Current Issues in Hereditary Breast Cancer
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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. 5% autosomal dominant Cancer-predisposition. 85% sporadic Environmental. Breast Cancer Epidemiology.

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Belgian Breast Meeting 13-14 October 2006 Dr C. Sibille

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Belgian breast meeting 13 14 october 2006 dr c sibille

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


Belgian breast meeting 13 14 october 2006 dr c sibille

5% autosomal dominant Cancer-predisposition

85%

sporadic

Environmental

Breast Cancer Epidemiology

10% multigenic low penetrance


Belgian breast meeting 13 14 october 2006 dr c sibille

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)


Belgian breast meeting 13 14 october 2006 dr c sibille

BRCA2 13q12-q13

BRCA1 17q21

Wooster et al, Science, 265 pp 2088-2090, 1994

Wooster et al, Nature, 378 pp 189-792, 1995

Halt et al, Science, 250 pp 1684-1689, 1990

Miki et al, Science, 266 pp 66-71, 1994

17

13

Autosomal dominant Cancer-predisposition

5% of hereditary breast and/or ovarian Cancer are due to deleterious mutations in BRCA1 or BRCA2 genes


Belgian breast meeting 13 14 october 2006 dr c sibille

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


Belgian breast meeting 13 14 october 2006 dr c sibille

Inherited Breast Ovarian Cancer predisposition linked to BRCA mutation

  • Clinic

  • Genetics

  • Histology

  • Management


Belgian breast meeting 13 14 october 2006 dr c sibille

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 : ProstateStomach Pancreatic Colon, Melanoma…


Belgian breast meeting 13 14 october 2006 dr c sibille

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. 2003 Vol. 72 (5) pp 1117-30

Breast

Ovary


Belgian breast meeting 13 14 october 2006 dr c sibille

Referral guidelines for risk assessment and genetic predisposition

  • Genealogic diagnosis (familial and personal history)

  • Tumor analysis

  • Molecular diagnosis


Belgian breast meeting 13 14 october 2006 dr c sibille

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 years1 BC case in a maleand/or 1 Ovarian Cancer case at any age


Belgian breast meeting 13 14 october 2006 dr c sibille

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

br 45

br 55


Belgian breast meeting 13 14 october 2006 dr c sibille

Two maternal aunts; one with ovarian Cancer age 60, one with breast Cancer age 70

br 70

ov 60

Died RTA

45


Belgian breast meeting 13 14 october 2006 dr c sibille

Histological Characteristics of tumor from BRCA1 mutation carriers :

Predominance of grade III invasive ductal carcinomas

Excess of medullary Breast Cancer

Oestrogen receptor (-)

HER2 (-)P53(+)


Belgian breast meeting 13 14 october 2006 dr c sibille

Histological Characteristics of tumor from BRCA2 mutation carriers :

Predominance of lobular carcinoma

Predominance of grade II carcinoma = Sporadic tumor

Oestrogen receptor (+)HER2 (-)CHEK2 (++)


Belgian breast meeting 13 14 october 2006 dr c sibille

Diagnosis on tumor : genomic expression profile


Belgian breast meeting 13 14 october 2006 dr c sibille

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


Belgian breast meeting 13 14 october 2006 dr c sibille

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

Inherited predisposition to Breast Cancer linked to BRCA genes : Molecular Diagnosis

Molecular diagnosis on blood DNAGerminal deleterious mutation BRCA1 & BRCA2

BRCA2gene mutation


Belgian breast meeting 13 14 october 2006 dr c sibille

1

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

Germinal deleterious mutation BRCA2


Belgian breast meeting 13 14 october 2006 dr c sibille

Genetic Characteristics : BRCA1 & BRCA2 functions

Tumor suppressor genes : caretaker (DNA repair)


Belgian breast meeting 13 14 october 2006 dr c sibille

Genetic Characteristics : BRCA1 & BRCA2 functions

Tumor suppressor genes : caretaker (DNA repair)


Belgian breast meeting 13 14 october 2006 dr c sibille

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


Belgian breast meeting 13 14 october 2006 dr c sibille

HERCEPTIN

E2

-

?

EGF

ER

HER2

EGFR

Src

Ras

Raf

MEK

BRCA1

ERK

- Cell proliferation


Belgian breast meeting 13 14 october 2006 dr c sibille

Clinical Management of BRCA1/BRCA2 mutations carriers

3 options :

- Surgery- Surveillance- Chemoprevention


Belgian breast meeting 13 14 october 2006 dr c sibille

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 ...


Belgian breast meeting 13 14 october 2006 dr c sibille

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. 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

Prévalence de lésions mammaires prémalignes élevée

  • Hermsen BB et al.,Int. J. Cancer; April 2006


Belgian breast meeting 13 14 october 2006 dr c sibille

Clinical Management of BRCA1/BRCA2 mutations carriers

Management : Patients and asymptomatic individuals

- Ovary : no ultrasound surveillance

  • Bilateral Salpingo-Oophorectomy (BSO) (40 - 45 years)

  • BSO before menopause if :

  • Oei AL et al., Br J Cancer 2006; 94(6):814-819Surveillance 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):223-229Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study


Belgian breast meeting 13 14 october 2006 dr c sibille

Clinical Management of BRCA1/BRCA2 mutations carriers

Patients and asymptomatic individual

* Multi-disciplinary management (clinique du sein)

* Genetic counseling protocol type

Genetic counseling

* Clinicpreparation : psychologist

* Selection criteria : genealogy

* 2 separate blood samples with signature of the informed consent


Belgian breast meeting 13 14 october 2006 dr c sibille

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


Belgian breast meeting 13 14 october 2006 dr c sibille

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):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


Belgian breast meeting 13 14 october 2006 dr c sibille

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 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


Belgian breast meeting 13 14 october 2006 dr c sibille

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


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