genetics and breast cancer screening · adjuvant hormone therapy— tamoxifen •a selective...
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High Risk Breast Cancer Screening
Alterations in Screening Recommendations Based on Genetics
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Hereditary Cancers
• Characteristics
– Gene mutations w/ high penetrance
– Vertical transmission
– Association with other tumor types
– Early age of onset
– Autosomal dominant
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Familial Cancers
• Characteristics
– Generally do not exhibit the inheritance pattern
– Generally do not have same onset age
– Chance clustering of sporadic cases within families
• lower penetrance genes
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Hereditary/Familial High-Risk Assessment: Breast Cancer
• All suspected individuals offer genetic counseling
– family history
– genetic testing
• Genetic evaluation implications
– Prevention
– Screening
– Treatment
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Hereditary/Familial High-Risk Assessment: Breast Cancer
• Up to 10% of breast cancers are due to specific mutations in single genes that are passed down in a family
– BRCA1/2
– TP53 mutation Li Fraumeni Syndrome
– PTEN mutation Cowden Syndrome
– Others
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Hereditary/Familial High-Risk Assessment: Breast Cancer
• Offspring 50% chance of mutation
– Early onset breast cancer
– Risk of other tumors
– Autosomal dominant
– Highly penetrant
• Two-hit hypothesis still applies
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BRCA-Related Breast Cancer Syndrome
• Prevalence
– BRCA1 ~ 1 in 300
– BRCA2 ~ 1 in 800
• Over 90% of hereditary families with both breast and ovarian cancers are caused by BRCA-related mutations
• Ashkenazi Jewish population
– specific mutation found in ~ 1 in 40
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BRCA-Related Breast Cancer Syndrome
• Estimated lifetime risk for female breast cancer (by age 70)
– BRCA1 57%
– BRCA2 49%
• Penetrance variable
• Risk is excessive enough to consider more intensive screening strategies
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Li Fraumeni Syndrome
• Li Fraumeni
– TP53 gene mutation
– ~1% of hereditary breast cancers
• Highly penetrant
• Premenopausal breast cancers
• Her2 (+) breast cancers
– Core cancers sarcoma, breast, adrenal, brain
– Estimated lifetime risk by age 45 60%
– Estimated lifetime risk by age 70 95%
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Cowden Syndrome
• Cowden
– PTEN gene mutation
– 80% penetrance
– Lifetime risk of breast cancer ~25-50%
• Average age of 38-50 years at diagnosis
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High Risk Screening Modalites
• Mammography alone
– Does not reduce mortality in women with genetically increased risk
• False negative rate is higher
• May be less sensitive for aggressive tumors
• Ultrasound
– Similar sensitivity to that of mammography
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High Risk Screening Modalites
• MRI
– Sensitivity significantly higher compared with mammography
– In most all of the prospective trials, screening was annual
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Adjunct Screening Recommendations
• BRCA1/2 mutation carrier
– Age 18 Self breast exams/awareness
– Age 25 Semiannual clinical breast exams
– Ages 25-29 annual breast MRI screening
• Performed on days 7-15 of menstrual cycle
• Annual mammograms if MRI not available
– Ages 30-75 both annual mammogram + MRI
– After age 70 at discretion of physician/patient
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Adjunct Screening Recommendations
• Li Fraumeni mutation carrier
– Age 18 Self breast exams/awareness
– Age 20-25 Semiannual clinical breast exams
– Ages 20-29 annual breast MRI screening
– Ages 30-75 both annual mammogram + MRI
– After age 75 at discretion of physician/patient
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Adjunct Screening Recommendations
• Cowden carrier
– Age 18 Self breast exams/awareness
– Age 25 Semiannual clinical breast exams
• Or 5-10 years before earliest known breast ca
– Ages 30-75 annual breast MRI screening
• Or 5-10 years before earliest known breast ca
– After age 75 at discretion of physician/patient
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Adjunct Screening Recommendations
• Other circumstances
– Lifetime risk >20% based on history of LCIS or ADH/ALH
• Consider annual MRI – To begin at diagnosis but not less than age 30
– Lifetime risk >20% based on family history models
• Recommend annual breast MRI
• Begin 10yrs prior to youngest family member, not less than age 30
• Referral for genetic counseling
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Adjunct Screening Recommendations
• Other circumstances, cont…
– Prior thoracic RT between ages 10 and 30 y
• Current age <25 y annual clinical breast exam – beginning 8-10 years after RT
• Current age >/= 25y annual screening mammogram + clinical breast exam every 6-12mo + annual breast MRI – Beginning 8-10 years after RT
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Breast Cancer Staging
American Joint Committee on Cancer
(AJCC)
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Systemic Treatment of Breast Cancer
Hormone Therapy and Chemotherapy,
Curative and Palliative
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Systemic Therapy
• Invasive breast cancers
• Two forms
– Curative
– Palliative
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Curative Systemic Therapy
• Adjuvant Therapy
– Any systemic therapy given AFTER the curative treatment step (surgery)
• Neoadjuvant Therapy
– Any systemic therapy given BEFORE the curative treatment step
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Adjuvant Systemic Therapy-- treatment goal
• Goal
– To kill “stray” cells, or microscopic metastases
– Microscopic metastases divide over time settle somewhere recurrence
– Decrease the chances of recurrence and increase the chances of cure
– Treatment is CURATIVE
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Adjuvant Systemic Therapy-- options
• Adjuvant Hormone Therapy – ER+ or PR+ tumors
– Duration of treatment: 5-10 years
• Adjuvant Chemotherapy – Higher risk tumors
• Large
• Node positive
• Triple negative (ER-/PR-/Her2-)
• Her2 (+)
• High risk Oncotype Dx recurrence score
– Duration of treatment: 3-5 months
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Adjuvant Systemic Therapy-- indications
• Patient selection
– Stages I, II, and III invasive breast cancers
– Determined by
• tumor features
• tumor biology
• patient preference
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Adjuvant Systemic Therapy-- indications
• Medical decision making
– High risk of recurrence
• Triple negative (ER-/PR-/Her2-)
• Her2 (+)
• Lymph node (+)
– Treatment can reduce the risk of recurrence
– Benefit outweighs/balances toxicities
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Adjuvant Systemic Therapy-- risk of recurrence
• Tumor Risk Factors – Size – Grade – Node status – Receptor status
• ER, PR, Her-2 neu
• Adjuvant Online – a computer algorithm that takes information about a
specific woman’s cancer and produces survival and recurrence estimates for her based upon whether she receives one set of treatment versus another
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Adjuvant Systemic Therapy-- risk of recurrence
• Oncotype Dx – A multigene diagnostic test that determines the
individual risk of cancer recurrence in early-stage invasive breast cancer
– Identifies patients with minimal, if any, likelihood of benefit of chemotherapy
– Identifies patients with substantial likelihood of benefit from chemotherapy
– The Oncotype Dx Recurrence Score reveals the underlying tumor biology to help guide treatment decisions
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Age 61 43
Menopausal status Post Pre
Tumor type Ductal Ductal
Tumor size 4.0 cm 1.5 cm
Tumor grade 2 2
ER/PR status Positive Positive
Her2 status Negative Negative
Lymph node status Negative Negative
General health Excellent Excellent
Recurrence score 10 (low risk) 10 (low risk)
10yr risk of recurrence after 5 years of Tamoxifen
7% 7%
Prediction of chemotherapy benefit
Minimal Minimal
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Adjuvant Systemic Therapy— options
• Adjuvant Hormone Therapy
– ER+ or PR+ tumors
• Adjuvant Chemotherapy
– Higher risk tumors
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Adjuvant Hormone Therapy— options
• Menopausal status
– Pre-menopausal women
• Tamoxifen
– Post-menopausal women
• Tamoxifen
• Aromatase Inhibitors – Arimidex (anastrazole)
– Femara (letrozole)
– Aromasin (exemestane)
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Adjuvant Hormone Therapy— tamoxifen
• A selective estrogen receptor modulator
– SERMS bind to estrogen receptors throughout the body and act as estrogen agonists or antagonists depending on the target organ
• Bone agonist estrogen binds strengthens bone
• ER+ breast cancer cell antagonist estrogen does not bind cuts off crucial fuel supply kills cell
• Pre- and post-menopausal women
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Adjuvant Hormone Therapy— tamoxifen
• Side effects
– Vasomotor hot flashes
– 2-3% risk of thromboembolism (DVT most common)
– 1-2% risk of uterine cancer
– DOES NOT put patients in menopause
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Adjuvant Hormone Therapy— aromatase inhibitors
• AIs inhibit the enzyme, aromatase, which converts pre-estrogens to estrogens decreases fuel supply for tumor growth
– Adrenal glands
– Subcutaneous fat
– NOT THE OVARIES
• Post-menopausal women only
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Adjuvant Hormone Therapy— aromatase inhibitors
• Side effects
– Vasomotor hot flashes
– Arthralgias (30% risk)
– Accelerated osteoporosis
• Baseline Dexascan and then q2years
• Calcium and Vit D
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Adjuvant Chemotherapy— options
• Her2 (-) – Adriamycin/Cytoxan (AC) followed by Taxol (T)
• AC q2wks x 4 cycles T q2wks x 4 cycles – 4.5 months
• AC x 4 cycles weekly T x 12 weeks – 5 months
– Taxotere/Cytoxan (TC) • TC q3wks x 4 cycles
– 3 months
– Choice of treatment driven by physician/patient preference
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Adjuvant Chemotherapy— options
• Her2 (+) – Taxotere/Carboplatin/Herceptin (TCH)
– Followed by Herceptin maintenance • TCH q3wks x 6 cycles H q3wks to complete a full year
– AC followed by Taxol (T) /Herceptin (H) • AC q2wks x 4 cycles T q2wks/H q2wks x 4 cycles H q3wks
to complete a full year
– Taxol (T) + Herceptin (H) • Weekly T x12wks + weekly H x 12 weeks H q3wks to
complete a full year
– Newer agents: pertuzumab (Perjeta)
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Adjuvant Systemic Therapy
• Curative intent • Options
– Hormone Therapy (duration 5-10 years) – Chemotherapy (duration 3-5 months + 1 year of
Herceptin when indicated) – Both – Determined by risk features, tumor biology, patient
preference
• Sequence of treatment – Surgery adjuvant chemotherapy adjuvant
radiation adjuvant hormone therapy
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Palliative Systemic Therapy
• 20-30% of patients will develop metastases – Liver, lungs, bone, brain
• Less than 10% of newly diagnosed cases will be Stage IV
• Survival has improved – MS can exceed 2-3 years
• Higher in ER+ tumors
• Lower in triple negative tumors
• Her2 (+) tumors – Significant increase in survival since the advent of Herceptin
– May do better than Her2 (-) counterparts
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Palliative Systemic Therapy— hormone therapy
• ER+ tumors – Indolent
– Minimal symptoms
– No visceral involvement
• Options – Tamoxifen
– AIs
– Faslodex—a selective estrogen receptor downregulator (SERD)
– AIs or Faslodex + oral targeted agents
• Add Herceptin if also Her2 (+)
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Palliative Systemic Therapy— chemotherapy
• Palliative/non-curative – live longer and better
• More aggressive tumors – Symptomatic – Visceral involvement – Hormone refractory
• ChemoSENSITIVE • Many options
– No specific regimen is superior – Choice depends on patient selection, toxicity profile,
anticipated tolerance, treatment schedule – Her2-directed drugs incorporated when indicated