Hereditary Cancer Predisposition

Patricia A. Ganz, MD

Cancer is a Genetic Disease

NormalNormal

TumorTumor

Cancer Arises From Gene Mutations

Germline mutations Somatic mutationsSomatic mutations

Somatic Somatic mutation (eg, mutation (eg,

breast)breast)

MutatioMutation in egg n in egg

or or spermsperm

All cells All cells affected in affected in offspringoffspring

ParentParent ChildChild

ll Present in egg or spermPresent in egg or spermll Are heritable Are heritable ll Cause hereditary Cause hereditary

cancer syndromescancer syndromes

ll Occur in nongermline Occur in nongermline tissues tissues

ll Are nonheritableAre nonheritablell Later onsetLater onset

All Cancer is Genetic, Not All Cancer is Inherited

Fourth + mutation

Normal cell

Fourth + mutation

First mutation

Second mutation

Third mutation

Malignant cell

First mutation

Second mutation

Third mutation

Malignant cell

Sporadic CancerSporadic Cancer Hereditary CancerHereditary Cancer

Hereditary Versus Sporadic Cancer

SporadicSporadic

•• Onset of breast cancer usually < 50Onset of breast cancer usually < 50•• Ovarian cancer at any age Ovarian cancer at any age

(not always present)(not always present)•• Breast and ovarian cancer in the same Breast and ovarian cancer in the same

individualindividual•• Male breast cancerMale breast cancer•• Ashkenazi ancestryAshkenazi ancestry

HereditaryHereditary

Br, 42Br, 42

Ov, 71Ov, 71 Br, 45Br, 45

Br, 71Br, 71

Br, 63Br, 63

•• None of the breast None of the breast cancer is diagnosed cancer is diagnosed before 60 yrsbefore 60 yrs

•• No ovarian cancerNo ovarian cancer•• No clear pattern on one No clear pattern on one

side of family or the side of family or the otherother

The Key to Identification: Family History

ll Maternal and Maternal and paternal family paternal family historyhistory

ll Accurate risk Accurate risk assessmentassessment

ll Effective genetic Effective genetic counselingcounseling

ll Appropriate Appropriate medical followmedical follow--upup

When to Suspect Hereditary Cancer Syndrome

• Cancer in 2 or more relatives (on same side of family)

• Early age at diagnosis• Multiple primary tumors• Bilateral or multiple rare cancers• Constellation of tumors consistent with

specific cancer syndrome (eg, breast and ovary)

• Evidence of autosomal dominant transmission

• Ancestry

How Much Breast and Ovarian Cancer Is Hereditary?

SporadicSporadicFamily clustersFamily clustersHereditaryHereditary

Ovarian CancerOvarian CancerBreast CancerBreast Cancer

5%5%––10%10% >10%>10%

15%15%20% 20%

BRCA1 and BRCA2

BRCA2BRCA2 BRCA1BRCA1

Adapted from Adapted from Tools for Understanding GeneticsTools for Understanding GeneticsNational Human Genome Research InstituteNational Human Genome Research Institute

Office of Science Education and OutreachOffice of Science Education and Outreachwww.nhgri.nih.gov/DIR/VIPwww.nhgri.nih.gov/DIR/VIP

Inheritance Pattern: Autosomal Dominant with Incomplete Penetrance

ll Penetrance is often incompletePenetrance is often incompletell May appear to May appear to ““skipskip”” generations generations ll Individuals inherit altered cancer susceptibilityIndividuals inherit altered cancer susceptibility gene, gene,

not cancer not cancer

Normal Normal

Carrier, affected Carrier, affected with cancerwith cancer

Susceptible CarrierSusceptible Carrier

Sporadic cancerSporadic cancer

BRCA1-Associated Cancers:Lifetime Risk

Possible increased risk of other Possible increased risk of other cancers (eg, male breast, colon)cancers (eg, male breast, colon)

Breast cancerBreast cancer 50%50%85% (often early age at onset)85% (often early age at onset)

Second primarySecond primary breast cancerbreast cancer ~60%~60%

Ovarian cancerOvarian cancer 40%40%60%60%

BRCA2-Associated Cancers: Lifetime Risk

Increased risk of prostate and Increased risk of prostate and pancreatic cancers (magnitude pancreatic cancers (magnitude

unknown)unknown)

breast cancerbreast cancer50%50%85%85%

ovarian cancerovarian cancer10%10%27%27%

male breast cancermale breast cancer6%6%

Second primarySecond primary breast cancerbreast cancer ~50%~50%

BRCA1 and BRCA2 Mutations in the Ashkenazi Jewish Population

An estimated 1 in 40 Ashkenazi Jews An estimated 1 in 40 Ashkenazi Jews carries a carries a BRCA1BRCA1 or or BRCA2BRCA2 mutationmutation

Roa BB et al. Roa BB et al. Nat Genet Nat Genet 14:185, 1996 14:185, 1996 Oddoux C et al.Oddoux C et al. Nat Genet Nat Genet 14:188, 1996 14:188, 1996 Struewing JP. Struewing JP. N Engl J MedN Engl J Med 336:1401, 1997336:1401, 1997

185delAG185delAGPrevalence = ~1%Prevalence = ~1%

5382insC5382insCPrevalence = ~0.15%Prevalence = ~0.15%

6174delT6174delTPrevalence = ~1.5%Prevalence = ~1.5%

BRCA1BRCA1

BRCA2BRCA2

Breast Cancer Management Options• Surveillance:

– Self breast exam, Clinical breast exam, Mammogram, Breast MRI, and Breast Ultrasound.

– MRI has been shown to have higher sensitivity in BRCA carriers (77-91% for MRI vs. 33-36% for mammography)

• Chemoprevention: – Tamoxifen

• Prophylactic Surgery:– Bilateral Mastectomy is associated with ~90% reduction of

breast cancer risk in women with BRCA mutations– Bilateral Salpingo-Oophorectomy is associated with ~50%

reduction in breast cancer risk when done prior to menopause.

NEJM 2002;345:159-64. JAMA 2000; 283:617-24. J Clin Oncol 2005;23:8469-8476. JNCI 2001;93:1633-7.Lancet 2000;356:1876-1881. JAMA 2004;292:1317-1325.

Ovarian Cancer Management Options•• Surveillance: CASurveillance: CA--125, Pelvic exams, Transvaginal 125, Pelvic exams, Transvaginal

ultrasoundultrasound““There are no data demonstrating that screening these highThere are no data demonstrating that screening these high--risk women risk women

reduces their mortality from ovarian cancer. Nonetheless, [the areduces their mortality from ovarian cancer. Nonetheless, [the above bove screening measures] are recommended...screening measures] are recommended...””--NIH Consensus Guidelines, NIH Consensus Guidelines,

JAMA 1995;273:491JAMA 1995;273:491--77

•• Chemoprevention: Chemoprevention: Oral ContraceptivesOral Contraceptives

•• Prophylactic Bilateral SalpingoProphylactic Bilateral Salpingo--Oophorectomy:Oophorectomy: Ovarian cancer risk reduction of ~95%Ovarian cancer risk reduction of ~95% Breast cancer risk reduction of ~50% (premenopausal)Breast cancer risk reduction of ~50% (premenopausal)

NEJM 2002;346(21):1609-1615.NEJM 2002;346(21):1616-1622.NEJM 1998;339:424-428.

Genetic Predisposition Testing Is a Multi-Step Process

Provide Provide postpost--test test

counseling counseling and and

followfollow--upup

Identify Identify atat--risk risk

patientspatients

Provide Provide pretest pretest

counselingcounseling

Provide Provide informed informed consentconsent

Select and Select and offer testoffer test

Disclose Disclose resultsresults

• Anxiety/fear• Guilt• Self-esteem• Depression• Stigmatization• Grief • Anticipatory loss• Changes in family dynamics• How/when to inform at risk children/relatives

Psychological Issues in Testing

Genetic Testing Has Implicationsfor the Entire Family

• Consider the impact of testing on all family members

• Ultimately, testing is the individual’schoice

Questions???