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Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
Breast Cancer
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Breast Cancer


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  • 1. Breast Cancer Genetics:An Overview
    Kevin Sweet, MS, CGC
    Certified Genetic Counselor
    Clinical Associate Professor
    Division of Human Genetics
    Kevin Sweet discloses no significant financial interests or other relationships with commercial interests. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device.
    The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA
  • 2. What is Cancer?
    • Cancer is a term that encompasses a complex group of more than 100 different diseases that all share the primary characteristic of uncontrolled cell growth.
    • 3. Each individual type of cancer arises from a single cell that requires varying numbers of gene mutations for progression to the invasive state.
    • 4. Cancer is a term that encompasses a complex group of more than 100 different diseases that all share the primary characteristic of uncontrolled cell growth.
    • 5. Each individual type of cancer arises from a single cell that requires varying numbers of gene mutations for progression to the invasive state.
  • All Cancer is Genetic, but NOT All Cancer is Hereditary (Inherited)
    10-25% of all cancers are caused by inherited (germline) gene mutations
    More often the cumulative effect of genetic damage (somatic mutations) acquired over the individual’s lifetime leads to malignancy.
    Genes involved with cell signaling and proliferation pathways, repair of normal DNA damage, the mitotic cycle and apoptosis all contribute to the cancer phenotype.
    Numerous nongenetic factors, such as environmental radiation exposure, carcinogens from cigarette smoke, and even age are contributing factors.
  • 6. First mutation
    First mutation
    Second mutation
    Second mutation
    Third mutation
    Third mutation
    Malignant cell
    Malignant cell
    All Cancer is Genetic;
    Not All Cancer is Inherited
    Common cancer pathway due to somatic mutation
    Hereditary cancer pathway, where initial gene mutation is inherited
    Normal cell
  • 7. Breast Cancer is Common
    1in every 8 American women will be diagnosed with breast cancer in her lifetime
  • 8. Risk Factors for Breast Cancer
    Early menarche and late menopause
    Personal history
    Atypical hyperplasia
    Female hormone replacement therapy
    Family history/genetics
  • 9. Goal: ClassificationWho Needs What?
    Risk Classification
    Average (70%)
    Standard screening recommendations
    Personalized detection/prevention
    Family History
    Moderate (15-20%)
    Referral for genetic evaluation
    with personalized screening recommendations
    High (5-10%)
  • 10. Average Risk for Breast Cancer
    • Little or no family history of cancer and no other known risk factors
    • 11. Examples of average risk:
    • 12. One 1st degree relative (parent, sibling, child) diagnosed with breast cancer >50 yrs
    • 13. One or two 2nd degree relatives (aunts, uncles, grandparents) diagnosed >60 yrs
    • 14. Follow American Cancer Society screening recommendations
  • Moderate Risk for Breast Cancer
    • Clustering of cancer cases seen in a family
    • 15. Ages of onset not strikingly young (average age breast cancer dx is 62)
    • 16. However, risk for all first degree relatives increased
    • 17. Risk depends on number of family members affected, how closely related, ages of onset
    • 18. Multiple low-penetrance genes may play a role and interact with environmental triggers
  • Case 1: Moderate Risk Family
    Caucasian mix
    Swedish / Finnish
    Dx 79
    Dx 58
    65 yr
    Dx 65
    71 yr
    Breast CA
    40 yr
    15 yr
  • 19. Case 1: Risk Assessment Modeling
    • Gail Model: National Cancer Institute's website ( )
    • 20. 5 year risk of 1.2% / lifetime risk of 20.4%
    • 21. Claus Model: (BreastCa for Palm, version 1.0, copyright 2001)
    • 22. Lifetime risk of 18.8%
    The Gail model is limited because it does not incorporate second-degree relatives (e.g. aunts, grandmothers) or the age of onset of breast cancer in the family.
    The Claus model incorporates up to two relatives with breast cancer, taking into account their ages of onset, but does not include relatives with ovarian cancer or take into account nongenetic risk factors such as age at menarche.
  • 23. Case 1: Risk Based Management
    • Gail or Claus lifetime risk for breast cancer of
    • Low risk (2-3%) of BRCA1/2 gene mutation
    • 24. Ovarian (or other cancer) risk not increased
    • 25. Screening recommendations:
    • 26. Monthly breast self exam monthly
    • 27. Clinical breast exam every six months
    • 28. Mammogram once a year by age 40 (or 10 yrs prior to earliest diagnosis)
  • Case 1: Take Home Messages
    • Number of cancers in family is not as important as the ages at diagnosis
    • 29. which side of the family matters
    • 30. all on one side or some on each – not convergent!
    • 31. Perceived risk does not always equal actual risk
    • 32. genetic counseling/risk assessment may help
    • 33. Some low penetrant gene variants (SNPs) may account for moderate risk families with breast cancer
  • Breast Cancer Gene SNP Variants With Low Penetrance
    Genome-wide association studies have identified at least 17 gene variants which constitute risk-increasing alleles for breast cancer
    Drawbacks to currently available SNP based tests:
    Many of these breast cancer risk-increasing SNPs are either rare enough in the population that they do not contribute to many cases, or of low enough penetrance that possessing the risk-increasing allele does not significantly increase the individual's risk
    For example, the D allele of the D302N SNP in the caspase 8 (CASP8) gene has a frequency of 0.86, and conveys a rather low RR of 1.13
  • 34. Frequencies Of And Relative Risks Associated With Commercially Available SNPs For Breast Cancer
  • 35. Commercial GWA Offerings
    Some commercial GWA companies provide breast cancer risk estimates based on the number of these low penetrance alleles the individual possesses.
    Each company uses a different specific algorithm to combine the genotype data and produce their risk estimate.
  • 36. Breast Cancer Risk and SNPs
    RR associated with a risk-increasing SNP allele is often dose–dependent and complex; possessing two copies of the risk-increasing SNP allele often conveys more than twice the risk that possessing one copy of the risk-increasing allele does
    For example, for the rs2981582 SNP in the FGFR2 gene, the genotype specific RR of breast cancer (individual's risk compared to the risk in the general population) is 0.83 for carriers of two risk-reducing alleles (common allele homozygotes), 1.05 for carriersof one risk-increasing and one risk-reducing allele (heterozygotes) and1.38 for carriers of two risk-increasing alleles (rare allele homozygotes). This projects a lifetime risk of 10%for women who carry one risk-increasing allele and 13% for women who carry two risk-increasing alleles.
  • 37. High (hereditary) Risk Family
    Breast, dx 40
    d. 40
    Breast, dx 44
    d. 48
    50-70% lifetime
    risk for breast cancer
    Increased risk for other cancers
    Breast Cancer and
    Ovary, 42, 55
    d. 58
    dx 49
  • 38. Breast Cancer Gene VariantsWith High Penetrance
    5-10% of all breast cancer are strongly hereditary, with high penetrance and an autosomal dominant single gene determinant
    Always co-segregated with the disease in families
    See multiple generations of affected family members
    Gene mutation found equally in males and females
    Mutation carriers will have a heterozygous genotype, which means they will have a 50% risk of passing on the gene mutation to each of their offspring
  • 39. Highly Penetrant Genes For Breast Cancer
  • 40. Hereditary Breast and Ovarian Cancer Syndrome (HBOC)
    • ~50 to 75% of hereditary breast cancer caused by mutations in either the BRCA1 or BRCA2 gene
    • 41. Dominant deleterious mutations in either gene increase cancer risk dramatically
    • 42. Genetic testing for BRCA1 and BRCA2 gene mutations is available to women with personal or family cancer history meeting criteria
  • Features That Indicate Increased Likelihood of Having BRCA Mutations
    Multiple cases of early onset breast cancer in a family
    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 along with female breast cancer in a family
  • 43. Misconceptions
    • Cancer on the father’s side of the family doesn’t count
    • 44. Half of all women with hereditary breast cancer risk inherited it from their father
    • 45. Ovarian cancer is not a factor in breast cancer risk
    • 46. Ovarian cancer is an important indicator of hereditary risk, although it is not always present
    • 47. The most important thing in the family history is the number of women with breast cancer
    • 48. Age of onset of breast cancer is more important than the number of women with the disease
  • BRCA1-Associated Cancers:Risk by Age 70
    Breast cancer 50-85% (often early age at onset)
    Second primary breast cancer 20%-60%
    Ovarian cancer 15-45%
    Possible increased risk of other cancers (e.g., prostate)
  • 49. BRCA2-Associated Cancers: Risk by Age 70
    breast cancer
    male breast cancer
    ovarian cancer
    Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)
  • 50. BRCA1/2 Mutation Incidence
    • 1 in 800 women in the general population
    • 51. 5-8% of all women with breast cancer
    • 52. 18% of women with breast cancer <50 and one close relative with breast cancer <50
    • 53. 2% of all women of Ashkenazi Jewish ancestry
    • 54. 25% of all Ashkenazi Jewish women with ovarian cancer
  • Who to Test for BRCA?
    Determine family’s risk
    Individual’s cancer status
    History of breast and ovarian cancer in 1st and 2nd degree relatives
    Person affected with cancer
    Early onset breast preferably
    Ovarian at any age
    Assistance with surgical decision making
    Any Ashkenazi Jewish or Icelandic person
    Any person in family with known mutation
  • 55. Interpreting Test Results: Positive for a BRCA Deleterious Mutation
    Mostly frameshift and nonsense mutations
    Any mutation that prevents a functioning protein from being made is assumed to be deleterious, even if it has not been seen before
    Hundreds of deleterious mutations have been described in BRCA1 and BRCA2
  • 56. Interpreting Test Results: No Mutation Detected
    If there is a known BRCA mutation in the family:
    The risk of cancer is the same as that of the general population, despite a strong family history
    If there is not a known BRCA mutation in the family:
    A negative result rules out most, but not all, causes of hereditary breast and ovarian cancer
    Some unusual types of abnormalities in the BRCA genes, such as very large deletions, are not detected on standard analysis
  • 57. Interpreting Test Results: Variants of Uncertain Significance (VUS)
    Result seen in 5-10% of all BRCA test reports
    Mostly amino acid substitutions, also some variants in non-coding introns
    VUS have uncertain clinical significance so associated cancer risk unknown
    VUS may be further characterized by additional studies
  • 58. Case 2: BRCAMutation Positive Family
    Ruth is a 45 year old woman recently diagnosed with breast cancer.
    • Maternal family history is negative for cancer
    Paternal family history is significant for:
    • Paternal aunt with ovarian cancer age at 55
    • 59. Paternal grandmother with breast cancer age 42
  • Key
    -Breast CA
    -Ovarian CA
    Case 2: High Risk
    Dx 42
    d. 49
    Dx 55
    d. 56
    • 36-44% risk of BRCA mutation in proband
    • 60. 50% risk for each of her daughters
  • 61. Case 2: After Testing, Ruth has a Deleterious Mutation in the BRCA1Gene
    Dx 42
    d. 49
    Dx 55
    d. 56
    -Breast CA
    -Ovarian CA
  • 62. Surveillance-BRCA1 and BRCA2 Mutation Carriers
    Mammograms are not completely sensitive
    -MRI may be more sensitive, but less specific
    -Begin use of imaging at 25
    Breast physical examination is recommended
    -Encourage monthly breast self-exams (begin at 18)
    -Clinician performed exams 2-4 times per year (begin at
    Frequency of interval cancers suggests that six-month screening intervals may be preferable
    Modified from Burke W et al. JAMA. 1997; 277:997-1003.
    Scheuer L et al. J ClinOncol. 2002; 20: 1260-1268.
    Warner E et al. J ClinOncol. 2001; 19:3524-3531.
  • 63. Ovarian Cancer: Chemoprevention
    Oral Contraceptives
    40% to 50% risk reduction in general population
    after 3 years cumulative use
    Limited data available for BRCA-mutation carriers; preliminary study showed a 60% risk reduction with ≥6 years use
    May increase breast cancer risk
    CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997;
    Narod NEJM 339:424, 1998
  • 64. Prophylactic Oophorectomy
    Decreases risk of ovarian cancer by as much as 80% (primary peritoneal carcinoma may still occur)
    Reduces risk of breast cancer by 60% if done prior to age 40 and by 50% if done prior to age 50
    Induces surgical menopause
    Laparoscopic procedure reduces postsurgical morbidity
    Consider complete hysterectomy for management of menopause – unopposed, low-dose estrogen
    Rebbeck NEJM 346(21):1660, 2002; Kauf NEJM 346(21):1660, 2002; Rebbeck et al JNCI 101(2):80-7, 2009
  • 65. Case 2: Impact of Results Medical Management
    • Ruth (mutation positive)
    • 66. may want to consider oophorectomy
    • 67. Ruth’s daughters are negative for their mother’s BRCA mutation
    • 68. general population risk for breast and ovarian cancer
    • 69. follow American Cancer Society screening guidelines
    • 70. cannot pass the family’s BRCA mutation to their children
    • 71. Ruth’s sister (mutation positive)
    • 72. consider increased breast cancer screening +/- chemoprevention OR mastectomy and ovarian cancer screening OR oophorectomy (after child-bearing, <40)
  • Case 2: Take Home Messages
    • Risk assessment and genetic testing gives information to patient AND family members
    • 73. Some family members may want this information and some may not
    • 74. Genetic testing, when informative, can help individuals
    • 75. make decisions about early detection and risk-reduction
    • 76. relieve anxiety about cancer risk (if negative)
    • 77. Informed decision-making imperative
    • 78. Follow-up support and/or counseling sometimes necessary
  • Li-Fraumeni Syndrome (LFS)
    Germline mutations in the TP53 tumor suppressor gene cause Li-Fraumeni syndrome.
    These mutations are relatively rare, but they have almost complete penetrance.
    The lifetime risk for a primary cancer in someone with one mutant copy of the TP53 gene is close to 90%.
  • 79. Li-Fraumeni Syndrome
    As the TP53 gene is one of the key gatekeepers for cell cycle maintenance and regulation, germline mutation leads to very high risk for single and multiple primary cancers in mutation carriers.
    Osteosarcomas and soft tissue sarcomas are the signature cancers of LFS, although early onset breast cancer (20-30s), brain tumors, leukemias, lymphoma and adrenal tumors are also seen regularly.
  • 80. Cowden Syndrome
    Caused by germline mutations in the PTEN gene
    Mutation carriers are at increased risk for breast and thyroid cancer (30% and 10% increase in risk, respectively).
    As a tumor suppressor gene, PTEN is a key regulator of cell signaling pathways; disruption leads to both benign and malignant cellular overgrowth.
    Cowden syndrome is part of the more comprehensive PTENhamartoma tumor syndrome which also includes Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome.