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.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
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6
7
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10
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17
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25
26
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 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, McGill 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, 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 Montreal, Quebec, Canada
IHCC staff
POLAND
- country with high level
of genetic homogeneity !
Górski B. et al. AJHG, June 2000
POLISH FAMILIES WITH STRONG
AGGREGATION OF BREAST/OVARIAN
CANCERS (n=200)
 BRCA 1
 BRCA2
~65%
~4%
Górski B. et al. Int. J. Can, 2004
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
BRCA1 MULTIPLEX PCR
5382 insC
patients
(-) DNA
5382 insC
C61G
4153 delA
possitive
controls
BRCA1 FOUNDER MUTATIONS
IN POLAND
 GÓRSKI B. ET AL.
- PATENT NO P335917
- MULTIPLEX PCR - 50€
BRCA1 – REGISTRY
– SZCZECIN – POLAND
3256 CARRIERS
THE LARGEST REGISTRY
IN THE WORLD
Szczecin 30 January2006
BRCA1 – POSITIVE BREAST
CANCERS IN YOUNG WOMEN
IN POLAND
Lubiński J. et al. Br Can Res Treat 2005
BRCA1 mutations in patients
with breast cancer <51yrs
No
Center
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Białystok
Bielsko-Biała
Bydgoszcz
Gliwice
Kielce
Koszalin
Kraków
Lublin
Łódź
Olsztyn
Opole
Poznań I
Poznań II
Rzeszów
Szczecin
Warszawa
Wrocław
Zielona Góra
Total
No of patients
No of
DNA
No of tests
260
144
333
287
173
47
176
278
188
634
198
100
239
90
1043
161
58
369
4778
202
114
261
201
142
39
166
209
132
449
181
97
180
63
779
113
41
258
3627
202
114
261
201
142
39
166
209
132
445
181
97
180
63
770
113
41
256
3615
BRCA1 mutations
5382 ins C
C 61 G
4153 del A
3
4
2
6
7
6
1
11
5
5
6
1
1
4
4
10
1
8
2
10
6
3
6
4
4
12
2
4
2
25
8
4
3
2
1
15
1
136
52
11
BRCA1 mutations in patients
with breast cancer <51yrs
 4780 patients
 3629 (75,9%) blood samples
 3614 BRCA1 tests
 200 (5,5%) mutations
Pathologic/ clinical features of cancers
Feature
Group
BRCA1 – (+)
BRCA1 – (-)
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)
a. the largest diameter
2,44cm (n=113)
1,99cm (n=118)
b.  1 cm
14,16% (16/113)
15,25% (18/118)
1. H-p
2. Tumour size
Pathologic/ clinical features of cancers
Feature
Group
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)
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)
15,08% (19/126)
58,33% (91/156)
6. Family history (probant and I or II° relatives)
7. ER
CANCER RISKS
IN FIRST-DEGREE RELATIVES OF BRCA1
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
C61G
5382insC
4153delA
0.7
0.6
P=0.12
0.5
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
C61G
5382insC
4153delA
0.7
0.6
P=0.05
0.5
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
0.8
0.7
Proband Breast Cancer
0.6
Proband Ovarian Cancer
0.5
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
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. BRCA1 PROPHYLACTICS
 Oral contraceptives < 30yrs
> 30yrs
 Breast feeding
> 1 yrs
 Later menarche
per yr
 Tubal ligation
 Adnexectomy
 Tamoxifen
 Adnexectomy + tamoxifen
 Mastectomy
RISK
BR
OV
1.3
0.5
0.5
0.9
0.5
0.2
0.05
0.5
0.15
0.01
BRCA1 PROPHYLACTICS - POLAND
BREAST 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
BRCA1 PROPHYLACTICS - POLAND
OVARIAN 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
TAMOXIFEN AND
CONTRALATERAL BREAST
CANCER IN BRCA1
AND BRCA2 CARRIERS:
AN UPDATE
Gronwald J. et al. Int J Can 2005
NSABP P1 Results
OR
0.95 CI
ER Status
BRCA1
5 Tam
3 Placebo
1.67
0.41-8.00
1 ER +
6 ER 1 unknown
BRCA2
3 Tam
8 Placebo
0.38
0.06-1.56
6 ER+
3 ER2 unknown
The efficacy of tamoxifen for breast cancer prevention
in BRCA1/2 mutation carriers cannot be determined from P1 data
B. Weber 2005
Association between Tamoxifen and
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
HRT after BPO
in BRCA1/2 Mutation Carriers
 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
 Post BPO breast cancer risk reduction:
 68% reduction overall
 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 BRCA1/BRCA2
mutation carriers
BRCA1 PROPHYLACTICS
 Sodium selenite – pilot study
BRCA1 CARRIERS
N = 130 Se
3 Br/Ov Ca
N = 130 (-)
9 Br/Ov Ca
DETECTION OF EARLY BREAST CANCERS
IN BRCA1 MUTATION CARRIERS
USG
~20%
MAMMOGR.
~20%
MRI
~90%
Narod S. et al. 2003
Breast cancers with BRCA1
Treatment
 prophylactic adnexectomy
 tamoxifen
 mastectomy
10 yrs survival
 2×
 1.5×
 1.5×
Breast cancers with BRCA1
Treatment – Neo-Adjuvant therapy
Type
No
of CHTH
of patients
BRCA1 – 44
AT
15
Another types
29
Total
44
Non-BRCA1 – 41
AT
12
Another types
29
Total
41
CR
PR
No
response
0
4
4
6
25
31
9
0
9
0
2
2
12
25
37
0
2
2
Byrski T et al.: Clin Can Res 2006
Population
screenings
- Poland
 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!
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 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
 1,258 mln questionnaires
out of 1,45 mln of inhabitants
 the first worldwide large screening for
hereditary cancers
ECONOMICAL /
MEDICAL ASPECTS
BRCA 1
 MUTATION DETECTION COST
1650 €
 SURVEILLANCE COST
(USG, MAMMOGRAPHY, FNAB,
ADNEXECTOMY, TAMOXIFEN)
 RISK REDUCTION
 BREAST
60%  10%
(WITHOUT PROPHYLACTIC MASTECTOMY)
 OVARY
40% 
750 €
5%
BRCA 1
 PROPHYLACTICS:
 1 BREAST CA
~5 250 €
 OVARIAN CA
~4 500 €
 TREATMENT COST
OF BREAST/ OVARIAN CANCER:

> 6 000 €
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
DIRECT-TO-PATIENT BRCA1
TESTING: THE TWÓJ STYL
EXPERIENCE
Gronwald J. et al. Int J Can 2005
TWÓJ STYL
2001
5024 BRCA1 tests
198 (3,9%) mutations found
TWÓJ STYL
BRCA1 carriers unaffected n=63
2001
 36.5% - worry
 27.0% - shock
 22.0% - sadness
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
TWÓJ STYL
 two session counseling is
effective for diagnosing BRCA1
carriers in Poland
Gronwald J. et al. Br Can Res Treat 2005
BREAST CANCER GENETIC RISK
GENES
HIGH
MODERATE / LOW
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
BREAST CANCER RISK
DGN <50 yrs, n=3500
GENES MUTATIONS / POLYMORPHISMS
RR
X3
2,0
X2
1,4
X1
1,7
P16
1,7
NOD2
2,0
I157T
1,5
CHEK2 ex2splice
4,0
1100delC
2,0
NBS1
2,0
BRCA2
1,5
BRCA1
10,0
0,0
5,0
10,0
15,0
20,0
25,0
30,0
35,0 %
BREAST CANCER RISK
GENE INTERACTIONS
CHEK2 I157T
+
X1

OR 4.8
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%
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, ESO
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
United Kingdom
Coordinator – J. Lubiński
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
Electronic version
of the journal available on:
www.hccp-uicc.com
More information:
 www.hereditarycancer.net
 e-mail: ihcc@wp.pl
 phone: +48-91-466-15-32
fax:
+48-91-466-15-33