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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.

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Presentation on theme: "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."— Presentation transcript:

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

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

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, BRCA2 13q12-q13 Wooster et al, Science, 265 pp , 1994 Wooster et al, Nature, 378 pp , 1995

5 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

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

7 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 : Prostate Stomach Pancreatic Colon, Melanoma… Clinical characteristic in men :

8 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 BreastOvary Clinical characteristic

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

10 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

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

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

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

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

15 Diagnosis on tumor : genomic expression profile

16 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

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 Nonsense mutation Frameshift mutation Missense mutation

18 Germinal deleterious mutation BRCA 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 Tumor suppressor genes : caretaker (DNA repair) Genetic Characteristics : BRCA1 & BRCA2 functions

20 Tumor suppressor genes : caretaker (DNA repair)

21 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

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

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

24 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

25 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): 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): Clinical Management of BRCA1/BRCA2 mutations carriers Hermsen BB et al.,Int. J. Cancer; April 2006 Prévalence de lésions mammaires prémalignes élevée

26 Bilateral Salpingo-Oophorectomy (BSO) ( 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): Surveillance 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): Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study

27 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

28 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

29 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): 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 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 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): Conclusion : alternative to prophylactic mastectomy

31 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

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