breast cancer - current concepts
TRANSCRIPT
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BREAST CANCER
DR. R. RAJKUMAR M.D. D.M.
Dr. R. RAJKUMAR M.
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Breast Cancer
• Incidence:
– Invasive breast cancer 1
• 1.4 million new cases in 2008
– Past 25 years
• Breast cancer incidence rates have risen
globally
• Highest rates occurring in the westernized
countries
–Change in reproductive patterns
– Increased screening
–Dietary changes
–Decreased activity
• Mortality
– Mortality has been decreasing
– Especially in industrialized countries.1 American Cancer Society
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BREAST CANCER IN INDIA
• Around 1 lakh cases /yr
• Peak incidence - 55-59/yr
• Age shift
• Rising numbers
• Late presentation
• Lack of awareness and screening
• Aggressive cancers in young
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Age shift – cases in seen 30’s& 40’s
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• Young onset breast cancer
• High grade (aggressive) tumors
• High proliferative tumors
• ER negative tumors
• “Triple negative” (ER-/PR-/HER2-) tumors
INDIAN Women More Likely to Have:
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Importance of Pathology: Not all Breast Cancers Are the Same!!
Estrogen
Receptor (ER) +
75% of Breast
Cancer
HER-2 +
20-25% of Breast
Cancer
Tumor ER and HER2 status critical in selecting therapy in
both early stage and metastatic breast cancer
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Treatment of Early Stage Breast Cancer
• Breast cancer most curable when detected early
– Micrometastases (undetectable) can exist at time of diagnosis in many patients, leading to eventual recurrence
• Multidisciplinary care critical for best outcomes
– Surgery
– Radiation therapy
– Adjuvant systemic (drug) therapy reduces risk of recurrence and death
» Should be tailored to the patient and tumor
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No surgery
mastectomy
chemotherapy + endocrine therapy
chemotherapy + endocrine therapy +
HER2 targeted therapy
Incremental Benefit of Adjuvant
Treatments in Early Stage Breast
Cancer in USA
Survival
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Adjuvant (Early Stage) Endocrine Therapy in Breast Cancer
• Tamoxifen has substantial clinical efficacy, less cost, and several decades of use throughout world
– Still the standard for premenopausal
– Reasonable for many postmenopausal
– Longer duration (> 5 years) may benefit many patients
• Adjuvant aromatase inhibitors: small differences in recurrences (and in some trials deaths)
– Side effects different
• Ovarian suppression effective as a sole treatment
– Still unclear whether it adds to chemo/tamoxifen
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Early Breast Cancer Trialists’ Collaborative Group
Clinical Trials of Tamoxifen in Early Stage Breast Cancer: Disease-free Survival
ER Negative ER Positive
Adjuvant tamoxifen
significantly reduces
recurrence in ER positive
breast cancer
tamoxifen
control
Tamoxifen effective in both pre- and postmenopausal women
Adjuvant tamoxifen
doesn’t impact
recurrence in ER
negative breast cancer
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Adjuvant (Early stage) Chemotherapy in Breast Cancer
• Adjuvant chemotherapy reduces recurrences and deaths
– Reducing dose from that proven to be effective in clinical trials reduces benefit
– Chemotherapy drugs have significant side effects
• For unselected patients/tumors:
– anthracyclines better than CMF regimens
– taxanes add to anthracyclines – expensive
• Not all patients/tumors benefit from chemotherapy!
• ER-negative, high grade, HER-2+ tumors get most benefit from chemotherapy
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Chemotherapy Dose MattersAdjuvant Chemotherapy - 20 Year Follow-up
Milan StudyBonadonna G et al, N Engl J Med 332: 901-6,1995
0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.05 10 15 20
Years after Mastectomy
Disease-free survival
Pro
ba
bili
ty o
f R
ela
pse
-fre
e S
urv
iva
l
5 10 15 20
Years after Mastectomy
0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Overall survival
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
>85% of dose
<65% of dose
Control
65-84% of dose
If chemotherapy is given, it should be given at full dose
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Adjuvant (Early Stage) HER-2 Targeted Therapy
• Anti-HER2 monoclonal antibody trastuzumab(Herceptin) for 1 year is standard
– Reduces recurrence by 1/2 & deaths by 1/3 when added to chemo in early stage breast cancer
– Trastuzumab going off patent soon, and prices will drop
• All regimens include chemotherapy in addition to HER2 targeting therapy
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Molecular classification & Prognosis:
• Luminal A= Best prognosis
• Luminal B
• Luminal C
• Normal breast like
• Her 2+
• Basal like= Worst= Triple Negative
14
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SUBTYPE
Type Importance
Luminal A ER +, Best overall
survival, Best DFS
Luminal B ER,Her2+,Intermediate
Her 2 +ve ER-, Intermediate
Basal like ER-,PR-, Her2 - Worst
15
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BREAST CANCER
Stage IV
Any T any N M1
Examples of distant mestastatic disease
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BREAST CANCERSites of distant
metastases
Skin
Liver
Bone
Pleura
Lung
Lymph nodes
Brain
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Treatment of Metastatic Breast Cancer
• Metastatic breast cancer is not curable, but can be very treatable
• Goals:
–Control and regression of disease
–Prolongation of life
–Improvement in symptoms and quality of life
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Choices in the Treatment of Metastatic Breast Cancer
• Choice of treatment is based on many factors:
–Patient age, menopausal status, general health and functional status
–Tumor ER status, HER-2 status
–Previous treatments
–Extent and sites of disease
– Available therapies in the patient’s country
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Breast Cancer Systemic Therapies
• Drug treatments that can attack cancer cells throughout the body
–Endocrine therapy
–Chemotherapy
–Biologically-targeted therapy
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Endocrine Therapy in Breast Cancer
Estrogen
Cell
Growth
and
Division
Estrogen
Receptor
SERMS (tamoxifen),
SERDS Aromatase inhibitors, ovarian
suppression
Endocrine therapy effective only in ER-positive breast cancer
ER/PR staining: CRITICAL IN SELECTING THERAPY!
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Endocrine Therapy for Metastatic Breast Cancer
• Endocrine therapy is the preferred choice for ER+ metastatic breast cancer
– Less side effects than chemotherapy
• Exceptions:
– Concern or proof of endocrine resistance
– Need for fast response (location, symptoms)
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Hormonal Therapies (FDA indications)
• 1st line therapy:
–Tamoxifen, anastrozole (Arimidex), letrozole (Femara)
• 2nd line therapy:
–Fulvestrant (Faslodex), toremifene (Fareston), exemestane (Aromasin)
• “Palliative”
–Goserelin (LHRH analog, Zoladex)
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Chemotherapy
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Treatment of Metastatic Breast Cancer: Cytotoxic Agents
• Anthracyclines (doxorubicin, liposomal doxorubicin)
• Cyclophosphamide
• Taxanes (paclitaxel, docetaxel)
• Antimetabolites (5-FU, capecitabine)
• Gemcitabine
• Vinorelbine
• Carboplatin/cisplatin
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European School of Oncology Guideline: Chemotherapy for Metastatic Breast
CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009
• Sequential single agent chemotherapy generally preferred choice
– Less toxicity than combination chemo
– No data to support optimal sequence
• Combination chemotherapy reserved for patients with:
– rapid clinical progression
– life-threatening visceral metastases
– need for rapid symptom/disease control
• Chosen regimen should be evidence-based, with proven efficacy and acceptable toxicity
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Biologically-Targeted Therapy
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Her2/neu status
• Membrane-associated tyrosine kinase receptor (aka erbB2) related to EGF
–Expressed in breast cancers, DCIS, and some other tissues such as heart
–Overexpressed in 25-30% of breast cancers
–Associated with more aggressive disease and worse prognosis
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Measurement of Her2/neu
• Measured by immunohistochemistry (IHC)
– Graded 0, 1+, 2+, or 3+
– Based on characteristics of staining
– 0-1 = negative
– 2 = indeterminant, should be followed with FISH (fluorescent in situ hybridization) to determine status (amplified/not amplified)
– 3 = positive
• Fluorescence In Situ Hybridization (FISH) correlates with response to Herceptin, but more expensive
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Four US FDA-Approved Drugs with HER-2 as a Target
cell division
HER-2
nucleus
cancer cell
Trastuzumab (Herceptin)
Anti-HER-2 Antibody
Lapatinib (Tykerb)
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
Pertuzumab
Anti-HER-2 Antibody
T-DM1
Antibody-Drug
Conjugate
20-25% of breast
cancers overexpress
HER2
Only effective for HER2+ breast
cancer
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Trastuzumab (Herceptin)
• Humanized monoclonal antibody against her2/neu
• FDA approved for metastatic breast cancer in 1998
• Responses in patients with her2/neu positive breast cancer
– IHC 3+
– FISH positive
• Single agent therapy has 26% response rate as 1st
line therapy
• May be given as an IV infusion weekly or every 3 weeks
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European School of Oncology Guideline: HER2 Targeted Therapy
for Metastatic Breast CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009
• Anti-HER2 therapy should be offered early to all HER2+ metastatic breast cancer patients unless contraindicated (or unavailable)
• Optimal duration of anti-HER2 therapy for metastatic breast cancer (when to stop) unknown
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Complications of Breast Cancer Bone Metastases
Pain
Spinal cord
compression
Radiation
therapy
Orthopedic
surgery
Hypercalcemia
Fractures
The bone is the initial site of recurrence in 35-40% of breast cancer patients
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European School of Oncology Guideline: Bone Metastases in Breast Cancer
Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009
• Bone modifying agents should be routinely used in combination with other systemic therapy in patients with bone metastases
– Bisphosphonates (pamidronate, zoledronic acid)
– RANK ligand inhibitor (denosumab)
• Agents should be started early, if possible before onset of bone symptoms
• Should be continued even in presence of disease progression
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Zoledronic Acid (Zometa)
• Bisphosphonic acid – inhibitor of osteoclastic bone resorption
• Indicated for solid tumor patients with bone metastases
• 4 mg IV over 15-30 minutes
• Check serum creatinine before each administration
• Comparable in efficacy to pamidronate
•Rosen LS, Cancer J 7:377, 2001
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Systemic Treatment of Breast Cancer: Summary
• Main principles of modern oncology
– Multidisciplinary treatment
– Evidence-based medicine
– Individualized (tailored) therapy
• Keep in mind goals of therapy
– Adjuvant: curative intent
– Metastatic: incurable but treatable
• Include psychosocial and supportive care and symptom-related interventions
• Include patient preferences and active participation
– Patients, families and caregivers should be invited to participate in decision-making
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