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

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

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 17q21 Halt et al, Science, 250 pp 1684-1689, 1990 Miki et al, Science, 266 pp 66-71, 1994 13 BRCA2 13q12-q13 Wooster et al, Science, 265 pp 2088-2090, 1994 Wooster et al, Nature, 378 pp 189-792, 1995

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

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

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…

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

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

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 years 1 BC case in a male and/or 1 Ovarian Cancer case at any age

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

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

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

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

Diagnosis on tumor : genomic expression profile

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

Inherited predisposition to Breast Cancer linked to BRCA genes : Molecular Diagnosis Molecular diagnosis on blood DNA Germinal 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 controls Line 4: positive control Normal sequence C1928 BRCA2 Frameshift mutation 1928delC BRCA2

Genetic Characteristics : BRCA1 & BRCA2 functions Tumor suppressor genes : caretaker (DNA repair)

Genetic Characteristics : BRCA1 & BRCA2 functions Tumor suppressor genes : caretaker (DNA repair)

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

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

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

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 ...

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 Cancer Griebsch 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 Cancer Kriege 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’Group Andrieu 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

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):814-819 Surveillance 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):223-229 Mortality after bilateral salpingo-oophorectomy in BRCA1+2 mutation carrier: a prospective cohort study

Clinical Management of BRCA1/BRCA2 mutations carriers Patients and asymptomatic individual * Multi-disciplinary management (clinique du sein) * Genetic counseling protocol type Genetic counseling * Clinic preparation : psychologist * Selection criteria : genealogy * 2 separate blood samples with signature of the informed consent

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

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):223-229 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

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 Study Andrieu N et al., J Natl Cancer Inst. 2006; 98(8):535-544 Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Farmer H. et al., Nature 2005;434(7035):917-21

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