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