1. Current Issues in Hereditary Breast Cancer
Belgian Breast Meeting
13-14 October 2006
Dr C. Sibille
Centre de Génétique Humaine - U.C.L. - Cliniques Universitaires Saint-LUC

2. Breast Cancer Epidemiology
5% autosomal dominant Cancer-predisposition
85%
sporadic
Environmental
10% multigenic low penetrance

3. Autosomal dominant Cancer-predisposition
5% of hereditary Breast and/or ovarian Cancer are due to deleterious mutations in BRCA1 or BRCA2 genes
< 1% of hereditary predisposition to Breast Cancer are linked to additional genes like :
P53,CHK2 (Li-Fraumeni syndrome)
PTEN (Cowden’s disease)
STK11 (Peutz-Jeghers syndrome)
ATM (Heterozygote AT)

4. Autosomal dominant Cancer-predisposition
5% of hereditary breast and/or ovarian Cancer are due to deleterious mutations in BRCA1 or BRCA2 genes 17
BRCA1 17q21
Halt et al, Science, 250 pp , 1990
Miki et al, Science, 266 pp 66-71, 1994 13
BRCA2 13q12-q13
Wooster et al, Science, 265 pp , 1994
Wooster et al, Nature, 378 pp , 1995

5. Autosomal dominant Cancer-predisposition
Prevalence of BRCA germline mutation carrier : 1 in every 600 women
3% Breast Cancer patients diagnosed < 70 years
6% Breast Cancer patients diagnosed < 50 years are BRCA mutation carrier

6. Inherited Breast Ovarian Cancer predisposition linked to BRCA mutation
Clinic
Genetics
Histology
Management

7. Clinical characteristic
Clinical characteristic in women :
- Breast Cancer (<40 years)
- Bilaterality – multicentricity of Breast Cancer
- Associated Cancer : Ovarian Stomach Pancreatic Colon, Melanoma…
Clinical characteristic in men :
- Breast Cancer (BRCA2)
- Associated Cancer : Prostate Stomach Pancreatic Colon, Melanoma…

8. Clinical characteristic
Autosomal dominant predisposition with high penetrance and variable expression:
- Breast Cancer risk : BRCA1 65% BRCA2 45%
- Ovarian Cancer risk : BRCA1 39% BRCA2 11%
References : Antoniou A. et al. Am. J. Genet Vol. 72 (5) pp
Breast
Ovary

9. Referral guidelines for risk assessment and genetic predisposition
Genealogic diagnosis (familial and personal history)
Tumor analysis
Molecular diagnosis

10. Genealogic diagnosis Criteria :
Criteria of autosomal dominant inheritance
½ children affected in each generation
3 BC or more cases < 60 years in the same parental branch
2 BC or more cases < 50 years in the same parental branch
1 BC case < 35 years 1 BC case in a male and/or 1 Ovarian Cancer case at any age

11. Two paternal aunts with breast Cancer at ages 45 and 55 years

12. Two maternal aunts; one with ovarian Cancer age 60, one with breast Cancer age 70
Died RTA 45

13. Histological Characteristics of tumor from BRCA1 mutation carriers :
Predominance of grade III invasive ductal carcinomas
Excess of medullary Breast Cancer
Oestrogen receptor (-)
HER2 (-) P53(+)

14. Histological Characteristics of tumor from BRCA2 mutation carriers :
Predominance of lobular carcinoma
Predominance of grade II carcinoma = Sporadic tumor
Oestrogen receptor (+) HER2 (-) CHEK2 (++)

15. Diagnosis on tumor : genomic expression profile

16. Diagnosis on tumor : genomic expression profile
Classification within 5 genomic profiles
1. Basal Phenotype (Cytokeratine 5/6/14 , ER- , EGFR+) (BRCA1)
2. Luminal Phenotype type I (Cytokeratine 8/18 , ER++)
3. Luminal Phenotype type II (Cytokeratine 8/18 , ER++)
4. HER2+ Phenotype (HER2+ , ER-)
5. ‘Normal Phenotype’
Hedenfalk IA et al. Adv Cancer Res. 2002,84,1-34

17. Inherited predisposition to Breast Cancer linked to BRCA genes : Molecular Diagnosis
Molecular diagnosis on blood DNA Germinal deleterious mutation BRCA1 & BRCA2
BRCA2 gene mutation
A 11B 11C 11D 11E 11F a b cd e24
f g 27
Nonsense mutation
Frameshift mutation
Missense mutation

18. Germinal deleterious mutation BRCA21 2 3 4
Line 2: truncated BRCA2 protein (exon 10)
Line 1 and 3: negative controls
Line 4: positive control
Normal sequence C1928 BRCA2
Frameshift mutation 1928delC BRCA2

19. Genetic Characteristics : BRCA1 & BRCA2 functions
Tumor suppressor genes : caretaker (DNA repair)

20. Genetic Characteristics : BRCA1 & BRCA2 functions
Tumor suppressor genes : caretaker (DNA repair)

21. Genetic Characteristics : BRCA1 additional function
Transcriptional regulator
Cell cycle and centrosome regulator
Inducer of apoptosis
Inducer of ubiquitination
Expression modulator of oestrogen - receptor
Signaling inhibitor of oestrogen & IGF receptor

22. - Cell proliferation E2 - ? EGF ER HER2 EGFR Src Ras Raf MEK BRCA1 ERK
HERCEPTIN E2 - ?
EGF ER
HER2
EGFR
Src
Ras
Raf
MEK
BRCA1
ERK
- Cell proliferation

23. Clinical Management of BRCA1/BRCA2 mutations carriers
3 options :
- Surgery - Surveillance - Chemoprevention

24. Clinical Management of BRCA1/BRCA2 mutations carriers
Management : Patients and asymptomatic individuals
- Breast (women - men)
clinical exam 1/6 month, at 20 years
MRI 1/year, at 25 years
ultrasound 1/6 month
bilateral prophylactic mastectomy ...

25. Clinical Management of BRCA1/BRCA2 mutations carriers
MRI > mammography
US correlation for MRI-detected breast lesions in women with familial risk of breast cancer. Sim LS et al., Clin Radiol Jul;60(7):801-6.
Hereditary breast cancer growth rates and its impact on screening policy. Tilanus-Linthorst MM et al., Eur J Cancer Jul;41(11):
Cost effectiveness of screening with CE-MRI versus X-ray mammography of women at high familial risk of Breast Cancer Griebsch I. et al., Br.J. Cancer 2006;95(7):
Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for Breast Cancer Kriege M. et al., Breast Cancer Res. Treat in press
Effect of chest X-rays on the risk of Breast Cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators’Group Andrieu N. et al., J. Clin. Oncol. 2006;24(21):3361-6
Prévalence de lésions mammaires prémalignes élevée
Hermsen BB et al.,Int. J. Cancer; April 2006

26. Clinical Management of BRCA1/BRCA2 mutations carriers
Management : Patients and asymptomatic individuals
- Ovary : no ultrasound surveillance
Bilateral Salpingo-Oophorectomy (BSO) ( years)
BSO before menopause if :
Oei AL et al., Br J Cancer 2006; 94(6): Surveillance of women at hight risk for hereditary ovarian cancer is inefficient.
no wish of further pregnancy
ovarian tissue conservation
with HRT until 50 years
Domchek SM et al., Lancet Oncol 2006; 7(3): Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study

27. Clinical Management of BRCA1/BRCA2 mutations carriers
Patients and asymptomatic individual
* Multi-disciplinary management (clinique du sein)
* Genetic counseling protocol type
Genetic counseling
* Clinic preparation : psychologist
* Selection criteria : genealogy
* 2 separate blood samples with signature of the informed consent

28. Conclusion : interest of surveillance and BSO
1. Breast Cancer prevention
Radical mastectomy :
- efficacy :
Reduces Breast Cancer risk (99 %)
Increases survival
1 % residual Breast Cancer risk (surgery dependant)
- Physical mutilation
- >5 % regrets

29. Conclusion : interest of surveillance and BSO
2. Ovarian Cancer Prevention
Oophorectomy reduces risk of :
- Ovarian Cancer (98%)
- Breast Cancer (58%)
Oophorectomy increases survival
Domchek SM et al., Lancet Oncol 2006; 7(3): Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study
Anderson K et al., Ann Intern Med. 2006; 144(6):I40 Cost-effectiveness of preventive strategies for women with BRCA1+2 mutation

30. Conclusion : alternative to prophylactic mastectomy
3. BSO , Surveillance, Chemoprevention
Breast Cancer surveillance
Prophylactic oophorectomy
Life style risk diminution (oestrogen, alcohol, nutrition, physical exercise)
Antioestrogens ?
other (chemoprevention with PARA inhibitors , ...)
Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1+2 Carrier Cohort Study Andrieu N et al., J Natl Cancer Inst. 2006; 98(8):
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Farmer H. et al., Nature 2005;434(7035):917-21

31. Conclusion
4. Requirement of multi-disciplinary collaboration for the follow-up of symptomatic or asymptomatic mutation BRCA1/2 carrier
Gynecologist
Oncologist
Radiologist
Anatomopathologist
Geneticist
Psychologist
General practicionner
Gynecologist
Preventive medecine
Radiologist
Geneticist
Psychologist