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Management of carriers of hereditary predisposition to breast cancer

Management of carriers of hereditary predisposition to breast cancer. Marc Abramowicz Medical Genetics, ULB Centre des tumeurs ULB – Erasme / Bordet. Cancer Genetics. In tumors (tumor DNA = somatic DNA) : Molecular pathology; tumorigenesis routes. Genetic Epigenetic

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Management of carriers of hereditary predisposition to breast cancer

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  1. Management of carriers of hereditary predisposition to breast cancer Marc AbramowiczMedical Genetics, ULB Centre des tumeurs ULB – Erasme / Bordet

  2. Cancer Genetics • In tumors (tumor DNA = somatic DNA) : Molecular pathology; tumorigenesis routes. • Genetic • Epigenetic • In patients (constitutional DNA = germ-line DNA) : Cancer risk profiling, from inherited mutations/polymorphisms

  3. 10-12% women will develop breast cancer All breast cancer cases (> 10% women) No genetic factor Minor genetic factor(s) Major genetic factor (high penetrance gene)

  4. Hereditary breast/ovarian cancer • Genetically heterogeneous • BRCA1 • BRCA2 • Others (?) and extended syndromes: Li-Fraumeni, Cowden, … • Penetranceincomplete and age- (and gender-) dependent • 50 – 80 %, breast; 15– 60 %, ovary • Phenocopies: chance coincidence of cancer in same families • No specific cancer phenotype • Br+ov: >80% of multiple familial cases • Bronly: >50% of multiple familial cases (Ford et al 1998)

  5. Hereditary breast and ovarian cancer 5-10% of breast cancers are inherited • Familial occurence, mendelian pattern • Heterozygous for one single gene • multiples primary tumours • Early onset (mean age, breast: 42 yrs)

  6. Penetrance, BRCA1 – linked breast cancer Struewing et al. 1997, NEJM 336: 1401-8.

  7. Penetrance, BRCA2 – linked ovarian cancer Struewing et al. 1997, NEJM 336: 1401-8.

  8. Penetrance of breast cancer • Biased in familiesascertained for high incidence of breast cancer • Meta-analysis of 10 studies < high-riskclinicsand population-based setting Chen & Parmigiani JCO 2007

  9. Penetrance of breast cancer • Biased in familiesascertained for high incidence of breast cancer • Meta-analysis of 10 studies < high-riskclinicsand population-based setting Chen & Parmigiani JCO 2007 • But depends on low-penetranceallelestoo: someeffect of familyhistoryevenafter exclusion of BRCA mutation

  10. BRCA1 ≠ BRCA2but no difference in clinical care as of today • BRCA1 activates transcription of ER geneESR1 Hosey 2007 J NatlCancinst • BRCA1 required for differentiation of stem cell, and progenitorcell (ER-) intoluminalcell : Liu-S et al 2008 PNAS • … and other cellular functions Cf: BRCA1 carrier tumorsoften ER- (75%); many Basal-like type ER-, PR-, HER2- (44%) Lakhani et al 2005 Clin CancRes BRCA2 carrier tumorsmostly ER+ (75%), ductalcarcinomas, luminal type Foulkes 2004 Clin CancRes

  11. Genetictesting and geneticcounseling

  12. Genetic analysis BRCA1&2 • Labor-intensive (3 months) ; expensive • Mutation detectionefficacy 70 % • Some mutations in introns, in genepromoters,… • BRCA3 ? • Psycho and social impact of testing • False +, false -. False reassurance. => Not performed in each patient withbreast or ovarian cancer(ASCO 1996; ASCO 2003)

  13. Hereditary breast/ovarian cancer Care management of this patient must include DNA sampling, in order to counsel her daughter appropriately in the future.

  14. DNA analysis and genetic counseling • If hereditary cancer plausible (Proba BRCA mutation > 10%) • 2 women < 50 yrs (any age if bilateral) (1st degree, 2nd if paternal) • 1 breast < 50 yrs + 1 ovary, any age • 4 women, breast only • 1 woman breast + ovary • 1 woman < 35 yrs • Test affected relative first.With informed consent. Via genetic counseling. • In women with cancer history: • Breast recurrence risk; ovarian risk; family implications • In asymptomatic relatives: PGT(Presymptomatic Genetic Testing) • NO SAMPLING AT FIRST VISIT. • Counsel on: Breast risk; ovarian risk; Medical options; Family implications • Psycho support. Anticipate results of PGT, and adjust • Duplicate DNA sampling

  15. DNA analysis and genetic counseling • If hereditary cancer plausible (Proba BRCA mutation > 10%) • 2 women < 50 yrs (any age if bilateral) (1st degree, 2nd if paternal) • 1 breast < 50 yrs + 1 ovary, any age • 4 women, breast only • 1 woman breast + ovary • 1 woman < 35 yrs • Test affected relative first.With informed consent. Via genetic counseling. • Reassure 50% of first-degree relatives • In mutation carriers, provide risk management strategy • optimum = ? • Bilateral prophyllactic ovario-annexectomy:  Ov. Ca risk,  Br.Ca risk,  overall mortality • Prophyllactic radical mastectomy ? • Breast surveillance

  16. II.3 K sein 48 ans, DCD 50 II.4 K sein 35 ans, ovaire 51 ans III.4 K sein 39 ans mutation g30877delA pLys339ArgfsX2 de BRCA1 * *Mutation tronquante pLys339ArgfsX2 de BRCA1,  Prévoir ovariectomie chez III.4, tester II.4

  17. Management of carriers

  18. Prophyllactic mastectomy in asymptomatic carrier ? • Reducesrisk by >95% only if total (not subcutaneous) • Rebbeck et al J Clin Oncol 2004 (PROSE study), and referencestherein • No evidence for significantsurvivalbenefitas comparedwith surveillance only • No level 1 evidence, unclearotherevidence • Prospective, randomized, 2-blindstudyunfeasible • No effect on ovarianrisk. => Only in carefullyselected, fullyinformed, mastectomy-requesting patients => Optimal age for procedure = ?

  19. Age-related penetrance

  20. Bilateral mastec if unilateral cancerin BRCA1or2 carrier ? • Reduces by 90% risk of recurrence, ipsi or heterolateral (same as in asymptomatic mutation carrier) • Does not reducemortalityas comparedwith surveillance–only group Van Sprundel et al. Br J Cancer 2005

  21. Guidelines in asymptomatic BRCA1/2 carriers: (1) OVARIES • Risk-ReducingSalpingo-Oophorectomyat 35-50 yrs: •  Ov.Carisk by >95%Kauff et al 2002 NEJM; Rebbeck et al. 2002 NEJM; Rutter et al. 2003 J Natl C Inst; Eisen et al. 2005 JCO •  Br.Carisk by 50% if BRCA1 mutation Eisen et al. AJHG 2000; Kauff et al. NEJM 2002; Rebbeck et al. NEJM 2002; •  overallmortalityRebbeck et al. NEJM 2002; Domchek et al. Lancet 2006 • But unclear if samebenefit in BRCA2 as in BRCA1(Kauff 2008 JCO)

  22. Guidelines in asymptomatic BRCA1/2 carriers: (2) BREAST • Prophyllactic total mastectomy ? Unclearbenefit in terms of survival •  Br ca risk by 90% (95% if +RRSO) Rebbeck et al 2004 JCO • Breast surveillance: • monthly self-exam? No provenbenefit • mammograms± USMammograms reduce breast cancer death by 22% after 50 yrs (Humphrey 2002 Ann Int Med)BUT: denser breast / faster doubling size in younger womenUltrasounds improve detection rate (Kuhl 2005 JCO) • clinical breast exam by experienced MD: improves detection in some studies (Warner 2004 JAMA) • MRI (Kriege et al NEJM 2004): more Ss, lessSp => likelycost effective if high a priori risk: BRCA1; BRCA2 with dense breasts • Tamoxifen? Only BRCA2. Raloxifen, AIs? Unclear(King et al. 2001 JAMA; Robson & Offit 2007 NEJM)

  23. Guidelines in asymptomatic BRCA1/2 carriers (3) • optimum = ? • Bilatprophylsalpingo-oophorectomyat 35-50 yrs: •  Ov.Carisk by >95%Kauff et al 2002 NEJM; Rebbeck et al. 2002 NEJM; Rutter et al. 2003 J Natl C Inst; Eisen et al. 2005 JCO •  Br.Carisk by 50% if BRCA1 mutation Eisen et al. AJHG 2000; Kauff et al. NEJM 2002; Rebbeck et al. NEJM 2002; •  overallmortalityRebbeck et al. NEJM 2002; Domchek et al. Lancet 2006 • Breast surveillance: monthly self-exam; mammograms± US; clinical breast exam. MRI. (Kriege et al NEJM 2004) • Prophyllactic total mastectomy ? Unclearbenefit => only in carefullyselected, fullyinformed patients

  24. Trends • Identify low-penetrance alleles • Risk profiling ? • Targeted prevention ? • Pathway-specific therapies • Pharmacogenetics

  25. Somemolecular data

  26. Major (monogenic) hereditary predisposition to breast cancer Robson & Offit 2007

  27. Major (monogenic) and minor (polygenic) hereditary predisposition to breast cancer Robson & Offit 2007

  28. A cellular pathway of DNA repair and chromosome integrity Walsh & King 2007 Cancer cell

  29. What does this teach us? • Lowpenetranceallelesmodulatehigh-penetrancegenes (egAntoniou 2008 AJHG) • BRCA1 deficientcelllines are sensitive to Xrays; Etoposide; Bleomycin: double-strand DNA breaks, and Platinumdrugs: DNA cross-links => platinumclinical trials in BRCA1-deficienttumor patients

  30. What does this teach us? • Lowpenetranceallelesmodulatehigh-penetrancegenes (egAntoniou 2008 AJHG) • BRCA1 deficientcelllines are sensitive to Xrays; Etoposide; Bleomycin: double-strand DNA breaks, and Platinumdrugs: DNA cross-links => platinumclinical trials in BRCA1-deficienttumor patients • Poly-ADP-ribose polymerase (PARP) requiredat initial step of DNA repair => PARP inhibitors in BRCA1 or 2-deficienttumor patients

  31. Low-penetrancealleles

  32. Majority ? of breast cancers • Somesusceptibility stems fromcombination of severalgenes, eachwithlowpenetrance • Twinstudies: concordant MZ ~25% (Ahlbom et al 1997 JNCI; Baker et al 2005 Biometrics) • SNPs; CNVs (?); polygenic • A few genesknown in 2008… more data are coming • CHEK2, ATM, PALB2, BRIP1; …, FGFR2, • Some of the samegenesmodifyseverity of BRCA1&2 course • No routine testing • Environment (hormones, diet, otherfactors) • Epigeneticeffects? Already in utero ??

  33. Families with > 4 cases of breast cancer Am J Hum Genet 62:676-9, 1998 The most important conclusion from this analysis is that a large proportion, perhaps the majority, of families with five or fewer cases of breast cancer and no ovarian or male breast cancer cases are not due to either BRCA1 or BRCA2.

  34. Most women with breast cancer have no affected relative; most women with affected relatives will not develop br ca. If cancer, not at young age. Age of relative at Δ has little effect. Familial breast cancer: 58209 cases + 101986 controls Collaborative group, Lancet 358:1389-99, 2001

  35. Trends • Identify low-penetrance alleles • Risk profiling ? • Targeted prevention ? • Pathway-specific therapies • Pharmacogenetics

  36. Age-related penetrance

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