Breast Cancer Genetics

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Breast Cancer Genetics

• Joanne Jeter, MD
• April 29, 2008

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Objectives

• When to review family medical hx?
• Who needs genetic evaluation? 
• Genetic evaluation options, costs, where to
  obtain?
• New findings/ testing

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Hereditary Breast-Ovarian Cancer

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Red Flags for Hereditary Cancers

• Earlier age than would be expected
• Bilateral disease
• Multiple cancers in the same individual
• More than 2 family members with the same cancer
  on same side of family
• Evidence of autosomal dominant inheritance of
  associated cancers in pedigree

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Special Considerations for Hereditary
Breast/Ovarian Cancer

• Men with breast cancer
• Ashkenazi Jewish women with breast or ovarian
  cancer
• History of melanoma, prostate, colon, pancreatic
  cancers

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Major Breast Cancer Risk Factors

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Other Cancers Associated with BRCA

• Melanoma
• Pancreatic Cancer
• ? Colon

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Age of Diagnosis

• Hereditary
• Breast 41
• Ovarian 40-50
• Prostate 63

• Sporadic
• Breast 62
• Ovarian 60
• Prostate 71

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Management of BRCA Carriers -- Screening

• Breast self-examination
• Clinical breast exam q6mo starting at 25
• Annual mammography starting at 25
• Annual breast MRI starting at 25
• Transvaginal U/S q6mo starting at 35
• CA125 q6mo starting at 35

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Management of BRCA Carriers -- Surgical

• Prophylactic mastectomy
• Prophylactic oophorectomy

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Management of BRCA Carriers -- Chemoprevention

• Tamoxifen
• Raloxifene?
• Other drugs?

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Management of BRCA Carriers Family Education

• Discussion/evaluation of at-risk family members
  for testing
• Each sibling or child has a 50 chance of having
  the mutation
• Men can carry the mutation as well

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Breast Cancer Genetics in the Hispanic Population

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BRCA in Hispanics

• BRCA1 mutation in 3.5 of Hispanic breast cancer
  patients
• 30.9 of Hispanic patients with high-risk
  features had BRCA1/2 mutations (expected 19.6)
• 185delAG common (24 of mutations)

JAMA 2007298(24)2869-76
CEBP 200514(7)1666-71
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Other Inherited Genes in Breast Cancer

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Other Genetic Conditions Associated with
Increased Breast Cancer Risk
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Li-Fraumeni Syndrome

• Early onset of breast cancer, sarcoma,
  adrenocortical carcinoma, brain tumors, lung
  cancer, leukemia
• Associated with mutations in TP53, ?CHEK2
• Specific diagnostic criteria

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Cowden Syndrome Diagnostic Criteria

• Major Criteria
• Breast cancer
• Thyroid cancer
• Endometrial cancer
• Macrocephaly
• Lhermitte-Duclos disease (dysplastic cerebellar
  gangliocytoma)

• Minor Criteria
• Other thyroid lesions
• Mental retardation
• Hamartomatous intestinal polyps
• Fibrocystic breasts
• Lipomas
• Fibromas
• GU tumors or malformations

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Ataxia-Telangiectasia

• Autosomal recessive
• Mutations in ATM
• Clinical Characteristics
• Progressive cerebellar ataxia
• Facial and conjunctival telangiectasias
• Combined immunodeficiency
• Growth retardation

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Ataxia-Telangiectasia and Cancer

• Homozygotes
• Leukemia/lymphoma in 40
• Increased risk of solid tumors
• Heterozygotes
• 15.7-fold increase in breast cancer

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CHEK2

• Regulates the function of BRCA1
• Recent meta-analysis suggests that heterozygotes
  for CHEK21100delC have 37 risk of breast cancer
  by 70
• Clinical testing not routinely recommended by
  thought leaders at this time based on technical
  issues with the study

JCO 26542-548, 2008
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Practical Considerationsin Genetic Evaluation

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When should the family history be taken?

• Initial visit of the patient
• Genetic testing is sometimes used in decision
  making for the initial management of breast
  cancer
• Important to check for updates on a regular basis!

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Who should be evaluated?

• Individuals with
• Early-onset breast cancer
• Two primary breast cancers
• Both breast and ovarian cancer
• Two breast primaries or breast and ovarian cancer
  in close relatives from the same side of the
  family

NCCN Practice Guidelines in Oncology
Genetic/Familial High-Risk Assessment Breast
and Ovarian, Version 1.2007
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Who should be evaluated?

• Individuals with clustering of breast cancer on
  the same side of the family as
• Male breast cancer
• Thyroid cancer
• Sarcoma
• Adrenocortical carcinoma
• Endometrial cancer
• Pancreatic cancer
• Brain tumors
• Dermatologic manifestations
• Leukemia/lymphoma

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Who should be evaluated?

• Any man with breast cancer
• Members of a family with a known mutation in a
  breast cancer susceptibility gene
• Individuals with family history of one or more
  ovarian cancers
• Individuals in populations at risk
• Ashkenazi Jewish with breast or ovarian cancer at
  any age

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ASCO Recommends Genetic Testing When

• The individual has a personal or family history
  of features suggestive of a genetic cancer
  susceptibility condition
• The test can be adequately interpreted
• The results will aid in diagnosis or influence
  the medical or surgical management of the patient
  or family members at hereditary risk for cancer

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When should children be evaluated?

• Onset of the disease is in childhood
• Effective interventions are available
• Genetic test results can be adequately interpreted

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Options for Genetic Evaluation

• Myriad Laboratories is the only commercial
  provider of BRCA1 and BRCA2 testing
• Assessment by genetic counselor or other genetics
  professional
• Testing through health care professional
• Direct-to-consumer testing

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ASCO Statement

• Oncologists should consider offering genetic
  testing only if they are able to provide or make
  available adequate genetic education and
  counseling as well as access to preventive and
  surveillance options. Otherwise, they should
  consider referring the patient and family for
  these services.

J Clin Oncol 21(12), 20032397-2406
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What should be covered in pre-test counseling?

• Information on the specific test being performed
• Implications of a positive and negative result
• Possibility that the test will not be informative
• Options for risk estimation without genetic
  testing
• Risk of passing a mutation to children
• Technical accuracy of the test

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What should be covered in pre-test counseling?

• Fees involved in testing and counseling
• Psychological implications of test results
  (benefits and risks)
• Risks of insurance or employer discrimination
• Confidentiality issues
• Options and limitations of medical surveillance
  and strategies for prevention
• Importance of sharing genetic test results with
  at-risk relatives

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What should be covered in post-test counseling?

• Assess patient response to results disclosure
• Review meaning of result
• Discuss plans for sharing result with family
  members
• Discuss plan for medical follow-up
• Provide access to updated risk information

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Possible BRCA Test Outcomes

• Definitive
• True positive Deleterious mutation identified
• True negative Known family mutation not
  identified in tested individual

• Uninformative
• No mutation found in individual and no mutation
  identified in family
• Variant of uncertain significance

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Benefits of BRCA Testing

• Identifies high-risk individuals
• Identifies noncarriers in families with known
  mutation
• Allows early detection and risk reduction
  strategies
• May relieve anxiety

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Risks and Limitations of BRCA Testing

• Does not detect all mutations therefore cannot
  definitively rule out hereditary risk
• True negatives are still at population risk of
  breast and ovarian cancer
• Efficacy of some interventions is not well
  established
• May result in anxiety or survivor guilt
• May heighten concerns about insurance

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Costs of BRCA Testing

• Full sequencing 3120
• Single mutation testing for known mutation 385
• Insurance coverage varies

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Insurance Discrimination

• Health Insurance Portability and Accountability
  Act (HIPAA)
• Protects those with group health insurance from
  being denied coverage or having to pay a higher
  rate
• Genetic Information Nondiscrimination Act (GINA)
• Prohibits discrimination by employers and health
  insurers on basis of genetic tests
• In the Senate very soon
• Life or disability insurance remains an issue

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Tucson Resources

• Joanne Jeter, MD Medical Oncologist
• [phone]
• Jessica Ray, MS, CGC Genetic Counselor
• [phone]
• Arizona Cancer Center Main Line
• (520) 694-CURE (694-2873)

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Other Resources

• National Comprehensive Cancer Network
• http//www.nccn.org/professionals/physician_gls
  / PDF/genetics_screening.pdf
• National Society of Genetic Counselors
• http//www.nsgc.org/
• PDQ Genetics http//www.cancer.gov/cancertopics/p
  dq/genetics
• GeneTests
• http//www.geneclinics.org/