Belgian Breast Meeting 13-14 October 2006
Dr C. Sibille
Centre de Génétique Humaine - U.C.L. - Cliniques Universitaires Saint-LUC
Current Issues in Hereditary Breast Cancer
Breast Cancer Epidemiology
10% multigenic low penetrance
5% autosomal dominant Cancer-predisposition
85%sporadic Environmental
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)
Autosomal dominant Cancer-predisposition
5% of hereditary breast and/or ovarian Cancer are due to deleterious mutations in BRCA1 or BRCA2 genes
17
BRCA1 17q21Halt et al, Science, 250 pp 1684-1689, 1990Miki et al, Science, 266 pp 66-71, 1994
13
BRCA2 13q12-q13Wooster et al, Science, 265 pp 2088-2090, 1994Wooster et al, Nature, 378 pp 189-792, 1995
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
Autosomal dominant Cancer-predisposition
Inherited Breast Ovarian Cancer predisposition linked to BRCA mutation
•Clinic
•Genetics
•Histology
•Management
Clinical characteristic in women :
- Breast Cancer (<40 years)
- Bilaterality – multicentricity of Breast Cancer
- Associated Cancer : Ovarian Stomach Pancreatic Colon, Melanoma…
Clinical characteristic
- Breast Cancer (BRCA2)
- Associated Cancer : ProstateStomach Pancreatic Colon, Melanoma…
Clinical characteristic in men :
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. 2003 Vol. 72 (5) pp 1117-30
Breast Ovary
Clinical characteristic
• Genealogic diagnosis (familial and personal history)
• Tumor analysis
• Molecular diagnosis
Referral guidelines for risk assessment and genetic predisposition
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
Genealogic diagnosis
Two paternal aunts with breast Cancer at ages 45 and 55 years
br 45 br 55
Two maternal aunts; one with ovarian Cancer age 60, one with breast Cancer age 70
br 70 ov 60 Died RTA45
Histological Characteristics of tumor from BRCA1 mutation carriers :
Predominance of grade III invasive ductal carcinomas
Oestrogen receptor (-)HER2 (-)P53(+)
Excess of medullary Breast Cancer
Predominance of lobular carcinoma
Predominance of grade II carcinoma = Sporadic tumor
Oestrogen receptor (+)HER2 (-)CHEK2 (++)
Histological Characteristics of tumor from BRCA2 mutation carriers :
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
Diagnosis on tumor : genomic expression profile
Inherited predisposition to Breast Cancer linked to BRCA genes : Molecular Diagnosis
Molecular diagnosis on blood DNAGerminal deleterious mutation BRCA1 & BRCA2
BRCA2 gene mutation
1 2 3 45 6 7 89 10 11A 11B 11C 11D 11E 11F 1213 14 15 16 17 18 a b cd e24 f g 27
Nonsense mutation
Frameshift mutation
Missense mutation
Germinal deleterious mutation BRCA2
1 2 3 4
Line 2: truncated BRCA2 protein (exon 10)Line 1 and 3: negative controlsLine 4: positive control
Normal sequence C1928 BRCA2
Frameshift mutation 1928delC BRCA2
Tumor suppressor genes : caretaker (DNA repair)
Genetic Characteristics : BRCA1 & BRCA2 functions
Genetic Characteristics : BRCA1 & BRCA2 functions
Tumor suppressor genes : caretaker (DNA repair)
• Transcriptional regulator
• Cell cycle and centrosome regulator
• Inducer of apoptosis
• Inducer of ubiquitination
• Expression modulator of oestrogen - receptor
• Signaling inhibitor of oestrogen & IGF receptor
Genetic Characteristics : BRCA1 additional function
ERER
E2E2
SrcSrc
RasRas
RafRaf
MEKMEK
ERKERK-- Cell proliferation Cell proliferation
EGFREGFR
EGFEGF
BRCA1BRCA1
HER2HER2
??
HERCEPTINHERCEPTIN
--
Clinical Management of BRCA1/BRCA2 mutations carriers
3 options :
- Surgery
- Surveillance
- Chemoprevention
• clinical exam 1/6 month, at 20 years
• MRI 1/year, at 25 years
• ultrasound 1/6 month
• bilateral prophylactic mastectomy ...
Clinical Management of BRCA1/BRCA2 mutations carriers
- Breast (women - men)
Management : Patients and asymptomatic individuals
• MRI > mammography
• US correlation for MRI-detected breast lesions in women with familial risk of breast cancer.Sim LS et al., Clin Radiol. 2005 Jul;60(7):801-6.
• Hereditary breast cancer growth rates and its impact on screening policy. Tilanus-Linthorst MM et al., Eur J Cancer. 2005 Jul;41(11):1610-7.
• Cost effectiveness of screening with CE-MRI versus X-ray mammography of women at high familial risk of Breast CancerGriebsch I. et al., Br.J. Cancer 2006;95(7):801-810
• Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for Breast CancerKriege M. et al., Breast Cancer Res. Treat. 2006 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’GroupAndrieu N. et al., J. Clin. Oncol. 2006;24(21):3361-6
Clinical Management of BRCA1/BRCA2 mutations carriers
• Hermsen BB et al.,Int. J. Cancer; April 2006
Prévalence de lésions mammaires prémalignes élevée
• Bilateral Salpingo-Oophorectomy (BSO) (40 - 45 years)
• BSO before menopause if :
- Ovary : no ultrasound surveillance
• no wish of further pregnancy
• ovarian tissue conservation
• with HRT until 50 years
• Oei AL et al., Br J Cancer 2006; 94(6):814-819Surveillance of women at hight risk for hereditary ovarian cancer is inefficient.
Clinical Management of BRCA1/BRCA2 mutations carriers
Management : Patients and asymptomatic individuals
• Domchek SM et al., Lancet Oncol 2006; 7(3):223-229Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study
Genetic counseling
* Clinic preparation : psychologist
* Selection criteria : genealogy
* 2 separate blood samples with signature
of the informed consent
Clinical Management of BRCA1/BRCA2 mutations carriers
Patients and asymptomatic individual
* Multi-disciplinary management (clinique du sein)
* Genetic counseling protocol type
Radical mastectomy :
- efficacy : • Reduces Breast Cancer risk (99 %)
• Increases survival
• 1 % residual Breast Cancer risk (surgery dependant)
- Physical mutilation
- >5 % regrets
1. Breast Cancer prevention
Conclusion : interest of surveillance and BSO
Conclusion : interest of surveillance and BSO
Oophorectomy reduces risk of :
- Ovarian Cancer (98%)
- Breast Cancer (58%)
Oophorectomy increases survival
2. Ovarian Cancer Prevention
• Domchek SM et al., Lancet Oncol 2006; 7(3):223-229Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study
• Anderson K et al., Ann Intern Med. 2006; 144(6):I40Cost-effectiveness of preventive strategies for women with BRCA1+2 mutation
• Breast Cancer surveillance• Prophylactic oophorectomy
• Life style risk diminution (oestrogen, alcohol,
nutrition, physical exercise)
• Antioestrogens ?
• other (chemoprevention with PARA inhibitors , ...)
3. BSO , Surveillance, Chemoprevention
• Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1+2 Carrier Cohort StudyAndrieu N et al., J Natl Cancer Inst. 2006; 98(8):535-544
• Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategyFarmer H. et al., Nature 2005;434(7035):917-21
Conclusion : alternative to prophylactic mastectomy
4. Requirement of multi-disciplinary collaboration for the follow-up of symptomatic or asymptomatic mutation BRCA1/2 carrier
Conclusion
• Gynecologist
• Oncologist
• Radiologist
• Anatomopathologist
•Geneticist
• Psychologist
• General practicionner
• Gynecologist
• Preventive medecine
• Radiologist
• Geneticist
• Psychologist