THE LATEST ADVANCES THE LATEST ADVANCES IN CLINICAL GENETICS IN CLINICAL GENETICS

OF HEREDITARY BREAST OF HEREDITARY BREAST CANCERCANCER

J. LubińskiJ. Lubiński

12 December 2005, Chennai, India12 December 2005, Chennai, India

INTERNATIONAL HEREDITARY CANCER CENTERINTERNATIONAL HEREDITARY CANCER CENTERPOMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLANDPOMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND

Lubinski JLubinski J..11, Górski B., Górski B.11, Cybulski C., Cybulski C.11, Huzarski T., Huzarski T.11, Byrski T., Byrski T.11, Gronwald J., Gronwald J.11, Jakubowska A., Jakubowska A.11, Stawicka , Stawicka M.M.22, Gozdecka-Grodecka S., Gozdecka-Grodecka S.33, Szwiec M., Szwiec M.44, Urbański K., Urbański K.55, Mituś J., Mituś J.55, Marczyk E., Marczyk E.55, Dziuba J., Dziuba J.11, Wandzel , Wandzel

P.P.66, Surdyka D., Surdyka D.77, Haus O., Haus O.88, Janiszewska H., Janiszewska H.88, Dębniak T., Dębniak T.11, Tołoczko-Grabarek A., Tołoczko-Grabarek A.11, , Mędrek K.Mędrek K.11, Masojć B., Masojć B.11, Mierzejewski M., Mierzejewski M.11, Kowalska E., Kowalska E.11, Zientek H., Zientek H.99, Pamuła J., Pamuła J.99, Metcalfe K., Metcalfe K.1010, ,

Tung N.Tung N.1111, Foulkes WD., Foulkes WD.1212, Offit K., Offit K.1313, Gershoni R., Gershoni R.1414, Daly M., Daly M.1515, Kim-Sing Ch., Kim-Sing Ch.1616, Olsson H., Olsson H.1717, , Ainsworth P.Ainsworth P.1818, Eisen A., Eisen A.1919, Saal H., Saal H.2020, Friedman E., Friedman E.2121, Olopade O., Olopade O.2222, Osborne M., Osborne M.2323, Weitzel J., Weitzel J.2424, ,

Lynch H.Lynch H.2525, Ghadirian P., Ghadirian P.2626, Sun P., Sun P.1010, Narod SA., Narod SA.1010 and Hereditary Breast Cancer Clinical Study Group and Hereditary Breast Cancer Clinical Study Group1 1 Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, PolandDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland2 2 Prophylactic and Epidemiology Center, Poznan, PolandProphylactic and Epidemiology Center, Poznan, Poland3 3 Poznan Medical UniversityPoznan Medical University4 4 Regional Oncology Hospital, Opole, PolandRegional Oncology Hospital, Opole, Poland5 5 Regional Oncology Center, Kraków, PolandRegional Oncology Center, Kraków, Poland6 6 Regional Oncology Hospital, Bielsko-Biała, PolandRegional Oncology Hospital, Bielsko-Biała, Poland7 7 Regional Oncology Hospital, Lublin, PolandRegional Oncology Hospital, Lublin, Poland8 8 Department of Clinical Genetics, Bydgoszcz Medical University, PolandDepartment of Clinical Genetics, Bydgoszcz Medical University, Poland9 9 Oncology Center, Gliwice, PolandOncology Center, Gliwice, Poland10 10 Centre for Research in Women’s Health, University of Toronto, CanadaCentre for Research in Women’s Health, University of Toronto, Canada11 11 Beth Israel Deaconess Hospital, Boston, USABeth Israel Deaconess Hospital, Boston, USA12 12 Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, CanadaProgram in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Canada1313 Department of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, USADepartment of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA14 14 Institute of Genetics, Rambam Medical Center, Haifa, IsraelInstitute of Genetics, Rambam Medical Center, Haifa, Israel1515 Division of Population Science, Fox Chase Cancer Center, Philadelphia, USADivision of Population Science, Fox Chase Cancer Center, Philadelphia, USA16 16 British Columbia Cancer Agency, Vancouver, British Columbia, CanadaBritish Columbia Cancer Agency, Vancouver, British Columbia, Canada17 17 The Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, SwedenThe Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden18 18 London Regional Cancer Center, London, Ontario, CanadaLondon Regional Cancer Center, London, Ontario, Canada19 19 Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada 20 20 Hereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, USAHereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, USA2121 Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, IsraelOncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel22 22 Center for Clinical Cancer Genetics, University of Chicago, Chicago, USACenter for Clinical Cancer Genetics, University of Chicago, Chicago, USA23 23 Strang Cancer Prevention Center, New York, USAStrang Cancer Prevention Center, New York, USA24 24 City of Hope Hospital, Duarte, CA, USACity of Hope Hospital, Duarte, CA, USA25 25 Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, USADepartment of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, USA26 26 Epidemiology Research Unit, Centre hospitalier de l’Université de Montréal (CHUM), Hôtel-Dieu, University of Montreal, Quebec, CanadaEpidemiology Research Unit, Centre hospitalier de l’Université de Montréal (CHUM), Hôtel-Dieu, University of Montreal, Quebec, Canada

IHCC staffIHCC staff

POLANDPOLAND

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

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

POLISH FAMILIES WITH STRONG POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN AGGREGATION OF BREAST/OVARIAN

CANCERS (n=200)CANCERS (n=200)

BRCA 1 BRCA 1 ~65%~65% BRCA2BRCA2 ~4%~4%

BRCA 1 BRCA 1 ~65%~65% BRCA2BRCA2 ~4%~4%

Górski B. et al. Int. J. Can, 2004Górski B. et al. Int. J. Can, 2004

POLISH PANEL POLISH PANEL OF BRCA1 MUTATIONSOF BRCA1 MUTATIONS

5382 ins C5382 ins C C 61 GC 61 G 4153 del A4153 del A

5382 ins C5382 ins C C 61 GC 61 G 4153 del A4153 del A

90% of mutations90% of mutations90% of mutations90% of mutations

Górski B. et al. Int. J. Can, 2004Górski B. et al. Int. J. Can, 2004

BRCA1 MULTIPLEX PCRBRCA1 MULTIPLEX PCRpossitive possitive controlscontrols

possitive possitive controlscontrols

4153

del

A41

53 d

elA

4153

del

A41

53 d

elA

C61

GC

61G

C61

GC

61G

5382

insC

5382

insC

5382

insC

5382

insC

(-)

DN

A(-

) D

NA

(-)

DN

A(-

) D

NA

5382

insC

5382

insC

5382

insC

5382

insC

patientspatientspatientspatients

BRCA1 FOUNDER MUTATIONS BRCA1 FOUNDER MUTATIONS IN POLANDIN POLAND

GÓRSKI B. ET AL. GÓRSKI B. ET AL. - PATENT NO P335917- PATENT NO P335917- MULTIPLEX PCR - - MULTIPLEX PCR - 5500€€

GÓRSKI B. ET AL. GÓRSKI B. ET AL. - PATENT NO P335917- PATENT NO P335917- MULTIPLEX PCR - - MULTIPLEX PCR - 5500€€

BRCA1 – REGISTRY BRCA1 – REGISTRY – SZCZECIN – POLAND– SZCZECIN – POLAND

3225 CARRIERS3225 CARRIERS3225 CARRIERS3225 CARRIERS

THE LARGEST REGISTRY THE LARGEST REGISTRY IN THE WORLDIN THE WORLD

THE LARGEST REGISTRY THE LARGEST REGISTRY IN THE WORLDIN THE WORLD

Szczecin 7 December 2005Szczecin 7 December 2005

BRCA1 – POSITIVE BREAST BRCA1 – POSITIVE BREAST CANCERS IN YOUNG WOMEN CANCERS IN YOUNG WOMEN

IN POLANDIN POLAND

BRCA1 – POSITIVE BREAST BRCA1 – POSITIVE BREAST CANCERS IN YOUNG WOMEN CANCERS IN YOUNG WOMEN

IN POLANDIN POLAND

Lubiński J. et al. Br J. Can 2005Lubiński J. et al. Br J. Can 2005

BRCA1 mutations No Center No of patients

No of DNA

No of tests 5382 ins C C 61 G 4153 del A

1 Białystok 260 202 202 3 4 2 2 Bielsko-Biała 144 114 114 6 3 Bydgoszcz 333 261 261 7 6 1 4 Gliwice 287 201 201 11 5 5 Kielce 173 142 142 5 6 1 6 Koszalin 47 39 39 1 7 Kraków 176 166 166 4 4 8 Lublin 278 209 209 10 1 9 Łódź 188 132 132 8 2 10 Olsztyn 634 449 445 10 6 3 11 Opole 198 181 181 6 4 12 Poznań I 100 97 97 4 13 Poznań II 239 180 180 12 2 14 Rzeszów 90 63 63 4 2 15 Szczecin 1043 779 770 25 8 4 16 Warszawa 161 113 113 3 17 Wrocław 58 41 41 2 1 18 Zielona Góra 369 258 256 15 1 Total 4778 3627 3615 136 52 11

BRCA1 mutations No Center No of patients

No of DNA

No of tests 5382 ins C C 61 G 4153 del A

1 Białystok 260 202 202 3 4 2 2 Bielsko-Biała 144 114 114 6 3 Bydgoszcz 333 261 261 7 6 1 4 Gliwice 287 201 201 11 5 5 Kielce 173 142 142 5 6 1 6 Koszalin 47 39 39 1 7 Kraków 176 166 166 4 4 8 Lublin 278 209 209 10 1 9 Łódź 188 132 132 8 2 10 Olsztyn 634 449 445 10 6 3 11 Opole 198 181 181 6 4 12 Poznań I 100 97 97 4 13 Poznań II 239 180 180 12 2 14 Rzeszów 90 63 63 4 2 15 Szczecin 1043 779 770 25 8 4 16 Warszawa 161 113 113 3 17 Wrocław 58 41 41 2 1 18 Zielona Góra 369 258 256 15 1 Total 4778 3627 3615 136 52 11

BRCA1 mutations in patients BRCA1 mutations in patients with breast cancer <51yrswith breast cancer <51yrs

4780 patients4780 patients 3629 (75,9%) blood samples3629 (75,9%) blood samples 3614 BRCA1 tests3614 BRCA1 tests 200 (5,5%) mutations200 (5,5%) mutations

4780 patients4780 patients 3629 (75,9%) blood samples3629 (75,9%) blood samples 3614 BRCA1 tests3614 BRCA1 tests 200 (5,5%) mutations200 (5,5%) mutations

BRCA1 mutations in patients BRCA1 mutations in patients with breast cancer <51yrswith breast cancer <51yrs

Pathologic/ clinical features of cancersPathologic/ clinical features of cancers

Group Feature

BRCA1 – (+) BRCA1 – (-)

1. H-p

a. medullary 30,11% (53/176) 4,15% (8/193)

b. ductal G3 18,75% (33/176) 10,36% (20/193)

c. ductale G1-G2 10,8% (19/176) 12,95% (25/193)

d. tubulo-lobular - (0/176) 6,22% (12/193)

e. lobular 5,68% (10/176) 27,98% (54/193)

f. other 3,41% (6/176) 8,81% (17/193)

g. post CHTH 23,86% (42/176) 23,32% (45/193)

h. undefined 7,39% (13/176) 6,22% (12/193)

2. Tumour size

a. the largest diameter 2,44cm (n=113) 1,99cm (n=118)

b. 1 cm 14,16% (16/113) 15,25% (18/118)

Group Feature

BRCA1 – (+) BRCA1 – (-)

1. H-p

a. medullary 30,11% (53/176) 4,15% (8/193)

b. ductal G3 18,75% (33/176) 10,36% (20/193)

c. ductale G1-G2 10,8% (19/176) 12,95% (25/193)

d. tubulo-lobular - (0/176) 6,22% (12/193)

e. lobular 5,68% (10/176) 27,98% (54/193)

f. other 3,41% (6/176) 8,81% (17/193)

g. post CHTH 23,86% (42/176) 23,32% (45/193)

h. undefined 7,39% (13/176) 6,22% (12/193)

2. Tumour size

a. the largest diameter 2,44cm (n=113) 1,99cm (n=118)

b. 1 cm 14,16% (16/113) 15,25% (18/118)

Group Feature

BRCA1 – (+) BRCA1 – (-)

3. Multicentricity 12,37% (12/97) 24,79% (30/124)

4. Bilaterality 18,13% (33/182) 2,22% (4/180)

5. LN metastases 36,09% (48/133) 48,65% (72/148)

6. Family history (probant and I or II° relatives)

a. breast CA 55,31% (99/182) 12,22% (22/180)

b. ovarian CA 25,14% (45/182) 6,11% (11/180)

c. breast or ovarian CA 57,14 (104/182) 15,56%(28/180)

7. ER 15,08% (19/126) 58,33% (91/156)

Group Feature

BRCA1 – (+) BRCA1 – (-)

3. Multicentricity 12,37% (12/97) 24,79% (30/124)

4. Bilaterality 18,13% (33/182) 2,22% (4/180)

5. LN metastases 36,09% (48/133) 48,65% (72/148)

6. Family history (probant and I or II° relatives)

a. breast CA 55,31% (99/182) 12,22% (22/180)

b. ovarian CA 25,14% (45/182) 6,11% (11/180)

c. breast or ovarian CA 57,14 (104/182) 15,56%(28/180)

7. ER 15,08% (19/126) 58,33% (91/156)

Pathologic/ clinical features of cancersPathologic/ clinical features of cancers

CANCER RISKS CANCER RISKS IN FIRST-DEGREE RELATIVES OF BRCA1 IN FIRST-DEGREE RELATIVES OF BRCA1

MUTATION CARRIERS:MUTATION CARRIERS:EFFECTS OF MUTATION AND PROBAND EFFECTS OF MUTATION AND PROBAND

DISEASE STATUSDISEASE STATUS

J. Gronwald, JMG 2005J. Gronwald, JMG 2005

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

2525 3030 3535 4040 4545 5050 5555 6060 6565 7070 7575

C61GC61G

5382insC5382insC

4153delA4153delA

0.00.0

P=0.12P=0.12

Age (years)Age (years)

CumulativeCumulative incidence ofincidence of breast cancerbreast cancer in first-degree relativesin first-degree relatives by mutation by mutation

CCumulativeumulative incidence ofincidence of ovarian cancerovarian cancerin first-degree relativesin first-degree relatives by mutationby mutation

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

2525 3030 3535 4040 4545 5050 5555 6060 6565 7070 7575

C61GC61G

5382insC5382insC

4153delA4153delA

0.00.0

P=0.05P=0.05

Age (years)Age (years)

CumulativeCumulative incidence ofincidence of breast cancerbreast cancer in first-in first-degree relativesdegree relatives by cancer siteby cancer site of the probandof the proband

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

2525 3030 3535 4040 4545 5050 5555 6060 6565 7070 7575

Proband Breast Cancer Proband Breast Cancer

Proband Ovarian CancerProband Ovarian Cancer

0.00.0

P=0.005P=0.005

Age (years)Age (years)

CumulativeCumulative incidence ofincidence of ovarian cancerovarian cancer in first-in first-degree relativesdegree relatives by cancer siteby cancer site of the probandof the proband

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

2525 3030 3535 4040 4545 5050 5555 6060 6565 7070 7575

Proband Breast Cancer Proband Breast Cancer

Proband Ovarian CancerProband Ovarian Cancer

0.00.0

P=0.98P=0.98

Age (years)Age (years)

A. BRCA1 PROPHYLACTICSA. BRCA1 PROPHYLACTICS RISKRISK BR OV BR OV

Oral contraceptives Oral contraceptives < 30yrs< 30yrs 1.31.3>> 30yrs 30yrs

0.50.5 Breast feeding Breast feeding > 1 yrs > 1 yrs 0.50.5 Later menarche Later menarche per yr per yr 0.90.9 Tubal ligation Tubal ligation

0.50.5 Adnexectomy Adnexectomy 0.20.2

0.050.05 TamoxifenTamoxifen 0.50.5 Adnexectomy + tamoxifen Adnexectomy + tamoxifen 0.150.15 MastectomyMastectomy 0.010.01

RISKRISK BR OV BR OV

Oral contraceptives Oral contraceptives < 30yrs< 30yrs 1.31.3>> 30yrs 30yrs

0.50.5 Breast feeding Breast feeding > 1 yrs > 1 yrs 0.50.5 Later menarche Later menarche per yr per yr 0.90.9 Tubal ligation Tubal ligation

0.50.5 Adnexectomy Adnexectomy 0.20.2

0.050.05 TamoxifenTamoxifen 0.50.5 Adnexectomy + tamoxifen Adnexectomy + tamoxifen 0.150.15 MastectomyMastectomy 0.010.01

BRCA1 PROPHYLACTICS - POLANDBRCA1 PROPHYLACTICS - POLAND

BREAST CANCERBREAST CANCER

Cases

N = 348 Controls N =348

Odds Ratio*

p-value

Age at menarche 13.5 13.8 0.9a 0.004

Parity 2.1 2.0 1.2b 0.02

Smoking 46% 46% 1.1 0.69

Coffee 74% 78% 0.8 0.21

Breastfeeding > 1 year 22% 27% 0.5 0.02

Cases

N = 348 Controls N =348

Odds Ratio*

p-value

Age at menarche 13.5 13.8 0.9a 0.004

Parity 2.1 2.0 1.2b 0.02

Smoking 46% 46% 1.1 0.69

Coffee 74% 78% 0.8 0.21

Breastfeeding > 1 year 22% 27% 0.5 0.02

BRCA1 PROPHYLACTICS - POLANDBRCA1 PROPHYLACTICS - POLAND

OVARIAN CANCEROVARIAN CANCER

Oral contraceptives Cases

N = 150 Controls N = 150

Odds Ratio

p-value

Ever 8% 14% 0.4 0.04

Ever, <= 2yrs 6% 4% 0.8 0.69

Ever, > 2yrs 2% 10% 0.2 0.01

Oral contraceptives Cases

N = 150 Controls N = 150

Odds Ratio

p-value

Ever 8% 14% 0.4 0.04

Ever, <= 2yrs 6% 4% 0.8 0.69

Ever, > 2yrs 2% 10% 0.2 0.01

TAMOXIFEN AND TAMOXIFEN AND CONTRALATERAL BREAST CONTRALATERAL BREAST

CANCER IN BRCA1 CANCER IN BRCA1 AND BRCA2 CARRIERS: AND BRCA2 CARRIERS:

AN UPDATEAN UPDATE

TAMOXIFEN AND TAMOXIFEN AND CONTRALATERAL BREAST CONTRALATERAL BREAST

CANCER IN BRCA1 CANCER IN BRCA1 AND BRCA2 CARRIERS: AND BRCA2 CARRIERS:

AN UPDATEAN UPDATE

Gronwald J. et al. Int J Can 2005Gronwald J. et al. Int J Can 2005

NSABP P1 ResultsNSABP P1 Results

OROR 0.95 CI0.95 CI ER StatusER Status

BRCA1BRCA1 5 Tam5 Tam

3 Placebo3 Placebo

1.671.67 0.41-8.000.41-8.00 1 ER +1 ER +

6 ER -6 ER -

1 unknown1 unknown

BRCA2BRCA2 3 Tam3 Tam

8 Placebo8 Placebo

0.380.38 0.06-1.560.06-1.56 6 ER+6 ER+

3 ER-3 ER-

2 unknown2 unknown

The efficacy of tamoxifen for breast cancer prevention in BRCA1/2 mutation carriers cannot be determined from P1 data

B. Weber 2005B. Weber 2005

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

Univariate analysis Odds ratio [95%CI)

p-value

Multivariate analysis Odds ratio [95%CI)

p-value

All subjects Tamoxifen any use, Never Ever

1,00 0,45 [0,29-070] 0,0004

1,00 0,47 [0,30-0,74] 0,001

BRCA1 carriers Tamoxifen any use, Never Ever

1,00 0,48 [0,29-079] 0,004

1,00 0,50 [0,30-0,85] 0,01

BRCA2 carriers Tamoxifen any use, Never Ever

1,00 0,39 [0,16-0,94] 0,03

1,00 0,42 [0,17-1,02] 0,05

Univariate analysis Odds ratio [95%CI)

p-value

Multivariate analysis Odds ratio [95%CI)

p-value

All subjects Tamoxifen any use, Never Ever

1,00 0,45 [0,29-070] 0,0004

1,00 0,47 [0,30-0,74] 0,001

BRCA1 carriers Tamoxifen any use, Never Ever

1,00 0,48 [0,29-079] 0,004

1,00 0,50 [0,30-0,85] 0,01

BRCA2 carriers Tamoxifen any use, Never Ever

1,00 0,39 [0,16-0,94] 0,03

1,00 0,42 [0,17-1,02] 0,05

408 BRCA1/2 Mutation Carriers408 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 yearsPost operative follow up 3.4 years

408 BRCA1/2 Mutation Carriers408 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 yearsPost operative follow up 3.4 years

HRT after BPO HRT after BPO in BRCA1/2 Mutation Carriers in BRCA1/2 Mutation Carriers

Post BPO breast cancer risk reduction:Post BPO breast cancer risk reduction: 68% reduction overall68% reduction overall 64% reduction in women who took HRT64% reduction in women who took HRT

Post BPO breast cancer risk reduction:Post BPO breast cancer risk reduction: 68% reduction overall68% reduction overall 64% reduction in women who took HRT64% reduction in women who took HRT

Rebbeck et al, JCO in press, 2005Rebbeck et al, JCO in press, 2005

Hormone replacement therapy Hormone replacement therapy appears to be safe after appears to be safe after

prophylactic adnexectomy prophylactic adnexectomy in premenopausal BRCA1/BRCA2 in premenopausal BRCA1/BRCA2

mutation carriersmutation carriers

Hormone replacement therapy Hormone replacement therapy appears to be safe after appears to be safe after

prophylactic adnexectomy prophylactic adnexectomy in premenopausal BRCA1/BRCA2 in premenopausal BRCA1/BRCA2

mutation carriersmutation carriers

BRCA1 PROPHYLACTICSBRCA1 PROPHYLACTICS

Sodium selenite – pilot studySodium selenite – pilot study Sodium selenite – pilot studySodium selenite – pilot study

BRCA1 CARRIERSBRCA1 CARRIERSBRCA1 CARRIERSBRCA1 CARRIERS

N = 130 SeN = 130 SeN = 130 SeN = 130 Se 3 Br/Ov Ca3 Br/Ov Ca3 Br/Ov Ca3 Br/Ov Ca

9 Br/Ov Ca9 Br/Ov Ca9 Br/Ov Ca9 Br/Ov CaN = 130 (-)N = 130 (-)N = 130 (-)N = 130 (-)

DETECTION OF EARLY BREAST CANCERS DETECTION OF EARLY BREAST CANCERS IN BRCA1 MUTATION CARRIERSIN BRCA1 MUTATION CARRIERS

USGUSG MAMMOGR.MAMMOGR. MRIMRI~20%~20% ~20%~20%

~90%~90%

USGUSG MAMMOGR.MAMMOGR. MRIMRI~20%~20% ~20%~20%

~90%~90%

Narod S. et al. 2003Narod S. et al. 2003

10 yrs survival10 yrs survival prophylactic adnexectomyprophylactic adnexectomy 2× 2× tamoxifen tamoxifen 1.5× 1.5× mastectomymastectomy 1.5× 1.5×

10 yrs survival10 yrs survival prophylactic adnexectomyprophylactic adnexectomy 2× 2× tamoxifen tamoxifen 1.5× 1.5× mastectomymastectomy 1.5× 1.5×

Breast cancers with BRCA1 Breast cancers with BRCA1 TreatmentTreatment

Population Population screeningsscreenings

- Poland- Poland

4% (~200) of BRCA1 4% (~200) of BRCA1 carriers among 5000 carriers among 5000 relatives of women relatives of women with breast cancer dgn with breast cancer dgn < 50 yrs or ovarian < 50 yrs or ovarian cancer dgn cancer dgn at any ageat any age

Thanks to Thanks to geneticists geneticists - oncologists from 20 - oncologists from 20 Polish centers!Polish centers!

4% (~200) of BRCA1 4% (~200) of BRCA1 carriers among 5000 carriers among 5000 relatives of women relatives of women with breast cancer dgn with breast cancer dgn < 50 yrs or ovarian < 50 yrs or ovarian cancer dgn cancer dgn at any ageat any age

Thanks to Thanks to geneticists geneticists - oncologists from 20 - oncologists from 20 Polish centers!Polish centers!

POPULATION SCREENING POPULATION SCREENING FOR CANCER FAMILY FOR CANCER FAMILY

SYNDROMES IN WEST – SYNDROMES IN WEST – POMERANIA, POLANDPOMERANIA, POLAND

WEST – POMERANIA HEALTH CARE INS. COMPWEST – POMERANIA HEALTH CARE INS. COMP

FAMILY DOCTORSFAMILY DOCTORS

IHCC POMERANIAN MEDICAL UNIVERSITY, IHCC POMERANIAN MEDICAL UNIVERSITY, SZCZECINSZCZECIN

FAMILY DOCTORS – PROJEFAMILY DOCTORS – PROJECCT T ININITIATORSITIATORS

1.1. Andrzej Raczyński NPZOZ „Asklepios” Bobolice Andrzej Raczyński NPZOZ „Asklepios” Bobolice 2.2. Jarosław Kopciewicz - SPZOZ Pyrzyce Jarosław Kopciewicz - SPZOZ Pyrzyce 3.3. Cygal Lucyna - SZOZ nr 3 Kołobrzeg Cygal Lucyna - SZOZ nr 3 Kołobrzeg 4.4. Krzysztof Jankowiak - NZOZ „Zdrowie” Drawsko Krzysztof Jankowiak - NZOZ „Zdrowie” Drawsko

Pomorskie Pomorskie 5.5. Wiesława Fabian - NZOZ Szczecin Wiesława Fabian - NZOZ Szczecin 6.6. Józef Dmochowski - ZOZ „Zdrowie” Barwice Józef Dmochowski - ZOZ „Zdrowie” Barwice 7.7. Paweł Szycko - NZOZ Podimed - Szczecinek. Paweł Szycko - NZOZ Podimed - Szczecinek. 8.8. Tadeusz Cieślak - NZOZ - „Hipokrates” - Złocieniec.Tadeusz Cieślak - NZOZ - „Hipokrates” - Złocieniec.

1.1. Andrzej Raczyński NPZOZ „Asklepios” Bobolice Andrzej Raczyński NPZOZ „Asklepios” Bobolice 2.2. Jarosław Kopciewicz - SPZOZ Pyrzyce Jarosław Kopciewicz - SPZOZ Pyrzyce 3.3. Cygal Lucyna - SZOZ nr 3 Kołobrzeg Cygal Lucyna - SZOZ nr 3 Kołobrzeg 4.4. Krzysztof Jankowiak - NZOZ „Zdrowie” Drawsko Krzysztof Jankowiak - NZOZ „Zdrowie” Drawsko

Pomorskie Pomorskie 5.5. Wiesława Fabian - NZOZ Szczecin Wiesława Fabian - NZOZ Szczecin 6.6. Józef Dmochowski - ZOZ „Zdrowie” Barwice Józef Dmochowski - ZOZ „Zdrowie” Barwice 7.7. Paweł Szycko - NZOZ Podimed - Szczecinek. Paweł Szycko - NZOZ Podimed - Szczecinek. 8.8. Tadeusz Cieślak - NZOZ - „Hipokrates” - Złocieniec.Tadeusz Cieślak - NZOZ - „Hipokrates” - Złocieniec.

JANUARY 2001 – MAY 2002JANUARY 2001 – MAY 2002

1,258 mln questionnaires 1,258 mln questionnaires out of 1,45 mln of inhabitantsout of 1,45 mln of inhabitants

the first worldwide large screening for the first worldwide large screening for hereditary cancershereditary cancers

1,258 mln questionnaires 1,258 mln questionnaires out of 1,45 mln of inhabitantsout of 1,45 mln of inhabitants

the first worldwide large screening for the first worldwide large screening for hereditary cancershereditary cancers

ECONOMICAL / ECONOMICAL / MEDICAL ASPECTSMEDICAL ASPECTS

BRCA 1BRCA 1 MUTATION DETECTION COSTMUTATION DETECTION COST

750 750 €€

SURVEILLANCE COSTSURVEILLANCE COST1650 1650 €€

(USG, MAMMOGRAPHY, FNAB, (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN)ADNEXECTOMY, TAMOXIFEN)

RISK REDUCTIONRISK REDUCTION

BREASTBREAST 60% 60% 10% 10% (WITHOUT PROPHYLACTIC MASTECTOMY)(WITHOUT PROPHYLACTIC MASTECTOMY)

OVARYOVARY 40%40% 5%5%

MUTATION DETECTION COSTMUTATION DETECTION COST750 750 €€

SURVEILLANCE COSTSURVEILLANCE COST1650 1650 €€

(USG, MAMMOGRAPHY, FNAB, (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN)ADNEXECTOMY, TAMOXIFEN)

RISK REDUCTIONRISK REDUCTION

BREASTBREAST 60% 60% 10% 10% (WITHOUT PROPHYLACTIC MASTECTOMY)(WITHOUT PROPHYLACTIC MASTECTOMY)

OVARYOVARY 40%40% 5%5%

BRCA 1BRCA 1

PROPHYLACTICS: PROPHYLACTICS:

1 BREAST CA1 BREAST CA ~5 250 ~5 250 €€

OVARIAN CAOVARIAN CA ~4 500 ~4 500 €€

TREATMENT COST TREATMENT COST OF BREAST/ OVARIAN CANCER:OF BREAST/ OVARIAN CANCER:

> 6 000 > 6 000 €€

PROPHYLACTICS: PROPHYLACTICS:

1 BREAST CA1 BREAST CA ~5 250 ~5 250 €€

OVARIAN CAOVARIAN CA ~4 500 ~4 500 €€

TREATMENT COST TREATMENT COST OF BREAST/ OVARIAN CANCER:OF BREAST/ OVARIAN CANCER:

> 6 000 > 6 000 €€

2000-2003 BRCA1 mutation carriers 2000-2003 BRCA1 mutation carriers with breast/ovarian cancers N=50with breast/ovarian cancers N=50

treatment coststreatment costs 21 428 PLN21 428 PLN

social security costssocial security costs 34 086 PLN34 086 PLN

GP per capita lostGP per capita lost 195 071 PLN195 071 PLN

250 586 PLN250 586 PLN

average annual costaverage annual cost 62 646 PLN62 646 PLN

treatment coststreatment costs 21 428 PLN21 428 PLN

social security costssocial security costs 34 086 PLN34 086 PLN

GP per capita lostGP per capita lost 195 071 PLN195 071 PLN

250 586 PLN250 586 PLN

average annual costaverage annual cost 62 646 PLN62 646 PLNMarska N, US 2004Marska N, US 2004

DIRECT-TO-PATIENT BRCA1 DIRECT-TO-PATIENT BRCA1 TESTING: THE TESTING: THE TWÓJ STYLTWÓJ STYL

EXPERIENCEEXPERIENCE

DIRECT-TO-PATIENT BRCA1 DIRECT-TO-PATIENT BRCA1 TESTING: THE TESTING: THE TWÓJ STYLTWÓJ STYL

EXPERIENCEEXPERIENCE

Gronwald J. et al. Int J Can 2005Gronwald J. et al. Int J Can 2005

TWÓJ STYL TWÓJ STYL

2001 2001

5024 BRCA1 tests5024 BRCA1 tests

198 (3,9%) mutations found198 (3,9%) mutations found

5024 BRCA1 tests5024 BRCA1 tests

198 (3,9%) mutations found198 (3,9%) mutations found

TWÓJ STYL TWÓJ STYL BRCA1 carriers unaffected n=63 BRCA1 carriers unaffected n=63

20012001

36.5% - worry 36.5% - worry 27.0% - shock 27.0% - shock 22.0% - sadness22.0% - sadness

36.5% - worry 36.5% - worry 27.0% - shock 27.0% - shock 22.0% - sadness22.0% - sadness

TWÓJ STYL TWÓJ STYL BRCA1 carriers unaffected n=63 BRCA1 carriers unaffected n=63

20042004

66% -66% - used preventive used preventive measuresmeasures

98% - 98% - would recommendwould recommend testingtesting

66% -66% - used preventive used preventive measuresmeasures

98% - 98% - would recommendwould recommend testingtesting

Gronwald J. et al. JAMA 2005Gronwald J. et al. JAMA 2005Gronwald J. et al. JAMA 2005Gronwald J. et al. JAMA 2005

TWÓJ STYLTWÓJ STYL

two session counseling is two session counseling is effective for diagnosing BRCA1 effective for diagnosing BRCA1 carriers in Polandcarriers in Poland

two session counseling is two session counseling is effective for diagnosing BRCA1 effective for diagnosing BRCA1 carriers in Polandcarriers in Poland

Gronwald J. et al. JAMA 2005Gronwald J. et al. JAMA 2005Gronwald J. et al. JAMA 2005Gronwald J. et al. JAMA 2005

BREAST CANCER GENETIC RISKBREAST CANCER GENETIC RISK

GENESGENESGENESGENES

HIGHHIGHHIGHHIGH MODERATE / LOWMODERATE / LOWMODERATE / LOWMODERATE / LOW

NETWORK OF CANCER FAMILY SYNDROME NETWORK OF CANCER FAMILY SYNDROME REGISTERS IN EASTERN EUROPEREGISTERS IN EASTERN EUROPE

2000-20022000-2002

NETWORK OF CANCER FAMILY SYNDROME NETWORK OF CANCER FAMILY SYNDROME REGISTERS IN EASTERN EUROPEREGISTERS IN EASTERN EUROPE

2000-20022000-2002

EU PROJECTEU PROJECT

LIN ANAL FAM AGGR BREAST LIN ANAL FAM AGGR BREAST COLON CA GENES COLON CA GENES

2004-20062004-2006

LIN ANAL FAM AGGR BREAST LIN ANAL FAM AGGR BREAST COLON CA GENES COLON CA GENES

2004-20062004-2006

EU PROJECTEU PROJECT

BREAST CANCER RISKBREAST CANCER RISK

DGN <50 yrs, n=3500DGN <50 yrs, n=3500

0,00,0 5,05,0 10,010,0 15,015,0 20,020,0 25,025,0 30,030,0 35,0 %35,0 %

BRCA1BRCA1

BRCA2BRCA2

NBS1NBS1

1100delC1100delC

ex2spliceex2splice

I157TI157T

NOD2NOD2

P16P16

X1X1

X2X2

X3X3

RRRR

2,02,0

1,41,4

1,71,7

1,71,7

2,02,0

1,51,5

4,04,0

2,02,0

2,02,0

1,51,5

10,010,0

CHEK2CHEK2

GENES MUTATIONS / POLYMORPHISMSGENES MUTATIONS / POLYMORPHISMS

BREAST CANCER RISKBREAST CANCER RISK

GENE INTERACTIONSGENE INTERACTIONS

CHEK2 I157TCHEK2 I157TCHEK2 I157TCHEK2 I157T

XX11XX11

OR 4.8OR 4.8OR 4.8OR 4.8

++++

MOLECULAR CONSTITUTIONAL MOLECULAR CONSTITUTIONAL

CHANGES IDENTIFIED FOR > 70% CHANGES IDENTIFIED FOR > 70%

OF BREAST CANCERS IN POLANDOF BREAST CANCERS IN POLAND

EU PROJECTEU PROJECT

Population specific panels Population specific panels of DNA markers for detection of DNA markers for detection

of moderate risk of breast of moderate risk of breast and colon cancers and colon cancers

and their market applicationand their market application

Population specific panels Population specific panels of DNA markers for detection of DNA markers for detection

of moderate risk of breast of moderate risk of breast and colon cancers and colon cancers

and their market applicationand their market application

PARTICIPANTSPARTICIPANTSAustraliaAustralia The NetherlandsThe Netherlands

CanadaCanada PolandPoland

CyprusCyprus PakistanPakistan

EstoniaEstonia RussiaRussia

GermanyGermany Serbia and MontenegroSerbia and Montenegro

GreeceGreece SlovakiaSlovakia

KoreaKorea SwedenSweden

LatviaLatvia United KingdomUnited Kingdom

Coordinator – J. LubińskiCoordinator – J. Lubiński

WORKPACKAGESWORKPACKAGES 1: 1: Organization of international network of registriesOrganization of international network of registries

2: 2: Elaboration ofElaboration of population specific panels ofpopulation specific panels of DNA markersDNA markers

3: 3: Market protection of markers by patentsMarket protection of markers by patents

4: 4: Technical optimization ofTechnical optimization of DNA testing based on established panelsDNA testing based on established panels ofof markersmarkers

5: 5: Establishment of rules to beEstablishment of rules to be respected when proposedrespected when proposed testing is testing is offeredoffered

6: 6: Organization ofOrganization of networks ofnetworks of outpatient clinics applying developedoutpatient clinics applying developedDNA testingDNA testing

7: 7: Promotion ofPromotion of developed DNA testingdeveloped DNA testing

1: 1: Organization of international network of registriesOrganization of international network of registries

2: 2: Elaboration ofElaboration of population specific panels ofpopulation specific panels of DNA markersDNA markers

3: 3: Market protection of markers by patentsMarket protection of markers by patents

4: 4: Technical optimization ofTechnical optimization of DNA testing based on established panelsDNA testing based on established panels ofof markersmarkers

5: 5: Establishment of rules to beEstablishment of rules to be respected when proposedrespected when proposed testing is testing is offeredoffered

6: 6: Organization ofOrganization of networks ofnetworks of outpatient clinics applying developedoutpatient clinics applying developedDNA testingDNA testing

7: 7: Promotion ofPromotion of developed DNA testingdeveloped DNA testing

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

www.hccp-uicc.com

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

www.hccp-uicc.com

More information:More information:

www.hereditarycancer.netwww.hereditarycancer.net

e-mail:e-mail: ihcc@wp.plihcc@wp.pl

phone:phone: +48-91-466-15-+48-91-466-15-3232fax: fax: +48-91-466-15-+48-91-466-15-33 33

www.hereditarycancer.netwww.hereditarycancer.net

e-mail:e-mail: ihcc@wp.plihcc@wp.pl

phone:phone: +48-91-466-15-+48-91-466-15-3232fax: fax: +48-91-466-15-+48-91-466-15-33 33