Breast CA - Genetics Flashcards
BRCA1 and BRCA2 (tumor suppressor genes)
Increased incidence:
- breast cancer
- ovarian cancer
- fallopian tube cancer
- prostate cancer
- melanoma (BRCA2)
- pancreatic cancer (BRCA2)
- BRCA1: predisposition for triple negative breast cancer
- BRCA2: predisposition to ER-positive disease.
Management of women who are BRCA mutation-positive
- See table “Screening Recommendations for Breast Cancer” for screening recommendations in high-risk individuals
- Discuss option of risk-reducing mastectomy
- Recommend risk-reducing salpingo-oophorectomy (typically between 35 – 40 y and upon completion of childbearing)
BRCA - Progression genes
HER2 (Human Epidermal Growth Factor Receptor-2, erbB-2) proto-oncogene
1) Amplified/overexpressed in approximately 20-25% of all breast cancers
2) Amplification/overexpression generally imparts a poorer prognosis
3) Used primarily to select patients who will benefit from HER2-directed therapy
BRCA and HER2
IHC Score 0
- IHC Score: 0
- Surgical Specimen Staining: No reactivity or membranous activity in < 10% tumor cells
- Biopsy Specimen Staining: No reactivity or no membranous reactivity in any tumor cell
- HER2 Overexpression: Negative
BRCA and HER2
IHC Score 1+
- IHC Score: 1+
- Surgical Specimen Staining: Faint membranous reactivity in > 10% tumor cells; cells reactive only in part of their membrane
- Biopsy Specimen Staining: Tumor cell cluster faint or barely perceptible membranous reactivity irrespective of % tumor cells positive
- HER2 Overexpression: Negative
BRCA and HER2
IHC Score 2+
- IHC Score: 2+
- Surgical Specimen Staining: Weak to moderate complete,
basolateral or lateral membranous reactivity in > 10%
tumor cells - Biopsy Specimen Staining: Tumor cell cluster with weak to moderate complete, basolateral or lateral membranous reactivity irrespective of % tumor cells positive
- HER2 Overexpression: Equivocal – confirm by FISH or other method. If FISH+ and IHC 2+, then HER2 Positive
BRCA and HER2
IHC Score 2+
- IHC Score: 3+
- Surgical Specimen Staining: Strong complete, basolateral or lateral membranous reactivity in > 10% tumor cells
- Biopsy Specimen Staining: Tumor cell cluster > 5 or more with strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor
cells positive - HER2 Overexpression: POSITIVE
BRCA Risk Factors
- > 60% of breast cancer patients have no identifiable risk factors beyond female gender and aging
- Age
- Family history of breast cancer (1 or 2 degree)
- Reproductive history
-> Younger age at menarche (typically defined as ≤ 12 y/o)
-> Older age at menopause (typically defined as ≥ 55 y/o)
-> Age at birth of first child ≥ 30 y/o - History of LCIS or atypical hyperplasia (ALH or ADH)
- Early thoracic irradiation
- Increased body mass index (BMI)
- Current or prior estrogen and progesterone hormone tx
- Alcohol consumption
- Breast density and mammographic patterns
BRCA Prevention (Risk Reduction)
- Prophylactic mastectomies
- Bilateral oophorectomy
- Primary prevention trials
-> Tamoxifen vs. placebo: FDA approved tamoxifen for breast cancer risk reduction for women at increased risk based on P-1 study results
-> Tamoxifen vs. Raloxifene - STAR trial (NSABP P-2): tamoxifen is superior to raloxifene in reducing invasive breast cancer; however, both remain valid options
-> Aromatase inhibitors (AIs) - 65% relative reduction in invasive breast cancers in the exemestane group
NSABP Breast Cancer Prevention Trial
TAMOXIFEN vs Placebo
BENEFITS
Benefits:
- reduction in risk of invasive (49%) and noninvasive breast cancers (50%)
- reduction in invasive breast cancers in women with LCIS (56%) and with atypical hyperplasia (86%)
- reduced incidence of ER-positive tumors, but not ER-negative tumors
- Reduction in incidence of invasive and noninvasive breast cancers persisted with 7 years of follow up.
Absolute risk reduction was 21.4 cases per 1,000 women over 5 years
NSABP Breast Cancer Prevention Trial
TAMOXIFEN vs Placebo
RISK
Risks:
- increased incidence of endometrial cancer in postmenopausal women
- thromboembolic events (pulmonary embolism (PE) significantly increased in women ≥50 y/o)
- hot flashes
- cataracts
Tamoxifen vs. Raloxifene - STAR trial (NSABP P-2)
BENEFITS
Benefits:
- similar reduction in incidence of invasive breast cancers; - numerically fewer cases of noninvasive breast cancer with tamoxifen;
- no difference in fractures or total deaths.
Tamoxifen vs. Raloxifene - STAR trial (NSABP P-2)
RISKS
Risks:
- statistically greater number of patients with endometrial hyperplasia
- VTE [PE + deep vein thrombosis (DVT)], and cataracts with tamoxifen than raloxifene;
- numerically more endometrial cancers and myocardial infarction (MI) with tamoxifen compared to raloxifene
Update with 81 months of follow-up:
Significant increase in risk of invasive breast cancer in patients who received raloxifene compared to tamoxifen (RR 1.24, 95% CI: 1.05–1.47); thus tamoxifen is superior to
raloxifene in reducing invasive breast cancer; however, both remain valid options
NCIC CTG MAP.3 trial
Aromatase inhibitors (AIs)
- Exemestine vs Placebo
BENEFITS
65% relative reduction in invasive breast cancers in the exemestane group
CIC CTG MAP.3 trial
Aromatase inhibitors (AIs)
- Exemestine vs Placebo
RISKS
Risks:
more common in the exemestane group:
- Arthritis
- hot flashes
- fatigue
- sweating
- insomnia
- diarrhea
- nausea
- joint pain
- muscle pain
not statistically different:
- fractures
- osteoporosis,
- cardiovascular events
- deaths
