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THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER

THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER. J. Lubiński. INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND. 12 December 2005, Chennai, India.

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THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER

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  1. THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER J. Lubiński INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND 12 December 2005, Chennai, India

  2. Lubinski J.1, Górski B.1, Cybulski C.1, Huzarski T.1, Byrski T.1, Gronwald J.1, Jakubowska A.1, Stawicka M.2, Gozdecka-Grodecka S.3, Szwiec M.4, Urbański K.5, Mituś J.5, Marczyk E.5, Dziuba J.1, Wandzel P.6, Surdyka D.7, Haus O.8, Janiszewska H.8, Dębniak T.1, Tołoczko-Grabarek A.1, Mędrek K.1, Masojć B.1, Mierzejewski M.1, Kowalska E.1, Zientek H.9, Pamuła J.9, Metcalfe K.10, Tung N.11, Foulkes WD.12, Offit K.13, Gershoni R.14, Daly M.15, Kim-Sing Ch.16, Olsson H.17, Ainsworth P.18, Eisen A.19, Saal H.20, Friedman E.21, Olopade O.22, Osborne M.23, Weitzel J.24, Lynch H.25, Ghadirian P.26, Sun P.10, Narod SA.10 and Hereditary Breast Cancer Clinical Study Group 1 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland 2 Prophylactic and Epidemiology Center, Poznan, Poland 3 Poznan Medical University 4 Regional Oncology Hospital, Opole, Poland 5 Regional Oncology Center, Kraków, Poland 6 Regional Oncology Hospital, Bielsko-Biała, Poland 7 Regional Oncology Hospital, Lublin, Poland 8 Department of Clinical Genetics, Bydgoszcz Medical University, Poland 9 Oncology Center, Gliwice, Poland 10 Centre for Research in Women’s Health, University of Toronto, Canada 11 Beth Israel Deaconess Hospital, Boston, USA 12 Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Canada 13 Department of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA 14 Institute of Genetics, Rambam Medical Center, Haifa, Israel 15 Division of Population Science, Fox Chase Cancer Center, Philadelphia, USA 16 British Columbia Cancer Agency, Vancouver, British Columbia, Canada 17 The Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden 18 London Regional Cancer Center, London, Ontario, Canada 19 Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada 20 Hereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, USA 21 Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel 22 Center for Clinical Cancer Genetics, University of Chicago, Chicago, USA 23 Strang Cancer Prevention Center, New York, USA 24 City of Hope Hospital, Duarte, CA, USA 25 Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, USA 26 Epidemiology Research Unit, Centre hospitalier de l’Université de Montréal (CHUM), Hôtel-Dieu, University of Montreal, Quebec, Canada

  3. IHCC staff

  4. POLAND - country with high level of genetic homogeneity !

  5. Górski B. et al. AJHG, June 2000

  6. POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200) • BRCA 1 ~65% • BRCA2 ~4% Górski B. et al. Int. J. Can, 2004

  7. POLISH PANEL OF BRCA1 MUTATIONS • 5382 ins C • C 61 G • 4153 del A 90% of mutations Górski B. et al. Int. J. Can, 2004

  8. BRCA1 MULTIPLEX PCR possitive controls patients 5382 insC 5382 insC 4153 delA (-) DNA C61G

  9. BRCA1 FOUNDER MUTATIONS IN POLAND • GÓRSKI B. ET AL. - PATENT NO P335917- MULTIPLEX PCR - 50€

  10. BRCA1 – REGISTRY – SZCZECIN – POLAND 3225 CARRIERS THE LARGEST REGISTRY IN THE WORLD Szczecin 7 December 2005

  11. BRCA1 – POSITIVE BREAST CANCERS IN YOUNG WOMEN IN POLAND Lubiński J. et al. Br J. Can 2005

  12. BRCA1 mutations in patients with breast cancer <51yrs

  13. BRCA1 mutations in patients with breast cancer <51yrs • 4780 patients • 3629 (75,9%) blood samples • 3614 BRCA1 tests • 200 (5,5%) mutations

  14. Pathologic/ clinical features of cancers

  15. Pathologic/ clinical features of cancers

  16. CANCER RISKS IN FIRST-DEGREE RELATIVES OF BRCA1 MUTATION CARRIERS: EFFECTS OF MUTATION AND PROBAND DISEASE STATUS J. Gronwald, JMG 2005

  17. 0.8 C61G 0.7 5382insC 0.6 4153delA P=0.12 0.5 0.4 0.3 0.2 0.1 0.0 25 30 35 40 45 50 55 60 65 70 75 Age (years) Cumulativeincidence ofbreast cancerin first-degree relativesby mutation

  18. 0.8 C61G 0.7 5382insC 0.6 4153delA 0.5 P=0.05 0.4 0.3 0.2 0.1 0.0 25 30 35 40 45 50 55 60 65 70 75 Age (years) Cumulativeincidence ofovarian cancerin first-degree relativesby mutation

  19. 0.8 0.7 Proband Breast Cancer Proband Ovarian Cancer 0.6 0.5 P=0.005 0.4 0.3 0.2 0.1 0.0 25 30 35 40 45 50 55 60 65 70 75 Age (years) Cumulativeincidence ofbreast cancerin first-degree relativesby cancer siteof the proband

  20. 0.8 0.7 Proband Breast Cancer Proband Ovarian Cancer 0.6 0.5 P=0.98 0.4 0.3 0.2 0.1 0.0 25 30 35 40 45 50 55 60 65 70 75 Age (years) Cumulativeincidence ofovarian cancerin first-degree relativesby cancer siteof the proband

  21. A. BRCA1 PROPHYLACTICS RISK BR OV • Oral contraceptives < 30yrs 1.3> 30yrs 0.5 • Breast feeding > 1 yrs 0.5 • Later menarche per yr 0.9 • Tubal ligation 0.5 • Adnexectomy 0.2 0.05 • Tamoxifen 0.5 • Adnexectomy + tamoxifen 0.15 • Mastectomy 0.01

  22. BRCA1 PROPHYLACTICS - POLAND BREAST CANCER

  23. BRCA1 PROPHYLACTICS - POLAND OVARIAN CANCER

  24. TAMOXIFEN AND CONTRALATERAL BREAST CANCER IN BRCA1 AND BRCA2 CARRIERS: AN UPDATE Gronwald J. et al. Int J Can 2005

  25. NSABP P1 Results The efficacy of tamoxifen for breast cancer prevention in BRCA1/2 mutation carriers cannot be determined from P1 data B. Weber 2005

  26. Association between Tamoxifen and the risk of contralateral breast cancer

  27. HRT after BPO in BRCA1/2 Mutation Carriers • 408 BRCA1/2 Mutation Carriers • 184 women with BPO (65% took HRT) • 224 women without BPO (7% took HRT) • Post operative follow up 3.4 years • Post BPO breast cancer risk reduction: • 68% reduction overall • 64% reduction in women who took HRT Rebbeck et al, JCO in press, 2005

  28. Hormone replacement therapy appears to be safe after prophylactic adnexectomy in premenopausal BRCA1/BRCA2 mutation carriers

  29. BRCA1 PROPHYLACTICS • Sodium selenite – pilot study BRCA1 CARRIERS N = 130 Se 3 Br/Ov Ca N = 130 (-) 9 Br/Ov Ca

  30. DETECTION OF EARLY BREAST CANCERS IN BRCA1 MUTATION CARRIERS USG MAMMOGR. MRI ~20% ~20% ~90% Narod S. et al. 2003

  31. Breast cancers with BRCA1 Treatment 10 yrs survival • prophylactic adnexectomy  2× • tamoxifen  1.5× • mastectomy  1.5×

  32. Population screenings- Poland

  33. 4% (~200) of BRCA1 carriers among 5000 relatives of women with breast cancer dgn < 50 yrs or ovarian cancer dgn at any age • Thanks to geneticists - oncologists from 20 Polish centers!

  34. POPULATION SCREENING FOR CANCER FAMILY SYNDROMES IN WEST – POMERANIA, POLAND WEST – POMERANIA HEALTH CARE INS. COMP FAMILY DOCTORS IHCC POMERANIAN MEDICAL UNIVERSITY, SZCZECIN

  35. FAMILY DOCTORS – PROJECT INITIATORS 1. Andrzej Raczyński NPZOZ „Asklepios” Bobolice 2. Jarosław Kopciewicz - SPZOZ Pyrzyce 3. Cygal Lucyna - SZOZ nr 3 Kołobrzeg 4. Krzysztof Jankowiak - NZOZ „Zdrowie” Drawsko Pomorskie 5. Wiesława Fabian - NZOZ Szczecin 6. Józef Dmochowski - ZOZ „Zdrowie” Barwice 7. Paweł Szycko - NZOZ Podimed - Szczecinek. 8. Tadeusz Cieślak - NZOZ - „Hipokrates” - Złocieniec.

  36. JANUARY 2001 – MAY 2002 • 1,258 mln questionnaires out of 1,45 mln of inhabitants • the first worldwide large screening for hereditary cancers

  37. ECONOMICAL / MEDICAL ASPECTS

  38. BRCA 1 • MUTATION DETECTION COST 750 € • SURVEILLANCE COST 1650 €(USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN) • RISK REDUCTION • BREAST 60%  10% (WITHOUT PROPHYLACTIC MASTECTOMY) • OVARY 40%  5%

  39. BRCA 1 • PROPHYLACTICS: • 1 BREAST CA ~5 250 € • OVARIAN CA ~4 500 € • TREATMENT COST OF BREAST/ OVARIAN CANCER: • > 6 000 €

  40. 2000-2003 BRCA1 mutation carriers with breast/ovarian cancers N=50 • treatment costs 21 428 PLN • social security costs 34 086 PLN • GP per capita lost 195 071 PLN 250 586 PLN • average annual cost 62 646 PLN Marska N, US 2004

  41. DIRECT-TO-PATIENT BRCA1 TESTING: THE TWÓJ STYL EXPERIENCE Gronwald J. et al. Int J Can 2005

  42. TWÓJ STYL 2001 • 5024 BRCA1 tests • 198 (3,9%) mutations found

  43. 36.5% - worry • 27.0% - shock • 22.0% - sadness TWÓJ STYL BRCA1 carriers unaffected n=632001

  44. TWÓJ STYL BRCA1 carriers unaffected n=632004 • 66% - used preventive measures • 98% - would recommend testing Gronwald J. et al. JAMA 2005

  45. two session counseling is effective for diagnosing BRCA1 carriers in Poland TWÓJ STYL Gronwald J. et al. JAMA 2005

  46. BREAST CANCER GENETIC RISK GENES HIGH MODERATE / LOW

  47. NETWORK OF CANCER FAMILY SYNDROME REGISTERS IN EASTERN EUROPE2000-2002 EU PROJECT

  48. LIN ANAL FAM AGGR BREAST COLON CA GENES 2004-2006 EU PROJECT

  49. BREAST CANCER RISKDGN <50 yrs, n=3500 GENES MUTATIONS / POLYMORPHISMS RR X3 X2 X1 P16 NOD2 I157T ex2splice CHEK2 1100delC NBS1 BRCA2 BRCA1 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 %

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