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

• In patients (constitutional DNA = germ-line DNA) :

Cancer risk profiling, from inherited mutations/polymorphisms

10-12% women will develop breast cancer

No genetic factor

Major genetic factor

(high penetrance gene)

All breast cancer cases (> 10% women)

Minor genetic factor(s)

Hereditary breast/ovarian cancer

• Genetically heterogeneous

– BRCA1

– BRCA2

– Others (?) and extended syndromes: Li-Fraumeni, Cowden, …

• Penetrance incomplete 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

Br only: >50% of multiple familial cases (Ford et al 1998)

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)

Penetrance, BRCA1 – linked breast cancer

Struewing et al. 1997, NEJM 336: 1401-8.

Penetrance, BRCA2 – linked ovarian cancer

Struewing et al. 1997, NEJM 336: 1401-8.

Penetrance of breast cancer

• Biased in families ascertained for high incidence of breast cancer

• Meta-analysis of 10 studies < high-risk clinics and population-based

setting

Chen & Parmigiani JCO 2007

Cumulative

incidence by age

70

95% Confidence

Interval

BRCA1 .57 .47 - .66

BRCA2 .49 .40 - .57

Penetrance of breast cancer

• Biased in families ascertained for high incidence of breast cancer

• Meta-analysis of 10 studies < high-risk clinics and population-based

setting

Chen & Parmigiani JCO 2007

• But depends on low-penetrance alleles too: some effect of family

history even after exclusion of BRCA mutation

Cumulative

incidence by age

70

95% Confidence

Interval

BRCA1 .57 .47 - .66

BRCA2 .49 .40 - .57

BRCA1 ≠ BRCA2

but no difference in clinical care as of today

• BRCA1 activates transcription of ER gene ESR1

Hosey 2007 J Natl Canc inst

• BRCA1 required for differentiation of stem cell, and progenitorcell (ER-) into luminal cell :

Liu-S et al 2008 PNAS

• … and other cellular functions

Cf: BRCA1 carrier tumors often ER- (75%); many Basal-like type ER-, PR-, HER2- (44%)

Lakhani et al 2005 Clin Canc Res

BRCA2 carrier tumors mostly ER+ (75%), ductal carcinomas, luminal type

Foulkes 2004 Clin Canc Res

GENETIC TESTING AND

GENETIC COUNSELING

Genetic analysis BRCA1&2

• Labor-intensive (3 months) ; expensive

• Mutation detection efficacy 70 %

– Some mutations in introns, in gene

promoters,…

– BRCA3 ?

• Psycho and social impact of testing

• False +, false -. False reassurance.

=> Not performed in each patient with

breast or ovarian cancer(ASCO 1996; ASCO 2003)

Hereditary breast/ovarian cancer

Care management of this patient must

include DNA sampling, in order to counsel

her daughter appropriately in the future.

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

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

*

*Mutation tronquante pLys339ArgfsX2 de BRCA1,

Prévoir ovariectomie chez III.4, tester II.4

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

MANAGEMENT OF CARRIERS

Prophyllactic mastectomy in asymptomatic

carrier ?

• Reduces risk by >95% only if total (not subcutaneous)

– Rebbeck et al J Clin Oncol 2004 (PROSE study), and references therein

• No evidence for significant survival benefit as compared with

surveillance only

– No level 1 evidence, unclear other evidence

– Prospective, randomized, 2-blind study unfeasible

• No effect on ovarian risk.

=> Only in carefully selected, fully informed, mastectomy-requesting

patients

=> Optimal age for procedure = ?

Age-related penetrance

Bilateral mastec if unilateral cancer

in BRCA1or2 carrier ?

• Reduces by 90% risk of recurrence, ipsi or heterolateral (same as in

asymptomatic mutation carrier)

• Does not reduce mortality as compared with surveillance–only group

Van Sprundel et al. Br J Cancer 2005

Guidelines in asymptomatic BRCA1/2

carriers: (1) OVARIES

• Risk-Reducing Salpingo-Oophorectomy at 35-50 yrs:

– Ov.Ca risk 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.Ca risk by 50% if BRCA1 mutation Eisen et al. AJHG 2000; Kauff et al. NEJM 2002; Rebbeck et al. NEJM

2002;

– overall mortalityRebbeck et al. NEJM 2002; Domchek et al. Lancet 2006

• But unclear if same benefit in BRCA2 as in BRCA1(Kauff 2008 JCO)

Guidelines in asymptomatic BRCA1/2

carriers: (2) BREAST

• Prophyllactic total mastectomy ? Unclear benefit in termsof survival– Br ca risk by 90% (95% if +RRSO) Rebbeck et al 2004 JCO

• Breast surveillance: – monthly self-exam? No proven benefit

– mammograms ± USMammograms reduce breast cancer death by 22% after 50 yrs (Humphrey 2002 Ann Int Med)BUT: denser breast / faster doubling size in younger women

Ultrasounds 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, less Sp => likely costeffective 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)

Guidelines in asymptomatic BRCA1/2

carriers (3)

• optimum = ?

• Bilat prophyl salpingo-oophorectomy at 35-50 yrs:

– Ov.Ca risk 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.Ca risk by 50% if BRCA1 mutation Eisen et al. AJHG 2000; Kauff et al. NEJM 2002; Rebbeck et al. NEJM 2002;

– overall mortalityRebbeck 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 ? Unclear benefit => only in carefully selected, fully informed patients

Trends

• Identify low-penetrance

alleles

• Risk profiling ?

• Targeted prevention ?

• Pathway-specific

therapies

• Pharmacogenetics

SOME MOLECULAR DATA

Major (monogenic) hereditary predisposition

to breast cancer

Robson & Offit 2007

Major (monogenic) and minor (polygenic)

hereditary predisposition to breast cancer

Robson & Offit 2007

A cellular pathway of DNA repair and

chromosome integrity

Walsh & King 2007 Cancer cell

What does this teach us?

• Low penetrance alleles modulate high-penetrance genes

(eg Antoniou 2008 AJHG)

• BRCA1 deficient cell lines are sensitive to Xrays;

Etoposide; Bleomycin: double-strand DNA breaks, and

Platinum drugs: DNA cross-links

=> platinum clinical trials in BRCA1-deficient tumor

patients

What does this teach us?

• Low penetrance alleles modulate high-penetrance genes

(eg Antoniou 2008 AJHG)

• BRCA1 deficient cell lines are sensitive to Xrays;

Etoposide; Bleomycin: double-strand DNA breaks, and

Platinum drugs: DNA cross-links

=> platinum clinical trials in BRCA1-deficient tumor

patients

• Poly-ADP-ribose polymerase (PARP) required at initial

step of DNA repair

=> PARP inhibitors in BRCA1 or 2-deficient tumor

patients

LOW-PENETRANCE ALLELES

Majority ? of breast cancers

• Some susceptibility stems from combination of several

genes, each with low penetrance

– Twin studies: concordant MZ ~25% (Ahlbom et al 1997 JNCI; Baker et al 2005 Biometrics)

– SNPs; CNVs (?); polygenic

– A few genes known in 2008… more data are coming

• CHEK2, ATM, PALB2, BRIP1; …, FGFR2,

– Some of the same genes modify severity of BRCA1&2 course

– No routine testing

• Environment (hormones, diet, other factors)

• Epigenetic effects? Already in utero ??

Families with > 4 cases of breast cancer

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.

Am J Hum Genet 62:676-9, 1998

Familial breast cancer: 58209 cases + 101986 controls Collaborative group, Lancet 358:1389-99, 2001

• 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.

Trends

• Identify low-penetrance

alleles

• Risk profiling ?

• Targeted prevention ?

• Pathway-specific

therapies

• Pharmacogenetics

Age-related penetrance