Hereditary Breast

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Hereditary Breast Ovarian Cancer

• Debbie Terespolsky
• Clinical Geneticist

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Common question

• There is cancer in my family. Am I at increased
  risk of getting cancer?
• Pattern of cancer in family
• Type of cancer
• Age at diagnosis of cancer
• Discuss screening
• Referral to genetics if appropriate

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Objectives

• Overview of role of genetics in cancer
• Known hereditary breast/ovarian cancer syndrome
  genes
• BRCA1/BRCA2
• Genetics clinic

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All cancer is genetic

• Genetic code controls all cell growth
• Cell cycle
• Several classes of genes
• Promote growth
• Suppress growth
• Repair damaged DNA
• Series of checks and balances to maintain the
  rate of new cell growth and cell death

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Mutations causing cancer

• Activating gain-of-function mutations of one
  allele of a proto-oncogene (RET MEN2)
• Loss of function of both alleles of a
  tumour-suppressor gene
• Chromosomal translocations that cause
  misexpression of genes or create chimeric genes
  (CML)

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Tumour suppressor genes

• BRCA1 and BRCA2
• Contribute to cancer through loss of function of
  both alleles of the gene
• Involved in sporadic and hereditary breast cancer

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Sporadic cancer
At birth
30 50 years
50 70 years
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2-hit hypothesis
At birth
30 50 years
50 70 years
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2-hit hypothesis

• Germline mutation exists in all tissues
• Second hit can cause a tumour whenever it occurs
  in one of the numerous cells of a tissue
• Initial tumour may arise at multiple sites

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Tumour suppressor genes

• Highly heterogeneous
• gate-keepers directly regulate cell growth
  (RB1)
• caretakers repair DNA damage and maintain
  cell integrity (BRCA1/2)

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BRCA1 and BRCA2

• Proteins interact with RAD51 protein in cell
  cycle
• Functions in repair of damaged DNA
• Regulate activities of other genes
• Critical role in embryo development

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Breast and ovarian Cancer
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Breast cancer

• Most common cancer amongst Canadian women
• 1 in 9 women
• In 2006
• 22,300 women diagnosed
• 5,300 women will die
• 160 men, 45 will die

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Ovarian Cancer

• 1 in 70 women
• 2,300 new cases in 2006

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Familial clustering

• 15
• Common environment exposures
• Common lifestyle
• Chance
• Hereditary

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Hereditary cancer
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Hereditary susceptibility to breast cancer
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BRCA1

• Discovered 1994
• Chromosome 17q21
• gt 600 mutations
• Missense
• Nonsense
• Frameshift insertion/deletion

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BRCA1

• Increased risk of
• Breast
• Ovarian
• Prostate
• Colorectal

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BRCA2

• Discovered 1996
• Chromosome 13q12.3
• 450 mutations
• Insertions
• deletions

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BRCA2

• Fanconi anaemia
• Increased risk of
• Breast
• Ovarian
• Prostate
• Pancreas
• Mutations in midsection of gene
• Increased ovarian cancer
• Decreased prostate cancer

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BRCA1 and BRCA2

• Autosomal dominant
• Ethnic specific mutations
• Ashkenazi Jewish
• 185 2 bp deletion BRCA1
• 5382 1 bp insertion BRCA1
• 6174 1 bp deletion BRCA2

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BRCA1 and BRCA2

• Up to an 85 chance for a woman to develop breast
  cancer up to age 70 years
• Average age mid-40s
• For affected patients, the risk of second primary
  is 40-60
• Increased risk male breast cancer (6-10)

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BRCA1

• 16-44 lifetime risk to develop ovarian cancer
  (serous invasive ca most common) includes
  fallopian tubes
• Increased risk of prostate cancer (8-16) and
  male breast cancer
• Other possible associated cancers
• Pancreas
• Colorectal

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BRCA2

• Increased risk of ovarian cancer (10-25)
• Increased risk for prostate (8-16) and male
  breast cancer
• Pancreas
• Other

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Likelihood of BRCA1 Mutation

• No family history 0.13
• Br ca lt40 6
• 2 br ca lt40 37
• Br ca lt50 ov ca lt50 46
• 2 ov ca lt50 61
• 2 br ca 2 ov ca 91
• adapted from Cole et al., 1998

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Clinical relevance

• Importance of ovarian cancer and BRCA1/2
• Serous ovarian cancer most likely to be due to
  BRCA1/2 mutation

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Clinical characteristics of individuals with
BRCA1/2 mutations

• No br lt50 no ov 3.9
• Br lt50 4.4
• More than 1 Br lt50 11
• Ov any age no br lt50 3.9
• More than 1 ov no br 8.5
• Br lt50 and ov any age 16.4
• Frank et al, 2002

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Clinical characteristics of individuals with
BRCA1/2 mutations

• Proband with br lt40
• No br lt50 no ov 13.2
• Br lt50 29.7
• More than 1 Br lt50 50.7
• Ov any age no br lt50 24.1
• More than 1 ov no br 23.5
• Br lt50 and ov any age 56.3
• Frank et al, 2002

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Clinical characteristics of individuals with
BRCA1/2 mutations

• Importance of ovarian cancer history regardless
  of age
• Insufficient evidence to merit testing BRCA1/2
  based on dx of DCIS
• Importance of both BRCA1 and BRCA2 in male breast
  cancer

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Ductal carcinoma in-situ

• DCIS is a part of the breast/ovarian cancer
  syndromes defined by BRCA1 and BRCA2
• Mutation rates similar to those found for
  invasive breast cancer.
• Screen patients with breast cancer with an
  appropriate personal or family history of breast
  and/or ovarian cancer according to high-risk
  protocols, regardless of whether they are
  diagnosed with in situ or invasive breast cancer.

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Referral to Genetics

• Guidelines available
• Detailed family history
• Confirmation of pathology
• Risk assessment
• Surveillance
• Genetic testing

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Issues for patients and families

• Right to know or NOT to know
• Sharing of information
• Privacy
• Reproduction decision making
• Testing of minors

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Who is eligible for testing

• Breast cancer lt 35
• Two breast cancer lt 50
• gt 2 breast cancer
• Serous ovarian cancer
• Breast and ovarian
• Bilateral breast cancer one lt 50
• Male breast cancer

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Best testable

• Affected individual
• If no affected, unaffected with gt 10 risk of
  having BRCA1/2 mutation

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Genetic testing

• Protein truncation testing (PTT)
• Sequencing
• MLPA (multiplex ligation probe amplification)
• DHPLC (denaturing high performance liquid
  chromatography)

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Genetic testing

• Turn-around-time
• New tests more efficient
• Myriad in USA

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Results

• Mutation detected
• Mutation not detected
• Missed
• Involves another gene
• Individuals cancer is not hereditary
• True negative result
• Population risk

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Management for BRCA carriers

• Enhanced surveillance
• Mammogram, CBE,
• Transvaginal u/s, CA-125
• Chemoprevention
• Prophylactic surgery
• Bilateral mastectomy
• BSO/TAH

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Risk reduction

• Bilateral prophylactic mastectomy
• 90 decrease in breast ca
• BSO TAH
• 50 decrease in breast ca (lt50 yrs)
• gt50 decrease in ovarian ca

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Cancer
Br, died at 33
Br _at_68, 69
3
ovarian
Br _at_ 33,35
2
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Cancer
Stroke _at_82
MI _at_76
Ov
Abd
Br _at_62
63
2
2
2
40
Br _at_46
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Cancer
Stroke _at_82
MI _at_76
cervical
stomach
Br _at_62
63
2
2
2
40
Br _at_51
44
5
3
40
dx34
2
3
2
2
2
45
65
62
35
3
69
65
dx40s
dx57
2
42
40
38
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Multidisciplinary team

• Family physician
• Oncologist
• Surgeon
• Gynaecologist
• Geneticist
• Psychologist/social worker

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Family physicians role

• Family history
• Assess likelihood of inherited breast cancer
• Offer referral if appropriate
• Pre-referral discussion of what to expect at
  genetics appointment
• Post-referral counselling
• Implementation of surveillance/treatment plans

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Perspective

• 20 women have a family history of breast cancer
• lt5 of women are at high risk for a genetic
  predisposition

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Management general population

• Annual CBE not later than age 30. If family
  history, begin 10 years earlier than youngest age
  at diagnosis of affected relative
• Annual or bi-annual mammogram starting from age
  40-50, or 10 years earlier than youngest age at
  diagnosis of affected relative
• BSE

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The Future

• Education of population
• Risk assessment
• surveillance
• New surveillance
• New treatments
• Genotype phenotype correlation
• BRCA3/4