ENDOMETRIAL SCREENING AND CANCER PREVENTION IN LYNCH SYNDROME: The POET study. Prof. Shirley Hodgson St.George s Hospital, London.

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1 ENDOMETRIAL SCREENING AND CANCER PREVENTION IN LYNCH SYNDROME: The POET study Prof. Shirley Hodgson St.George s Hospital, London.

2 Endometrial cancer (EC) Fourth most common cancer in women (1.5-3% lifetime risk), median age at diagnosis 63y.(55-65y); 65y); 80% present with postmenopausal bleeding Overall 5y. survival 65%-88% (88% in Lynch vs 82%) (breast cancer 71.5%; cervical cancer 68.9%) Stage II-IV IV survival rates 50% in sporadics; ; up to 72% in Lynch syndrome (n.s( n.s.;.; 66 Lynch vs 50 sporadics) Stage I 5y. survival: 92% Lynch, 91% sporadics (Boks et al 2002, Vasen et al 94)

3 WHO Classification of Endometrial Cancer ENDOMETRIOID (several variants) SEROUS PAPILLARY CLEAR CELL MUCINOUS SQUAMOUS UNDIFFERENTIATED MIXED Several other rare variants have been described

4 Type I EC Prototype is endometrioid Ca (other=mucinous mucinous) Perimenopausal and early postmenopausal Associated with oestrogen excess, obesity, hypertension, diabetes Precursor is endometrial hyperplasia Usually low grade ER positive MSI+ Mutations in PTEN, β-catenin, k-ras Relatively good prognosis

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7 Type II EC Prototype is uterine serous Ca (also clear cell Ca) Elderly postmenopausal Not associated with oestrogen excess No associated endometrial hyperplasia Arises from endometrial intraepithelial carcinoma Usually high grade and advanced stage ER negative p53 mutations and chromosome instability Poor prognosis

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9 Type 1 EC Pathogenesis

10 WHO (1994)/ISGP: Endometrial Hyperplasia 1. Simple hyperplasia a) without atypia b) with atypia 2. Complex hyperplasia a) without atypia b) with atypia

11 Significance of Hyperplasia non-atypical hyperplasias (simple and complex) have low risk of progression to EC. usually treated with hormonal agents. atypical hyperplasias may coexist with, and have significant risk of progression to EC. usually treated by surgery; some treated hormonally

12 EC in Lynch Syndrome Commonest extracolonic malignancy More common in women than CRC Loss of MLH1 or MSH2 staining in tumour, 77% MSI+, 68% loss of PTEN Vasen et al:msh %, MLH1 25% Wijnen et al: MSH2 31%, MLH1 29%, MSH6 73% Hendriks et al: MSH6 71% Lifetime risk: Dunlop et al 42% Aarnio et al 60%% Frogatt et al 51% Other estimates up to 65% lifetime risk (e.g. Baltimore) Lower recent estimates from Germany and Spain (14-26%)

13 Characteristics of EC in Lynch Syndrome most endometrioid,, but higher proportion of non-endometrioid (including clear cell and serous) younger age at diagnosis, median 48y (27-72y) 72y) more often poorly differentiated more Crohn s-like lymphoid infiltrate more tumour infiltrating lymphocytes with lymphovascular invasion

14 National Cancer Institute of Milan (Hereditary Colorectal Cancer Registry): 126 women, 41 slides reviewed. 22 (53.6%) pure endometrioid cancers 19 (46.3%) non-endometrioid cancers (with or without an endometrioid component) Many were high FIGO grade no distinct histopathological features

15 Pathology of EC in Lynch Syndrome (Lu et al 2006)

16 Cancers in families with different mutations 64 MLH1 families, 470 individuals Stomach 5% Other 11% Urothelial 2% Brain 1% Skin 2% Breast 4% 64 MSH2 families, 480 individuals Ovarian 2% Endometrial 8% Colorectal 65% 4 MSH6 families, 38 individuals Skin 4% Ovarian 4% Stomach 5% Other 8% Urothelial 8% Brain 1% Stomach 8% Other 18% Urothelial 5% Breast 5% Endometrial 12% Colorectal 55% Breast 3% Skin 3% Endometrial 24% Colorectal 37%

17 Endometrial Surveillance in Lynch Syndrome Rijcken et al 2003 Dove-Edwin et al women with HNPCC 179 TVS 17 abnormal on TVS endometrial biopsy 3/17 atypical hyperplasia 1 interval cancer 269 women Not exclusively mutation carriers 522 US only, some TVS, some abdominal No cancers detected 2 interval cancers

18 Surveillance in Lynch Syndrome (Jarvinen et al 2006) 175 women,759 person-y,503 screens,74% EB. 14 EC (8%); 11 diagnosed by surveillance, 8+1 by EB (2 interval EC, 1at prophy hysterectomy) TVS detected 4 but missed 6 EC EB detected 14 cases of CAH in addition No deaths from EC in surveillance group in 5y; 6 deaths in 83 symptomatic patients in 13.7y. 14.3% significant abnormalities detected, 5% of screening visits in 3.7y

19 Prophylactic surgery Consensus guidelines: Insufficient evidence to recommend (Burke 1997) Hysterectomy unpopular with patients: Preference for screening by TVS (Collins et al 2005) Unpopular with Genetic counsellors (Matloff et al 2000)

20 Chen et al 2007 Decision analysis: surgery at 30y vs screening % EC in surgical arm 3.7% EC in screening arm 8.3% EC in controls Survival estimates: 79.98y for surgical arm, 79.31y for screening arm, 77.41y for controls

21 Lecuru et al 2007 cont.d 57 women with HNPCC on annual surveillance 86 EB, 75 successful 14 atrophic 12 secretory 6 polyps 15 patients had hysterectomy: 3 simple hyperplasia (6%) 2 endometrioid EC, also diagnosed at hysteroscopy (3%)

22 Pistorius et al asymptomatic postmenopausal women with HNPCC had prophylactic hysterectomy, age range 47-59y, 3 with proven MSH2 mutations, MSI+ EC stage T1b N0 M0 detected in two patients

23 Hormonal prevention Estrogens promote type 1 EC development Progestogens inhibit EC development Mirena IUS releases 20mcg/d levonorgestrel locally, reduces endometrial thickness and inhibits hyperplasia and atypia (e.g.with Tamoxifen)

24 Morphological Effects of Mirena IUS on Endometrium stromal pseudo-decidualisation decidualisation (Gardner et al 2000) Atrophy of glands, surface papillary pattern stromal inflammatory infiltrate (may or may not indicate endometritis) reduced irregular endometrial thickening in 6 women on Tamoxifen (Turnbull et al 1998)

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26 Oestrogen HRT + Mirena 16 well conducted studies in recent meta- analysis 1100 patients included Endometrial suppression achieved in all studies Amenorrhoea in % 100% post menopausal patients 31-80% of premenopausal patients

27 Mirena IUS and Tamoxifen RCT Reduced numbers of endometrial polyps and complex hyperplasia in treated arm of trial Mirena IUS and EC treatment? Mirena IUS reported to cause regression of EC in anecdotal cases but 2 reports of EC developing with Mirena in situ

28 One Stop clinics for endometrial surveillance in women at risk of Lynch St George s, n =35 All women had TVS sonohysterography Pipelle biopsy 5/35 moderate pain 1/35 severe pain All satisfied or very satisfied with technique Syndrome Leeds, n=27 All women had TVS + hysteroscopy Minimal pain or discomfort reported No change in SF-36 or HADS scores associated with procedure

29 Pilot Study, St.George s 15 women with Lynch Syndrome, 42y (24-56y) Pipelle (11 prolif.,1 secretory,1 menstrual). Mirena IUS inserted (9 mild, 4 moderate, 2 severe discomfort); one removed for early bleeding; 7 had spotting, 7 had no vaginal bleeding. Mirena IUS removed at 6 months: 8 biopsies showed pseudo-decidualisation decidualisation of endometrium. 5 opted to continue with Mirena IUS.

30 Conclusions Need for a chemoprevention study Risk reducing surgery not widely practised Surveillance of uncertain benefit Local progestogens good candidate Mirena IUS well established in benign gynaecological conditions and as contraceptive Highly motivated patient population

31 Prospective Chemoprevention Trial M.D.Anderson..Karen..Karen Lu Women with Lynch syndrome (n=42 so far) Women 30-60y randomised to OCP or depot medroxyprogesterone acetate for 3 months. TVS and biopsy at entry and 3m. 4.2% AEH or EC at initial biopsy Ultrasound not helpful for diagnosis

32 POET Prevention of Endometrial Tumours

33 POET Trial plan Ascertain women (with intact uterus) aged 35-65y: either proven HNPCC mutation carriers, or with CRC or other HNPCC-related cancer from an Amsterdam-positive family Exclude women on chemotherapy, those planning pregnancy or pregnant, those planning hysterectomy

34 Mirena IUS randomised trial; overview Informed consent into Trial if satisfies entry criteria. Baseline clinical exam., TVS and biopsy If normal, randomise to Mirena IUS for 4y, or control (with surveillance). Baseline questionnaires, including POMS. See those randomised into treatment arm at day 5 of cycle, for Mirena IUS insertion. TVS and biopsy annually; anonymised data sent to centre Second POMS questionnaire at 3y Annual questionnaires re hormone exposure, satisfaction and health.

35 Design Women with HNPCC, Lynch Syndrome Surveillance being annual TVS and endometrial biopsies (EB) by Pipelle (or hysteroscopy), to document AEH and carcinoma; pathology confirmed Full Gynaecological Evaluation Normal Endometrium OR Simple OR Complex Non- Atypical Endometrium Hyperplasia = ELIGIBLE Atypical Endometrium =INELIGIBLE Mirena IUS (4 years) + Surveillance (4.3 years) N=110 Surveillance (4.3 years) N=110 Treatment Surveillance

36 POET Trial Registration Trial Sponsor: Co-sponsorship between St George's, University of London (SGUL) & Queen Mary and Westfield College, University of London (QMUL) Chief Investigator: Prof. Shirley Hodgson Chairman: Prof. Peter Sasieni Study coordinator at CPTU: Miss Laura White EudraCT No: NRES No: 05/Q0803/59 Protocol No. ISRCTN

37 Key Facts Primary Aim To determine if treatment with intrauterine progestogen reduces the incidence of Atypical Endometrial Hyperplasia (AEH) and Endometrial Cancer (EC) in women with Lynch syndrome. Minimum 220 patients, maximum 600 patients years old 4.3 year follow-up 18 month recruitment Endpoint: AEH or EC Phase III LSLV (Last Subject Last Visit) planned for January 2013 Recruitment open to UK (International sites to be added, but not initially under the CPTU)

38 Current Status Sites registered: 26 Sites with SSA: 16 R&D: 7 Sites ready to randomise: 6 Randomising: 2 Latest versions of POET study documents, including protocol (Version 3, 31/01/2007) and approval letters, available to download from the library section of the POET website:

39 POET Website Address web address for POET trial:

40 POET website poet.nameonthe.net) From the website, it is possible to:- Access study documents via the Library link at top Download the MREC and MHRA approval letters View details of amendments to MREC and MHRA Randomise new patients Access information about POET patients Order/confirm receipt/dispense Mirenas Update contact details

41 Electronic Data Capture (EDC) (2/4)

42 Example of part of the randomisation form

43 Funding 600 for each patient randomised completing the study Partial payments will be made if data or samples are incomplete Refer to contractual agreement for further information