#182 Hereditary Breast and Ovarian Cancer Syndrome Flashcards
What mutations account for most cases of hereditary breast and ovarian cancer syndrome?
BRCA1 and BRCA2
What percent of cases of epithelial ovarian cancer are due to germline mutations in BRCA1 and BRCA2?
9-24%
What percent of cases of breast cancer are due to germline mutations in BRCA1 and BRCA2?
4.5%
What chromosome is BRCA1 on?
Chromosome 17
What chromosome is BRCA2 on?
Chromosome 13
What is the BRCA gene?
Tumor suppressor genes that encode proteins that function in the DNA repair process
What is the carrier frequency of BRCA1 or BRCA2 mutation in general population?
1 in 300 to 1 in 800 individuals
What populations have a higher risk of BRCA?
Ashkenazi (Central and Eastern European) Jews, French Canadians, and Icelanders
What is the frequency of BRCA gene mutation carrier status in Ashkenazi Jews?
1 in 40
What gene is associated with Li-Fraumeni Syndrome? Increased risk of breast cancer? Increased risk of ovarian cancer?
TP53. Increased risk of breast cancer. No increased risk of ovarian cancer.
What gene is associated with Peutz-Jehger Syndrome? Increased risk of breast cancer? Increased risk of ovarian cancer?
STK11. Increased risk of breast cancer. Increased risk of sex cord stromal tumors
Does RAD51C and RAD51D gene mutation lead to increased risk of breast cancer? Increased risk of ovarian cancer?
No increased risk of breast cancer. Increased risk of ovarian cancer
What gene is associated with Cowden syndrome? Increased risk of breast cancer? Increased risk of ovarian cancer?
PTEN. Increased risk of breast cancer. No increased risk of ovarian cancer.
People with BRCA1 mutation are at increased risk of what cancers?
Breast, ovarian (fallopian tube, peritoneal), prostate
People with BRCA2 mutation are at increased risk of what cancers?
Breast, ovarian (fallopian tube, peritoneal), prostate, melanoma, pancreatic
What is the mean cumulative risk of breast cancer for BRCA1 mutation carriers?
57%
What is the mean cumulative risk of breast cancer for BRCA2 mutation carriers?
49%
For BRCA mutation carriers with breast cancer, what is the 10 year actuarial risk of developing subsequent ovarian cancer for BRCA1 and BRCA2?
- 7% with BRCA1
6. 8% for BRCA2
What is the risk of ovarian cancer (including fallopian tube and primary peritoneal cancer) by age 70 in women with BRCA1 mutation?
39-46%
What is the risk of ovarian cancer (including fallopian tube and primary peritoneal) by age 70 in women with BRCA2 mutation?
10-27%
What histopathology is typically associated with ovarian cancers in women with BRCA mutations?
Serous or endometrioid. Typically high grade
A woman with a high-grade ovarian cancer has what % chance of germline BRCA1 or BRCA2 mutation?
9-24%
Are mucinous ovarian cancers part of BRCA-related tumor spectrum? Borderline ovarian tumors?
do not appear to be related to BRCA-related tumor spectrum
What is the lifetime risk of pancreatic cancer with a BRCA2 mutation?
Up to 7%
At what age should a woman diagnosed with breast cancer (with no significant family hx) be referred for additional genetic evaluation?
45yo
For which of the follow diagnosis is it appropriate to refer a patient for genetic evaluation at any age: epithelial ovarian, tubal, peritoneal, breast?
epithelial ovarian, tubal, peritoneal
Breast cancer diagnosed at what age with a family history of close relative with breast cancer at <50yo or epithalial, tubal, or peritoneal at any age, is appropriate to refer for genetic evaluation?
50yo or less
Breast cancer diagnosed at what age with a limited or unknown family history is appropriate for referral for genetic evaluation?
50yo or less
*Limited FH = fewer than two first-degree or second-degree female relatives surviving beyond 45 years
Genetic evaluation for patient with breast cancer is appropriate at any age when a patient has how many close relatives with breast cancer?
Two or more close relatives
A woman diagnosed with breast cancer with a family history of two or more close relatives with what kind(s) of cancer qualifies for further genetic evaluation?
Breast, pancreatic, aggressive prostate cancer (Gleason score equal or >7)
In a patient with two breast cancer primaries, what would qualify her for further genetic evaluation?
If first cancer diagnosed before age 50
For which patients without diagnosis of cancer would you offer genetics evaluation for increased risk of cancer syndrome?
First degree or several close relatives meeting criteria for themselves to be genetically screened; clost relative with known BRCA1 or BRCA2 mutation, close relative with male breast cancer
When would you offer a patient with pancreatic cancer genetic evaluation for hereditary breast and ovarian cancer syndromes?
If they have two or more close relatives with breast, ovarian, tubal, peritoneal, pancreatic, or aggressive prostate cancer (Gleason score equal or >7)
What does the federal Genetic Information Nondiscrimination Act of 2008 protect against and not protect against?
Protects against health and employment discrimination based on genetic information, but does not apply to other forms of insurance (life or disability insurance)
What are the types of BRCA mutation testing?
Single-site testing, targeted multisite mutation testing, comprehensive gene sequencing, and BRCA rearrangement testing
True or false: Women with BRCA mutation should undergo routine ovarian cancer screening with measurement of serum CA 125 level or TVUS?
Generally not recommended.
Could consider between age 30-35yo until choose to do risk reducing BSO
What is the only intervention proven to reduce ovarian cancer-specific mortality among women with BRCA mutation?
Risk-reducing BSO
Does use of combined hormonal contraceptives decrease the risk of ovarian cancer in BRCA carriers?
Yes
By how much do combined hormonal contraceptives affect the risk of ovarian cancer in BRCA1 and BRCA2 carriers after 1 year use?
After 1 year, decrease ovarian cancer risk 33-80% for BRCA1 and 58-63% for BRCA2 carriers
How is the risk of breast cancer affected by use of oral hormonal contraceptives in BRCA carriers?
No clear increased risk
Carriers of what genetic mutations should be offered risk reducing BSO?
BRCA 1 and 2, BRIP1, RAD51C, and RAD51D, and lynch sydrome
At what age should you offer risk reducing BSO for carrier of BRIP1 mutation?
Ages 45-50
At what age should you offer risk reducing BSO for carrier of RAD51C mutation?
Ages 45-50
At what age should you offer risk reducing BSO for carrier of RAD51D mutation?
Ages 45-50
By how much does a BSO reduce the risk of ovarian, fallopian tube, or peritoneal cancer in patients with BRCA1 or BRCA2?
Approximately 80% risk reduction
Does a risk reducing BSO change mortality in women with BRCA1 or BRCA2 mutation?
Yes! Decreases overall mortality
When is a risk reducing BSO recommended for carriers of BRCA1 mutation?
typically age 35-40yo
When is a risk reducing BSO recommended for carriers of BRCA2 mutation?
Typically age 40-45yo
What percent of women with BRCA1 or BRCA2 mutation will be diagnosed with ovarian cancer before age 40?
2-3%
What percent of BRCA1 carriers will develop ovarian cancer by age 50?
10-21%
What percent of BRCA2 carriers will develop ovarian cancer by age 50?
No more than 3%
What percent of BRCA2 carriers will develop breast cancer by age 50?
26-35%
Apart from reducing risk of ovarian, fallopian, peritoneal cancer, does BSO have any other benefits for patients with BRCA mutation?
Decreases risk of breast cancer development. Maximum benefit achieved the earlier the ovaries are removed.
Is risk reducing bilateral salpingectomy an option for women with BRCA mutations?
Not currently recommended
By what % does bilateral salpingectomy decrease the risk of ovarian cancer in the general population?
Up to 65%
In broad terms, what options are available to reduce the risk of breast cancer among women with BRCA mutation?
Increased surveillance with more intensive screening, chemoprevention, surgery
What, if any, breast cancer surveillance is recommended for BRCA mutation carriers <30yo?
from 25-29 recommend clinical breast exam q6-12mo and annual radiographic screening (preferred MRI w/ contrast)
Why is annual MRI preffered over mammogram for women 25-29 with BRCA mutation for screening?
Evidence of radiation exposure leading to increased risk of breast cancer (in European women, no replicated in North American cohort)
What is the recommended breast cancer surveillance for women >30yo with BRCA mutation?
Annual mammography and annual breast MRI w/ contrast, alternating every 6 months
How does MRI compare to mammography in terms of sensitivity for detecting breast cancer?
More sensitive (MRI)
What screening modality(s) is most sensitive in detecting breast cancer in high-risk BRCA mutation carriers?
Combination of MRI, mammography, and clinical breast exam
How does breast MRI compare to mammography in terms of false-positive test rate, recall, and unneeded biopsy?
MRI has higher false-positive rates, higher recall rates, higher unneeded biopsy rates
How does tamoxifen, as chemoprophylaxis, affect risk of breast cancer among women with BRCA2?
May reduce breast cancer risk by approximately 62% (does not affect risk of breast cancer for BRCA1)
How does tamoxifen, as chemoprophylaxis, affect risk of breast cancer among women with BRCA1?
Does not reduce the risk of breast cancer. (decreases risk of breast cancer by ~62% for BRCA2)
What % of BRCA1 breast cancers are ER positive? of BRCA2?
Only 10-24% of BRCA1 breast cancers are ER positive. 65-79% of BRCA2 breast cancers are ER positive
How does raloxifene use affect risk of breast cancer?
Decreases risk of hormone receptor positive breast cancer in general population, does not affect BRCA mutation carriers
How does risk-reducing bilateral mastectomy affect risk of breast cancer in women with BRCA mutation?
Decreases risk by 85-100% depending on type of mastectomy procedure
If women with BRCA mutation is diagnosed with unilateral breast ca, should you offer bilateral mastectomy?
Yes. 30% risk of contralateral recurrence in 10 years
What is the risk of contralateral breast cancer recurrence in BRCA carrier within 10 years of initial diagnosis?
30%
Risk reducing BSO affects risk of breast cancer in BRCA mutation carriers by what %?
Decreases risk by 37-100%
When performing a risk-reducing BSO, where should the IP ligament be ligated?
2cm proximal to the end of the identifiable ovarian tissue, to ensure that all ovarian and tubal tissue is completely removed
Is it recommended to do frozen pathology at the time of risk reducing BSO?
No. Most malignancies are found occult
Why is it important for the pathologist to know if a BSO is a risk-reducing BSO?
If for risk-reducing (eg BRCA), need to serially section and look for microscopic disease rather than just check representative sections
Is a microscopic ovarian cancer or fallopian tube cancer more likely to be diagnosed of prophylactic risk-reducing BSO for BRCA1 and BRCA2 mutation carriers?
More likely fallopian tube cancer
Should women who underwent prophylactic BSO for BRCA carrier status receive hormone therapy to mitigate effects of early menopause? What effects?
Women who are unaffected by breast cancer should be offered hormone therapy. Help decrease risk of heart disease and bone loss
How should you counsel BRCA+ women s/p BSO without breast cancer about hormone therapy?
Estrogen-only or combined has limited data, but does not seem to significantly diminish protective effect of BSO on breast cancer risk reduction. However, long-term hormone therapy affect is unknown
What surveillance for primary peritoneal cancer should be performed for women after risk-reducing salpingo-oophorectomy?
No lab or imaging surveillance indicated. Counsel about symptom awareness
What is the risk of peritoneal cancer in all BRCA carriers?
1-6% cumulative risk
In what years did the BRCA testing change, how did it change, and why does this matter?
In 2009, started using large gene rearrangement testing in BRCA genes (ie, the BRCA Rearrangement Test)
In 2013, started multigene panel testing.
Important because you may need to retest individuals who are high risk and had negative testing before these new tests were available
What surgeries should you counsel a woman with BRCA mutation about?
Risk-reducing bilateral mastectomy and risk-reducing bilateral salpingo-oophorectomy
What is required for a risk-reducing BSO (what tissue removed, what needs to be inspected, etc)?
All tissue from ovaries and fallopian tubes should be removed. Thorough visualization of peritoneal surfaces with pelvic washings
