BREAST CANCER

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BREAST CANCER

• Lawrence E. Flaherty M.D.
• Professor of Medicine and Oncology
• Karmanos Cancer Institute
• Wayne State University

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Breast Cancer Incidence

• U.S Incidence
• Affects 1 in 8 women living to age 85
• Total Cases 2008 211,000
• Total Deaths 2008 40,500 (1/6 female
  deaths)
• Ethnic incidence
• Caucasians Hispanic Asian African
  Amer
• African Americans higher stage and mortality
• Stage at presentation localized 58 (node -)
• - regional 32 (node / stage III)

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Breast Cancer Risk Factors
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Breast Cancer Risk Factors

• Personal History
• ? Biopsy Pathology
  Relative Risk (RR)
• Lobular Carcinoma in situ 8-10
• Ductal Carcinoma in situ 8-10
• Atypical Ductal Hyperplasia 4-5
• Atypical Lobular Hyperplasia 4-5
• Hyperplasia 1.5-2.0
• ?Prior Biopsy - Any 1.3-1.6

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Breast Cancer Risk Factors

• Age
• Age Incidence
• by age 30 1 in 2,525
• by age 40 1 in 217
• by age 50 1 in 50
• by age 60 1 in 24
• by age 70 1 in 14
• by age 80 1 in 10

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Breast Cancer Risk Factors

• Family History
• Affected Relationship RR
  Percentage
• 1 1st degree 2.45 9-21
• 2 1st degree 11-48
• 1 2nd degree 1.82 8-14
• 2 2nd degree
  9-26
• 1st degree sisters, mother, daughters
• 2nd degree cousins, grandparents
• Range affected by the age of diagnosis of
  affected family individual younger higher

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Breast Cancer Risk Factors

• Reproductive/Other
• Feature RR
• Menarche lt age 12 1.2
• 1st Live Birth gt age 30 1.9
• Menopause after age 55 1.5
• HRT Long Term exposure 1.1-1.4
• Radiation Exposure - Hodgkin's/Mantle RT

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Monthly Incidence 1998 thru 2002 (for women 50
and older) Stable Incidence
Incidence Per 100,000 Women / Month
Year of Diagnosis
16
Updated with an Additional Year of Data Monthly
Incidence 1998 thru 2003 Decrease In 2003
Incidence Per 100,000 Women / Month
Year of Diagnosis
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Effect Seen in All SEER 9 Registries Relative
Reduction (2003 vs 2000/2001)
All Registries
San Franscisco Connecticut Detroit Hawaii Iowa New
Mexico Seattle Utah Atlanta
Relative reduction in incidence ()
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Effect Only Evident In Subsets Of Patients 50 and
Older
Any Age
lt 40 40 49 50 64 65 74 75 84
Relative reduction in incidence ()
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Influence of ER Status
Any ER
ER ER
Relative reduction in incidence ()
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Usage of Hormonal Agents in the US
www.drugtopics.com/drugtopics/
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Change In Use The Prevalence Of Use Of HT
Pre/Post WHI (Estimates Derived From HMO Data)
50
45
40
35
30
Pre-WHI
Of Population Treated
25
Dec-02
20
15
10
5
0
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
Use and Decrease Mainly in Women 50 and Older
Buist et al. Obstet Gynecol 2004104104250.
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Mammography

• Established Guidelines
• Annual 2 view study in women 50 years of age and
  older
• Meta - analysis
• 13 randomized trials
• 26 reduction in breast cancer

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Mammography

• Controversy in Age 40-49
• Recommended by American Cancer Society (ACS), the
  National Cancer Institute (NCI), the American
  Medical Association (AMA) and the American
  College of Surgeons (ACS) - CoC
• Earlier detection and mortality benefits smaller
• Less cost effective
• Leave decision to the individual well informed
  women
• Identify higher risk populations within your
  practice

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Mammography

• Earlier Routine Mammograms
• High Risk Groups
• strong family history
• multiple family members with breast and or
  ovarian cancer, particularly when occurring at an
  early age
• personal history of thoracic radiation therapy
• Hodgkins disease
• screening beginning 10 years earlier than the age
  of the youngest affected family member, but not
  before age 25

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Mammography - Ordering

• Screening
• Patient without physical finding or symptoms
• MLO - mediolateral oblique (side)
• CC - craniocaudal (above)
• Diagnostic
• new symptoms - lump, thickening, skin change
• additional imaging including magnification
• additional evaluation including US

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Mammography - Reporting

• BIRADS - Breast Imaging Reporting and Data System
• Category Assessment Recommendations
• 0 Incomplete Additional views
• 1 Negative Routine - 12 months
• 2 Benign Routine - 12 months
• 3 Probable Benign F/U short term - 6 mos.
• 4 Suspicious Biopsy considered
• 5 Cancer suggested Appropriate action

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Breast Cancer Diagnosis

• Fine Needle Aspiration
• Ultrasound Guided Core Biopsy
• Excisional or Incisional Biopsy

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Breast Cancer Diagnosis

• FNA - Fine Needle Aspiration
• simple - 21-23 gauge needle - 5-10 cc syringe
• relatively atraumatic
• sensitivity of 73-99
• ideal for simple cyst aspiration
• cant distinguish in-situ vs invasive cancer

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Breast Cancer Diagnosis

• CNB - Core Needle Biopsy
• 14 - 20 gauge cutting needle
• greater trauma
• high sensitivity - 100
• distinguishes between invasive and in-situ
• stereotactic with mammography and US
• may completely remove small areas

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Breast Cancer Diagnosis

• Open Biopsy (incisional or excisional)
• any suspicious finding
• clinical or radiologic finding with negative FNA
  or CNB
• atypia on FNA or CNB
• 20-50 associated with malignancy on open biopsy
• recurring cyst

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Breast Cancer Non-Invasive
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Breast Cancer Pathology

• Non Invasive
• Lobular (LCIS) Ductal (DCIS)
• Invasive
• Low Risk Standard (high) Risk
• Pure Tubular Ductal
• Pure Mucinous/Colloid Lobular
• Pure Papillary Medullary
• Pure Medullary ? Mixed
• Squamous

atypical and mixed
Requires careful pathology review
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Breast Cancer Non-Invasive Lobular (LCIS)

• Features
• Increased risk of subsequent invasive cancer (
  1/yr)
• Likely to be bilateral
• Management Options
• Observation ( negative surgical margins NOT
  required)
• No SLNBx or ALND is necessary
• Bilateral mastectomies can be considered
• Potential candidates for Tamoxifen or
  chemoprevention trials
• Work-Up/Follow-Up
• Bilateral mammogram, then yearly
• Exam every 6-12 months

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Breast Cancer Non-Invasive Ductal (DCIS)

• Incidence
• Incidence 4,800 50,000 in past 20 years
• Represents 20 of new cancer diagnosis in U.S.
• Risk
• Pre-invasive to invasive ductal cancer (IDC)
• Increased risk of subsequent invasive cancer
  ( 1/yr)
• Features
• 90 found on mammogram 76 as micro Ca
• Likely to be unilateral
• ER in 70 (lower in high grade)
• Her 2 neu in 50 (higher in high grade)

Note if diagnosed by core biopsy 10-15 will
have invasive component at excision
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Breast Cancer Non-Invasive Ductal (DCIS)

• Management Options Surgery - Breast
• 1). Complete Excision Alone
• 2). Complete Excision RT
• 3). Mastectomy

Possible for low risk lesion, but low risk
difficult to define
Relative Contraindications 1 in 2 or more
quadrants 2 diffuse or malignant appearing
Ca 3 persistent margins 4 not RT
candidates prior RT pregnancy CTD
lupus/scleroderma

• Margins need to be negative,
• gt1mm, less than 10 mm. 2-3 mm usually recommended

Post excision Imaging - specimen mammogram
and/or - post lump mammogram
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Breast Cancer Non-Invasive Ductal (DCIS)

• Management Options Radiation Therapy
• Excision Alone recommended
• Post Mastectomy unnecessary
• No effect on mortality
• Decreases Breast Recurrence Risk by 50 (1
  ½/yr)
• Treatment is to Breast Only
• Contraindications
• Omitted in low risk?
• controversial
• lt 5mm, low grade, unicentric

Relative Contraindications 1 in 2 or more
quadrants 2 diffuse or malignant appearing
Ca 3 persistent margins 4 not RT
candidates prior RT pregnancy CTD
lupus/scleroderma
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Breast Cancer Non-Invasive Ductal (DCIS)

• Management Options Systemic Therapy
• NSABP B-24 (BCS /- RT) Tamoxifen No
  Tamoxifen
• Invasive 4.1 7.2
• Non-Invasive 4.2 6.2
• 8.2 13.4
• 5 absolute difference at 6 yrs
• No survival advantage (97-98)
• Tamoxifen indicated if there are no
  contraindications
• ER analysis necessary?
• Follow-Up - Visits every 6-12 months
• Yearly mammograms
• Yearly pelvic if intact uterus on Tamoxifen)

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Breast CancerNon Invasive - Ductal (DCIS)
Surgical Management Lymph Nodes

• Excision
• ALND unnecessary
• SLNBx optional but recommended if
• 1). Palpable
• 2). In the tail

• Mastectomy
• SLNBx recommended
• ALND unnecessary unless palpable and SLNBx
  unavailable

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Breast Cancer - Invasive
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Breast Cancer - Invasive

Lumpectomy RT

Mastectomy
Surgery
Lymph Nodes
Micrometastasis Risk
Medical Oncology
Size Lymph node/ Grade ER/PR Her 2-neu
Adjuvant Therapy
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Breast Cancer - Invasive

Micrometastasis Risk (1-99)
Size Lymph node/ Grade ER/PR Her 2-neu
Medical Oncology
Adjuvant Therapy
Hormonal Rx
Chemotherapy

• gt1.0 cm
• or node
• or Her 2-neu
• IV 2-6 months
• 25-75 RRR

ER or PR Oral x 5yrs ( ?) 33-50 RRR Pre
Tamoxifen Post - AIs
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Breast Cancer - Invasive

• Stages I IIB IIIA (T3 gt 5 cm, N1 only)
• Management Priorities
• Surgery
• Adjuvant Chemotherapy
• Hormonal Rx Radiation Rx

can be given together or sequentially with RT
first
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Breast Cancer - Invasive

• Stages I IIB IIIA (T3 gt 5 cm, N1 only)
• Breast Surgery Breast
• Mastectomy Breast Conservation Surgery (BCS)
  RT
• Margins 2mm minimum
• BCS contraindications
• Absolute 1) Prior RT
• 2) RT during pregnancy
• 3) multicentric disease
• 4) diffuse/susp/malignant micro Ca
• Relative - 1) large tumor (gt5cm) cosmesis
• 2) periareolar
• 3) CTD (lupus/scleroderma)

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Breast Cancer - Invasive

• Stages I IIB IIIA (T3 gt 5 cm, N1 only)
• Breast Surgery Axilla
• ALND (axillary lymph node dissection)
• - indicated in clin/path node at time of
  initial dx
• - largely prognostic
• - level I/II if gross disease level III
• - optional ? In clinically negative with
• serious co-morbidity
• elderly (age undefined)
• if no influence on adjuvant therapy choices
• favorable tumors

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Breast Cancer - Invasive

• Stages I IIB IIIA (T3 gt 5 cm, N1 only)
• Breast Surgery Axilla
• SLNBx (Sentinel Lymph Node Biopsy)
• - largely replacing ALND as initial management
• - requires experienced team (path and imaging)
• - serial sectioning H E (cytokeratin IHC
  controversial)
• - if recommend ALND level I/II (ACOSOG trial)
• - relative contraindications multicentric
  disease, gt5cm, prior chemo/hormonal therapy

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Breast Cancer - Invasive

• Adjuvant Therapy for Breast Cancer
• What features identify risk ?
• How are they used to predict risk?
• Who is a Candidate?
• What is the benefit?

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 1) Lymph Node Status (extent )
• 2) Tumor Histology
• 3) Tumor Size
• 4) Grade
• 5) ER/PR Status
• 6) Her 2 neu status

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 1) Lymph Node Status (extent )
• - most powerful prognostic feature
• - strongly predictive 0, 1-3, 4-9, gt10
• - extent an issue in the era of SLNBx
• N1 if 0.2mm or gt
• N0 if true negative or
• lt 0.2mm or clusters by IHC, RT-PCR,
• - Extra nodal extension doesnt change risk
• - Risk Range 30 90

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Breast Cancer Pathology

• Non Invasive
• Lobular (LCIS) Ductal (DCIS)
• Invasive
• Low Risk Standard (high) Risk
• Pure Tubular Ductal
• Pure Mucinous/Colloid Lobular
• Pure Papillary Medullary
• Pure Medullary ? Mixed
• Squamous

Requires careful pathology review, with same
treatment recommendations when they reach 3.0cm
atypical and mixed
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Molecular profiling
78 Individual Tumors 4 Normal Breast
Individual Genes
Sorlie et al. PNAS 9810869, 2001
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Molecular profiling
Sorlie et al. PNAS 9810869, 2001
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Note Does not include lobular CA (5-10
frequency)
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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 3) Tumor Size
• - based on the largest diameter of the
  invasive component
• - if multiple tumors, based on the size of the
  largest
• - most important prognostic factor after LN

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 4) Tumor Grade
• Grade Prognosis
• I well/low better
• II moderate standard
• III high/poor standard
• - subjective - interobserver variability
  problematic
• - moderate initially better but poor long
  term
• - Nottingham (1-3)

• tubular formation
• Degree of nuclear pleomorphism
• Mitotic index

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 5) ER/PR Status
• Prognostic modest
• Predictive strong (for hormonal rx benefit)
• Assay by IHC and reported as
• negative (0-1)
• weakly pos (1-10)
• strongly pos (10-100)

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 5) ER/PR Status
• Prognostic modest
• Predictive strong (for hormonal rx benefit)
• Allreds Score
• Percentage Intensity Score
• 1 lt1 0 none 0-2 neg
• 2 1-10 1 weak 3-8 pos
• 3 10-33 2 intermed
• 4 33-66 3 strong
• 5 gt66

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 6) Her -2 neu status
• - oncogene, overexpressed protein
• - EGFR family of growth receptor tyrosine
  kinase
• - both prognostic and predictive
• - over expressed in 20-30 of breast tumors,
  but rarely in lobular
• - assessed by IHC (herceptest 0, 1, 2, 3) or
• by FISH (gene amp pos or neg)
• - FISH gold standard

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Breast Cancer - Invasive

• Risk Prediction for Adjuvant Therapy
• Invasive Component Features
• 6) Her -2 neu status
• - shorter time to relapse and survival
• - greater benefit with Adria based adjuv
  regimens
• - in pts also ER possible less benefit from
  tamoxifen favors use of AIs
• - ongoing trials in adjuvant setting

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Breast Cancer - Invasive

• Adjuvant Therapy for Breast Cancer
• What features identify risk ?
• How are they used to predict risk?
• Who is a Candidate?
• What is the benefit?

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Breast Cancer InvasiveAdjuvant Therapy

• Assessing Risk Mortality at 10 years
• Node negative (overall 1-30)
• Typical 60 y.o with grade 2 and ER pos
• Risk approx - 8 / 1 .0 cm of tumor size
• increase by 20 for ER neg
• increase by 20 for grade III
• Node positive (overall 30 - 90)
• Use risk for node negative features
• add 10-15 for 1st node then 5 for each
  additional node

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Adjuvant!
A program for aiding health professionals in
making estimates of outcome of patients with
invasive cancer who have undergone definitive
local therapy (without prior radiation or
systemic therapy) and who are now deciding on
whether to get systemic adjuvant therapy.
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Information Input
Natural Mortality
Tx Efficacy
Br Ca Mortality
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Breast Cancer InvasiveAdjuvant Therapy

• Assessing Risk Mortality at 10 years
• www.adjuvantonline.com
• - breast cancer relapse and mortality
• - tumor size, grade, node groupings, ER
• - assesses benefit from hormonal and chemorx
• - limitations
• size 1.1 2.0, 2.1 3.0, etc
• LNs 1-3, 4-9, gt9
• ER - positive, negative
• no her-2 neu
• mortality at 10 yrs - ? Sufficient
• relapse rate gtgtgt OS , includes ?local

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Breast Cancer - Invasive

• Adjuvant Therapy for Breast Cancer
• What features identify risk ?
• How are they used to predict risk?
• Who is a Candidate?
• What is the benefit?

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Integrating / Presenting Information
The Biology Of The Patient
Decision
Treatment Efficacy / Toxicity
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Adjuvant Guidelines (Never A Mention Of Numbers)
A Relic Of The Empire !
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Breast Cancer InvasiveAdjuvant Therapy

• Chemotherapy Hormonal Therapy Both
• Guiding Principles
• Not Recommended
• node neg lt/ 5mm
• May be considered in
• node neg, 6-10 mm with unfavorable features
• angiolymphatic invasion
• high nuclear/histo grade (PD/III)
• her-2neu (FISH)
• ER/PR -

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How Much Of A Reduction In Breast Cancer Would
Make The Adjuvant Worthwhile ?
Bimodal Distribution Of Answers
Of Patients Responding
Reduction Breast Cancer Mortality Minimally
Acceptable
North American Study Australian Study
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Breast Cancer InvasiveAdjuvant Therapy

• Chemotherapy Hormonal Therapy Both
• Guiding Principles
• Discussion!
• Candidates invasive tumors gt/ 1.0 cm or node
  Risk benefit ratio needs to be
  individualized - benefit
• - toxicity
• - co-morbidities
• Chemotherapy
• - benefit in all under 70 years old
• - polychemotherapy should be used
• - relative risk reduction is 25-33

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Breast Cancer - Invasive

• Adjuvant Therapy for Breast Cancer
• What features identify risk ?
• How are they used to predict risk?
• Who is a Candidate?
• What is the benefit?

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Adjuvant Regimens and their Benefit

• Generation Regimens Relative DFS/OS
• 1st CMF (6) or AC (4) 20-25
• 2nd CA(E)F (6) 20-25
• AC (4)-gt T (4) q3wk
• TC (4) q 3wk
• 3rd TAC (6) 20-25
• AC (4) -gt T (4) q2wk
• AC (4) q 3 -gt T x 12 wk

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Breast Cancer - Invasive

• Adjuvant Therapy for Breast Cancer
• What features identify risk ?
• How are they used to predict risk?
• Who is a Candidate?
• What is the benefit?

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Breast Cancer InvasiveAdjuvant Therapy

• Chemotherapy Hormonal Therapy Both
• Guiding Principles
• Hormonal Therapy
• - ER and/or PR positive patients should be
  considered regardless of age
• - ER / PR negative patients should not be rxed
• If patient is a candidate for both chemo and
  hormonal therapy chemo is given 1st.

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Breast Cancer InvasiveAdjuvant Therapy

• Adjuvant Hormonal Options
• Premenopausal
• Tamoxifen x 5 years
• Oophorectomy (surgical or RT)
• LHRH alone x 5 years
• LHRH Tamoxifen or AI (subject of
  ongoing trials)
• Postmenopausal
• Aromatase Inhibitor (AI) x 5 years ?
  Tamoxifen x 5 years

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Breast Cancer Hormonal Therapy

• Background
• ? Up to 75 of breast cancer will be ER and or
  PR positive
• ? Estrogen remains their main stimulant to
  growth and development
• ? Estrogen deprivation has been the major
  treatment approach
• ? Surgery historically 1st
• Pre-menopausal - oophorectomy
• Post-menopausal - adrenalectomy
• hypophysectomy

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Breast Cancer Hormonal Therapy

• Medical Management
• - largely replaced surgical management
• - major therapeutic option has been Tamoxifen
• - SERM (selective estrogen receptor modulator)
• others Raloxifene (Evista), Toremifene
• - mixed agonist and antagonist effects
• - agonist effects may be partially responsible
  for loss of effect in breast cancer

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Breast Cancer Hormonal Therapy

• Medical Management
• - largely replaced surgical management
• - major therapeutic option has been Tamoxifen
• - associated with
• - 2 fold increase in thromboembolism
• - 2.5 fold increase in endometrial cancer -
  prevents bone demineralization - adjuvant
  therapeutic effect
• 28 reduction in mortality
• (98 overview)

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Breast Cancer Hormonal Therapy

• Medical Management
• - can better strategies be developed to block
  estrogen effect by blocking estrogen production?
• Aromatase Inhibitors

androstenedione
testosterone
aromatase
estrone
estradiol
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Inhibition ofEstrogen-Dependent Growth
Estrogen biosynthesis
Nucleus
Tumor cell
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Breast Cancer Hormonal Therapy

• Medical Management
• - can better strategies be developed to block
  estrogen effect by blocking estrogen production?
• Aromatase Inhibitors
• - at menopause 95 of estrogen production is
  lost
• - the source of remaining estrogen production
  is
• breast cells
• breast cancer cells
• adipose tissue mesenchymal cells
• bone, liver, and muscle

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Breast Cancer InvasiveAdjuvant Therapy

• Adjuvant Hormonal Options Aromatase Inhibitors
• - mechanism of action makes them only of value
  in patients that are postmenopausal
• - nonsteroidal (inhibitor reversible)
• anastrozole Arimidex (1mg/d)
• letrozole Femara (2.5 mg/d)
• - steroidal (inactivator irreversible)
• exemestane Aromasin (25mg/d)
• - clinical results metastatic disease
• - more effective than tamoxifen (RR/RFS/OS)
• - considered 1st line hormoal rx in MBC

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Aromatase Inhibitor (AIs) in the Adjuvant Setting

• Background Hormonal Therapy
• AIs as Initial Adjuvant Therapy
• ATAC Trial
• BIG 1-98 Trial
• Switching to AIs from Tamoxifen (2-3 yrs)
• IES Trial
• Meta Analysis (ARNO/ABCSG-8/ITA)
• AIs after Tamoxifen
• Updated MA-17 data
• Open Trials and Conclusions

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ATAC Trial Probability of Recurrence in
Receptor-Positive Population
HR 95 CI p-value
AN vs TAM 0.78 0.65-0.93 0.007
Anastrozole (AN) Tamoxifen (TAM)
Patients with recurrence ()
Absolutedifference 2.6
Absolutedifference 1.8
0
6
12
18
24
30
36
42
48
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Time to event (months)
No. of patients at risk
AN TAM
2617 2598
2533 2516
2436 2386
2243 2180
1258 1210
602 574
Censoring non-BC deaths before recurrence
Source With permission from Buzdar A.
Presentation. SABCS, 2002 Abstract 13.
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Significant Difference in Pre-defined Adverse
Events
proportion with ³10 gain in body weight from
baseline to year 2
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Aromatase Inhibitor (AIs) in the Adjuvant Setting

• Background Hormonal Therapy
• AIs as Initial Adjuvant Therapy
• ATAC Trial
• BIG 1-98 Trial
• Switching to AIs from Tamoxifen (2-3 yrs)
• IES Trial
• Meta Analysis (ARNO/ABCSG-8/ITA)
• AIs after Tamoxifen
• Updated MA-17 data
• Open Trials and Conclusions

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Aromatase Inhibitor (AIs) in the Adjuvant Setting

• Background Hormonal Therapy
• AIs as Initial Adjuvant Therapy
• ATAC Trial
• BIG 1-98 Trial
• Switching to AIs from Tamoxifen (2-3 yrs)
• IES Trial
• Meta Analysis (ARNO/ABCSG-8/ITA)
• AIs after Tamoxifen
• Updated MA-17 data
• Open Trials and Conclusions

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Annual Risk of Recurrence by Hormone Receptor
Status
0.3
ER (n2257)
ER (n1305)
0.2
Recurrence hazard rate
0.1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years

• A large proportion of breast cancer recurrences
  occur gt5 y postsurgery
• The annual risk of late recurrence is higher in
  ER tumors

Saphner et al. J Clin Oncol. 1996142738.
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Relapse-Free Survival Decreases Consistently
Regardless of ER/PgR Status
All Patients
1.0
0.9
ER/PgR (n430)
0.8
Proportion disease-free
0.7
ER and/or PgR (n778)
0.6
0.5
Plt0.001
0.4
20
15
10
5
Years postdiagnosis

• Late recurrences (gt5 y) more frequent in ER
  and/or PgR tumors

Hortobagyi et al. Proc Am Soc Clin Oncol.
20042323. Abstract 585. Courtesy of G.
Hortobagyi.
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7 Years Follow-Up of NSABP-B-14 5 versus gt 5
Years of Adjuvant Tamoxifen Node-Negative,
ER-Positive
Disease-free survival
Relapse-free survival
Survival
100
90
80
p 0.03
p 0.13
p 0.07
Percent
70
No. No. of of pts events 5 y 569 106 gt5
y 583 137
No. of deaths 39 57
No. of events 34 47
60
50
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
Years
Placebo
Tamoxifen
Source Fisher B et al. Five versus more than
five years of Tamoxifen J Natl Cancer Inst
200193684-90, by permission of Oxford
University Press. Abstract
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Letrozole versus Placebo in Women Completing at
Least 5 Years of Adjuvant Tamoxifen
Protocol ID CAN-NCIC-MA17 Accrual 5,187 (Closed)
EligibilityPostmenopausal ER- and/or
PR-positive or unknown Previously treated with
adjuvant tamoxifen for 4.5 to 6 years
Letrozole x 5 y
R
Placebo x 5 y
Source Goss P et al. N Engl J Med
2003349(19)1793-802. Abstract
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MA.17 Results Disease-Free Survival by Treatment
Duration (contd)
93
87

• Increasing benefit in estimated DFS with
  treatment duration

Goss et al. N Engl J Med. 2003349TBD.
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Hormonal Therapy - Conclusions

• Aromatase Inhibitors
• Post Menopausal Women ER and/or PR
• Drug of Choice 1st Line Metastatic Breast
  Cancer
• Initial Consideration in the Adjuvant Setting
• Anastrozole (Arimidex) or Letrozole (Femara)
• Considered for any pt. presently receiving
  Tamoxifen
• Exemestane (Aromasin) or Anastrozole
  (Arimidex)
• Considered for any pt completing 5 yrs of
  Tamoxifen
• Letrozole (Femara) or Exemestane (Aromasin)

Within 1-5 years from the completion of
Tamoxifen
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Breast Cancer InvasiveAdjuvant Therapy

• Adjuvant Hormonal Options Aromatase Inhibitors
• - Optimal Treatment duration unclear
• - Possibly better for prevention 75 v 49
  (tam)
• - Side effects more favorable than Tam
• no increased endometrial cancer
• no increased vascular events
• fewer hot flashes (5)
• less vaginal bleeding/ discharge (10)
• - Side effects less favorable than Tam
• greater osteopenia/porosis and fxstures (1-3)
• greater musculoskeletal disorders -
  arthralgias

97
Breast Cancer InvasivePrognostic and
Predictive Gene Assays
98
Oncotype DX 21 Gene Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies

PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2
ESTROGEN ER PR Bcl2 SCUBE2
RS



0.47 x
HER2
Group Score

-
0.34 x ER Group Score

1.04 x Proliferation Group Score
0.10 x Invasion Group Score

0.05 x CD68

-
0.08 x GSTM1

GSTM1
-
0.07 x BAG1


INVASION Stromolysin 3 Cathepsin L2
BAG1
CD68
REFERENCE Beta-actin GAPDH RPLPO GUS TFRC
HER2 GRB7 HER2
Paik S, et al. NEJM 2004
99
NSABP B-14 Clinical Validation Study of
Oncotype DX

• 668 NSABP B-14 tamoxifen treated patients
• Performance exceeded standard measures of patient
  age and tumor size

Habel et al (SABCS 2004) in Kaiser Permanente
Study reinforces the NSABP findings in a
community-based patient population
Paik S, et al. NEJM 2004
100
Oncotype DX Clinical ValidationB-14 Results
DRFS (cont)
Risk Group of 10-yr
Rate of 95 CI
Patients Recurrence Low (RS lt18) 51
6.8 4.0, 9.6 Intermediate (RS 18-30)
22 14.3 8.3, 20.3 High (RS
31) 27 30.5 23.6, 37.4
Test for the 10-year DRFS comparison between the
low-and high-risk groups p lt0.00001
101
B-14 Overall Benefit of Tamoxifen
All Patients (N 645)
102
B-14 Benefit of Tamoxifen
By Recurrence Score Risk Category
Low Risk (RSlt18)
Int Risk (RS 18-30)
N 171 142
N 85 69
Interaction p0.06
High Risk (RS31)
N 99 79
103
Chemotherapy Benefit and Oncotype DX
NSABP B-20 Chemo Benefit Study in N, ER Pts
Tam MF

• Design
• Objective Determine the magnitude of the
  chemotherapy benefit as a function of 21- gene
  Recurrence Score assay

Randomized
Tam CMF
Tam
104
B-20 Results
Tam vs Tam Chemo All 651 Pts
1.0
0.9
0.8
0.7
0.6
DRFS
0.5
0.4
0.3
0.2
N Events 424 33 227
31
All Patients
Tam Chemo
0.1
p 0.02
Tam
0.0
0
2
4
6
8
10
12
Years
105
B-20 Results

• Tam vs Tam Chemo Low Risk (RS lt 18)

10 yr
96
95
N Events 218 11 135
5
p 0.76
Paik, et al. PSABCS, 2004
106
B-20 Results

• Tam vs Tam Chemo Int Risk (RS 1830)

10 yr
89
90
Paik, et al. PSABCS, 2004
107
B-20 Results

• Tam vs Tam Chemo High Risk (RS 31)

10yr
88
60
Paik, et al. PSABCS, 2004
108
B-20 Absolute Increase in DRFS at 10 Years
n 353
Low RSlt18
n 134
Int RS18-30
n 164
High RS 31
0 10 20 30
40
Increase in DRFS at 10 Yrs (mean SE)
109
Oncotype Dx 21 Gene Recurrence Score Assay
Predictive in NSABP B-20 and Informs TAILORx
0.4
0.3
TAILORx Intergroup Trial Chemoendo vs endo
Distant Recurrence at 10 Years
Benefit from CMF
0.2
0.1
0.0
0
10
20
30
40
50
Recurrence Score
Sparano, TBCI San Antonio, 2005 Paik JCO 2006
Recurrence Score
Minimal, if any, Chemo Benefit
Clear Chemo Benefit
110
Overall Conclusions Oncotype DXTM

• Data reflects evaluation in postmenopausal, node
  negative, hormone receptor positive patients.
  There is no data to date on other subsets,
  (premenopausal, node positive, etc)
• Prognostic
• Predicts tamoxifen benefit
• Predicts chemotherapy (CMF) benefit
• Low RS associated with minimal chemotherapy
  benefit
• High RS associated with large chemotherapy
  benefit

111
Breast Cancer InvasiveThe Role of Targeted
Therapy -Herceptin
112
Joint Analysis of HER2 Adjuvant Trials2 Arms of
Intergroup N9831 NSABP-31
Control Group (n1,979) AC ? T
AC
T
N9831 Group A
AC
T
B-31 Group 1
Trastuzumab Group (n1,989) AC ? TH
AC
T
N9831 Group C
H
AC
T
B-31 Group 2
H
AC (doxorubicin/cyclophosphamide
60/600 mg/m2 q3w 4) T (paclitaxel
80 mg/m2/wk 12) T (paclitaxel 175
mg/m2 q3w 4 or 80 mg/m2/wk 12)
H (trastuzumab 4 mg/kg loading dose 2 mg/kg/wk
51)
113
Joint Analysis Disease-Free Survival
AC?TH
87
85
AC?T
75

67
N Events AC?T 1679 261 AC?TH 1672 134
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831 ASCO 2005
114
Cardiac Toxicity Summary in 3 Adjuvant
Trastuzumab Studies
ASCO 2005 Special Session
115
B-31 Post-AC LVEF and Age Are Independent
Predictors of Trastuzumab-Associated CHF
Age
LVEF ()
P(Age)0.04 P(LVEF)lt0.0001
116
Breast Cancer Adjuvant Herceptin

• Points to remember
• 1). Trials included patients with normal LVEF,
  excluded pts with cardiomyopathy, CHF, prior
  MI, and arrhythmias
• 2). No data on q 2week taxanes with GF support
  
• 3). 7 of patients didnt start Herceptin
• 30 required at least one dose delay
• 19 discontinued herceptin prior to one
  year
• (14.3 asymptomatic decrease, 4.3
  symptomatic)
• 4). No difference among subsets age, nodes,
  size, ER status
• 5). Only 10 of patients were node negative
  (not significant)

117
Breast Cancer - Invasive

• Stages I IIB IIIA (T3 gt 5 cm, N1 only)
• Work-Up H and P
• CBC/SMA
• Chest X-Ray
• Bilateral mammograms/US
• Path Review
• Histology Size
• Margins Histology
• Node Status Her 2 neu
• ER/PR

118
Breast Cancer - Invasive

• Stages I IIB IIIA (T3 gt 5 cm, N1 only)
• Work-Up Optional
• Bone Scan
• Abdominal imaging
• Breast MRI
• - If ChemoRx Adria candidates
• MUGA or ECHO
• Port Placement

Recommended if 1) Abnormal labs 2) Symptoms 3)
High Risk T3 or N1
119
Breast Cancer InvasiveAdjuvant Therapy

• Radiation Therapy
• Post lumpectomy
• - indicated in all
• Post mastectomy recmded (chest wall
  supraclav)
• - gt 5 cm (T3) tumors
• - gt 3 lymph nodes
• - surgical margins (close lt 1mm)
• Post mastectomy consider and controversial
• - 1-3 nodes
• - benefit may require rx of IM nodes
  (controversial IM nodes in non-US trials
  demonstrating benefit)

120
Breast Cancer InvasivePre-operative Rx -
Neoadjuvant
121
ASCO - Breast CancerSurveillance Guidelines

• Postoperative, Post adjuvant chemotherapy
• Evidence based
• Recommended Frequency
• History and Physical every 3- 6 mos x 3yrs
• every 6-12 mos x 2yrs
• Breast Self-exam monthly
• Mammography yearly
• Pelvic exam yearly
• Patient Symptom Education
• with appropriate eval of any new sxs

If on tamoxifen with an intact uterus
122
ASCO - Breast CancerSurveillance Guidelines

• Postoperative, Post adjuvant chemotherapy
• Evidence based
• Not Recommended
• Complete Blood Count (CBC)
• Automated Chemistry (SMA)
• Routine Chest x-ray
• Bone Scan
• Liver imaging (US or CT)
• Tumor markers (CA 15-3, CA 27.29, CEA)
• Endometrial bx or US if no sxs on Tamoxifen

123
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Principles of Management
• 1) Tissue confirmation is important
• ER, her-2 (esp if unavailable from original)
• 2) Complete re-staging is appropriate
• 3) Therapy is palliative
• 4) Therapy requires re-evaluation every 3-6
  mos.
• 5) Treatment should be individualized based on
• - local regional urgencies
• - hormonal sensitivity
• - candidacy for chemotherapy
• - candidacy for herceptin

124
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Local Regional Urgencies
• - may require regional RT or surgery or
  interventional proceedures prior to or
  along with systemic rx
• 1) Brain mets 8) Obtructions of
• 2) Cord compression - biliary tree
• 3) Choroid disease - ureteral / trachea
• 4) Pleural effusion - bowel / esophageal
• 5) Pericardial effusion 9) Localized disease
• 6) Pathologic fracture - intractable pain
• 7) Impending fracture - skin integrity / ulcer

125
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

Tissue confirmation - restaging
Local regional urgencies
Systemic therapies
ER -
ER
Chemotherapy
Hormonal therapy
Her -
Her
1st line
At PD
2nd line
1st line
H Taxane
3rd line
2nd line
H Navelbeine
4th line
126
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

Tissue confirmation - restaging
Local regional urgencies
Systemic therapies
ER -
ER
Chemotherapy
Hormonal therapy
Her -
Her
1st line
At PD
2nd line
1st line
H Taxane
3rd line
2nd line
H Navelbeine
4th line
127
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Hormonal Therapy
• - palliation is the goal along with minimal
  toxicity
• - whenever possible hormonal better than chemo
• Candidates
• - those pts with ER and/or PR positive disease
• - with bone, soft tissue, or lung disease
• - asymptomatic visceral disease
• - selected ER/PR negative
• - findings above with long disease free
  interval (5-10 yrs)

128
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Hormonal Therapy
• Benefit
• - 50-80 (Responses SD)
• - response duration 6-12 months (some 2-10
  years
• - gt benefit associated with gt ER/PR positivity
• - 10 of ER/PR neg pts respond to hormones
• Treatment Change
• - only for disease progression (sypmtomatic ?)
• - serial hormonal rx if response or prolonged
  SD to prior hormonal rx
• - subsequent hormonal benefit likely
  shorter

129
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Hormonal Therapy
• Post Menopausal
• - AIs superior to Tamoxifen
• - Prior Tamoxifen ? AI (Letrozole,
  Anastrozole)
• ? AI steroidal inhibitor (Exemestane)
• ? Fulvesterant (Faslodex)
• ? Tamoxifen (if not previously used)
• ? Megesterol Acetate (Megace)
• ? Fluoxymesterone (Halotestin)
• ? Ethinylestradiol

130
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Hormonal Therapy
• Pre Menopausal
• ? Tamoxifen
• ? LHRH agonist or oophorectomy
• /- Tamoxifen or AI ? (as in post menopausal)
• ? Megesterol Acetate (Megace)
• ? Fluoxymesterone (Halotestin)
• ? Ethinylestradiol

131
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

Tissue confirmation - restaging
Local regional urgencies
Systemic therapies
ER -
ER
Chemotherapy
Hormonal therapy
Her -
Her
1st line
At PD
2nd line
1st line
H Taxane
3rd line
2nd line
H Navelbeine
4th line
132
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Chemotherapy
• Her 2 neu disease (20-30 of patients)
• - associated with increased risk of CNS
  metastasis
• - Herceptin therapy considered standard and
  1st line
• - associated with survival advantage
• - Hercetin alone 20-25 response rate
• - combined with chemo survival advantage
• - benefit of continuing once progression occurs
  ???
• - RR of HCRx 50-80 - some prolonged

133
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Chemotherapy
• Her 2 neu disease

synergy Taxanes Navelebine Cisplatin Carbopl
atin
non-synergistic Xeloda Gemcitabine
avoid anthracyclines
Standard - Hercetin Taxane alone or Taxane
Carboplatin
134
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Chemotherapy
• Her- 2 neu neg (70-80 of patients)
• - treatment is palliative
• - use the least toxic therapy whenever
  possible
• - weekly taxanes better than q 3 week
• - some evidence to support doublet over single
  agent therapy (TxX and TG)
• - response should be assessed every 2-4 months
• - active drugs include anthracyclines,
  taxanes, platinum compds, 5-FU (xeloda),
  methotrexate, gemcitabine, navelbeine
• - RR 50-80 of 6-12 mos., some longer

135
ECOG 2100 Phase III TrialProgression-Free
Survival
Pac. Bev. 11.4 mos
Paclitaxel 6.11 mos
HR 0.51 (0.43-0.62) Log Rank Test P lt 0.0001
484 events reported
Miller et al. Breast Cancer Res Treat.
200594(Suppl 1)S6. Abstract 3.
136
Systemic Recurrence Stage IV Metastatic Breast
Cancer (MBC)

• Is There a Role for the Surgical Resection of a
  Primary Breast Cancer in the Presence of
  Metastatic Disease ?

137
Breast Surgery for Women Presenting with Stage IV
Breast Cancer

• Goals Compared survival between women who
  received therapeutic surgery (S) to the breast
  versus those who did not receive surgical therapy
  (NS)
• Design Retrospective
• 170 patients with Stage IV breast cancer
  1998-2005
• 44 underwent therapeutic resection

Barkley CR et al SABCS 2007 poster 5085
138
Breast Surgery for Women Presenting with Stage IV
Breast Cancer

• Overall unadjusted median survival
• Therapeutic resection 4.05 years
• No therapeutic resection 2.36 years (p0.02)
• Overall survival with adjustments (age, number of
  sites of metastasis, chemotherapy, endocrine
  therapy, trastuzumab, ER status)
• Therapeutic resection 5.34 years
• No therapeutic resection 2.36 years (p0.0004)

139
Breast Surgery for Women Presenting with Stage IV
Breast Cancer

• Conclusions
• Therapeutic surgery significantly improves
  survival in patients with Stage IV breast cancer
• Optimal timing to integrate surgery remains
  unclear
• Prospective trial is warranted to confirm these
  results

140
Optimal loco-regional treatment of the primary
tumor in metastatic breast cancer patients is
associated with a significant survival advantage

• SEER 9-Registries Database
• Determine overall survival (OS) and the breast
  cancer specific survival (BCSS)
• 8761 women,
• 3905 no surgery, median BCSS 17 mo
• 2070 lumpectomy, median BCSS 28 mo
• 2786 mastectomy, median BCSS 31 mo
• 46.6 BCS patients received XRT
• BCSS 24 mo without XRT vs 31mo with XRT (p
  lt0.0001)
• 39.6 mastectomy patients received XRT
• 32 without XRT vs 31 months with XRT (p 0.330)

Vlastos G et al SABCS 2007 Poster 5077
141
Optimal loco-regional treatment of the primary
tumor in metastatic breast cancer patients is
associated with a significant survival advantage

• Conclusions confirms previous results on benefit
  of complete surgical treatment of primary tumor
  in metastatic breast cancer patients.
• Strongly suggests that adjuvant local radiation
  therapy improve patients survival.

Vlastos G et al SABCS 2007 Poster 5077
142
Breast Cancer Prevention TrialResultsP1
and STAR
143
BCPT Design Schema
Fisher et al. J Natl Cancer Inst
1998901371-1388.
144
BCPT Results Overview

• Median follow-up 54.6 months (25 of women
  received 5 years of therapy)
• Tamoxifen group
• 49 reduction in invasive breast cancer
• 50 reduction in noninvasive breast cancer
• 45 reduction in incidence of hip fractures
• No effect on ischemic heart disease
• Increased number of vascular events and
  endometrial cancer in women over 50

Analysis included women who had LCIS at
baseline. Fisher et al. J Natl Cancer Inst
1998901371-1388.
145
BCPT Results Cumulative Rate of Invasive Breast
Cancer
Events
Rate per 1000
4
0
Placebo 175 43.4 Tamoxifen 89
22.0
Placebo
3
0
P lt 0.00001
Rate/1000
2
0
Tamoxifen
1
0
0
0
1
2
3
5
4
Years
Fisher et al. J Natl Cancer Inst
1998901371-1388.
146
BCPT Results Invasive Breast Cancer Cases in
All Age Groups
1
8
0
175
P
l
a
c
e
b
o
1
6
0
Tamoxifen
1
4
0
1
2
0
1
0
0
89
Number of Invasive Breast Cancers
8
0
68
57
6
0
50
38
4
0
25
26
2
0
0
T
o
t
a
l
3
5
-
4
9
5
0
-
5
9
6
0

Age Group
Fisher et al. J Natl Cancer Inst
1998901371-1388.
147
BCPT Results Cumulative Rate of Noninvasive
Breast Cancer
Events
Rate per 1000
4
0
Placebo 69 15.9 Tamoxifen 35 7.7
3
0
Rate/1000
2
0
Placebo
1
0
Tamoxifen
0
0
1
2
3
5
4
Years
Analysis included women who had LCIS at
baseline. Fisher et al. J Natl Cancer Inst
1998901371-1388.
148
Endometrial Cancer Perspective

• Breast and endometrial cancer share common risk
  factors
• Annual endometrial cancer rate in BCPT
• Placebo group 0.9 per 1000
• Tamoxifen group 2.3 per 1000
• Early stage endometrial cancer is highly curable
  (gt96 survival)
• Consequences of endometrial cancer are not
  equivalent to consequences of breast cancer

Fisher et al. J Natl Cancer Inst
1998901371-1388.
149
BCPT Results Vascular Events
38
4
0
P
l
a
c
e
b
o
35
Tamoxifen
3
0
25
24
22
19
18
2
0
Number of Events
1
0
6
0
PE
TIA
DVT
CVA
PE pulmonary embolism DVT deep vein
thrombosis CVA cerebral vascular accident
(stroke) TIA transient ischemic attack
Fisher et al. J Natl Cancer Inst
1998901371-1388.
150
NSABP STAR Schema

• Risk-Eligible
• Post-Menopausal Women

• Age 35
• No history of
• cancer
• A-fib
• Clotting
• DM HTN

• STRATIFICATION
• Age
• Relative Risk
• Race
• History of LCIS

RALOXIFENE 60 mg/day x 5 years
TAMOXIFEN 20 mg/day x 5 years
151
STAR Average Annual Rate Number of Invasive
Breast Cancers
312
163
168
of events
152
STAR Cumulative Incidence of IBC
At Risk by Year of Rate/1000 Treatment 0 3 6
Events at 6 yrs. P-value Tamoxifen 9726 6653 809 1
63 25.1 0.83 Raloxifene 9745 6703 833 168 24.8
Cumulative Incidence (per 1000)
Time Since Randomization (months)
153
STAR Average Annual Rate and of Uterine
Cancers
RR 0.62, 95 CI 0.35 to 1.08
36
23
of events
154
STAR Endometrial Hyperplasia
Hysterectomies 244 111
155
STAR Average Annual Rates of Cataracts
RR 0.79 95 CI(0.68 0.92)
394
313
of events
156
STAR of Osteoporotic Fractures
157
STAR Thromboembolic Events
At Risk by Year of Rate/1000 Treatment 0 3 6
Events at 6 yrs. RR Tamoxifen 9726 6682 814 141 21
.0 0.70 Raloxifene 9745 6764 836 100 16.0
P-value 0.01
Cumulative Incidence (per 1000)
Time Since Randomization (months)
158
STAR Average Annual Rate and of In Situ
(DCIS LCIS) Cancers
RR 1.40 95 CI 0.98 to 2.00
80
57
of events
159
STAR Summary

• R is as effective as T in the prevention of
  primary IBC.
• R is less effective than T in the prevention of
  LCIS DCIS (not statistically different).
• Compared to T, R use results in
• Fewer thromboembolic events
• Fewer endometrial cancers and
• Fewer cataracts