THE CHOICES FOR

BREAST CANCER
TREATMENT
Nadia Califaretti MD
FRCPC
Medical Oncologist
GRRCC

No conflicts of
interest

Goal

To review current information on

making an informed decision
about adjuvant treatment of early
stage breast cancer.

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.

Mortality Rates in Patients

With Breast Cancer Aged
50 to 69 Years
Annual death rate
per 100,000 women

105

UK

90
60

USA

45
75
30
15
0
1950

1960

1970

1980

1990

2000

Year
Reprinted with permission from Elsevier Science. Lancet 2000.

Early Stage Breast

Cancer
Many women are cured with surgery

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

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

Early Breast Cancer

Treatment Schema
SURGERY

Adjuvant
Adjuvant
Radiation
Chemotherapy +/- Endocrine Tx

Adjuvant
Trastuzumab

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

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?

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

CALGB 9741 Trial: Dose Dense vs Standard Do

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; 21:1431-1439 2003

MA.21 Relapse-Free Survival:

All Patients

CEF
EC-T
P = 0.001 (stratified)

CEF
EC/T
AC/T

7017
0170
2

AC-T

2 yr

4 yr

451
441
405

125
101
113

MA.21 Results: RFS

Treatment

3 year RFS*

CEF

90.1 %

EC/T

89.5 %

AC/T

85.0 %

* Adjusted for Stratification

Percentage of patients
(%)

Case No. 1: Recurrence Risk

(10 yr)
Benefit from Chemotherapy

57.6%

29.6%

None

G1

G2

G3

Percentage of patients
(%)

Case No. 1:
Survival Benefit from
Chemotherapy
(Alive in 10 years)
82.4%
65.2%

None

G1

G2

G3

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.

MA.5 Incidence Of CRA

(ER+)
SIX MOS
<39
40-44
>45

CEF
62%
82%
82%

CMF
28%
68%
83%

TWELVE MOS
<39
40-44
>45

47%
80%
89%

36%
76%
90%

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

Tamoxifen: Improvement
in Disease-Free Survival
Recurrence as First Event
100

% Recurrence-free

80

79.2

74.9

70

50

Node -ve

75.6

64.3

58.3

59.7 Node +ve

60

40

Tamoxifen
(~5 y)
Placebo

44.5

30

Absolute Recurrence Reduction

20

Node -ve: 14.9% SD 1.4: 2P<0.00001

Node +ve: 15.2% SD 2.5: 2P<0.00001

10
0

Tamoxifen
(~5 y)
Placebo

87.4

90

10+

Years
Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists Collaborative Group, 1451, 1998,
with permission from Elsevier Science.

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

Inhibition of
Estrogen-Dependent Growth
Antiestrog
ens
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis

Aromata
se
inhibitor
s

Inhibition
of growth
Cancer cell

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.

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; 1994:1399-1488.

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. 2004;44:195-217.

2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913.
3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.
4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

ErbB Receptor Tyrosine

Kinases

Four receptors:
ErbB-1 (EGFR,
HER-1)
ErbB-2 (HER2/neu)
ErbB-3 (HER-3)
ErbB-4 (HER-4)
ErbB-1

ErbB-2

ErbB-3

1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.

2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913.
3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.
4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

ErbB-4

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. 2004;44:195-217.
.

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. 2004;44:195-217.

2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110.
3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913.
4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.
5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137.

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. 2002;7(Suppl 4):2-8.

2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9S15.
3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175182.
4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:335.Woodburn J. Pharmacol Ther. 1999;82:2415.

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 immunemediated cytotoxicity

1. Arteaga C. Breast Cancer Res. 2003b;5:96-100.

2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.
3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.
4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173.

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%

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.

Trastuzumab And
Cardiotoxicity

erbB2 plays a critical role in the

developing embryonic heart (gene
deletion=mouse 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

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

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

Case No. 2 Continues

First generation protocols
AC
benefit
Second generation protocols
AC-Taxol, FEC-100
benefit
Third generation protocols
Dose dense AC-Taxol, FEC-D

7%

12%

16% benefit

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

Early (Upfront) Adjuvant

Trials
Surgery
0-5 years

ATAC

TAM
ANASTRO
ANASTRO + TAM

TEAM

TAM
EXEM

BIG1-98

TAM
LETRO
R

TAM
LETRO

LETRO
TAM

DFS: Reduction of Event

Rate
in the Adjuvant
Setting
Follow-up
Rel. Red.
Abs. Red.
(mo)

120

47

12 (5 yrs)

Early

TAM 5 vs none

Early

ANA 5 vs TAM 5

68

13

3.3 (6 yrs)

Early

LET 5 vs. TAM 5

25.8

19

2.6 (5 yrs)

Early
seq.

TAM 2 EXE 3 vs
TAM 5

30.6

32

4.7 (3 yrs)

Early
seq.

TAM 2 ANA 3 vs
TAM 5

28

40

3.1 (3 yrs)

Extende
LETRO 5 vs placebo 30
d

42

4.6 (4 yrs)

Review: Mouridsen HT, January 2005

EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thrlimann et al. ASCO 2005; Coombes
et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262
20

Relative Effect of AIs on Post MP

Recurrences at 5 Years

38% recurrences with no adjuvant treatment

(EBCTCG)
47% risk reduction with Tamoxife
Further 26%
risk reduction
with AI

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

Total Cholesterol in BIG 198: Summary

Serum cholesterol decreased by

~ 12% in the tamoxifen group
and was fairly stable in the
letrozole group

AIs and Bone

NORMAL BONE

OSTEOPOROTIC BONE

VERTEBRAL COMPRESSION
FRACTURE

Osteoporosis/Fractures
Reported in Adjuvant AI
Trials
Study

FU(MO)

AI

Ref.Drug

Event

AI vs Ref.(%)

ATAC

68

ANA

TAM

Fracture

11.0 vs 7.7

<0.0001

BIG 198

26

LETRO

TAM

Fracture

5.8 vs 4.1

NI

IES

31

EXEM

TAM

Fracture
Osteoporosis

3.1 vs 2.3
7.4 vs 5.7

0.08
0.05

ARNO

28

ANA

TAM

Fracture

2.4 vs 2.1

NI

MA-17

28

LETRO

Placebo

Fracture
Osteoporosis

3.6 vs 2.9
5.8 vs 4.5

0.24
0.07

ATAC Trialists Group Lancet 2005;365:60; Thrlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med
2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med
2003;349:1793.
Mouridsen 0305

ATAC: Bone Fracture Adverse

Events at Treatment
Completion Analysis
Anastrozole
% of patients
n=3092

Tamoxif
en
% of
patients
n=3094

p-value

Joint Disorders

35.6 (27.8)

29.5
(21.2)

<0.0001

All Fractures
- spine
- hip
- wrist

11.0 (5.8)
1.5
1.2
2.3

7.7 (3.7)
0.9
1.0
2.0

<0.0001
0.03
0.5
0.4

(Bisphosphonate
9.6
6.4
usage) ATAC Trialists Group. SABCS 2004. Lancet 2005; 365: 60-62.

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

ATAC BMD Substudy

No bisphosphonates allowed
2 years A => 4% loss in LS
3.2% loss in hip
2 years Tam => 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

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

Patient Recommendations
On AIs

BMD performed at baseline and q1218mos

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 >3% LS or >5%
FN, add a bisphosphonate

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

Chemotherapy Related
Cardiotoxocity

Anthracyclines

Daunorubicin, doxorubicin, idarubicin,

epirubicin, and mitoxantrone

Toxicity effects

Acute (during administration)

Early (Several days to mos following)

Arrhythmias, pericarditis-myocarditis
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

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

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 longterm health concerns
Evidence-based, informative discussion to review risks
and benefits for each patient is of critical importance

Thank you for

your attention