Patricia A. Ganz, MD February 13, 2013

1. Hereditary Cancer
Predisposition
Patricia A. Ganz, MD

2. Cancer is a Genetic Disease
NormalNormal
TumorTumor

3. Cancer Arises From Gene
Mutations
Germline mutations Somatic mutationsSomatic mutations
SomaticSomatic
mutation (eg,mutation (eg,
breast)breast)
MutatioMutatio
n in eggn in egg
oror
spermsperm
All cellsAll cells
affected inaffected in
offspringoffspring
ParentParent ChildChild
ll Present in egg or spermPresent in egg or sperm
ll Are heritableAre heritable
ll Cause hereditaryCause hereditary
cancer syndromescancer syndromes
ll Occur in nongermlineOccur in nongermline
tissuestissues
ll Are nonheritableAre nonheritable
ll Later onsetLater onset

4. 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

5. Hereditary Versus Sporadic
Cancer
SporadicSporadic
•• Onset of breast cancer usually < 50Onset of breast cancer usually < 50
•• Ovarian cancer at any ageOvarian cancer at any age
(not always present)(not always present)
•• Breast and ovarian cancer in the sameBreast 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 breastNone of the breast
cancer is diagnosedcancer is diagnosed
before 60 yrsbefore 60 yrs
•• No ovarian cancerNo ovarian cancer
•• No clear pattern on oneNo clear pattern on one
side of family or theside of family or the
otherother

6. The Key to Identification: Family
History
ll Maternal andMaternal and
paternal familypaternal family
historyhistory
ll Accurate riskAccurate risk
assessmentassessment
ll Effective geneticEffective genetic
counselingcounseling
ll AppropriateAppropriate
medical followmedical follow--upup

7. 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

9. How Much Breast and
Ovarian Cancer Is Hereditary?
SporadicSporadic
Family clustersFamily clusters
HereditaryHereditary
Ovarian CancerOvarian CancerBreast CancerBreast Cancer
5%5%––10%10% >10%>10%
15%15%
20%20%

10. BRCA1 and BRCA2
BRCA2BRCA2 BRCA1BRCA1
Adapted fromAdapted from Tools for Understanding GeneticsTools for Understanding Genetics
National Human Genome Research InstituteNational Human Genome Research Institute
Office of Science Education and OutreachOffice of Science Education and Outreach
www.nhgri.nih.gov/DIR/VIPwww.nhgri.nih.gov/DIR/VIP

11. Inheritance Pattern: Autosomal
Dominant with Incomplete Penetrance
ll Penetrance is often incompletePenetrance is often incomplete
ll May appear toMay appear to ““skipskip”” generationsgenerations
ll Individuals inherit altered cancer susceptibilityIndividuals inherit altered cancer susceptibility gene,gene,
not cancernot cancer
NormalNormal
Carrier, affectedCarrier, affected
with cancerwith cancer
Susceptible CarrierSusceptible Carrier
Sporadic cancerSporadic cancer

12. BRCA1-Associated Cancers:
Lifetime Risk
Possible increased risk of otherPossible 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%

13. BRCA2-Associated Cancers:
Lifetime Risk
Increased risk of prostate andIncreased risk of prostate and
pancreatic cancers (magnitudepancreatic cancers (magnitude
unknown)unknown)
breast cancerbreast cancer
50%50%85%85%
ovarian cancerovarian cancer
10%10%27%27%
male breast cancermale breast cancer
6%6%
Second primarySecond primary breast cancerbreast cancer ~50%~50%

14. BRCA1 and BRCA2 Mutations in
the Ashkenazi Jewish Population
An estimated 1 in 40 Ashkenazi JewsAn estimated 1 in 40 Ashkenazi Jews
carries acarries a BRCA1BRCA1 oror BRCA2BRCA2 mutationmutation
Roa BB et al.Roa BB et al. Nat GenetNat Genet 14:185, 199614:185, 1996
Oddoux C et al.Oddoux C et al. Nat GenetNat Genet 14:188, 199614:188, 1996
Struewing JP.Struewing JP. N Engl J MedN Engl J Med 336:1401, 1997336:1401, 1997
185delAG185delAG
Prevalence = ~1%Prevalence = ~1%
5382insC5382insC
Prevalence = ~0.15%Prevalence = ~0.15%
6174delT6174delT
Prevalence = ~1.5%Prevalence = ~1.5%
BRCA1BRCA1
BRCA2BRCA2

15. 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.

16. Ovarian Cancer Management Options
•• Surveillance: CASurveillance: CA--125, Pelvic exams, Transvaginal125, Pelvic exams, Transvaginal
ultrasoundultrasound
““There are no data demonstrating that screening these highThere are no data demonstrating that screening these high--risk womenrisk women
reduces their mortality from ovarian cancer. Nonetheless, [the areduces their mortality from ovarian cancer. Nonetheless, [the abovebove
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.

17. Genetic Predisposition Testing
Is a Multi-Step Process
ProvideProvide
postpost--testtest
counselingcounseling
andand
followfollow--upup
IdentifyIdentify
atat--riskrisk
patientspatients
ProvideProvide
pretestpretest
counselingcounseling
ProvideProvide
informedinformed
consentconsent
Select andSelect and
offer testoffer test
DiscloseDisclose
resultsresults

18. • 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

19. Genetic Testing Has Implications
for the Entire Family
• Consider the
impact of testing
on all family
members
• Ultimately,
testing is the
individual’s
choice

20. Questions???