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THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER

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Presentation on theme: "THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER"— Presentation transcript:

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
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 - country with high level of genetic homogeneity !
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 patients 4153 delA 5382 insC
(-) DNA C61G

10 BRCA1 FOUNDER MUTATIONS IN POLAND
GÓRSKI B. ET AL. - PATENT NO P MULTIPLEX PCR - 50€

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

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

13 BRCA1 mutations in patients with breast cancer <51yrs

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

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 Cumulative 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 OR 0.95 CI ER Status B. Weber 2005 BRCA1 5 Tam
3 Placebo 1.67 1 ER + 6 ER - 1 unknown BRCA2 3 Tam 8 Placebo 0.38 6 ER+ 3 ER- 2 unknown The efficacy of tamoxifen for breast cancer prevention in BRCA1/2 mutation carriers cannot be determined from P1 data B. Weber 2005

27 Association between Tamoxifen and the risk of contralateral breast cancer

28 HRT after BPO in 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

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 N = 130 (-) 9 Br/Ov Ca

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

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

33 Population screenings - Poland

34 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!

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

36 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.

37 1,258 mln questionnaires out of 1,45 mln of inhabitants
JANUARY 2001 – MAY 2002 1,258 mln questionnaires out of 1,45 mln of inhabitants the first worldwide large screening for hereditary cancers

38 ECONOMICAL / MEDICAL ASPECTS

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

40 BRCA 1 PROPHYLACTICS: 1 BREAST CA ~5 250 € OVARIAN CA ~4 500 €
TREATMENT COST OF BREAST/ OVARIAN CANCER: > €

41 2000-2003 BRCA1 mutation carriers with breast/ovarian cancers N=50
treatment costs PLN social security costs PLN GP per capita lost PLN PLN average annual cost PLN Marska N, US 2004

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

43 TWÓJ STYL 5024 BRCA1 tests 198 (3,9%) mutations found

44 TWÓJ STYL BRCA1 carriers unaffected n=63 2001
36.5% - worry 27.0% - shock 22.0% - sadness TWÓJ STYL BRCA1 carriers unaffected n=

45 TWÓJ STYL BRCA1 carriers unaffected n=63 2004
66% - used preventive measures 98% - would recommend testing Gronwald J. et al. JAMA 2005

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

47 BREAST CANCER GENETIC RISK
GENES HIGH MODERATE / LOW

48 NETWORK OF CANCER FAMILY SYNDROME REGISTERS IN EASTERN EUROPE 2000-2002
EU PROJECT

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

50 BREAST CANCER RISK DGN <50 yrs, n=3500
GENES MUTATIONS / POLYMORPHISMS RR 2,0 1,4 1,7 1,5 4,0 10,0 X3 X2 X1 P16 NOD2 I157T CHEK2 ex2splice 1100delC NBS1 BRCA2 BRCA1 0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 %

51 BREAST CANCER RISK GENE INTERACTIONS
CHEK2 I157T + X1 OR 4.8

52 MOLECULAR CONSTITUTIONAL CHANGES IDENTIFIED FOR > 70% OF BREAST CANCERS IN POLAND

53 EU PROJECT Population specific panels of DNA markers for detection of moderate risk of breast and colon cancers and their market application

54 Coordinator – J. Lubiński
PARTICIPANTS Australia The Netherlands Canada Poland Cyprus Pakistan Estonia Russia Germany Serbia and Montenegro Greece Slovakia Korea Sweden Latvia United Kingdom Coordinator – J. Lubiński

55 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

56 Electronic version of the journal available on: www.hccp-uicc.com

57 More information: www.hereditarycancer.net e-mail: ihcc@wp.pl
phone: fax:


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