Breast Cancer Genetics

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Breast Cancer Genetics

• Sandhya Pruthi, MD
• Assistant Professor of Medicine Mayo College of
  Medicine
• Mayo Clinic
• Rochester, MN

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Breast Cancer, U.S. Women
Age-adjustedincidence rate/100,000
Survival probability
Year
Ries et al SEER Cancer Statistics Review, 2007
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Risk Factors for Breast Cancer
Relative risk
Age
HRT
Age atmenarche
Age atmenopause
Oralcontraceptives(1975)
Alcoholconsumption
Prophylacticoophorectomy
Mammographicbreast density
Previous benigndisease
Family history
Postmenopausal
McPherson K et al BMJ 321625, 2000
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Sporadic80
Hereditary 5
Familialhistory 15
CP1336569-3
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"Sporadic" Breast Cancer No Family History of
Breast Cancer

• 10-12 lifetime risk
• Why?
• Etiology unknown
• Interaction of environmental and genetic factors
• Endogenous and exogenous hormone exposures

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"Familial Breast Cancer"

• Not isolated event in family
• not "sporadic"
• No clear hereditary pattern either
• Having relative with breast cancer indicates
  modestly increased risks in relatives
• Speculation regarding the combination of
  multiple low "penetrance" genes interacting with
  environmental exposures

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"Hereditary" Breast Cancer

• Attributed to a mutation in a particular gene
  which is present in every cell of the body and
  can be passed on to the next generation.

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The Family History Is the Key

• The genetic risks associated with hereditary
  breast cancer eclipse the risks associated with
  other factors

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Features That Indicate Increased Likelihood of
Having BRCA Mutations

• Multiple cases of early onset breast cancer
• Ovarian cancer (with family history of breast or
  ovarian cancer)
• Breast and ovarian cancer in the same woman
• Bilateral breast cancer
• Ashkenazi Jewish heritage
• Male breast cancer

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Some Factors That Influence Risk Perception

• Family experience with cancer
• Personality traits
• Disease perception
• Family relationships
• Educational level
• Cultural, social, and religious factors

ASCO
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Predicting Risk "What is My Risk of Getting
Breast Cancer?"

• 2004 Institute of Medicine Report on breast
  cancer screening
• Individual risk assessment is essential to
  improve early detection of breast cancer
• Two main types of risk assessment
• Chance of developing breast cancer over one's
  lifetime
• Chance of their being a mutation in a high-risk
  gene such as BRCA 1 or BRCA 2

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Assessing the Risk of Breast Cancer

• Average risk 12 life time risk
• Epidemiologic risk factors
• Risk Prediction Models
• Genetic Susceptibility Testing

Several factors influence the selection of a
risk prediction method for an individual woman
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Genetic Testing

• Psychological Do you want to know?
• Why or why not?
• Now or maybe later?
• Increased anxiety or knowledge is power?
• Guilt about children
• Altered self esteem/image
• How do you tell the relatives?
• What are you going to do with the information?

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Case 1

• 42 yr old woman presents with a strong family
  history of breast/ovarian cancer and wants to
  know what is her risk of developing breast
  cancer?
• Mother breast cancer at age 44 years
• Sister breast cancer- age 38 yrs
• Sister breast cancer age 29 and ovarian cancer
  age 42 yrs
• GoPo, Oral contraceptive pills for 20 yrs,
  non-smoker, no alcohol

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Case 1

• Past Surgical History Uterine fibroids and s/p
  hysterectomy and prophylactic salpingo-oophorecto
  my for uterine fibroids
• Recommendations
• Consultation with a genetic counselor to discuss
  the role of genetic testing
• Consider chemoprophylaxis with Tamoxifen
• Discussed lifestyle modification
• Discussed role of prophylactic mastectomy

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Breast Cancer Risk Assessment Tool5 Factors
Significant Predictors ofLifetime Risk of Breast
Cancer
Gail Model
www.breastcancerprevention.com www.cancer.gov/bcri
sktool/
CP1277389-11
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Gail Model "Nongenetic Risk Factors"
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The Gail Model Can Underestimate Hereditary Risk
of Breast Cancer
Breast, 44
Breast, 38
Breast, 29 Ovary, 42
This womans breast cancer risk would be greatly
underestimated
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Claus Tables

• Statistical model to calculate cumulative breast
  cancer risk based on family history
• Risk estimates derived from the family history of
  5,000 breast cancer cases (age 20-54) and
  age-matched controls in US
• Family history of breast cancer is the only risk
  factor red
• Does not include reproductive or hormonal risk
  factors
• Published tables vs computerized versions

Claus EB et al. Cancer 73643, 1994 Amir et al, J
Med Genet 2003,40807-814
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Claus Table Example
1o relative with breast cancer Age at dx
Age of woman 29 39 49 59 69 79
20-29 .007 .025 .062 .116 .171 .211
30-39 .005 .017 .044 .086 .130 .165
40-49 .003 .012 .032 .064 .101 .132
70-79 .001 .005 .015 .035 .062 .088
Claus EB et al. Cancer 73643, 1994 Armstrong et
al, NEJM, Feb 2000
ASCO
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Predicted Probability of a BRCA1 Mutation (
Couch Model)
Average age at Dx of Br Ca 50-54 55-59 59
Probability () Br Ca only family 17.4 11.7 7.7 5
.0 3.2 2.1 1.3
Probability () Br Ca/Ov Ca family 55.0 43.5 32.7
23.4 16.2 10.8 7.1
(Avg of 3.5 cancers/family)
Couch FJ et al. N Engl J Med 3361409, 1997
ASCO
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Other Breast Cancer Risk Assessment Models

• Tyrer-Cuzick Model ( IBIS model)
• Combination of extensive family history,
  endogenous estrogen exposure and benign breast
  disease history
• Estimates lifetime risk for developing breast
  cancer
• BRCAPRO Model
• Includes information on both affected and
  unaffected relatives
• Provides an estimate for the likelihood of
  finding a BRCA 1 or 2 mutation in a family
• Amir et al, J Med Genet 2003,40807-814

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Genetic Counseling

• If the family history is concerning for possible
  genetic predisposition to hereditary breast
  cancer strong consideration should be given for
  genetic counseling and possible BRCA testing
• Testing should be done through a formal program
  that provides specialized genetic counseling for
  BRCA testing
• Individuals need to be informed and aware of
  risks, benefits and limitations of testing

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Genetic Predisposition Testing Is a Multistep
Process
Provide posttest counseling and follow-up
Disclose results
Select and offer test
Provide informed consent
Provide pretest counseling
Identify at-risk patients
Geller G et al JAMA 19972771476-1474 Offit K.
Clinical Cancer Genetics Risk Counseling and
management. New York Wiley-Liss,
1998 Schneider K. Counseling about Cancer
Strategies for Genetic Counseling. 2nd ed. New
York John Wiley Sons 2001
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Benefits, Risks, and Limitations of BRCA Testing
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BRCA1-Associated Cancers Lifetime Risk
Breast cancer 50-85 (often early age at onset)
Second primary breast cancer 40-60
Ovarian cancer 15-45
Possible increased risk of other cancers (eg,
prostate, colon)
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BRCA2-Associated Cancers Lifetime Risk
breast cancer (50-85)
male breast cancer (6)
ovarian cancer (10-20)
Increased risk of prostate, laryngeal, and
pancreatic cancers (magnitude unknown)
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Here Are The Soloists Single Gene
Predisposition to Breast Cancer
Contribution to Hereditary Breast
Cancer 2545 1530 Gene BRCA1 BRCA2 TP53 (Li-Fraumeni) PTEN
(Cowden) STK11 (Peutz-Jegher) CDH1 (hereditary
diffuse diffuse gastric cancer) Undiscovered
causes
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Strategies for Breast Cancer Risk Reduction
Very High Risk
Risk stratification
Management
Very strong familyhistory of possiblegenetic
predis-position or Known BRCA 1or BRCA 2
geneticmutation (HereditaryBreast
OvarianCancer HBOC)

• Q 6 month CBE
• Annual mammogram (age 25 or 5-10 yrsbefore
  youngest 1st degree relative )
• Additional imaging ( breast MRI)
• Breast health awareness
• Consider chemoprevention (role ofTamoxifen in
  HBOC)
• Consider clinical trial
• Consider prophylactic mastectomy
• Consider prophylactic oophorectomy
• Lifestyle modification
• Discuss genetics consultation

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Case 1- Follow- up

• Genetic consultation
• Her mother agrees to undergo genetic testing and
  is positive for the BRCA 2 gene mutation
• The patient decides to pursue gene testing and is
  also found to carry the same BRCA 2 gene mutation
  
• Counseled regarding prophylactic mastectomy-"not
  interested"
• Decides to initiate Tamoxifen chemoprophylaxis
• Wants to continue with close surveillance and
  asks about breast imaging options

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Surveillance Options for Breast Cancer in
BRCA-Mutation Carriers

• Monthly breast self-exams (begin by age 18)
• and
• Early clinical surveillance (begin at age 25)
• Every 6 month clinical breast exams
• Annual mammography
• Additional imaging
• Annual breast MRI ( beginning age 30) in
  conjunction with mammography

Modified from Cancer Genetics Studies Consortium
Consensus Statement Burke W et al. JAMA 277997,
1997
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Breast MRI
Contrast enhancement compared to surrounding
breast tissue due to tumor-associated
neovascularity
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American Cancer Guidelines 2007

• Annual screening breast MRI in conjunction with
  mammography based on VERY HIGH RISK criteria
• 20-25 lifetime risk of developing breast
  cancer
• Strong family Hx of breast or ovarian ca
• Women treated with chest wall radiation before
  age 30

• BRCA 1 or 2 gene mutation carriers

Risks, benefits and limitations of breast MRI
CA Cancer J Clin 5775, 2007
CP1277389-37
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CP1336569-33
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MRI and Mammography Screening for High-Risk Women
Kriege et al Netherlands NEJM, 2004
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Surveillance Options for Ovarian Cancer in
BRCA-Mutation Carriers

• No proven methodology
• Annually or semiannually, starting at 25-35
• Transvaginal ultrasound w/color Doppler imaging
• CA-125

There are no data demonstrating that screening
these high-risk women reduces their mortality
from ovarian cancer. Nonetheless, these
measures are recommended.
NIH Consensus Conference, JAMA 273491, 1995
Berliner et al- J Genetic Counsel ( 2007)
16241-260
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Risk Reduction Mastectomy (RRM) or Prophylactic
Mastectomy

• Removes most but not all breast tissue
• May significantly reduce breast cancer risk in
  women with a strong family history
• 90 reduction in breast cancer risk
• Rebbeck et al, J Clin Onc 2004221055-62
• Hartmann et al, NEJM 199934077-84
• Total (simple) mastectomy removes more breast
  tissue than subcutaneous mastectomy
• The absolute risk after RRM has not been clearly
  defined

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Prophylactic Salpingo-Oophorectomy

• Risk-reducing salpingo-oophorectomy (RRSO)
• Ovarian cancer estimated risk reduction 80-95
• Breast cancer risk reduction by 40-50
• Peritoneal cancer may still occur (0.2
  annually)
• Laparoscopic oophorectomy reduces postsurgical
  morbidity
• Induces surgical menopause

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Prophylactic Surgery Issues

• Childbearing considerations
• Quality of life
• Body image, self-esteem
• Loss of nipple sensitivity
• Management of surgical menopause
• Residual cancer risk
• Hormone Therapy if less than 50 yrs
• Consider short term/low dose estrogen for quality
  of life symptoms

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Chemoprevention of Breast Cancer
Tamoxifen
49 reduction of breast cancer incidence in
high-risk women (mean follow-up of 4 years)

• Breast cancer prevention trial A subgroup
  analysis did suggest Tamoxifen may reduce breast
  cancer risk in BRCA 2 mutation carriers but not
  BRCA 1 carriers

King et al, JAMA 20012862251-6 Fisher et al,
JNCI 1998901371-1388
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Chemoprevention of Ovarian Cancer
Oral Contraceptives
In general population, OCs reduce risk of ovarian
cancer 40 to 50 after 3 years cumulative use

• Modest increase in the risk of breast cancer with
  long-term use ( more than 5 years) especially
  among young BRCA 1 mutation carriers

King et al, JAMA 20012862251-6 Fisher et al,
JNCI 1998901371-1388
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Case 1 Follow-up

• Screening mammogram Normal
• Screening Breast MRI
• Right breast revealed a 6 mm area of enhancement
  worrisome for malignancy
• US guided bx- confirms invasive ductal carcinoma
• Elects to proceed to breast conservation surgery
• Stops Tamoxifen and initiates an Aromatase
  Inhibitor ( 5 years of therapy)

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Key Points in Genetic Testing for Breast Cancer

• Genetic testing can identify individuals at risk
  for hereditary breast and ovarian cancer
• Empiric risk models are available to assess risk
  of breast and ovarian cancer
• Efficacy of interventions for BRCA mutation
  carriers is still unproven
• Patients who are not at high risk can be spared
  anxiety and the need for increased surveillance
• Always recommend a genetic consult prior to gene
  testing
• GeneClinics www.geneclinics.org

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Concerns Over Health Care Discrimination

• Perceived risk much greater than actual risk
• Legal protection for health insurance state
  laws
• In the USA- Federal Genetic Information
  Nondiscrimination Act (GINA) of 2008
• Protects individuals undergoing genetic testing
• Prohibits insurers from raising premium or
  contribution rates on basis of genetic
  information
• Protection from employment discrimination
• For information about GINA, go to www.genome.gov