Genetic Testing forHereditary CancerSusceptibilityGenetic Testing forHereditary CancerSusceptibility
The Ohio State UniversityThe Ohio State University
Clinical Cancer Genetics ProgramClinical Cancer Genetics Program
Comprehensive Cancer CenterComprehensive Cancer Center
Learning ObjectivesLearning Objectives
The presentation will enable the participant to:The presentation will enable the participant to:
1. Explain the difference between hereditary and non-hereditary cancers.1. Explain the difference between hereditary and non-hereditary cancers.
2. Point out the clinical characteristics of hereditarycancer.2. Point out the clinical characteristics of hereditarycancer.
3. Summarize the importance of counseling prior togenetic testing for hereditary cancer.3. Summarize the importance of counseling prior togenetic testing for hereditary cancer.
4. Identify the current benefits and limitations ofgenetic testing for hereditary cancer4. Identify the current benefits and limitations ofgenetic testing for hereditary cancer
Most cancers are not inherited
5-10% hereditary
10-15% familial
75-85% sporadic
Who is at high risk for cancer?
History is the key…
CLUES:
Cancer in 2 or more close relatives(on same side of family)
Early age at diagnosis
Bilateral/multiple cancers
Multiple rare cancers
Multiple primary tumors (breast and ovary;colon and uterus)
Evidence of autosomal dominanttransmission
CAUTION
Family History is Unreliable
Many patients do not know the detailsof their family history.
––Specific sites of tumors unknown
––Ages of onset unknown
Historical information needs to beverified in order to accurately assessrisk.
Initial pedigree
After review of records
StomachCa
Prostate
problems
Bone Ca
d. 48
Breast Ca
dx 45
d. 48
Ovarian Ca
dx 43, d. 49
Prostate Ca
dx 50
Histories are dynamic
With the passage of time, additionaldiagnoses may have been made.
These changes may affect thelikelihood of a hereditary cancersyndrome.
Initial History
2 years later
Colon Ca, 50
Colon Ca, 50
Endometrial
Ca, 44
Colon polyps, 48
Autosomal Dominant - Incomplete Penetrance
lPenetrance is often incompletelPenetrance is often incomplete
lMay appear to “skip” generationslMay appear to “skip” generations
Individuals inherit altered cancer susceptibility gene,not cancerIndividuals inherit altered cancer susceptibility gene,not cancer
NormalNormal
Carrier, affectedwith cancerCarrier, affectedwith cancer
Susceptible CarrierSusceptible Carrier
Sporadic cancerSporadic cancer
GeneticCounseling
Genetic Counseling:Purpose
Appreciate the way heredity contributes tocancer
Understand an individual’s risk of developingcancer
Understand the options for dealing with anincreased risk for cancer
Choose a course of action for managingcancer risk that seems personallyappropriate (genetic testing, screening orlong-term follow up)
Genetic Counseling:What happens
Collection of personal and family history(3 generation pedigree)
Education and risk assessment
Options for genetic testing and medicalmanagement
––Discussion of risks, benefits and limitations
––Screening/Chemoprevention/Prophylaxis
Follow-up
––Provide psychosocial support
––Family members
Breast Cancer
Breast cancer is common
1 in every 8 American women willbe diagnosed with breast cancer inher lifetime
Misconceptions
Cancer on the father’s side of the familydoesn’t count
––Half of all women with hereditary risk inherited itfrom their father
Ovarian cancer is not a factor in breastcancer risk
–Ovarian cancer is an important indicator ofhereditary risk, although it is not always present–Ovarian cancer is an important indicator ofhereditary risk, although it is not always present
The most important thing in the familyhistory is the number of women with breastcancer
–Age of onset of breast cancer is more importantthan the number of women with the disease–Age of onset of breast cancer is more importantthan the number of women with the disease
Causes of HereditaryBreast Cancer
GeneGene
BRCA1BRCA1
BRCA2BRCA2
TP53 (Li Fraumeni)TP53 (Li Fraumeni)
PTEN (Cowden)PTEN (Cowden)
Undiscovered genesUndiscovered genes
Contribution to HereditaryBreast CancerContribution to HereditaryBreast Cancer
20%–40%20%–40%
10%–30%10%–30%
<1%<1%
<1%<1%
30%–70%30%–70%
The Hereditary Breast andOvarian Cancer Syndrome (HBOC)
Multiple cases of early onset breastcancerMultiple cases of early onset breastcancer
Ovarian cancerOvarian cancer
Breast and ovarian cancer in the samewomanBreast and ovarian cancer in the samewoman
Bilateral breast cancerBilateral breast cancer
Male breast cancerMale breast cancer
Ashkenazi Jewish heritageAshkenazi Jewish heritage
BRCA1-AssociatedCancers: Risk by age 70
Possible increased risk of othercancers (e.g., prostate)
Breast cancer 50-85% (often early age at onset)
Second primary breast cancer 20%-60%
Ovarian cancer 15-45%
BRCA2-AssociatedCancers: Risk by age 70
Increased risk of prostate,laryngeal, and pancreaticcancers (magnitude unknown)
breast cancer
(50-85%)
ovarian cancer
(10-20%)
male breast cancer
(6%)
Breast, dx 40Breast, dx 40
d. 43d. 43
Ovary, dx 45Ovary, dx 45
d. 47d. 47
Prostate, dx 58Prostate, dx 58
Breast, dx 33Breast, dx 33
4242
BRCA-mutation positivefamily
Unaffected
Affectedwith cancer
3838
3535
Mutation carrier
d. 83d. 83
Relevance of AshkenaziJewish descent
1 in 40 (2.5%) Ashkenazi Jews (malesand females) carry a BRCA1 or BRCA2mutation
The carrier rate in non-Jewishpopulations is 1/400 (0.25%)
3 mutations (2 in BRCA1 and 1 inBRCA2) account for 95% of HBOC
Likelihood of developing breast cancer:Likelihood of developing breast cancer:
–Gail model–Gail model
–Claus model–Claus model
Likelihood of having a BRCA1 or 2 mutationLikelihood of having a BRCA1 or 2 mutation
–Myriad risk tables–Myriad risk tables
–BRCAPRO, Couch, Shattuck-Eidens–BRCAPRO, Couch, Shattuck-Eidens
Likelihood of other breast cancer syndrome(Cowden, Li Fraumeni)Likelihood of other breast cancer syndrome(Cowden, Li Fraumeni)
–Pedigree analysis–Pedigree analysis
Breast/Ovarian Cancer RiskAssessmentBreast/Ovarian Cancer RiskAssessment
BRCA1/2 Mutation Prob in aWoman with Breast Ca <50
Any relativewithBr Ca < 50?Any relativewithBr Ca < 50?
Anyrelativewith OvCa?Anyrelativewith OvCa?
Proband withBilateral Br orOv Ca?Proband withBilateral Br orOv Ca?
Probability(%)Probability(%)
88
2525
4444
5555
6262
8181
Possible Results
Positive
Negative
––True negative
Negative result when family mutation known
Negative result in affected person
––Different gene? Can’t find mutation?
Uninformative
––Negative in unaffected individual
––Variant of uncertain significance
Additional information/testing needed
Important considerationswhen ordering testImportant considerationswhen ordering test
Mutation detection rate?Mutation detection rate?
Methods usedMethods used
Frequency of variants of uncertainsignificanceFrequency of variants of uncertainsignificance
–10-12% in Caucasians and 40% in AA!–10-12% in Caucasians and 40% in AA!
Testing technology always improvingTesting technology always improving
–Importance of ability to re-contactpatients–Importance of ability to re-contactpatients
Breast Cancer: Surveillance
Monthly BSE beginning at age 18Monthly BSE beginning at age 18
CBE every 6 months starting at age 25 (or5-10y before the earliest dx in family)CBE every 6 months starting at age 25 (or5-10y before the earliest dx in family)
Annual mammography starting at age 25(or 5-10y before the earliest dx in family)Annual mammography starting at age 25(or 5-10y before the earliest dx in family)
MRI now being used in conjunction withmammogram; increased sensitivity butdecreased specificity
Breast Cancer:Chemoprevention
Matched case-control study
––209 women with bilateral breast ca and BRCA1or BRCA2 mutation
––384 women with unilateral breast ca and BRCA1or BRCA2 mutation
Tamoxifen protected againstcontralateral breast cancer
––BRCA1 odds ratio 0.38 (95% CI 0.19–0.74)
––BRCA2 odds ratio 0.63 (95% CI 0.20–1.50)
Narod Lancet 356:1876, 2000
Prophylactic Mastectomy
Total mastectomy is recommendedmethod, if mastectomy is done.
Significantly reduces breast cancer risk inwomen with a family history (90%)
In women with a BRCA1 or BRCA2mutation, prophylactic bilateral totalmastectomy reduces the incidence ofbreast cancer at 3 years follow-up
Hartman NEJM 340:77, 1999; Meijers-Heijboer NEJM 345: 1499, 2001
Ovarian Cancer:Surveillance
**NIH Consensus Conference, JAMA 273:491, 1995
“There are no data demonstrating that screeningthese high-risk women reduces their mortality from ovariancancer. Nonetheless, [these measures] arerecommended.”*
Pelvic examination and transvaginal ultrasoundwith color Doppler imaging every 6 monthsbeginning at age 30-35 (or 5-10 years prior tothe earliest dx in the family)
Concurrent serum CA-125
Ovarian Cancer:Chemoprevention
Limited data available for BRCA-mutation carriers;preliminary study showed a 60% risk reduction with≥6 years use
Increases breast cancer risk in carriers by 1.2-1.4 fold
Oral Contraceptives
CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997;
Narod NEJM 339:424, 1998
40% to 50% risk reduction in general population
after 3 years cumulative use
Prophylactic Oophorectomy
Decreases risk of ovarian cancer by 95% (primaryperitoneal carcinoma may still occur)*
Reduces risk of breast cancer by 63% if done priorto age 40 and by 50% if done prior to age 50
Induces surgical menopause
Laparoscopic procedure reduces postsurgicalmorbidity
Consider complete hysterectomy for managementof menopause – unopposed, low-dose estrogen
Rebbeck NEJM 346(21):1660, 2002; Kauf NEJM 346(21):1660, 2002
* 5-10% of carriers will have occult malignancy at time of PO -many in the fallopian tube
Benefits and Limitations ofBRCA Testing
Benefits
••Identifies high-riskindividuals
••Identifies noncarriers infamilies with a knownmutation
••Allows early detection andprevention strategies
••May relieve anxiety
Risks and Limitations
••Does not detect all mutations
••Continued risk of sporadic cancer(those who test neg may havefalse sense of assurance)
••Efficacy of interventions unproven
••May result in psychosocialor economic harm
Case 1: RuthCase 1: Ruth
Ruth is a 45 year old woman recently diagnosedwith breast cancer and is concerned about the riskto her daughters, ages 18 and 22. You inquireabout family health history and find out thefollowing information:Ruth is a 45 year old woman recently diagnosedwith breast cancer and is concerned about the riskto her daughters, ages 18 and 22. You inquireabout family health history and find out thefollowing information:
–Maternal family history is negative for cancer–Maternal family history is negative for cancer
–Paternal family history is significant for:–Paternal family history is significant for:
Paternal aunt with ovarian cancer age at 55Paternal aunt with ovarian cancer age at 55
Paternal grandmother with breast cancerage 42Paternal grandmother with breast cancerage 42
Case 1: PedigreeCase 1: Pedigree
Key
-Breast CA
-Ovarian CA
Dx 55
d. 56
Dx 42
82 yrs
Ruth
45
English/Irish
German
37
28
60
58
18
22
Case 1: BRCA1/2 RisksCase 1: BRCA1/2 Risks
Risk of BRCA1/2 mutation:Risk of BRCA1/2 mutation:
–36-44% risk of mutation in patient–36-44% risk of mutation in patient
Referral for Cancer Genetic Counseling isappropriate
–For cancer risk assessment and discussion ofgenetic testing for BRCA1/2–For cancer risk assessment and discussion ofgenetic testing for BRCA1/2
Case 1: PedigreeCase 1: Pedigree
Key
-Breast CA
-Ovarian CA
Dx 55
d. 56
Dx 42
82 yrs
Ruth
45
English/Irish
German
60
58
18
22
BRCA1 2800delAA
42
35
50% risk to daughters50% risk to daughters
Both negative for
specific mutation
BRCA1 +ive
BRCA1 +ive
s/p TAH/BSO
Case 1: Impact of results –medical managementCase 1: Impact of results –medical management
RuthRuth
–may want to consider oophorectomy–may want to consider oophorectomy
Ruth’s daughtersRuth’s daughters
– General pop’n risk for breast and ovarian cancer –follow ACS guidelines– General pop’n risk for breast and ovarian cancer –follow ACS guidelines
–Cannot pass this on to their children–Cannot pass this on to their children
Ruth’s sisterRuth’s sister
–Consider increased breast cancer screening +/-chemoprevention OR mastectomy/MRI and ovariancancer screening and oophorectomy (after child-bearing, ~40)–Consider increased breast cancer screening +/-chemoprevention OR mastectomy/MRI and ovariancancer screening and oophorectomy (after child-bearing, ~40)
Ruth’s 1st cousinRuth’s 1st cousin
–Consider increased breast cancer screening +/-chemoprevention or mastectomy/MRI–Consider increased breast cancer screening +/-chemoprevention or mastectomy/MRI
Case 1: Impact of results -psychosocialCase 1: Impact of results -psychosocial
Ruth feels relieved about daughtersbut overwhelmed about risk of ovariancancerRuth feels relieved about daughtersbut overwhelmed about risk of ovariancancer
–timing–timing
Ruth’s daughters are happyRuth’s daughters are happy
Ruth’s sister feels empowered byinformationRuth’s sister feels empowered byinformation
Ruth’s other sister wants nothing to dowith this and won’t go to the doctorRuth’s other sister wants nothing to dowith this and won’t go to the doctor
Case 1: Take HomeMessagesCase 1: Take HomeMessages
Risk assessment and genetic testing givesinformation to patient AND family membersRisk assessment and genetic testing givesinformation to patient AND family members
–Some family members may want this informationand some may not–Some family members may want this informationand some may not
Genetic testing, when informative, can helpindividuals make decisions about earlydetection and risk-reductionGenetic testing, when informative, can helpindividuals make decisions about earlydetection and risk-reduction
Can also relieve anxiety about cancer risk (ifnegative)Can also relieve anxiety about cancer risk (ifnegative)
Informed decision-making imperativeInformed decision-making imperative
Follow-up support and/or counselingsometimes necessaryFollow-up support and/or counselingsometimes necessary
Case 2: AlisonCase 2: Alison
Alison is a 40 year old daughter of one of your patients.While attending her mother’s appointment, she asks youfor information about the “breast cancer gene test”.She states she wants this test.Alison is a 40 year old daughter of one of your patients.While attending her mother’s appointment, she asks youfor information about the “breast cancer gene test”.She states she wants this test.
You ask her about her family history:You ask her about her family history:
–Mother with breast cancer - age 58–Mother with breast cancer - age 58
–Maternal aunt with breast cancer – age 65–Maternal aunt with breast cancer – age 65
–Paternal grandmother with breast cancer – age 79–Paternal grandmother with breast cancer – age 79
She feels that with her family history, breast cancer isinevitableShe feels that with her family history, breast cancer isinevitable
Case 2: PedigreeCase 2: Pedigree
Dx 58
65 yr
Dx 65
71 yr
Dx 79
d.81
Caucasian mix
Swedish / Finnish
Key:
-Breast CA
Alison
40 yr
15 yr
Menses began at age 11
1st child at age 25
No other risk factors
Case 2: Risk AssessmentCase 2: Risk Assessment
Gail Model:Gail Model:
–5 year risk of breast cancer 1.2%; Lifetime risk of20.4%–5 year risk of breast cancer 1.2%; Lifetime risk of20.4%
Claus Model:Claus Model:
–Lifetime risk for breast cancer of 18.8%–Lifetime risk for breast cancer of 18.8%
Myriad table:Myriad table:
–3.4% risk of BRCA1/2 mutation using family history–3.4% risk of BRCA1/2 mutation using family history
Pedigree analysis:Pedigree analysis:
–no indications of other breast cancer syndromes–no indications of other breast cancer syndromes
Patient concernsPatient concerns
“Moderate/Familial” Risk“Moderate/Familial” Risk
Clustering of cancer cases seen in the familyClustering of cancer cases seen in the family
Ages of onset not strikingly youngAges of onset not strikingly young
Risks for first degree relatives increasedRisks for first degree relatives increased
–Risk depends on number of family membersaffected, how closely related, ages of onset–Risk depends on number of family membersaffected, how closely related, ages of onset
Multiple low-penetrance genes may play arole and interact with environmental triggersMultiple low-penetrance genes may play arole and interact with environmental triggers
Case 2: PedigreeCase 2: Pedigree
Dx 58
65 yr
Dx 65
71 yr
Dx 79
d.81
Caucasian mix
Swedish / Finnish
Key:
-Breast CA
Alison
40 yr
15 yr
Case 2: AssessmentCase 2: Assessment
Patient is in “Moderate/Familial” risk categoryPatient is in “Moderate/Familial” risk category
Can begin breast cancer screening by age 35Can begin breast cancer screening by age 35
Ovarian cancer risk not increasedOvarian cancer risk not increased
Counseling issues:Counseling issues:
–Low risk for BRCA1 or BRCA2 mutation–Low risk for BRCA1 or BRCA2 mutation
–Screening and preventive strategies–Screening and preventive strategies
–Psychosocial – perceived risk, fears–Psychosocial – perceived risk, fears
–Future research?–Future research?
Case 2: Take HomeMessagesCase 2: Take HomeMessages
Number of cancers in family is not asimportant as the ages at diagnosisNumber of cancers in family is not asimportant as the ages at diagnosis
–Side of family matters as well (all on oneside or some on each)–Side of family matters as well (all on oneside or some on each)
Perceived risk does not always equalactual riskPerceived risk does not always equalactual risk
–Genetic counseling/risk assessment canhelp–Genetic counseling/risk assessment canhelp
Genetic counseling/risk assessmentdoes not always lead to genetic testingGenetic counseling/risk assessmentdoes not always lead to genetic testing
Case 3 - VeraCase 3 - Vera
Vera is a 38 year old microbiologistconcerned about her breast cancer riskVera is a 38 year old microbiologistconcerned about her breast cancer risk
Family history of breast and ovariancancer in 2nd and 3rd degree relativesFamily history of breast and ovariancancer in 2nd and 3rd degree relatives
Wants gene testingWants gene testing
Case 3 - PedigreeCase 3 - Pedigree
dx 55
dx 31 R brca
dx 50 L brca
d. 75 CVA
Vera
38
62
58
dx 55 colon
or ovarian ca
d. 56
ItalianItalian
]
[
64
7
Menses began at age 12
1st child at age 31
No other risk factors
Case 3 - AssessmentCase 3 - Assessment
Gail risk = 14.3%Gail risk = 14.3%
Claus = General populationClaus = General population
a priori risk of mutation in Vera =3.75-16% (1.25-7%)a priori risk of mutation in Vera =3.75-16% (1.25-7%)
a priori risk of mutation in Vera’s aunt= 15-64% (5-28%)a priori risk of mutation in Vera’s aunt= 15-64% (5-28%)
Recommended genetic testing forVera’s auntRecommended genetic testing forVera’s aunt
Case 3 – CounselingissuesCase 3 – Counselingissues
Vera did not feel comfortable contacting herauntVera did not feel comfortable contacting heraunt
Vera wanted to be tested herselfVera wanted to be tested herself
–Genetic counseling covered risks, benefits andlimitations of testing–Genetic counseling covered risks, benefits andlimitations of testing
–Always try to start testing with an affectedindividual–Always try to start testing with an affectedindividual
Inconclusive resultInconclusive result
–Negative in Vera – not true negative–Negative in Vera – not true negative
–Variant of uncertain significance–Variant of uncertain significance
Case 3 – Test resultsCase 3 – Test results
dx 55
dx 31 R brca
dx 50 L brca
d. 75 CVA
Vera
38
62
58
dx 55 colon
or ovarian ca
d. 56
ItalianItalian
]
[
65
7
+ BRCA2 N517S+ BRCA2 N517S
Variant of uncertainVariant of uncertain
significancesignificance
Variants of uncertainsignificance (VUS)Variants of uncertainsignificance (VUS)
10-12% of people tested for BRCA1/2 willhave a VUS10-12% of people tested for BRCA1/2 willhave a VUS
Use lab data to determine significanceUse lab data to determine significance
–incidence in controls–incidence in controls
–amino acid change and position in gene–amino acid change and position in gene
–segregation in family – free testing for VUS incertain family members–segregation in family – free testing for VUS incertain family members
–FUNCTIONAL STUDIES–FUNCTIONAL STUDIES
On research basis onlyOn research basis only
Most are NOT disease causing but can takeyears to determine thisMost are NOT disease causing but can takeyears to determine this
Case 3 - Test resultsCase 3 - Test results
dx 55
dx 31 R brca
dx 50 L brca
d. 75 CVA
Vera
38
62
58
dx 55 colon
or ovarian ca
d. 56
ItalianItalian
]
[
65
7
+ BRCA2 N517S+ BRCA2 N517S
+ BRCA2 N517S+ BRCA2 N517S
N517S is true mutationN517S is true mutation
N517S is not true mutationN517S is not true mutation
(1 in 4 chance of sharing by chance)(1 in 4 chance of sharing by chance)
Follow Vera as high riskFollow Vera as high risk
until proven otherwiseuntil proven otherwise
Case 3 - Test resultsCase 3 - Test results
Decides toDecides to
have comprehensivehave comprehensive
BRCA1/2 testingBRCA1/2 testing
dx 55
dx 31 R brca
dx 50 L brca
d. 75 CVA
Vera
38
62
58
dx 55 colon
or ovarian ca
d. 56
ItalianItalian
]
[
65
7
+ BRCA2 N517S+ BRCA2 N517S
+ BRCA1 C61G+ BRCA1 C61G
True Negative!True Negative!
+ BRCA2 N517S+ BRCA2 N517S
Follow ACS guidelinesFollow ACS guidelines
Take Home Messages –Case 3Take Home Messages –Case 3
Always try to start testing with anaffected individualAlways try to start testing with anaffected individual
Some patients have higher risk of VUSthan a true mutationSome patients have higher risk of VUSthan a true mutation
Pre-test counseling for VUS importantPre-test counseling for VUS important
Don’t assume other family memberswon’t be interested in testingDon’t assume other family memberswon’t be interested in testing
Summary
When Should GeneticTesting Be Considered?
Significant family cancer history
Reasonable likelihood of carrying amutation (affected usually tested first)
Results will influence medicalmanagement
Patient wants information(empowerment)
Genetic testing should always beperformed in the context of geneticcounseling
––Discuss all medical and social concerns
––Provide psychosocial support
It is easier to review the implicationsof testing prior to obtaining results
When Should GeneticTesting Be Considered?
Pros and Cons of
Genetic Testing
Pros:
Improved cancer risk management
Information for individual and family members
Lifestyle decision making
Cons:
Limited testing is available, especially formoderate risk families
Results indicate probability, not certainty
Insurance issues, confidentiality
Insurance issuesInsurance issues
HIPAA protects patients with grouphealth insurance from geneticdiscriminationHIPAA protects patients with grouphealth insurance from geneticdiscrimination
–Some gaps–Some gaps
GINA –Passed the House; Senate votependingGINA –Passed the House; Senate votepending
–Cover gaps in HIPAA–Cover gaps in HIPAA
Most states have state laws in placeMost states have state laws in place
–Wide variability in coverage–Wide variability in coverage
http://www.cancerdiagnosis.nci.nih.gov/specimens/50_state_survey/appendix_a.htmhttp://www.cancerdiagnosis.nci.nih.gov/specimens/50_state_survey/appendix_a.htm
Implicationsfor the Entire Family
Consider theimpact of testingon all familymembers.
Ultimately,testing is theindividual’schoice.
