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  • 1. THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER J. Lubiński 11 February 2006, Cyprus INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND
  • 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.  
  • 6. Górski B. et al. AJHG, June 2000
  • 7. POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200)
    • BRCA 1 ~65%
    • BRCA2 ~4%
    Górski B. et al. Int. J. Can, 2004
  • 8. 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
  • 9. BRCA1 MULTIPLEX PCR possitive controls 4153 delA C61G 5382 insC (-) DNA 5382 insC patients
  • 10. BRCA1 FOUNDER MUTATIONS IN POLAND
    • GÓRSKI B. ET AL. - PATENT NO P335917 - MULTIPLEX PCR - 5 0 €
  • 11. BRCA1 – REGISTRY – SZCZECIN – POLAND 3256 CARRIERS THE LARGEST REGISTRY IN THE WORLD Szczecin 30 January2006
  • 12. BRCA1 – POSITIVE BREAST CANCERS IN YOUNG WOMEN IN POLAND Lubiński J. et al. Br Can Res Treat 2005
  • 13. BRCA1 mutations in patients with breast cancer <51yrs
  • 14.
    • 4780 patients
    • 3629 (75,9%) blood samples
    • 3614 BRCA1 tests
    • 200 (5,5%) mutations
    BRCA1 mutations in patients with breast cancer <51yrs
  • 15. Pathologic/ clinical features of cancers
  • 16. Pathologic/ clinical features of cancers
  • 17. CANCER RISKS IN FIRST-DEGREE RELATIVES OF BRCA1 MUTATION CARRIERS: EFFECTS OF MUTATION AND PROBAND DISEASE STATUS J. Gronwald, JMG 2005
  • 18. Cumulative incidence of breast cancer in first-degree relatives by mutation 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 25 30 35 40 45 50 55 60 65 70 75 C61G 5382insC 4153delA 0.0 P=0.12 Age (years)
  • 19. C umulative incidence of ovarian cancer in first-degree relatives by mutation 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 25 30 35 40 45 50 55 60 65 70 75 C61G 5382insC 4153delA 0.0 P=0.05 Age (years)
  • 20. Cumulative incidence of breast cancer in first-degree relatives by cancer site of the proband 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 25 30 35 40 45 50 55 60 65 70 75 Proband Breast Cancer Proband Ovarian Cancer 0.0 P=0.005 Age (years)
  • 21. Cumulative incidence of ovarian cancer in first-degree relatives by cancer site of the proband 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 25 30 35 40 45 50 55 60 65 70 75 Proband Breast Cancer Proband Ovarian Cancer 0.0 P=0.98 Age (years)
  • 22. 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
  • 23. BRCA1 PROPHYLACTICS - POLAND BREAST CANCER
  • 24. BRCA1 PROPHYLACTICS - POLAND OVARIAN CANCER
  • 25. TAMOXIFEN AND CONTRALATERAL BREAST CANCER IN BRCA1 AND BRCA2 CARRIERS: AN UPDATE Gronwald J. et al. Int J Can 2005
  • 26. 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 6 ER+ 3 ER- 2 unknown 0.06-1.56 0.38 3 Tam 8 Placebo BRCA2 1 ER + 6 ER - 1 unknown 0.41-8.00 1.67 5 Tam 3 Placebo BRCA1 ER Status 0.95 CI OR
  • 27. Association between Tamoxifen and the risk of contralateral breast cancer
  • 28.
    • 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
    HRT after BPO in BRCA1/2 Mutation Carriers
    • Post BPO breast cancer risk reduction:
      • 68% reduction overall
      • 64% reduction in women who took HRT
    Rebbeck et al, JCO in press, 2005
  • 29. Hormone replacement therapy appears to be safe after prophylactic adnexectomy in premenopausal BRCA1/BRCA2 mutation carriers
  • 30. BRCA1 PROPHYLACTICS
    • Sodium selenite – pilot study
    BRCA1 CARRIERS N = 130 Se 3 Br/Ov Ca 9 Br/Ov Ca N = 130 (-)
  • 31. DETECTION OF EARLY BREAST CANCERS IN BRCA1 MUTATION CARRIERS USG MAMMOGR. MRI ~20% ~20% ~90% Narod S. et al. 2003
  • 32.
    • 10 yrs survival
    • prophylactic adnexectomy  2×
    • tamoxifen  1.5×
    • mastectomy  1.5×
    Breast cancers with BRCA1 Treatment
  • 33. Breast cancers with BRCA1 Treatment – Neo-Adjuvant therapy Byrski T et al.: Clin Can Res 2006
  • 34. Population screenings - Poland
  • 35.
    • 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!
  • 36. POPULATION SCREENING FOR CANCER FAMILY SYNDROMES IN WEST – POMERANIA, POLAND WEST – POMERANIA HEALTH CARE INS. COMP FAMILY DOCTORS IHCC POMERANIAN MEDICAL UNIVERSITY, SZCZECIN
  • 37. FAMILY DOCTORS – PROJE C T IN ITIATORS 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.
  • 38. JANUARY 2001 – MAY 2002
    • 1,258 mln questionnaires out of 1,45 mln of inhabitants
    • the first worldwide large screening for hereditary cancers
  • 39. ECONOMICAL / MEDICAL ASPECTS
  • 40. 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%
  • 41. BRCA 1
    • PROPHYLACTICS:
      • 1 BREAST CA ~5 250 €
      • OVARIAN CA ~4 500 €
    • TREATMENT COST OF BREAST/ OVARIAN CANCER:
      • > 6 000 €
  • 42. 2000-2003 BRCA1 mutation carriers with breast/ovarian cancers N=50
    • treatment costs ~5 500 €
    • social security costs ~8 800 €
    • GP per capita lost ~50 000 €
    • ~64 300 €
    • average annual cost ~16 000 €
    Marska N, US 2004
  • 43. DIRECT-TO-PATIENT BRCA1 TESTING: THE TWÓJ STYL EXPERIENCE Gronwald J. et al. Int J Can 2005
  • 44. TWÓJ STYL 2001
    • 5024 BRCA1 tests
    • 198 (3,9%) mutations found
  • 45. TWÓJ STYL BRCA1 carriers unaffected n=63 2001
    • 36.5% - worry
    • 27.0% - shock
    • 22.0% - sadness
  • 46. TWÓJ STYL BRCA1 carriers unaffected n=63 2004
    • 66% - used preventive measures
    • 98% - would recommend testing
    Gronwald J. et al. Br Can Res Treat 2005
  • 47. TWÓJ STYL
    • two session counseling is effective for diagnosing BRCA1 carriers in Poland
    Gronwald J. et al. Br Can Res Treat 2005
  • 48. BREAST CANCER GENETIC RISK GENES HIGH MODERATE / LOW
  • 49. NETWORK OF CANCER FAMILY SYNDROME REGISTERS IN EASTERN EUROPE 2000-2002 EU PROJECT
  • 50. LIN ANAL FAM AGGR BREAST COLON CA GENES 2004-2006 EU PROJECT
  • 51. BREAST CANCER RISK DGN <50 yrs, n=3500 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 % BRCA1 BRCA2 NBS1 1100delC ex2splice I157T NOD2 P16 X1 X2 X3 RR CHEK2 GENES MUTATIONS / POLYMORPHISMS 10,0 1,5 2,0 2,0 4,0 1,5 2,0 1,7 1,7 1,4 2,0
  • 52. BREAST CANCER RISK GENE INTERACTIONS CHEK2 I157T X 1 OR 4.8  +
  • 53. MOLECULAR CONSTITUTIONAL CHANGES IDENTIFIED FOR > 70% OF BREAST CANCERS IN POLAND
  • 54. PENETRATION AND PROPORTION OF CANCERS 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 0% 20% 40% 60% 80% 100% PENETRATION PROPORTION Lubiński J. 6.05.2004 Madrit, ESO
  • 55. > 90% OF CANCERS HAVE GENETIC CONSTITUTIONAL BACKGROUND Lubiński J. 6.05.2004 Madrit, ESO
  • 56. EU PROJECT Population specific panels of DNA markers for detection of moderate risk of breast and colon cancers and their market application
  • 57. PARTICIPANTS Coordinator – J. Lubiński The Netherlands United Kingdom Latvia Sweden Greece Slovakia Germany Serbia and Montenegro Estonia Poland Cyprus
  • 58. WORKPACKAGES
    • 1: Organization of international network of registries
    • 2: Elaboration of population specific panels of DNA markers
    • 3: Market protection of markers by patents
    • 4: Technical optimization of DNA testing based on established panels of markers
    • 5: Establishment of rules to be respected when proposed testing is offered
    • 6: Organization of networks of outpatient clinics applying developed DNA testing
    • 7: Promotion of developed DNA testing
  • 59. Electronic version of the journal available on: www.hccp-uicc.com
  • 60. More information:
    • www.hereditarycancer.net
    • e-mail: [email_address]
    • phone: +48-91-466-15-32 fax: +48-91-466-15-33