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Cancer Genetics > Breast and Ovarian Cancers > Flashcards

Breast and Ovarian Cancers Flashcards

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1
Q

What is the cause of most breast and ovarian cancer?

A
  • Most breast and ovarian cancer is sporadic (approx. 80%) due to mutations acquired over a lifetime.
  • In most cases cause is unknown.
  • Age, environment, lifestyle (obesity) all known to play a role.
  • Sporadic cancer is generally later onset than hereditary.
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2
Q

What is the lifetime risk for a female of developing breast cancer?

A

11% lifetime risk

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3
Q

What % of women with breast cancer have a family history?

A

Approx 20%

  • 10-15% will be familial due to environmental factors/undiscovered gene mutations.
  • 5-10% will be hereditary due to inherited gene mutations - BRCA1/2 mutations, Li Fraumeni (PT53), Cowden syndrome (PTEN).
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4
Q

How do the features of hereditary breast cancer differ from those of sporadic cancer?

A
  • Higher risk of cancer
  • Younger age of onset
  • Multiple primary cancers
  • increased risk of other cancers (in BRCA1/2/ mutations these include ovarian/fallopian tube/peritoneal/pancreas/prostate).
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5
Q

What chromosome is BRCA1 located on?

A
  • BRCA1 = chromosome 17
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6
Q

What chromosome is BRCA2 located on?

A
  • BRCA2 = chromosome 13
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7
Q

What pattern of inheritance do the BRCA 1 and 2 mutations follow?

A
  • Autosomal Dominant
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8
Q

Outline BRCA1/2 mutations.

A
  • Germline mutations result in loss of one wt allele.
  • Loss of other allele occurs - somatic mut or LOH.
  • Mutations in BRCA1/2 occur throughout the coding region
  • Most lead to truncated protein when translated.
  • Variability in mutation detected in families.
  • Some mutations prevalent in certain populations in geographical/ethnic areas - Askenazi Jews, Sweden, Hungary, French Canada.
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9
Q

What do BRCA1/2 do?

A
  • Tumour Suppressor Genes that are involved in regulation of cell growth and maintenance of cell cycle.
  • Mutation leads to inability to regulate cell death, uncontrolled growth, and cancer.
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10
Q

What is the risk of breast cancer by 70Y for a female BRCA1/2 mut carrier?

A

50-85% in BRCA mut carriers compared to 11% in the general pop.

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11
Q

What is the risk of ovarian cancer by 70Y for a female BRCA1 mut carrier?

A

40-60% in BRCA1 mut carriers compared to 1-2% in the general pop.

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12
Q

What is the risk of ovarian cancer by 70Y for a female BRCA2 mut carrier?

A

10-20% in BRCA1 mut carriers compared to 1-2% in the general pop.

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13
Q

What is the risk of breast cancer by 70Y for a male BRCA2 mut carrier?

A

=6% in BRCA2 mut carriers compared to rare in the general pop.

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14
Q

Describe the breast cancers that tend to be seen in BRCA1 mutation carriers.

A
  • Poorly differentiated
  • High grade
  • High proliferation rate
  • 80% are triple negative (ER-/PR-/HER2-)
  • Basal like - CK5/6+, EGFR, Ckit, p53 mut, genomic instability
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15
Q

Describe the breast cancers that tend to be seen in BRCA2 mutation carriers.

A
  • Much more heterogenity than in BRCA1 associated tumours.

- Higher number are ER+

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16
Q

Describe the ovarian cancers that tend to be seen in BRCA1 mutation carriers.

A
  • Serous papillary.
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17
Q

Describe the ovarian cancers that tend to be seen in BRCA1/2 mutation carriers.

A
  • Endometrioid, serous.

- High grade cancers with mutation in p53.

18
Q

What non-familial risk factors are known to increase the risk of patients developing breast/ovarian cancer?

A

BREAST/OVARIAN CANCER:

  • Early menarche/late menopause
  • Never having given birth
  • High BMI/obesity

BREAST CANCER:

  • OCP use/hormonal exposure.
  • Breast irradiation (during puberty)
  • Breast density
  • Atypical hyperplasia / lobular carcinoma in situ
19
Q

What are the criteria that would lead you to suspect hereditary cancer and refer a patient for genetic counselling?

A
  • Multiple cases of breast or ovarian cancer on the same side of the family. In closely related relatives over more than 1 generation is usually significant.
  • A family member with breast cancer <35 years.
  • Family member with both breast cancer and ovarian cancer.
  • Ashkenazi Jewish heritage, particularly with relatives with breast or ovarian cancer.
  • Male breast cancer.
  • Bilateral breast cancer.
  • Hereditary pedigree can be done in the clinic.
  • Can identify patients by examination:

Peutz-Jeghers syndrome is associated with increased risk of GI cancers and breast and ovarian cancer. Patients have typical appearances including pigmentation of the lips, fingers, and buccal membranes.

Cowdens syndrome increases the risk of breast caner and there are specific skin changes and oral cobblestone appearances.

20
Q

What types of cancer is Peutz-Jehgers syndrome associated with?

A

Peutz-Jeghers syndrome is associated with increased risk of GI cancers and breast and ovarian cancer. Patients have typical appearances including pigmentation of the lips, fingers, and buccal membranes.

21
Q

What types of cancer is Cowdens syndrome associated with?

A

Cowdens syndrome increases the risk of breast caner and there are specific skin changes and oral cobblestone appearances.

22
Q

What models can we use for predicting the likelihood of developing breast cancer?

A
  • Gail model

- Claus model

23
Q

What models can be used to calculate the risk of having a BRCA1 or 2 mutation?

A
  • Myriad risk tables
  • BRCAPRO
  • BOADICEA - University of Cambridge computer model.
  • If someone has >20% risk of having a BRCA mutation then they should undergo genetic screening. Of those screened about 1 in 3 will be found to have a specific mutation.
24
Q

Ethical issues with genetic testing for cancer mutations:

A
  • Confidentiality/Privacy
  • Potential insurance, employment, social discrimination risks
  • Sharing information with at-risk relatives - positive results on one family member suggest risk in others.
  • Childbearing issues.
  • Uncertainty
25
Q

What is the process carried out by clinical genetics prior to testing a patient for cancer mutations?

A
  • Detailed family/medical history
  • Pathology reports/death certificates may be needed
  • Important to have psychosocial assessment / support
  • Discussion of risks, benefits, and limitations of test
  • Full informed consent prior to genetic testing
  • Most appropriate family member to test first?
  • Months before results are available
  • Discussion of types of results and what they mean
  • Personalised, risk-based screening and prevention options will be discussed
26
Q

What are the possible outcomes of testing a patient for a cancer variant?

A

1) . Positive result:
- deleterious mutation detected

2) . Negative:
- Has the mutation been previously identified in the family?
- If the mutation is known and we can find it in the family members but not the proband then the patient is a true negative
- If the mutation is unknown then the negative test is uninformative - it may mean that there is a deleterious mutation is present but hasn’t been detected, there is another gene mutation present, there is a variant of unknown significance.

27
Q

What are the options for a person with a positive BRCA test?

A

1) . Lifestyle alterations:
- Reduce dietary fat
- Avoid obesity
- Reduce alcohol consumption
- Regular exercise

2) . Mammography:
- offered to women 50-70 in normal risk population
- In BRCA1/2 mut carriers mammography and MRI is 12-monthly from age 30 years onwards
- MRI if surveillance is required before 30
- MRI is higher sensitivity than mammography (increased density in younger age groups).
- MRI has a higher sensitivity but lower specificity than mammography
- 2008 met-analysis found that the combined sensitivity of MRI screening and mammography had a 94% sensitivity, 77% specificity.

3) . Surveillance for Ovarian Cancer:
- Limitations of screening
- 6 monthly starting at age 30-35
- Pelvic exam
- Transvaginal US
- Serum CA-125 - only elevated in 50% of stage 1 ovarian cancers.
- CA125 has a low specificity as it is also elevated in benign conditions such as fibroids, endometriosis, menses, PID.

28
Q

What are the treatment options for BRCA1/2 carriers?

A

1). Chemoprevention:

  • Tamoxifen (5yrs) 60% reduction in risk of breast cancer in BRCA2 carriers (ER+) (NSABP P-1 trial)
  • Tamoxifen had no benefit in BRCA1 carriers - probably because BRCA1 tumours are ER- and we know Tamoxifen has no benefit in ER- breast cancers.
  • Oral contraceptives are known to reduce the risk of ovarian cancer but concern that will increase the risk of breast cancer.

2) . Prophylactic bilateral mastectomy:
- Approx. 90% reduction in breast cancer risk.
3) . Prophylactic bilateral oophorectomy:

  • up to 95% reduction in ovarian cancer risk.
  • approx. 50% reduction in breast cancer risk (if done premenopausal).
  • Should be carried out by age 35.
  • Fallopian tube should be removed to reduce the risk of fallopian tube and peritoneal cancers.
  • Much bigger operation than having a mastectomy - once the ovaries are removed the patient will have menopausal effects.
29
Q

Outline the importance of psychosocial support for BRCA mutation carriers.

A
  • 16-25% anxiety and/or depression.
  • Making big decisions regarding management.
  • Addressing family issues, self concept, body image.
  • Dealing with future concerns - i.e. child bearing, surgical menopause after oophorectomy.
30
Q

What chemotherapy drugs are used in breast cancer cases in oncology?

A

In oncology a number of chemotherapy drugs are used in breast cancer, either before surgery to shrink cancers down to make them operable, after surgery to mop up any micrometastatic disease in high risk patients, or in the metastatic setting.

In patients with BRCA1/2 mutations a number of chemotherapy drugs have been identified which seem to have a benefit in these particular groups of women.

1) . Anthracyclines - doxorubicin/epirubicin
2) . Taxanes - Docetaxel/paclitaxel
3) . DNA-damaging agents - platinum agents (cisplatin/carboplatin)
4) . Anti-metabolites - Gemcitabine
- Platinum agents and PARP inhibitors have shown to be successful in BRCA1/2 breast and ovarian cancers.

Triple negative breast cancers (most of BRCA1/2 breast cancers) seem to be very sensitive to cytotoxics compared to ER+ tumour but have inferior survival outcomes.

31
Q

What functions are BRCA1/2 involved in?

A
  • BRCA1/2 - TSGs - involved in DNA repair of double strand breaks and cell cycle checkpoint activation.
  • PARP is involved in single stranded DNA repair.
  • Tumours without a functional BRCA1 or 2 are sensitive to DNA damaging agents (e.g. cisplatin/carboplatin) and PARP inhibition (Olaparib, Veliparib, and Iniparib).
32
Q

What functions is PARP involved in?

A
  • PARP is involved in single stranded DNA repair.
33
Q

Name some PARP inhibitors.

A
  • Olaparib
  • Veliparib
  • Iniparib
34
Q

List the hereditary breast cancer syndromes.

A

Hereditary breast cancer syndromes:

  • Cowden
  • Li-Fraumeni
  • Hereditary diffuse gastric syndrome
  • PALB2 gene mutation
  • CHEK2 mutation
35
Q

What syndrome can increase the risk of ovarian cancer?

A
  • Hereditary nonpolyposis colorectal cancer (lynch syndrome) caused by mutations in mismatch repair genes increases ovarian cancer risk.
36
Q

What syndromes can increase the risk of both breast and ovarian cancer?

A

Breast and Ovarian Cancer:

  • Ataxia-telangiectasia
  • Peutz-Jeghers Syndrome
37
Q

Describe Peutz-Jeghers Syndrome.

A

Puetz-Jehghers Syndrome:

  • AD
  • Germline mutations in serine threonine kinase (STK11) (chromosome 19p13.3)
  • Hamartomatous polyps GI tract
  • Melanin deposits buccal mucosa, lips, fingers, and toes.
  • Increased risk for GU cancers, cancers of the lung, breast, uterus, and ovary.
  • Cumulative risk of cancer = 93%
  • Risk of breast cancer = 55%
  • Ovarian cancer risk 20% (non-epithelial sex cord tumours).
38
Q

Describe Li-Fraumeni Syndrome.

A

Li-Fraumeni Syndrome:

  • Patients usually diagnosed with cancers at a young age.
  • Sarcoma, Breast cancer (<45y), brain tumours, leukaemia (childhood), adrenal cortical carcinoma.
  • AD
  • Proband diagnosed with sarcoma <45y of age; and
    A first degree relative with cancer diagnosed <45y; and
    a first or second degree relative on the same side of the family with cancer diagnosed before 45 years of age OR a sarcoma at any age.
  • It is important that patients with Li-Fraumeni syndrome undergo screening froma young age.
  • Breast cancer surveillance methods, mammography or breast MRI debates - undefined gains - radiation sensitivity associated with TP53 mutations.
  • Annual mammogram / MRI starting at 20-25y (or 5-10 years before the earliest breast cancer in the family).
  • Risk-reducing mastectomy.
39
Q

Describe Cowdens syndrome.

A

Cowdens:

  • AD
  • Germline mutations in the PTEN TSG.
  • Multiple hamartoma syndrome.
  • Increased risk of early onset breast, uterine, and non-medullary thyroid cancer.
  • Breast cancer develops in 25-80% of female carriers.
  • Most breast cancers diagnosed premenopausally, and the majority do not have a family history of breast cancer.
  • Breast cancer screening starting at age 30 (mammography and MRI).
  • Prophylactic mastectomy.
  • Characterised by a number of cutaneous features that are present in most of these patients - including oral mucous papillomas (coalesce into ‘cobblestone’ surface), Trichilemmomams (facial), Acral keratoses (palmar/plantar), Papillomatous lesions.
  • Increased risk of breast, thyroid, endometrial, renal cell, melanoma, and colon cancers.
40
Q

Describe Hereditary Diffuse Gastric Cancer syndrome.

A

Hereditary Diffuse Gastric Cancer Syndrome:

  • AD
  • Germline mutations in CDH1/E-Cadherin Gene
  • Initially found in Maori families, since described in families from many ethnic groups.
  • Penetrance approx. 80%
  • Increased risk of breast cancer (lobular) 60% risk and colon cancer.
  • Breast cancer screening starting at age 35 (mammography and MRI).
  • Early prophylactic gastrectomy.
41
Q

Breast and Ovarian cancers BRCA1/2 Summary:

A
  • BRCA1/2 mutations - markedly elevated risks of breast and ovarian cancers.
  • Individuals with a strong family history - genetic testing - complete sequencing of BRCA1 and BRCA2 genes.
  • Multidisciplinary team should be involved in patient management - genetic counselors / specialsist

Cancer Genetics (21 decks)

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