(O)varia. Liesbeth de Vries UMCG

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1 (O)varia Liesbeth de Vries UMCG

2 Opbouw Vulvacarcinoom Endometriumcarcinoom Cervixcarcinoom Ovariumcarcinoom

3 Vulvacarcinoom 330 nieuwe tumoren/jaar Inguinale lymfekliermetastasen negatieve prognostische factor Behandeling: Lymphadenectomy als positieve klieren Adjuvante regionale bestraling na klierdebulking na standaard inguino femorale klierdissectie indien: >1 positieve klier klinisch N1,2 klieren die ook pathologisch blijken te zijn aangedaan extra-nodale groei Internationaal onduidelijkheid over nut adjuvante therapie Radiotherapie Chemotherapie Kleine studies

4 Retrospectieve Duitse vulvastudie in 29 centra patients with vulvar cancer 245 patients with unknown LN status (15%) 497 patients with LN metastases 243 patients with adjuvant Tx 288 patients without adjuvant Tx 910 node-negative patients 26 patients with unknown 26 patients with unknown Tx status (5%) 209 patients with adjuvant RT 86% 34 patients with adjuvant RCT 14%

5 AGO-CaRe-1: node positieve vulvacarcinoompatienten

6 GROINSS-V2 observational trial + stopping rules ongoing Therapie: Tumoren <4 cm Sentinel node negatief: geen lymfadenectomy Positieve liesklieren (20%): gerichte bestraling On hold Sept 2010: want liesrecidief 10% > 2 mm recidief 20% Nu weer accrual < 2 mm radiotherapie (50% sentinel nodes) > 2 mm lymfadenectomie, afhankelijk uitslag +/- rad ther (extranodaal enzo) Nu n=756, totaal aantal gepland 1500 (150 sentinel node < 2 mm)

7 Stadium 1 endometriumcarcinoom Adjuvante radiotherapie Laag stadium (FIGO 1988 stadium I-IIA; FIGO 2009 stadium I) met laag of laag-intermediair risicoprofiel alleen chirurgie. Laag stadium (FIGO 1988 stadium I-IIA; FIGO 2008 stadium I) met hoog-intermediair risicoprofiel radiotherapie. Vaginale brachytherapie voorkeur boven uitwendige radiotherapie. Stadium I (FIGO 1988 stadium I-IIA; FIGO 2008 stadium I) met hoog risicoprofiel, stadium II (FIGO 1988 stadium IIB; FIGO 2008 stadium II) en stadium III Uitwendige radiotherapie.

8 Klassieke studie 1980: Lindeman et al TAH-BSO 540 patients Conclusion: Only patients with poorly differentiated tumors (grade 3), which infiltrate more than half the myometrial thickness, might benefit from additional external radiotherapy No further treatment: 277 Vaginal IRCT Pelvic RT: 263

9 Update: Follow up endometriumcarcinoom Registry of Statistics Norway Survival Study population Individual linkage Causes of Death Registry Cancer Registry of Norway Incident secondary cancers Median follow-up 20.5 ( years)

10 Survival endometriumcarcinoom 568 patienten behandeld mediane follow-up 20,5 jaar Relapse free survival Overall survival

11 <60 jaar bij diagnose endometriumcarcinoom Overall survival Overall Risk secondary cancer

12 2de tumoren <60 jaar Localization EBRT (n=150) Control (n=145) n % n % Vulva/vagina 1 0,7 0 0 Bladder 6 4,0 1 0,7 Other urological cancer 1 0,7 1 0,7 Colorectal/anus 14 9,3 9 6,2 Skin 9 6,0 2 1,4 Small bowel Gastric, pancreas, gallbladder 6 4,0 6 4,1 Breast 8 5,3 9 6,2 Lung 2 1,3 1 0,7 Leukemia/Lymphoma 3 2,0 3 2,1 Sarcoma Other 4 2,7 2 1,4 Total 54 36, ,4

13 Toekomst Steeds minder radiotherapie Brachy minder belastend dan externe radiotherapie Rol chemotherapie

14 Medicamenteuze behandelopties vergevorderd endometriumcarcinoom 1 ste lijn: o Hormonale therapie: progestagenen o Chemotherapie: slecht gedifferentieerde en/of ER/PgR neg. tumor of als ongevoelig geworden voor hormoontherapie. 2 de lijn: Geen standaard Oncoline: bv tamoxifen

15 Molecular determinants van effect mtor inhibitie in 3 studies in endometriumcarcinoompatienten PI3K-AKT-mTOR pathways PTEN mutaties 30-70% Celcylcus Angiogenese etc

16 Moleculaire resultaten versus best response 73 tumoren:238 mutations in 19 oncogenes

17 Perfect man easier to find than perfect biomarker

18 Gemetastaseerd cervixcarcinoom Patienten vaak eerder cisplatin & radiotherapie gehad Behandeling Bij afstandsmetastasen: carboplatine + paclitaxel vertaling: Phase 3 study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a GOG study. Moore DH et al J Clin Oncol 2004;22: Cie Bom: cisplatine met topotecan kan als goed nierfunctie

19 Fase 3 paclitaxel + carboplatin vs paclitaxel + cisplatin in stage IVb cervixcarcinoom: JCOG0505. PFS Overall Survival cisplatine met topotecan

20 Prognose ovariumcarcinoom 2011

21 Dose-dense weekly paclitaxel in Stage II-IV ovarian cancer: JGOG Carboplatin AUC 6 Paclitaxel 180 mg/m 2 x 6-9 R Carboplatin AUC 6 Paclitaxel 80 mg/m 2 /wk x 3 x 6-9 Dose-dense paclitaxel > hematologic toxicity, and < patients completed all protocol therapy. Accrual 637 patients (631 intent to treat) Katsumata N, et al. Lancet. 2009;374:

22 Update progressie vrije overleving JGOG trial

23 Overall survival JGOG trial in relatie tot residuale ziekte histologisch subtype geen effect clear cell & mucineus

24 Conclusies Dose dense paclitaxel beter Al onderdeel NCCN guidelines Speciaal voor Japanners? Dose dense paclitaxel ook superieur bij borstkanker Confirmatory studies ongoing

25 Ovaria: targeted agents 1. Erlotinib: EGFR1 tyrosine kinase remmer: 1ste lijn: 2. Olaparib: PARP remmer: gerandomiseerde fase 2: recidief platinum sensitief 3. Bevacizumab: Platina resistent recidief fase 3

26 Randomised trial erlotinib vs observatie in 1 ste lijn ovariumcarcinoom Ovarian, tubal or peritoneal cancer FIGO stage high-risk I or II-IV (n=835) 6-9 courses platin-based chemotherapy No progression at the end of chemotherapy Randomisation Erlotinib 150mg daily orally 2 years Observation

27 PFS Erlotinib study Overall survival

28 Olaparib plus paclitaxel & carboplatin followed by olaparib maintenance in platinum-sensitive recurrent serous ovarian cancer patients. Phase 2 Patients with: Platinum-sensitive A serous histology or serous component Measurable disease 3 previous platinum-containing regimens Progression free 6 months following completion of last platinum-containing regimen n=81 n=81 R 1:1 Olaparib 200 mg bid (d1-10 every 21 days) + paclitaxel 175 mg/m 2 (iv, d1) + carboplatin AUC4 (iv, d1) Completion of 4-6 x 21-day cycles of chemotherapy Paclitaxel 175 mg/m 2 (iv, d1) + carboplatin AUC6 (iv, d1) n=66 n=55 Maintenance phase Olaparib 400 mg bid continuously All patients followed for objective radiologic progression and survival Maintenance phase No further study treatment

29 Progression free survival

30 ase 2 gerandomiseerde studie: olaparib in patiënten met response op platinum voor recidief sereus ovariumcarcinoom Platinum-sensitive high grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy: platinumbased with a maintained response Stable CA125 at trial entry Randomization stratification factors: Time to diseasse progression on penultimate platinum therapy Objective response to last platinum therapy Ethnic descent R 1:1 Olaparib 400 mg po bid Treatment until disease progression Placebo po bid Multinational study; 82 sites in 16 countries Ledermann et al, NEJM 2012

31 Progression free & overall survival

32 AURELIA trial in platinum resistente ovariumtumoren Platinum-resistant OC 2 prior anticancer regimens No history of bowel obstruction/ abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement R 1:1 Chemotherapy BEV 15 mg/kg q3w + chemotherapy Treat to PD/toxicity Treat to PD/toxicity Optional BEV monotherapy Investigators choice (without BEV)

33 Progression free survival Aurelia & Oceans (platinum sensitive recurrent disease) Aurelia Oceans Aghajanian C et al. J Clin Oncol 2012;30:

34 De biologie van kanker Oncogenes activatie Mutaties, amplificaties of translocaties in een nieuw eiwit Meest belangrijke Amplificaties: HER2-neu Translocaties: ALk, BCR-Abl, RAR-PML Mutaties B-RAF, EGFR, c-kit, Jak, Patch Tumor suppressors verlies VHL-angiogenese inhibitors BRCA1,2-PARP inhibitors

35 Genetica gynecologische tumoren Cervix en endometriumcarcinoom 1/3 drugable target Ovariumcarcinoom 160 mutaties in 15 drugable genes Nauwelijks afwijkingen Sereuze ovariumcarcinoom mn loss van tumorsuppressors Mn P53, BRCA loss

36 CGH analyse: serous ovariumcarcinoom- The Cancer Genome Atlas. Ziekte van genome instabiliteit Amplificaties en deleties

37 Somatische mutaties 2 ovariumcarcinomen

38 Conclusies discussiant Stop targeted therapy studies in sereus ovariumcarcinoom Sequence ovariumcarcinomen Gebruik nieuwe strategieën (Maak gebruik van genoominstabiliteit) ADC Immunotherapie

39 Low grade sereus ovariumcarcinoom PI3K and MEK inhibitor combinations Vaak K-Ras, B-Raf mutatie A phase 1 studie oraal BKM120 + GSK in patients with selected advanced solid tumors: Philippe Bedard et al PTEN Pan-PI3K BKM120 PI3K RAS Receptor tyrosine kinase RAF AKT Crosstalk MEK GSK112 MEK 1/2 FOXO ERK mtorc1 Cell survival Cell growth, metabolism Cell proliferation angiogenesis = frequently mutated in cancers

40 Best % change from baseline and best overall response: by treatment * * * * Denotes partial response

41 Take home messages Vulva- en endometriumcarcinoom: Rol radiotherapie aan het verschuiven (Sereus) Ovariumcarcinoom Weinig drugable targeted options Standaard: Carboplatin met (wekelijks) paclitaxel Low grade sereus ovariumcarcinoom Andere tumor met drugable targets Toekomst

42 Planning

43 The perfect biomarker and man?