Eierstok- en endometriumkanker: risicofactoren en nut van primaire/secundaire preventie

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1 Eierstok- en endometriumkanker: risicofactoren en nut van primaire/secundaire preventie Ignace Vergote Diensthoofd, Gynaecologie-Verloskunde Voorzitter, Leuvens Kanker Instituut (LKI) Vraag Bilaterale tubectomie bij een hysterectomie voor een benigne verlaagt de incidentie van tubo-ovariele carcinomen 1. Niet 2. Met 10% 3. Met 50% 4. Met 100% 1

2 Vraag Bilaterale tubectomie bij een hysterectomie voor een benigne verlaagt de incidentie van tubo-ovariele carcinomen 1. Niet 2. Met 10% 3. Met 50% 4. Met 100% Endometriumcarcinoom Risicofactoren = 1. oestrogenen Obesitas (E1 omzetting vet) hypertensie, diabetes Oestrogeen therapie (menopauze) zonder progestagenen Oestrogeen producerende tumoren (vnl. ovarieel, granulosceltumor (8% - ECA!). PCOS, nullipariteit en infertiliteit, vroege menarche, late menopauze Tamoxifen Leverinsufficiëntie (tragere afbraak E) Familiaal 2

3 Preventie van endometriumcarcinoom bij normaal risico Er is geen evidentie voor screening in de algemene populatie. Oestrogenen mogen niet gegeven worden zonder progestagenen in de menopauze. Routine screening is ook niet geindiceerd bij vrouwen die op tamoxifen staan (enkel onderzoeken bij vaginaal bloedverlies) OAC? 3

4 Hereditary Endometrial Cancer (HEC) HEC: 2%-5% of all EC diagnosis HNPCC (MMR-genes): YES! Familial site-specific EC BRCA? Cowden (PTEN)? Peutz-Jeghers (STK11)? Svampane L, et al. Arch Gynecol Obstet Nov 29 [Epub ahead of print]. 1. HNPCC Hereditary nonpolyposis colorectal cancer 4

5 HNPCC (Lynch) Germline mutations in one of the MMR Accounts for 2-5 (13)% of colon cancer (CRC) for 2%-3% of endometrial cancer Risk: up to 80 % lifetime risk CRC Tafe L, et al. Clin Chem. 2013;60(1): Reported Estimates of Lifetime Risks of Extracolonic Malignancies in Patients With HNCC Lifetime Risk, % Standardized Incidence Ratio Median Age at Diagnosis, Yrs Endometrial cancer Ovarian cancer Gastric cancer Small bowel cancer Pancreatic or biliary cancer Urinary tract cancer Brain tumors Skin cancer Lifetime risks depend on the type of mismatch repair gene mutated and the sex of the mutation carrier. Koornstra JJ, et al. Lancet Oncol. 2009;10(4):

6 Geno-Phenotype MLH1 some mutations in MLH1 are colon-specific MSH 2 higher risk extracolonic cancer compared to MLH1 mutations MSH6 clearly relatively higher risk for Endometrial cancer (some studies up to 71%) but still moderate risk for CRC (30%) Geary J, et al. Fam Cancer. 2008;7(2): Who s Candidate for Genetic Testing? For CRC: Amsterdam I-II, Bethesda criteria For EC:??? - Age and fam history (FH): low sensitivity Attempt to expand the criteria: * Pathologic findings Peritumoral lymphocytes Prominent lymphocytes, infiltrating the tumor Tumor heterogeneity 6

7 Surveillance/Prevention in HNPCC Site of Cancer Lower Age Limit, Years Examination Interval, Years Colorectum Colonoscopy 1-2 Uterus/ovaries Offer gynecologic examination, transvaginal ultrasound, aspiration biopsy (Pipelle) Stomach Upper gastrointestinal endoscopy only recommended in LS families from countries with high incidence of gastric cancer, preferably in research setting; Screening of all carriers >25 years for H pylori infection Urinary tract Surveillance (by urine cytology and ultrasound) of MSH2 carriers only in research setting or if results are systematically collected by LS registry Vasen H, et al. (Mallorca group). Gut. 2013;62(6): ; Colombo et al (Endometrium consensus) Radiother Oncol, 2015 Prevention Prophylactic surgery : Prophylactic HT+BSO at the age Chemoprevention o Aspirin (CAPP2 study): reduction in CRC and other cancers when taking aspirin 600 mg/d for 2-4y o o OAC: no data in HNPCC BRCA: risk EC en OC LNG-IUD 7

8 BRCA Hereditary Breast and Ovarian Cancer Syndrome BRCA and endometrial cancer No convincing evidence for association BRCA and EC Many studies: conflicting results Segev et al (2013) 1 : BRCA enhanced risk EC (P =.02), but only in patients who received tamoxifen Thompson (2002 )2: EC BRCA1, not in BRCA2 1. Segev Y, et al. Gynecol Oncol. 2013;130(1): ; Thompson D, et al. J Natl Cancer Inst. 2002;94(18):

9 BRCA and endometrial cancer Role in counseling prophylactic surgery: concomittant hysterectomy or not o Operative morbidity o Longer hospital stay Risk of developing EC Risk for EC is 3-4-fold for tam users, but 10 y absolute risk only 2% Not systematically advised UnlessTAM use (current or possibly necessary in future) Other reasons for concomitant hysterectomy: o o o Intramural part of the tubes Other (benign) endometrial pathology later on HST (E-P versus E only) Peutz-Jeghers 9

10 Absolute Rate and Cumulative Risk of Cancer in Peutz Jeghers Syndrome (Ages Years) Site Rate per 100,000 person-years Cumulative Risk From Age Years All cancers % Esophagus % Stomach % Small intestine % Colon % Pancreas % Lung % Testes % Breast % Uterus % Ovary % Cervix % Giardiello FM, et al. Gastroenterology. 2000;119(6): Cancer Type Age at Initiation Surveillance Breast (or earlier based on earliest age of onset in family) Breast self exam monthly Clinical exam + ultrasound breast semiannually Mammography annually (MRI offered as alternative) Colon 18 Colonoscopy every 2-3 years Pancreas Endoscopic ultrasound every 1-2 years (CT scan and/or CA-19-9 offered as options) Stomach and small intestine 8 18 Baseline upper endoscopy and small bowel series Upper endoscopy and small bowel series every 2-3 years Ovaries 25 Transvaginal ultrasound and serum CA-125 annually Uterus and cervix Peutz-Jegers Screening Pelvic exam with Pap smear annually Transvaginal ultrasound Testicles Birth Giardiello FM, et al. Clin Gastroentrol and Hep. 2006;4(4): ; NCCN guidelines. 10

11 Ovariumcarcinoom Risicofactoren en nut van preventie 9/02/ Ovariumcarcinoom risicofactoren Irritatie coeloom epitheel ovulatie ovariumcarcinoom (orale contraceptie lactatie - zwangerschap) Familiaal Endometriose (EAOC) histologisch type: - OAC verlaagt sereuze, endometrioide en clear cell, - HST verhoogt sereuze en endometrioide, - roken verhoogt het aantal mucineuze. Collaborative Group on Epidemiological studies of Ovarian Cancer: Lancet 2008, 371:303; PloS Med 2012, 9; Lancet 2015, 385:

12 Genetische basis Incidentie OvC: 1.5% 10% vd OvariumCa ~ hereditaire origine grootste deel BRCA 1 of 2 (85%) 4% hiervan zelfs zonder familiale belasting % ook sterk f(ethniciteit) 40% Ashk Joden met OvC dragen BRCA mutatie (founder mutations!) 9/02/ Syndroom Familiaal ovariumcarcinoma kadert in Gen (chromos) % heriditaire OvC % Risico op Ov ca op 70j leeftijd HBOC BRCA 1 (17q) Epith BRCA 2 (13q) Epith Site specific OvC BRCA 1 (17q) Epith Histologisch type HNPCC MLH1 (3p) MSH2 / 6 (2p) PMS1/ < 10 Epith Peutz-Jeghers STK 11 (19p) < 1 < 5 Sex cord stromal tumour Cowden PTEN (10q) < 1 < 5 NS Nevoid basal cell Ca Syndrome (Gorlin s) Multiple enchondromatosis (Ollier s disease PTCH (9q) <<1 < 5 Fibrosarcoma, carcinoma? << 1 < 5 Juveniele granulosacel T 12

13 Familiaal ovariumcarcinoma kadert in Syndroom Gen (chromos) % heriditaire OvC %Risico op Ov CA op 70j leeftijd HBOC BRCA 1 (17q) Epith BRCA 2 (13q) Epith Site specific OvC BRCA 1 (17q) Epith HNPCC MLH1 (3p) MSH2 / 6 (2p) PMS1/ < 10 Epith Histologisch type Peutz-Jeghers STK 11 (19p) < 1 < 5 Sex cord stromal tumour Cowden PTEN (10q) < 1 < 5 NS Nevoid basal cell Ca Syndrome (Gorlin s) Multiple enchondromatosis (Ollier s disease PTCH (9q) <<1 < 5 Fibrosarcoma, carcinoma? << 1 < 5 Juveniele granulosacel T BRCA en ovariumca preventie Opvolging met transvaginale echografie: onduidelijk of deze follow-up de mortaliteit en/of morbiditeit van OvC reduceert. Lage sensitiviteit Hoog aantal vals positieven Kan leiden tot onnodige ingrepen Tot op heden : pbso = meest optimale risk-reducing strategy (98%) in hoog risico populatie (+ tevens reductie BrC risk! 50-54%) Let wel: BRCA geassocieerd ovariumcarcinoom is vaak een hooggradig sereus TUBA carcinoom (STIC)! Belang van volledig resectie van de tubae! Fields MM, Cevlen E. Clin J Oncol Nurs Feb;10(1):77-81 Oei et al. British Journal of Cancer (2006) 13

14 Penetrantie BRCA1 en 2 Hartmann LC, NEJM, 2016, Vol 374,No 5 14

15 Richtlijnen UZ LEuven: Tijdstip pbso en FU Inconclusief Follow-up 1x/j pbso BrC-familie 40j 1x/j menop (BrC)-OvC familie 30j 40j of 5j regel Mutatie draagster 1x/6m BRCA 1 30j 40j BRCA 2 40j 50j Histology and Ovarian Cancer Gene Mucinous, n = 16: NO mutations Norquist BM, et al. JAMA Oncol Dec 30. [Epub ahead of print]. 15

16 UZ Leuven model for BRCA testing in ovarian cancer patients (cfr UK). Patient with breast/ovarian cancer BRCA testing Cancer Team Patient referred to Genetics Team if detailed discussions required Genetics Team Negative BRCA test Positive BRCA test Family member without cancer Clear protocols to delineate patient pathway Clear approval process for testing for non-geneticists including online training modules and resources George A, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 881PD. Relevance of Inherited Mutations Beyond BRCA1/2 in Women With Ovarian Cancer Genes Cases Controls Mean Age Relative Risk BRIP1 0.92% 0.09% /0.6% BARD1 0.12% 0.06% (P =.39) PALB2 0.28% 0.09% (P =.08) 63.8y (93%>50y) 55.5 y (53-60) 56 y (49-65) 3.4 (2-5) 5.8% at 80y NBN 0.28% 0.23% (P =.61) NA RAD51C 0.41% 0.07% 70% >50y RAD51D 0.35% 0.04% 92% >50y 5.2 (1.1-24) 5% at 70y 12 (1.5-90) 12% at 70y Ramus S, et al. J Natl Cancer Inst. 2015;107(11). pii: djv214. Song H, et al. J Clin Oncol. 2015;33(26): Norquist BM, et al. JAMA Oncol Dec 30. [Epub ahead of print]. 16

17 Courtesy of Mark Robson 17