Handbook of Genetic Counseling/Hereditary Breast Cancer - BRCA1 and BRCA2

Hereditary Breast Cancer - BRCA1 and BRCA2

Introduction and Contracting

• Introduce myself as a GC student
• Elicit any questions or concerns
• Find out about how she first found out that she had cancer
• Assess what she knows about hereditary breast cancer
• Find out how she feels about testing
• Address any immediate concerns
• Outline what will be done during visit
  • Other concerns will be answered in more detail
  • Review medical and family history
  • Hereditary vs. nonhereditary cancer
  • Genes associated with breast/ovarian cancer
  • General risks and risk for you and your family

Family and Medical History

• Review their medical history
• Explain the pedigree (looking for anything that might have a genetic component, but focusing in detail on cancers in the family)
• Obtain information on the family
• Affected members
  • Current age
  • Age of onset
  • Type and location of primary cancer (unilateral/bilateral)
    • Stage of cancer
    • Stage 0 is a noninvasive tumor
    • Stage I is a small locally invasive tumor w/out lymph node involvement
    • Stage II is a medium-sized tumor with or without lymph node involvement
    • Stage III is a locally advanced cancer, usually with axillary node matastases
    • Stage IV has already metastasized to distant sites
  • Other cancers
  • Environmental exposures
  • Any other health concerns
• Unaffected members
  • Current age
  • Health history
  • If deceased -age and cause

Hereditary vs. Sporadic Cancer

• Everybody is at risk for developing cancer and there are both non-genetic and genetic risk factors that may increase a person's risk for breast cancer (* are the main ones to mention)
  • Gender (99% of breast cancer occurs in women)
  • Age (77% occur after age 50)
  • Menarche before age 9 (RR 1.2)
  • Menopause after age 50-52 (RR 2.0)
  • Nulliparity (RR 2.0) except for BRCA mutation carriers, it makes them more likely to develop breast cancer by age 40 than nulliparous carriers
  • Previous history of breast biopsies
  • Atypical hyperplasia diagnosed by breast biopsy
  • Obesity
  • Hormone replacement therapy increase risk of breast cancer if used for more than 5-10 years. However HRT seems to decrease risk of ovarian cancer
  • Oral contraceptives may slightly increase risk, but it is dependent on dosage of progestin and estrogen. (Those using lower doses of estrogens and progestins did not seem to have an increased risk while those using the early contraceptives that were higher dosage did have some slight increase.)
  • Major cancer susceptibility genes may account for 5-10% of breast cancer
  • Less than 1 % associated with genetic syndromes such as Cowden, Bloom, Peutz-Jeghers, and Werner's syndromes.
• Lifetime risk of breast cancer in women is 11-12%
• Usually when a person gets breast cancer it is sporadic meaning the individual did not inherit a genetic predisposition for breast cancer
• A small percentage get cancer that is inherited (hereditary cancer)
  • 5-10% of breast cancer is inherited (2/3 (66%) of these are associated with BRCA1/2)
  • 5-10% of ovarian cancer is inherited (90% are BRCA1/2)
• Clues we look for in determining whether cancer is hereditary
  • Cancer in 2 close relatives on same side of family
  • More than one affected generation
  • Early age at diagnosis (under age 45-50 for breast cancer)
  • Bilateral/ multiple primary tumors
  • Rare/ unusual cancers (i.e. male breast cancer)
  • Combination of tumors consistent with specific cancer syndrome (i.e. individual with both breast and ovarian cancer)
• 15-20% of individuals with breast cancer are not likely to have a single gene predisposition to breast and ovarian cancer, but have more family members with breast cancer than we would expect simply by chance. These individuals have familial cancer. The reason for the higher prevalence of cancer in these families is unknown, but it may be the combination of a few predisposing genes as well as environmental factors.
• Explain the reasons we think their family is or is not at risk of having hereditary cancer

Genes Associated with Cancer

• Hereditary cancers are caused by a change in a specific gene
• Explain genes and chromosomes
• Explain location of the known genes that predispose a person to breast and ovarian cancer
  • BRCA1: chromosome 17q (women with it carry a 56-87% lifetime risk of breast cancer 5-8 X's the risk of general population)
  • BRCA2: chromosome 13q (37-85% lifetime risk of breast cancer, 10-20% risk of ovarian cancer compared to 1.5% for other women, 6% lifetime risk for male breast cancer which is over 100 fold increase compared to general pop risk in males)
• These are both tumor suppressor genes that control whether our cells are allowed to divide
• When there is a change in the gene it is turned off or doesn't function properly
• Changes in our genes are happening all the time due to environmental factors and to mistakes that can be made when a cell divides
• When both copies of the gene are inactivated, the cell doesn't know when it is allowed to divide and it will therefore divide uncontrollably.
• This can lead to cancer
• In the case of sporadic cancer both copies of the gene in the same cell have to be altered
• In heritable cancer, if you inherit an altered nonfunctional gene you only need one change to occur in the other copy of the gene in one cell to get cancer. So you are essentially one step closer to cancer and this may explain why we see earlier onset of hereditary cancer and a higher risk.

Risk Assessment

• Background risks:
  • Ashkenazi Jewish - 1/40 risk of carrying one of the 3 specific BRCA1 or BRCA2 mutations
  • Non-Ashkenazi: 1/400 risk of carrying any mutation in BRCA1 or BRCA2
• Risks can be estimated based on the family history
• Various models used to estimate risks of having one of these genes in the family
• When this was done for your family it was found that your risk of having BRCA1 or BRCA2 was _______________
• Just because someone has a mutation in one of these genes doesn't mean they will develop cancer but their risks of developing certain types of cancer increase
• Some individuals with a cancer predisposing gene will survive to an elderly age without developing cancer
• Among those that do develop cancer the age of onset varies
• It is uncertain why some individuals will have multiple primary cancers before age 50 while others with the same predisposing gene may not develop cancer until age 70
• The lifetime chance of getting breast cancer in the general population of women is about 11-12%.
• The risk is significantly increased in women with a mutation (50-85% for both BRCA1/2)
• The chance of having a second breast cancer that is not a recurrence is also very high in mutation carriers (40-60% BRCA1).
• The chance of having ovarian cancer is also significantly increased from about 1-2% in the general population up to about 15-45% in BRCA1 carriers and 10-20% in BRCA 2 carriers
• Males can be mutation carriers also and develop breast cancer (males that carry BRCA2 mutations have about 6% chance, a 100 fold increase)
• Other cancers possibly increased risk with BRCA1 mutation (prostate RR=3.3 and colon RR=4.0)
• BRCA2 mutation associated with increased prostate, laryngeal and pancreatic cancer risks (unknown magnitude of increased risk)

Testing Options

• BRCA1/BRCA2 testing is offered if the risk is calculated to be 10% or higher
• Testing usually begins with an affected family member because if they are found not to have a mutation then it tells us more information than if an unaffected member did not have a mutation in one of these genes
• If a mutation is found in that family member than it is less expensive to test unaffected family members because they look for that same mutation
• Types of testing
  • Comprehensive BRACAnalysis
    • sequencing of both BRCA1 and BRCA2
    • Myriad cost is $3100
  • Rapid BRACAnalysis
    • same as BRACAnalysis, but results in 7-10 days
    • Myriad cost is $3680
  • Single site BRACAnalysis
    • Single mutation analysis for individuals with known BRCA1 or BRCA2 mutations in the family
    • Myriad cost is $440
  • Multisite 3 BRACAnalysis (detects about 83% of mutations in this population 17% are carriers of other mutations)
    • Three mutation analysis for Ashkenazi individuals
    • Myriad cost is $535
    • If a negative result can do full sequencing

Test Results

• 3 possible results
• NEGATIVE --Neither of the two genes have changes in them. If this were the case it wouldn't rule out the suspicion that the family has a hereditary form of breast cancer. However, if there is no history of ovarian cancer it might ease their mind because then it could be assumed that their risk of ovarian cancer is probably not likely to be increased above the population risk
• VARIANT OF UNCERTAIN SIGNIFICANCE --There is a change but we are unsure of what it means and whether it would lead to an increased cancer risk (estimated to occur about 10% of time)
• POSITIVE --A change is found in the gene that would cause it not to make a functional protein and would therefore lead to an increased cancer risk
• Test results back in about 4-6 weeks
• The lab will call when they are about to send the results and we will make a follow-up appointment to go over what the results mean and what the options are

Testing Pros

• Know your risk more definitively
• Know risk to your children of carrying the gene
• Reduce anxiety often associated with not knowing
• Choose prevention options based upon results

Testing Cons

• Cost of the procedure
• Insurance issues ( i.e. whether or not they want their insurance company to pay for the test, but this is probably more of an issue for those that don't already have cancer)
• Fear of genetic discrimination, although there is no evidence that this is a problem (Should not be a problem if on a group health insurance plan due to HIPAA.)
• Adverse psychological effects
  • Transmitter guilt
  • Survivor guilt
  • Depression
  • Anxiety
• Other family members may not want to know
• Result may not be informative if a variant is found of uncertain significance and this may provoke even more anxiety and uncertainty

Screening Options

• More aggressive screening may be considered when there is an increased risk for developing breast or ovarian cancer
  • Breast screening
    • Mammography every year beginning at age 25-35 for mutation carriers
    • Clinical breast exam every 6 months beginning by age 20
    • Monthly self-breast exam beginning by age 18
  • Ovarian screening
    • Not shown to be effective in large-scale clinical trials
    • Transvaginal U/S w/ color doplar imaging, CA-125, and pelvic exam every 6-12 months starting age 25-35

Possible Prevention Options

• Prophylactic surgeries
• prophylactic mastectomy
• reduces breast cancer risk by 90% and death by 81% (Mayo Clinic retrospective study between 1960-1993 that did not include mutation status, but many were probably mutation carriers)
• reconstruction (TRAM transverse rectus abdominal muscle, silicone or saline implants)
• most women satisfied with mastectomy but may cause body image and self-esteem problems and they lose nipple sensitivity
• in individuals with mutations risk of second cancer if breast tissue remains is estimated to be 60% by age 70
• prophylactic oophorectomy
• reduces risk of ovarian cancer (BUT no guarantee because ovarian cancer can arise in the peritoneum so risk is reduced to about 2-5%)
• reduces breast cancer risk by up to 70% if removed before age 40 and 40% if removed between 40-49, not really significant change if removed after 50
• recommended after child bearing is complete
• Chemoprevention
• tamoxifen reduces breast cancer risk by 45% in high-risk women (but unknown if BRCA carriers have the same benefit) data suggest that in mutation carriers it is effective at reducing risk of second primary cancer in long term survivors and reduces contralateral breast cancer by 50-75%
• raloxifene may reduce breast cancer risk
• birth control pills used for a total of 6 years or more reduces ovarian cancer by 60% in BRCA mutation carriers and after 3 years reduces it by 40-50%, but may slightly increase breast cancer risk

Psychosocial Assessment

• Are there any other questions or concerns?
• Determine interest in options?
• Why does the person want or not want testing?
• What will the client do with the result (both positive and negative result)?
• Will she change medical management?
• Who will she share the result with?
• If testing is decided on determine if they would want to bring someone back with them when they receive their results.

References

• Olopade OI and Fackenthal JD. Breast Cancer Genetics: Implications for Clinical Practice. Hematology/oncology Clinics of North America. 2000.
• Identifying and Managing Hereditary Risk for Breast and Ovarian Cancer. American Medical Association. 2001.
• Genetic Counseling for Inherited Breast and Ovarian cancers: Background and Practical Strategies. Lecture by Karen Huelsman. Spring 2002.

Notes

The information in this outline was last updated in 2002.