High Risk Breast Cancer Screening

Alterations in Screening Recommendations Based on Genetics

Hereditary Cancers

• Characteristics

– Gene mutations w/ high penetrance

– Vertical transmission

– Association with other tumor types

– Early age of onset

– Autosomal dominant

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

Hereditary/Familial High-Risk Assessment: Breast Cancer

• All suspected individuals offer genetic counseling

– family history

– genetic testing

• Genetic evaluation implications

– Prevention

– Screening

– Treatment

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

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

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

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

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%

Cowden Syndrome

• Cowden

– PTEN gene mutation

– 80% penetrance

– Lifetime risk of breast cancer ~25-50%

• Average age of 38-50 years at diagnosis

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

High Risk Screening Modalites

• MRI

– Sensitivity significantly higher compared with mammography

– In most all of the prospective trials, screening was annual

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

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

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

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

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

Breast Cancer Staging

American Joint Committee on Cancer

(AJCC)

Systemic Treatment of Breast Cancer

Hormone Therapy and Chemotherapy,

Curative and Palliative

Systemic Therapy

• Invasive breast cancers

• Two forms

– Curative

– Palliative

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

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

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

Adjuvant Systemic Therapy-- indications

• Patient selection

– Stages I, II, and III invasive breast cancers

– Determined by

• tumor features

• tumor biology

• patient preference

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

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

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

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

Adjuvant Systemic Therapy— options

• Adjuvant Hormone Therapy

– ER+ or PR+ tumors

• Adjuvant Chemotherapy

– Higher risk tumors

Adjuvant Hormone Therapy— options

• Menopausal status

– Pre-menopausal women

• Tamoxifen

– Post-menopausal women

• Tamoxifen

• Aromatase Inhibitors – Arimidex (anastrazole)

– Femara (letrozole)

– Aromasin (exemestane)

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

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

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

Adjuvant Hormone Therapy— aromatase inhibitors

• Side effects

– Vasomotor hot flashes

– Arthralgias (30% risk)

– Accelerated osteoporosis

• Baseline Dexascan and then q2years

• Calcium and Vit D

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

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)

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

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

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 (+)

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