PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC… · CANCER...

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.

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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

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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)






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.






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

Derbyshire et al.





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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2021;14:263-274. Published OnlineFirst September 30, 2020.Cancer Prev Res Abigail E. Derbyshire, Jennifer L. Allen, Matthew Gittins, et al. Obese Women (PROTEC) Trial: A Feasibility StudyPROgesterone Therapy for Endometrial Cancer Prevention in

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