THE CHOICES FOR BREAST CANCER TREATMENT

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THE CHOICES FOR BREAST CANCER TREATMENT

• Nadia Califaretti MD FRCPC
• Medical Oncologist
• GRRCC

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No conflicts of interest
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Goal

• To review current information on making an
  informed decision about adjuvant treatment of
  early stage breast cancer.

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Objectives

• Case-based approach to evaluating the diagnosis
  and individualizing treatment.
• Understand the rationale for treatment.
• Review the three main treatment options
  chemotherapy, endocrine therapy, trastuzumab.
• Review current standard chemotherapy protocols.
• Interpret survival data.
• Interpret morbidity data.
• To review health issues after cancer treatment.

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Mortality Rates in Patients With Breast Cancer
Aged 50 to 69 Years
105
UK
90
60
USA
Annual death rateper 100,000 women
45
75
30
15
0
1950
1960
1970
1980
1990
2000
Year
Reprinted with permission from Elsevier Science.
Lancet 2000.
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Early Stage Breast Cancer

• Many women are cured with surgery alone
• Some women will have a systemic relapse
• All systemic relapses lead to death
• Medical oncologists role is to assess the risk
  of relapse/death for an individual woman and make
  recommendations on how to reduce this risk

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Decision Adjuvant Therapy

• An agent that is active in the metastatic setting
• Targets microscopic metastatic disease
• Should be effective on minimal foci
• Given blind no information on the efficacy
  for the individual patient
• Ideally should improve DFS and OS

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Early Breast Cancer Treatment Schema
SURGERY
Adjuvant Chemotherapy
Adjuvant Radiation /- Endocrine Tx
Adjuvant Trastuzumab
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Case No. 1

• 45-year-old female patient, healthy and preMP
• R breast lumpectomy, SLNB and axillary dissection
  6 weeks ago
• Pathology
• 2.5 cm size
• Tumour Grade II/III
• ER 80, PR 80
• Lymph nodes 3/12 involved
• HER 2 neu overexpression - positive

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Case No. 1 - Chemotherapy

• What is her recurrence risk over 10 years?
• Without any further treatment?
• With chemotherapy?
• What is her risk of dying from breast cancer
  within 10 years?
• Without any further treatment?
• With chemotherapy?

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Chemotherapy for PreMP BC

• First generation protocols
• AC x 4
• Second generation protocols
• AC-Taxol, FEC-100
• Third generation protocols
• Dose dense AC-Taxol, CEF

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CALGB 9741 Trial Dose Dense vs Standard Dose
AC-Taxol
(A) Disease-free survival by dose density 4
yr DFS 82 vs 75 (B) Overall survival by
dose density Severe neutropenia less frequent
on DD regimen with filgrastim.
Citron, M. L. et al. J Clin Oncol 211431-1439
2003
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MA.21 Relapse-Free Survival All Patients
CEF
EC-T
P 0.001 (stratified)
AC-T
2 yr
4 yr
701701702
125101113
CEF EC/T AC/T
451441405
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MA.21 Results RFS

• Adjusted for Stratification

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Case No. 1 Recurrence Risk (10 yr)Benefit from
Chemotherapy
57.6
Percentage of patients ()
29.6
None
G3
G1
G2
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Case No. 1 Survival Benefit from
Chemotherapy(Alive in 10 years)
82.4
65.2
Percentage of patients ()
None
G1
G2
G3
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Case No. 1 Endocrine Therapy

• After her 3rd cycle of CEF, the patient stops
  having menstrual periods.
• Upon completion of CEF, she is offered Tamoxifen
  as endocrine therapy.
• At the discussion of hormonal therapy she brings
  in her Google search for Femara (Letrozole),
  which is superior to tamoxifen in postMP women.

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MA.5 Incidence Of CRA (ER)
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EBCTCG (meta-analysis)

• Tamoxifen is an anti-estrogen
• 37,000 women in 55 trials of tam vs nil
• 70 had HR tumours, most PM
• For ER pre/postMP pts 5 years of tam results in
• 47 relative reduction in recurrence risk
  at 10y
• 26 relative reduction in mortality risk
• 47 reduction in contralateral ca risk

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Tamoxifen Improvement in Disease-Free Survival
Recurrence as First Event
100
Tamoxifen (5 y)
87.4
90
79.2
Placebo
80
74.9
Tamoxifen (5 y)
Node -ve
70
75.6
64.3
Placebo
60
59.7
58.3
Node ve
50
Recurrence-free
40
44.5
30
Absolute Recurrence Reduction
20
Node -ve 14.9 SD 1.4 2Plt0.00001 Node ve
15.2 SD 2.5 2Plt0.00001
10
0
5
10
0
Years
Reprinted from The Lancet, vol 351, Early Breast
Cancer Trialists Collaborative Group, 1451,
1998,with permission from Elsevier Science.
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Aromatase Inhibitors

• selectively block peripheral conversion of
  androstenedione to estrone
• occurs in ovary, adipose tissue, skin, muscle,
  liver, cancer cell
• net result inhibition of circulating estradiol
  in serum in PM women only
• eg anastrozole (Arimidex), letrozole (Femara)
  nonsteroidal
• eg. Exemestane (Aromasin) steroidal

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Inhibition ofEstrogen-Dependent Growth
Estrogen biosynthesis
Nucleus
Cancer cell
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Case No. 1 - Trastuzumab

• Upon completion of chemotherapy, MUGA scan
  reports EF 59.
• Her cancer was HER2neu overexpression
• Patient advised to consider Herceptin
  (trastuzumab) q3weeks for one year.

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ErbB2 (HER2/neu) Overexpression

• ErbB2 is a human epidermal growth factor receptor
  encoded by the ErbB2 gene
• ErbB2 is amplified in approximately 20 to 25 of
  metastatic breast cancers
• Adverse prognostic factor
• Confers resistance to some chemotherapy or
  hormone therapy
• Confers aggressive form of disease with
  significantly shortened disease-free survival and
  overall survival

Breast Cancer. In DeVita VT, et al. Cancer
Principles and Practice of Oncology. 7th ed. LWW
19941399-1488.
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ErbB Receptor Tyrosine Kinase System

• The ErbB system includes four growth factor
  receptors and their numerous ligands
• Important in human growth and development
• Active in proliferating cells, inactive in
  quiescent cells

1. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217.
2. Marmor M, et al. Int J Radiat Oncol Biol Phys.
200458903-913.
3. Rowinsky E. Horizons in Cancer Therapies From
Bench to Bedside. 200123-35.
4. Vlahovic G, Crawford J. Oncologist.
20038531-538.
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ErbB Receptor Tyrosine Kinases

• Four receptors
• ErbB-1 (EGFR, HER-1)
• ErbB-2 (HER-2/neu)
• ErbB-3 (HER-3)
• ErbB-4 (HER-4)

ErbB-1 ErbB-2 ErbB-3
ErbB-4
1. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217.
2. Marmor M, et al. Int J Radiat Oncol Biol Phys.
200458903-913.
3. Rowinsky E. Horizons in Cancer Therapies From
Bench to Bedside. 200123-35.
4. Vlahovic G, Crawford J. Oncologist.
20038531-538.
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ErbB-2 or HER-2/neu

• Because of a unique ECD conformation, does not
  bind to ligands, but is primed to dimerize
• Usually does not homodimerize
• Heterodimerization with other ErbB receptors is
  necessary for activation

Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol.
200444195-217.
.
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Common Mechanisms of ErbB Activation in Tumors
Receptor Overexpression

• Gene amplification results in overexpression of
  normal receptors
• Receptors spontaneously homodimerize
• Drives tumour growth

1. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217.
2. Holbro T, et al. Exp Cell Res.
2003a28499-110.
3. Marmor M, et al. Int J Radiat Oncol Biol Phys.
200458903-913.
4. Rowinsky E. Horizons in Cancer Therapies From
Bench to Bedside. 200123-35.
5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol.
20012127-137.
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Rationale for Inhibiting ErbB Receptors

• ErbB receptor inhibition may suppress cell
  growth, enhance cell death, and improve response
  to other cancer therapy in some tumors
• Inhibiting ErbB receptors may more selectively
  target cancer cells and spare normal cells,
  thereby reducing unwanted side effects of therapy

1. Baselga J. Oncologist. 20027(Suppl 4)2-8.
2. Nicholson R, et al. Eur J Cancer.
2001a37(Suppl 4)S9-S15.
3. Nicholson R, et al. Endocr Relat Cancer.
2001b8175-182.
4. Rowinsky E. Horizons in Cancer Therapies From
Bench to Bedside. 200123-35.
5. Woodburn J. Pharmacol Ther. 199982241-250.
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Monoclonal Antibodies

• Trastuzumab is humanized monoclonal antibody
  against EC domain of the HER-2 protein
• Mechanism of action
• Inhibit TK activation
• Induce receptor endocytosis and degradation
• Induce immune-mediated cytotoxicity

1. Arteaga C. Breast Cancer Res. 2003b596-100.
2. Holbro T, Hynes NE. Annu Rev Pharmacol
Toxicol. 200444195-217. 3. Rowinsky E. Horizons
in Cancer Therapies From Bench to Bedside.
200123-35. 4. Zwick E, et al. Endocr Relat
Cancer. 20018161-173.
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Results of Adjuvant Trastuzumab Trials

• NEJM 2005 HERA Trial and NSABP B-31/NCCTG
  N9831 Trial 1 year of adjuvant Herceptin after
  chemotherapy reduces the risk of a breast cancer
  recurrence by 50
• Brief median followup of 1-2 years
• SEs hypersensitivity with first infusion
• CHF 5

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Case No. 1 Continues

• After 10 treatments of Herceptin, her MUGA
  reveals EF 45 (baseline 59)
• Patient advised to stop Herceptin
• Even though patient is asymptomatic, referral is
  made to cardiologist
• Medical management and close follow-up by
  cardiologist.

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Trastuzumab And Cardiotoxicity

• erbB2 plays a critical role in the developing
  embryonic heart (gene deletionmouse death)
• In adult heart, erbB2 modifies cardiac response
  to stress
• Two-hit model erbB2 deficient heart is more
  susceptible to cardiotoxic effects of other
  stressors (eg. Anthracycline chemo) ? increased
  loss of cardiac myocytes

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Case No. 2

• 56 year old healthy postMP patient
• Left lumpectomy and axillary dissection 4 weeks
  ago
• Pathology
• 2.5cm invasive ductal ca nos
• Grade II/III
• 0/12 LN involved
• ER pos 90, PR pos 90
• HER2neu overexpression neg

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Case No. 2 - Chemotherapy

• Pt wants to be aggressive with treatment, but is
  frightened by the concept of chemotherapy
• Risk of relapse at 10years is 35
• Chemo options are reviewed

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Case No. 2 Continues

• First generation protocols
• AC
  7 benefit
• Second generation protocols
• AC-Taxol, FEC-100 12
  benefit
• Third generation protocols
• Dose dense AC-Taxol, FEC-D 16 benefit

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Case No. 2 Endocrine Therapy

• Baseline MUGA EF 55
• AC administered q 3 weeks x 4 cycles without
  serious effects
• After chemo completed she starts adjuvant
  letrozole 2.5mg po od for planned 5 years

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Early (Upfront) Adjuvant Trials
Surgery
0-5 years
ANASTRO TAM
TAM
EXEM
TAM
LETRO
R
TAM
LETRO
LETRO
TAM
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DFS Reduction of Event Rate in the Adjuvant
Setting
Review Mouridsen HT, January 2005
EBCTCG,Lancet 19983511451 ATAC Trialists
Group, Lancet 2004 Dec 08 Thürlimann et al.
ASCO 2005 Coombes et al., N Engl J Med
20043501080, Jakesz et al.,Lancet 2005366455,
Goss PE et al., JNCI 2005 971262
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Relative Effect of AIs on Post MP Recurrences at
5 Years
38 recurrences with no adjuvant treatment
(EBCTCG)
47 risk reduction with Tamoxifen
Further 26 risk reduction with AI
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ASCO Technology Assessment 2004

• Optimal adjuvant hormonal therapy for a PM woman
  with receptor cancer INCLUDES an AI as initial
  therapy OR after treatment with tamoxifen

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Total Cholesterol in BIG 1-98 Summary

• Serum cholesterol decreased by 12 in the
  tamoxifen group and was fairly stable in the
  letrozole group

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AIs and Bone
NORMAL BONE
OSTEOPOROTIC BONE
VERTEBRAL COMPRESSION FRACTURE
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Osteoporosis/Fractures Reported in Adjuvant AI
Trials
Study FU(MO) AI Ref.Drug
Event AI vs Ref.() P

A
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68
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BIG 198
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5.8
vs
4.1
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E
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AN
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28
L
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ebo
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r
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3.6
vs
2.9
0.2
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5.8
vs
4.5
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7
ATAC Trialists Group Lancet 200536560
Thürlimann et al. www.ibcsg.org Coombes et al. N
Engl J Med 20043501081 Jakesz et al. Breast
Cancer Res Treatm 200488S7(Abstract 2) Goss et
al. N Engl J Med 20033491793.
Mouridsen 0305
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ATAC Bone Fracture Adverse Events at Treatment
Completion Analysis
ATAC Trialists Group. SABCS 2004. Lancet 2005
365 60-62.
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How Serious Is This Difference?

• No placebo arm
• What fracture rate might normally be observed in
  a similarly aged population?
• 12-25 per 1000 patient years
• ATAC Tam 13.44 per 1000 pt years
• ATAC Arimidex 21.55 per 1000 pt years

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ATAC BMD Substudy

• No bisphosphonates allowed
• 2 years A gt 4 loss in LS
• 3.2 loss in hip
• 2 years Tam gt 1.9 gain in LS
• 1.2 gain in hip
• Considered small losses compared to the natural
  BMD loss that occurs in menopause
• Benefits of the drug outweigh this risk

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Patient Recommendations On AIs

• Stop smoking
• Reduce caffeine and alcohol intake
• Perform regular weight-bearing exercise
• Supplement with Calcium 1500mg/d and vitamin D
  800 IU/d
• Never take estrogen
• Raloxifene is contraindicated

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Patient Recommendations On AIs

• BMD performed at baseline and q12-18mos
• If patient has had an osteoporotic , add a
  bisphosphonate right away
• If there is evidence of OP, add bisphosphonate
  right away
• If there is osteopenia, evaluate other RFs and
  consider bisphosphonate
• If follow-up BMD loss gt3 LS or gt5 FN, add a
  bisphosphonate

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Case No. 2 Continues

• 4 years later she reports profound fatigue x 2
  mos
• Drops in to office to see her SCC, complaining of
  fatigue, wants to set up an appointment with
  oncologist
• SCC notes she is in rapid AFib and sends her to
  ER
• Cardiologist diagnoses her with
  anthracycline-induced cardiomyopathy requiring
  medical management

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Chemotherapy Related Cardiotoxocity

• Anthracyclines
• Daunorubicin, doxorubicin, idarubicin,
  epirubicin, and mitoxantrone
• Toxicity effects
• Acute (during administration)
• Arrhythmias, pericarditis-myocarditis
• Early (Several days to mos following)
• CHF with peak at 3 mos after last dose
• Late (years to decades following)
• CHF may develop up to 10-12 yrs after last
  anthracycline dose

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Cardiac Toxicity Anthracyclines

• Risk factors for the development of anthracycline
  cardiac toxicity
• Cumulative dose strongest risk factor
• Age
• Prior irradiation
• Concomitant administration of other agents
• Previous history of cardiac disease

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Conclusions

• Key advances in the management of breast cancer
  have been made in the last few years
• Adjuvant treatment is individualized to possibly
  include chemotherapy, hormone therapy and
  trastuzumab
• New treatments are intensive and may result in
  long-term health concerns
• Evidence-based, informative discussion to review
  risks and benefits for each patient is of
  critical importance

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Thank you for your attention