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New genetic cancer tests within gynecology Patrick Willems GENDIA Antwerp, Belgium

New genetic cancer tests within gynecology Patrick Willems GENDIA Antwerp, Belgium. Disclosure CEO and shareholder of GENDIA (private lab offering genetic tests) NO financial relationship with research bodies, medical

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New genetic cancer tests within gynecology Patrick Willems GENDIA Antwerp, Belgium

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  1. New genetic cancer tests • within gynecology • Patrick Willems • GENDIA • Antwerp, Belgium

  2. Disclosure • CEO and shareholder of GENDIA • (private lab offering genetic tests) • NO financial relationship with research bodies, medical • or pharmaceutical companies, hospitals or government • or

  3. New genetic tests • 1. GERMLINE MUTATIONS • NIPT • STID • WES / WGS • CANCER RISK • 2. SOMATIC MUTATIONS IN CANCER • DNA profiling of tumors • CT-DNA (liquid biopsy)

  4. New genetic tests • In procreation • NIPT and STID

  5. NIPT NON – INVASIVE PRENATAL TESTING Testing of cff DNA (cell free fetal DNA) from maternal blood during pregnancy for trisomy 21, 18 and 13, and fetalsex www.DOWNsyndromeNIPT.info

  6. NIPT NIPT currently is most common genetic test The most common genetic test : Approximately 1 millionNIPTs per year worldwide Future Market value : 4 billion US / year (price : 300 – 500 Euro per test)

  7. STID SCREENING TEST for INHERITED DISEASE With testing of common recessive diseases from parental blood before or during pregnancy If both parents are carrier of the same disease the fetus has a 25 % risk of being affected and prenatal testing (CVS/AC) can be offered www.STID-GENDIA.net

  8. STID for Recessive disorders

  9. New genetic tests • for cancer • CANCER RISK test • DNA profiling test • CT-DNA test

  10. Genetics of cancer • Majority of cancers are caused by somatic mutations only occuring in the tumor • Minority of cancers is inherited due to germline mutations occuring in all cells (also germline) : • Ovarian Cancer : 15 % • Breast Cancer : 10 % • Colon cancer : 5% • Prostate cancer : low • Lung cancer : very low

  11. CANCER RISK test in BOCGermline DNA testing Classical BOC testing • BRCA1/2 test • 2 genes in patients • Single mutations in family members • Selected families • Patientsaffectedwith BOC • Young patients • Multiplex families with multiple affected members • Ovarian Ca

  12. Germline DNA testing in BOC • BOC testing of BRCA1/2 onlyidentifies 50 % of mutations • BOC testing of BRCA1/2 misses therapeutic targets • Selected family testingonlyidentifies 50 % of mutations

  13. Germline DNA testing in BOC • BOC testing of BRCA1/2 onlyidentifies 50 % of mutations • BOC testing of BRCA1/2 misses therapeutic targets • Selected family testingonlyidentifies 50 % of mutations

  14. Germline mutations in BOC Breastcancer : 10 % is inherited • BRCA1 and BRCA2 mutations : 5 % • CHEK2, ATM, TP53, PALB2: 3-5 % • Othermutations : ? Ovariancancer : 15 % is inherited • BRCA1 and BRCA2 mutations : 10 % • HNPCC mutations : 1-2 % • Othermutations : ? • BRCA1/2 • CHEK2,ATM,TP53,PALB2,BARD1,BRIP1,CDH1,EPCAM,MLH1, • MSH2, MSH6,NBN,PMS2,PTEN,RAD51C,RAD51D,STK11

  15. Germline DNA testing in BOC • BOC testing of BRCA1/2 onlyidentifies 50 % of mutations • BOC testing of BRCA1/2 misses therapeutic targets • Selected family testingonlyidentifies 50 % of mutations

  16. Germline DNA testing in BOC PARP inhibitors for tumors withdeficient DNA repair : • Deficient DNA repairdue to mutations in BRCA1/2 • Deficient DNA repairdue to mutations in othergenes : BARD1, BRIP1, PALB2, ATM, CHEK2, PTEN, RAD51C, RAD51D, NBN, TP53, EPCAM, MLH1, MSH2, MSH6, PMS2 ,

  17. Germline DNA testing in BOC • BOC testing of BRCA1/2 onlyidentifies 50 % of mutations • BOC testing of BRCA1/2 misses therapeutic targets • Selected family testingonlyidentifies 50 % of mutations

  18. CGC-based genetic screening • Patients affected with BOC • Young patients • Multiplex families • Ovarian Ca CGC (Clinical Genetics Center) Criteria :

  19. BOC testing for all women 50 % of womenwith BOC mutation do notfulfill CGC criteria Mary-Claire King advocates genetic screening of all adult women (JAMA vol 312, Sept 2014)

  20. Breast cancer testing PREVIOUSLY : BRCA1/2 in selectedpatientswith high risk CURRENTLY : Screening of ALL BOC genes in ALL women

  21. Cancer risk test Sequencing of 30 cancer genes : 19 genes involved in BOC : BRCA1, BRCA2, ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM,MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53 + 11 genes involved in colon, uterine, pancreas, and skin cancer : APC, BAP1, BMPR1A, CDKN2A, CDK4, GREM1, MITF, MUTYH, POLD1, POLE, and SMAD4

  22. What if I have a mutation ? • Children have 50 % risk of inheriting the mutation • Ifalready BOC, personalised treatment eg withherceptin, PARP inhibitors • Ifunaffected : increased risk for BOC • Increased surveillance (MRI, Mammography, CA125, abdominalechography, CT-DNA liquid biopsy) • Profylacticsurgery : 51% bilateral mastectomy; 64% oophorectomy (Meijers H. The Lancet, june2000)

  23. New genetic tests • 1. GERMLINE MUTATIONS • NIPT • STID • WES / WGS • CANCER RISK • 2. SOMATIC MUTATIONS IN CANCER • DNA profiling of tumors • CT-DNA (liquid biopsy)

  24. DNA profiling of BOC tissue CURRENT TESTING of BOC tissue : • Estrogen receptor (ER) : tamoxifen (anti-E), anastrozole (anti-Aromatase) • Progesteron receptor (PR): mifepristone • HER2 : Herceptin FUTURE TESTING of BOC tissue : • DNA repairgenes: PARP inhibitors (Olaparib, Iniparib, Veliparib) • Microsatelliteinstability (MSI): immunotherapy • RNA signaturetodeterminethrneedof chemo • Driver genes : targetedtherapywith designer molecules

  25. Frequency of oncogenic mutations in different cancers

  26. Treatment of cancer • Surgery • Radiation • Chemotherapy • Personalised treatment

  27. Targeted treatment for cancer • Personalised targeted treatment inhibits specific mutations that cause cancer • These mutations are patient-specific • Therapy is dependent upon the specific mutation • Mutations can be detected by molecular studies of : . tumor material (biopsy) : FFPE, fresh or frozen . blood (liquid biopsy)

  28. cell-free DNA testing Cell-free DNA (cfDNA) in plasma of healthy individuals (Mandel and Métais,1948)

  29. cell-free DNA testing Cell-free DNA (cfDNA) in plasma of healthy individuals (Mandel and Métais,1948) cffDNA (NIPT) : Cell-free DNA from the fetus in the maternal circulation • A proportion of cfDNA in pregnant women is fetus-derived (cffDNA) : Lo et al. (1997) • Non-Invasive Prenatal testing (NIPT) : 2012 : start 2015 : > 1 million tests Market : 4 billion USD ctDNA (liquid biopsy) Cell-free DNA from the cancer cells in the circulation • Increased concentrations of cfDNA in the circulation of cancer patients : Leon et al. (1977) • A proportion of cfDNA is tumor-derived : Stroun et al. (1987) • Circulating tumor DNA (ctDNA) testing (liquid biopsy) : 2015 : start Market : 40 billion USD

  30. CT DNA test CT DNA test screens Circulating Tumor DNA from the cancer cells in blood (liquid biopsy)

  31. CT-DNA test on liquid biopsy 1. DESCRIPTION :96 mutations in 9 cancer genes 2. SAMPLE :blood in specific test kits with Streck tubes (GENDIA) 3. TURNAROUND TIME :3 weeks 4. PRICE :500-900 Euro

  32. Advantages liquid biopsies • No tissue biopsy needed • No FFPE fixation • Profiling the overall genotype of cancer • primary cancer • circulating cells • metastases • Better evaluation of : • reaction to therapy • development of resistance • Also screening of patients without tumor but high cancer risk

  33. Indications for CT DNA testing (liquid biopsy) • Follow up of patientswithcancerduring treatment • Screening of individuals at high risk forcancer • BRCA, HNPCC carriers • History of cancer • Family history of cancer • In thefuture : annual screening of alladults

  34. From patient testing towardspopulation screening Form testing of 1 gene in 1 % of the population suspected of a genetic disorder to : • Wholegenometesting (WGS) of the wholepopulation toidentifygermlinemutations 2. Annual screening forcancer DNA by liquid biopsy toidentifysomaticmutations

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