generalpopulation by 50% during and for at least 5 years
afterdiscontinuation of its use (16), and as such is likely to be
acost-effective prevention strategy for women with class-IIIobesity
(51). Here, we demonstrate that a LNG-IUS is accept-able to some
women with class-III obesity and that a clinicalefficacy trial
would be feasible. The specifics of trial designrequire careful
consideration because a large cohort withsufficient follow-up will
be challenging and expensive toachieve. Minimizing trial size,
duration of follow-up, and costis an important goal for women,
researchers, and funders ofsuch a trial. Although endometrial
cancer risk is high inwomenwith class-III obesity, absolute risk is
modulated by reproduc-tive, metabolic, and genetic factors (13,
52), as well as com-peting risks for death. More sophisticated risk
predictionmodels, calibrated for clinical use, must now be
developed toestablish the optimal prevention trial target
population, max-imize the benefits of participation, and reduce
unnecessaryharms (53).
Authors’ DisclosuresR.J. Edmondson reports personal fees from
Astra Zeneca, personal fees
from Arquer Diagnostics, and grants from Tesaro Inc. outside the
sub-mittedwork.H.C.Kitchener reports grants fromWilliamWalterWill
Trustand grants fromCentral Manchester Foundation Trust during the
conductof the study. No disclosures were reported by the other
authors.
Authors’ ContributionsA.E. Derbyshire: Data curation, formal
analysis, investigation, writing-
original draft, writing-review and editing. J.L. Allen:Data
curation, writing-review and editing.M.Gittins: Formal analysis,
supervision, writing-reviewand editing. B. Lakhiani: Data curation,
writing-review and editing.J. Bolton: Data curation, formal
analysis, writing-review and editing.J. Shaw: Formal analysis,
writing-review and editing. P.W. Pemberton:Data curation,
writing-review and editing. M. Needham: Data curation,supervision,
writing-review and editing. M.L. MacKintosh:
Supervision,writing-review and editing. R.J. Edmondson:
Supervision, writing-reviewand editing. H.C. Kitchener:
Conceptualization, resources, supervision,funding acquisition,
writing-original draft, writing-review and editing.E.J. Crosbie:
Conceptualization, resources, supervision,
fundingacquisition,methodology, writing-original draft,
writing-review and editing.
AcknowledgmentsWe would like to thank the women who participated
in this study. We
are grateful to all the clinical staff involved in their
carewhohelped facilitaterecruitment, especially Samantha Johnson
and Bryan Wilson. We wouldparticularly like to thank Linsey Nelson,
who contributed to study set-up,and Tina Pritchard, who supported
patient recruitment, provided nursingcare, and helped with
administrative tasks. We are grateful to the inde-pendent members
of the Trial Steering Committee, Professor SudhaSundar,
ProfessorMartin Rutter, Professor Steve Roberts, and Anne Lowryfor
providing study oversight.
A.E. Derbyshire was a Manchester University NHS Foundation
TrustClinical Research Fellow and E.J. Crosbie an NIHR Clinician
Scientist(NIHR-CS-012–009), and their work was supported through
the NIHRManchester Biomedical Research Centre (IS-BRC-1215–20007)
and theWilliam Walter Will Trust. This article presents independent
researchfunded by the NIHR. The views expressed are those of the
authors and notnecessarily those of the NHS, NIHR, or the
Department of Health.
The costs of publication of this article were defrayed in part
by thepayment of page charges. This article must therefore be
hereby markedadvertisement in accordance with 18 U.S.C. Section
1734 solely to indicatethis fact.
ReceivedMay 18, 2020; revised August 22, 2020; accepted
September 16,2020; published first September 30, 2020.
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