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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. 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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  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. 5% autosomal dominant Cancer-predisposition 85% sporadic Environmental Breast Cancer Epidemiology 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. 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

  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. 2003 Vol. 72 (5) pp 1117-30 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 years1 BC case in a maleand/or 1 Ovarian Cancer case at any age

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

  12. Two maternal aunts; one with ovarian Cancer age 60, one with breast Cancer age 70 br 70 ov 60 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. 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 DNA Germinal deleterious mutation BRCA1 & BRCA2 BRCA2gene mutation

  18. 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

  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. 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. 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

  26. 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

  27. 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

  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):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

  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 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

  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

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