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

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Presentation on theme: "THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER J. Lubiński 12 December 2005, Chennai, India INTERNATIONAL HEREDITARY CANCER CENTER."— Presentation transcript:

1 THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER J. Lubiński 12 December 2005, Chennai, India 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 Womens 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 13Department of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA 14 Institute of Genetics, Rambam Medical Center, Haifa, Israel 15Division 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, Childrens Hospital Medical Center, Cincinnati, USA 21Oncogenetics 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 lUniversité 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% BRCA 1 ~65% BRCA2~4% BRCA2~4% BRCA 1 ~65% BRCA 1 ~65% BRCA2~4% BRCA2~4% Górski B. et al. Int. J. Can, 2004

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

9 BRCA1 MULTIPLEX PCR possitive controls 4153 delA C61GC61G 5382 insC (-) DNA 5382 insC patientspatients

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

11 BRCA1 – REGISTRY – SZCZECIN – POLAND 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 4780 patients 4780 patients 3629 (75,9%) blood samples 3629 (75,9%) blood samples 3614 BRCA1 tests 3614 BRCA1 tests 200 (5,5%) mutations 200 (5,5%) mutations 4780 patients 4780 patients 3629 (75,9%) blood samples 3629 (75,9%) blood samples 3614 BRCA1 tests 3614 BRCA1 tests 200 (5,5%) mutations 200 (5,5%) mutations BRCA1 mutations in patients with breast cancer <51yrs

15 Pathologic/ clinical features of cancers

16

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

18 C61G 5382insC 4153delA 0.0 P=0.12 Age (years) Cumulative incidence of breast cancer in first-degree relatives by mutation

19 Cumulative incidence of ovarian cancer in first-degree relatives by mutation 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 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 Proband Breast Cancer Proband Ovarian Cancer 0.0 P=0.98 Age (years)

22 A. BRCA1 PROPHYLACTICS RISK BR OV RISK BR OV Oral contraceptives 30yrs 0.5 Oral contraceptives 30yrs 0.5 Breast feeding > 1 yrs 0.5 Breast feeding > 1 yrs 0.5 Later menarche per yr 0.9 Later menarche per yr 0.9 Tubal ligation 0.5 Tubal ligation 0.5 Adnexectomy Adnexectomy Tamoxifen 0.5 Tamoxifen 0.5 Adnexectomy + tamoxifen 0.15 Adnexectomy + tamoxifen 0.15 Mastectomy 0.01 Mastectomy 0.01 RISK BR OV RISK BR OV Oral contraceptives 30yrs 0.5 Oral contraceptives 30yrs 0.5 Breast feeding > 1 yrs 0.5 Breast feeding > 1 yrs 0.5 Later menarche per yr 0.9 Later menarche per yr 0.9 Tubal ligation 0.5 Tubal ligation 0.5 Adnexectomy Adnexectomy Tamoxifen 0.5 Tamoxifen 0.5 Adnexectomy + tamoxifen 0.15 Adnexectomy + tamoxifen 0.15 Mastectomy 0.01 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 BRCA1 5 Tam 3 Placebo ER + 6 ER - 1 unknown BRCA2 3 Tam 8 Placebo 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

28 408 BRCA1/2 Mutation Carriers 408 BRCA1/2 Mutation Carriers 184 women with BPO (65% took HRT) 184 women with BPO (65% took HRT) 224 women without BPO (7% took HRT) 224 women without BPO (7% took HRT) Post operative follow up 3.4 years Post operative follow up 3.4 years 408 BRCA1/2 Mutation Carriers 408 BRCA1/2 Mutation Carriers 184 women with BPO (65% took HRT) 184 women with BPO (65% took HRT) 224 women without BPO (7% took HRT) 224 women without BPO (7% took HRT) Post operative follow up 3.4 years Post operative follow up 3.4 years HRT after BPO in BRCA1/2 Mutation Carriers Post BPO breast cancer risk reduction: Post BPO breast cancer risk reduction: 68% reduction overall 68% reduction overall 64% reduction in women who took HRT 64% reduction in women who took HRT Post BPO breast cancer risk reduction: Post BPO breast cancer risk reduction: 68% reduction overall 68% reduction overall 64% reduction in women who took HRT 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 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 USGMAMMOGR.MRI ~20%~20%~90% USGMAMMOGR.MRI ~20%~20%~90% Narod S. et al. 2003

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

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 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! Thanks to geneticists - oncologists from 20 Polish centers! 4% (~200) of BRCA1 carriers among 5000 relatives of women with breast cancer dgn < 50 yrs or ovarian cancer dgn at any age 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! 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. 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 JANUARY 2001 – MAY ,258 mln questionnaires out of 1,45 mln of inhabitants 1,258 mln questionnaires out of 1,45 mln of inhabitants the first worldwide large screening for hereditary cancers the first worldwide large screening for hereditary cancers 1,258 mln questionnaires out of 1,45 mln of inhabitants 1,258 mln questionnaires out of 1,45 mln of inhabitants the first worldwide large screening for hereditary cancers the first worldwide large screening for hereditary cancers

38 ECONOMICAL / MEDICAL ASPECTS

39 BRCA 1 MUTATION DETECTION COST750 MUTATION DETECTION COST750 SURVEILLANCE COST1650 (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN) SURVEILLANCE COST1650 (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN) RISK REDUCTION RISK REDUCTION BREAST60% 10% (WITHOUT PROPHYLACTIC MASTECTOMY) BREAST60% 10% (WITHOUT PROPHYLACTIC MASTECTOMY) OVARY40% 5% OVARY40% 5% MUTATION DETECTION COST750 MUTATION DETECTION COST750 SURVEILLANCE COST1650 (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN) SURVEILLANCE COST1650 (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN) RISK REDUCTION RISK REDUCTION BREAST60% 10% (WITHOUT PROPHYLACTIC MASTECTOMY) BREAST60% 10% (WITHOUT PROPHYLACTIC MASTECTOMY) OVARY40% 5% OVARY40% 5%

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

41 BRCA1 mutation carriers with breast/ovarian cancers N=50 treatment costs PLN treatment costs PLN social security costs PLN social security costs PLN GP per capita lost PLN GP per capita lost PLN PLN PLN average annual cost PLN average annual cost PLN treatment costs PLN treatment costs PLN social security costs PLN social security costs PLN GP per capita lost PLN GP per capita lost PLN PLN PLN average annual cost 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 BRCA1 tests 5024 BRCA1 tests 198 (3,9%) mutations found 198 (3,9%) mutations found 5024 BRCA1 tests 5024 BRCA1 tests 198 (3,9%) mutations found 198 (3,9%) mutations found

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

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

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

47 BREAST CANCER GENETIC RISK GENESGENES HIGHHIGH MODERATE / LOW

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

49 LIN ANAL FAM AGGR BREAST COLON CA GENES EU PROJECT

50 BREAST CANCER RISK DGN <50 yrs, n=3500 0,05,010,015,020,025,030,0 35,0 % BRCA1 BRCA2 NBS1 1100delC ex2splice I157T NOD2 P16 X1 X2 X3 RR2,01,4 1,7 1,7 2,0 1,5 4,0 2,0 2,0 1,5 10,0 CHEK2 GENES MUTATIONS / POLYMORPHISMS

51 BREAST CANCER RISK GENE INTERACTIONS CHEK2 I157T X1X1X1X1 X1X1X1X1 OR

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 PARTICIPANTSAustralia The Netherlands CanadaPoland CyprusPakistan EstoniaRussia Germany Serbia and Montenegro GreeceSlovakia KoreaSweden Latvia United Kingdom Coordinator – J. Lubiński

55 WORKPACKAGES 1: Organization of international network of registries 1: Organization of international network of registries 2: Elaboration of population specific panels of DNA markers 2: Elaboration of population specific panels of DNA markers 3: Market protection of markers by patents 3: Market protection of markers by patents 4: Technical optimization of DNA testing based on established panels of markers 4: Technical optimization of DNA testing based on established panels of markers 5: Establishment of rules to be respected when proposed testing is offered 5: Establishment of rules to be respected when proposed testing is offered 6: Organization of networks of outpatient clinics applying developed DNA testing 6: Organization of networks of outpatient clinics applying developed DNA testing 7: Promotion of developed DNA testing 7: Promotion of developed DNA testing 1: Organization of international network of registries 1: Organization of international network of registries 2: Elaboration of population specific panels of DNA markers 2: Elaboration of population specific panels of DNA markers 3: Market protection of markers by patents 3: Market protection of markers by patents 4: Technical optimization of DNA testing based on established panels of markers 4: Technical optimization of DNA testing based on established panels of markers 5: Establishment of rules to be respected when proposed testing is offered 5: Establishment of rules to be respected when proposed testing is offered 6: Organization of networks of outpatient clinics applying developed DNA testing 6: Organization of networks of outpatient clinics applying developed DNA testing 7: Promotion of developed DNA testing 7: Promotion of developed DNA testing

56 Electronic version of the journal available on: Electronic version of the journal available on:

57 More information: phone: fax: phone: fax: phone: fax: phone: fax:


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