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THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER J. Lubiński INTERNATIONAL HEREDITARY THE LATEST ADVANCES IN CLINICAL GENETICS OF HEREDITARY BREAST CANCER J. Lubiński INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND 11 February 2006, Cyprus

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, 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Szczecin, Poland Prophylactic and Epidemiology Center, Poznan, Poland Poznan Medical University Regional Oncology Hospital, Opole, Poland Regional Oncology Center, Kraków, Poland Regional Oncology Hospital, Bielsko-Biała, Poland Regional Oncology Hospital, Lublin, Poland Department of Clinical Genetics, Bydgoszcz Medical University, Poland Oncology Center, Gliwice, Poland Centre for Research in Women’s Health, University of Toronto, Canada Beth Israel Deaconess Hospital, Boston, USA Program in Cancer Genetics, Department of Oncology and Human Genetics, Mc. Gill University, Montreal, Canada Department of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA Institute of Genetics, Rambam Medical Center, Haifa, Israel Division of Population Science, Fox Chase Cancer Center, Philadelphia, USA British Columbia Cancer Agency, Vancouver, British Columbia, Canada The Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden London Regional Cancer Center, London, Ontario, Canada Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada Hereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, USA Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel Center for Clinical Cancer Genetics, University of Chicago, USA Strang Cancer Prevention Center, New York, USA City of Hope Hospital, Duarte, CA, USA Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, USA Epidemiology Research Unit, Centre hospitalier de l’Université de Montréal (CHUM), Hôtel-Dieu, University of

IHCC staff IHCC staff

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

Górski B. et al. AJHG, June 2000 Górski B. et al. AJHG, June 2000

POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200) F BRCA 1 F BRCA POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200) F BRCA 1 F BRCA 2 ~65% ~4% Górski B. et al. Int. J. Can, 2004

POLISH PANEL OF BRCA 1 MUTATIONS F 5382 ins C F C 61 G POLISH PANEL OF BRCA 1 MUTATIONS F 5382 ins C F C 61 G F 4153 del A 90% of mutations Górski B. et al. Int. J. Can, 2004

BRCA 1 MULTIPLEX PCR 5382 ins. C patients (-) DNA 5382 ins. C C BRCA 1 MULTIPLEX PCR 5382 ins. C patients (-) DNA 5382 ins. C C 61 G 4153 del. A possitive controls

BRCA 1 FOUNDER MUTATIONS IN POLAND F GÓRSKI B. ET AL. - PATENT NO BRCA 1 FOUNDER MUTATIONS IN POLAND F GÓRSKI B. ET AL. - PATENT NO P 335917 - MULTIPLEX PCR - 50€

BRCA 1 – REGISTRY – SZCZECIN – POLAND 3256 CARRIERS THE LARGEST REGISTRY IN BRCA 1 – REGISTRY – SZCZECIN – POLAND 3256 CARRIERS THE LARGEST REGISTRY IN THE WORLD Szczecin 30 January 2006

BRCA 1 – POSITIVE BREAST CANCERS IN YOUNG WOMEN IN POLAND Lubiński J. et BRCA 1 – POSITIVE BREAST CANCERS IN YOUNG WOMEN IN POLAND Lubiński J. et al. Br Can Res Treat 2005

BRCA 1 mutations in patients with breast cancer <51 yrs BRCA 1 mutations in patients with breast cancer <51 yrs

BRCA 1 mutations in patients with breast cancer <51 yrs F 4780 patients F BRCA 1 mutations in patients with breast cancer <51 yrs F 4780 patients F 3629 (75, 9%) blood samples F 3614 BRCA 1 tests F 200 (5, 5%) mutations

Pathologic/ clinical features of cancers Pathologic/ clinical features of cancers

Pathologic/ clinical features of cancers Pathologic/ clinical features of cancers

CANCER RISKS IN FIRST-DEGREE RELATIVES OF BRCA 1 MUTATION CARRIERS: EFFECTS OF MUTATION AND CANCER RISKS IN FIRST-DEGREE RELATIVES OF BRCA 1 MUTATION CARRIERS: EFFECTS OF MUTATION AND PROBAND DISEASE STATUS J. Gronwald, JMG 2005

Cumulative incidence of breast cancer in first-degree relatives by mutation 0. 8 C 61 Cumulative incidence of breast cancer in first-degree relatives by mutation 0. 8 C 61 G 5382 ins. C 4153 del. A 0. 7 0. 6 0. 5 P=0. 12 0. 4 0. 3 0. 2 0. 1 0. 0 25 30 35 40 45 50 55 60 Age (years) 65 70 75

Cumulative incidence of ovarian cancer in first-degree relatives by mutation 0. 8 C 61 Cumulative incidence of ovarian cancer in first-degree relatives by mutation 0. 8 C 61 G 5382 ins. C 4153 del. A 0. 7 0. 6 0. 5 P=0. 05 0. 4 0. 3 0. 2 0. 1 0. 0 25 30 35 40 45 50 55 60 Age (years) 65 70 75

Cumulative incidence of breast cancer in firstdegree relatives by cancer site of the proband Cumulative incidence of breast cancer in firstdegree relatives by cancer site of the proband 0. 8 0. 7 Proband Breast Cancer 0. 6 0. 5 Proband Ovarian Cancer P=0. 005 0. 4 0. 3 0. 2 0. 1 0. 0 25 30 35 40 45 50 55 60 Age (years) 65 70 75

Cumulative incidence of ovarian cancer in firstdegree relatives by cancer site of the proband Cumulative incidence of ovarian cancer in firstdegree relatives by cancer site of the proband 0. 8 0. 7 Proband Breast Cancer 0. 6 Proband Ovarian Cancer 0. 5 P=0. 98 0. 4 0. 3 0. 2 0. 1 0. 0 25 30 35 40 45 50 55 60 Age (years) 65 70 75

A. BRCA 1 PROPHYLACTICS F Oral contraceptives < 30 yrs > 30 yrs F A. BRCA 1 PROPHYLACTICS F Oral contraceptives < 30 yrs > 30 yrs F Breast feeding > 1 yrs F Later menarche per yr F Tubal ligation 0. 5 F Adnexectomy F Tamoxifen F Adnexectomy + tamoxifen F Mastectomy RISK BR OV 1. 3 0. 5 0. 9 0. 2 0. 5 0. 15 0. 01 0. 05

BRCA 1 PROPHYLACTICS - POLAND BREAST CANCER BRCA 1 PROPHYLACTICS - POLAND BREAST CANCER

BRCA 1 PROPHYLACTICS - POLAND OVARIAN CANCER BRCA 1 PROPHYLACTICS - POLAND OVARIAN CANCER

TAMOXIFEN AND CONTRALATERAL BREAST CANCER IN BRCA 1 AND BRCA 2 CARRIERS: AN UPDATE TAMOXIFEN AND CONTRALATERAL BREAST CANCER IN BRCA 1 AND BRCA 2 CARRIERS: AN UPDATE Gronwald J. et al. Int J Can 2005

NSABP P 1 Results OR 0. 95 CI ER Status 1 ER + 6 NSABP P 1 Results OR 0. 95 CI ER Status 1 ER + 6 ER 1 unknown 6 ER+ 3 ER 2 unknown BRCA 1 5 Tam 3 Placebo 1. 67 0. 41 -8. 00 BRCA 2 3 Tam 8 Placebo 0. 38 0. 06 -1. 56 The efficacy of tamoxifen for breast cancer prevention in BRCA 1/2 mutation carriers cannot be determined from P 1 data B. Weber 2005

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

HRT after BPO in BRCA 1/2 Mutation Carriers F 408 BRCA 1/2 Mutation Carriers HRT after BPO in BRCA 1/2 Mutation Carriers F 408 BRCA 1/2 Mutation Carriers Ä 184 women with BPO (65% took HRT) Ä 224 women without BPO (7% took HRT) F Post operative follow up 3. 4 years F Post BPO breast cancer risk reduction: Ä 68% reduction overall Ä 64% reduction in women who took HRT Rebbeck et al, JCO in press, 2005

Hormone replacement therapy appears to be safe after prophylactic adnexectomy in premenopausal BRCA 1/BRCA Hormone replacement therapy appears to be safe after prophylactic adnexectomy in premenopausal BRCA 1/BRCA 2 mutation carriers

BRCA 1 PROPHYLACTICS F Sodium selenite – pilot study BRCA 1 CARRIERS N = BRCA 1 PROPHYLACTICS F Sodium selenite – pilot study BRCA 1 CARRIERS N = 130 Se 3 Br/Ov Ca N = 130 (-) 9 Br/Ov Ca

DETECTION OF EARLY BREAST CANCERS IN BRCA 1 MUTATION CARRIERS USG ~20% MAMMOGR. ~20% DETECTION OF EARLY BREAST CANCERS IN BRCA 1 MUTATION CARRIERS USG ~20% MAMMOGR. ~20% MRI ~90% Narod S. et al. 2003

Breast cancers with BRCA 1 Treatment F F F prophylactic adnexectomy tamoxifen mastectomy 10 Breast cancers with BRCA 1 Treatment F F F prophylactic adnexectomy tamoxifen mastectomy 10 yrs survival 2× 1. 5×

Breast cancers with BRCA 1 Treatment – Neo-Adjuvant therapy Byrski T et al. : Breast cancers with BRCA 1 Treatment – Neo-Adjuvant therapy Byrski T et al. : Clin Can Res 2006

Population screenings - Poland Population screenings - Poland

F 4% (~200) of BRCA 1 carriers among 5000 relatives of women with breast F 4% (~200) of BRCA 1 carriers among 5000 relatives of women with breast cancer dgn < 50 yrs or ovarian cancer dgn at any age F Thanks to geneticists - oncologists from 20 Polish centers!

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

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

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

ECONOMICAL / MEDICAL ASPECTS ECONOMICAL / MEDICAL ASPECTS

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

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

2000 -2003 BRCA 1 mutation carriers with breast/ovarian cancers N=50 F treatment costs ~5 2000 -2003 BRCA 1 mutation carriers with breast/ovarian cancers N=50 F treatment costs ~5 500 € F social security costs ~8 800 € F GP per capita lost ~50 000 € ~64 300 € F average annual cost Marska N, US 2004

DIRECT-TO-PATIENT BRCA 1 TESTING: THE TWÓJ STYL EXPERIENCE Gronwald J. et al. Int J DIRECT-TO-PATIENT BRCA 1 TESTING: THE TWÓJ STYL EXPERIENCE Gronwald J. et al. Int J Can 2005

TWÓJ STYL 2001 F 5024 BRCA 1 tests F 198 (3, 9%) mutations found TWÓJ STYL 2001 F 5024 BRCA 1 tests F 198 (3, 9%) mutations found

TWÓJ STYL BRCA 1 carriers unaffected n=63 2001 F F F 36. 5% - TWÓJ STYL BRCA 1 carriers unaffected n=63 2001 F F F 36. 5% - worry 27. 0% - shock 22. 0% - sadness

TWÓJ STYL BRCA 1 carriers unaffected n=63 2004 F 66% - used preventive measures TWÓJ STYL BRCA 1 carriers unaffected n=63 2004 F 66% - used preventive measures F 98% - would recommend testing Gronwald J. et al. Br Can Res Treat 2005

TWÓJ STYL F two session counseling is effective for diagnosing BRCA 1 carriers in TWÓJ STYL F two session counseling is effective for diagnosing BRCA 1 carriers in Poland Gronwald J. et al. Br Can Res Treat 2005

BREAST CANCER GENETIC RISK GENES HIGH MODERATE / LOW BREAST CANCER GENETIC RISK GENES HIGH MODERATE / LOW

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

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

BREAST CANCER RISK DGN <50 yrs, n=3500 GENES MUTATIONS / POLYMORPHISMS RR X 3 BREAST CANCER RISK DGN <50 yrs, n=3500 GENES MUTATIONS / POLYMORPHISMS RR X 3 2, 0 X 2 1, 4 X 1 1, 7 P 16 1, 7 NOD 2 2, 0 I 157 T 1, 5 CHEK 2 ex 2 splice 4, 0 1100 del. C 2, 0 NBS 1 2, 0 BRCA 2 1, 5 BRCA 1 10, 0 5, 0 10, 0 15, 0 20, 0 25, 0 30, 0 35, 0 %

BREAST CANCER RISK GENE INTERACTIONS CHEK 2 I 157 T + X 1 OR BREAST CANCER RISK GENE INTERACTIONS CHEK 2 I 157 T + X 1 OR 4. 8

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

PENETRATION AND PROPORTION OF CANCERS 90% 80% PENETRATION 70% 60% 50% 40% 30% 20% PENETRATION AND PROPORTION OF CANCERS 90% 80% PENETRATION 70% 60% 50% 40% 30% 20% 10% 0% 0% 20% 40% 60% 80% 100% PROPORTION Lubiński J. 6. 05. 2004 Madrit, ESO

> 90% OF CANCERS HAVE GENETIC CONSTITUTIONAL BACKGROUND Lubiński J. 6. 05. 2004 Madrit, > 90% OF CANCERS HAVE GENETIC CONSTITUTIONAL BACKGROUND Lubiński J. 6. 05. 2004 Madrit, ESO

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

PARTICIPANTS Cyprus Estonia Germany Greece Latvia The Netherlands Poland Serbia and Montenegro Slovakia Sweden PARTICIPANTS Cyprus Estonia Germany Greece Latvia The Netherlands Poland Serbia and Montenegro Slovakia Sweden United Kingdom Coordinator – J. Lubiński

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

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

More information: F www. hereditarycancer. net F e-mail: ihcc@wp. pl F phone: +48 -91 More information: F www. hereditarycancer. net F e-mail: [email protected] pl F phone: +48 -91 -466 -15 -32 fax: +48 -91 -466 -15 -33