Transcript Breast Cancer

Medical therapy: what is new, what is
useful.
toward a personalized treatment
Prof. Francesco Cognetti
Regina Elena National Cancer Institute
Rome, Italy
Breast Cancer: From Epidemiology to Treatment
Tunis, November 14th, 2008
Ten Leading Cancer Types for the Estimated New Cancer
Cases and Deaths, by Sex, United States, 2008
From Jemal, A. et al.
CA Cancer J Clin 2008;58:71-96.
Copyright ©2008 American Cancer Society
Cancer Mortality Rates over the Past 50 Years
EBCTCG, Lancet 2005
Five Year Relative Survival Rates for Breast
Cancer: 1973 - 2005
Localized Regional Distant
1973
85
53
<10
2002
98
83
26
Cancer survivors increased from 3 M to 9 M in the same period
CA, Jan 1973 and Jan 2007
Relative and absolute risk reduction
Intervention produces a 35% relative risk reduction
Initial risk
Initial risk
Final risk
Final risk
65%
42%
20%
13%
Node-negative
Difference:
7%
Node-positive
23%
Factors Influencing Selection of Systemic
Therapy for Primary Breast Cancer
Risk of recurrence
Or death
Benefit from
treatment
Optimal
Treatment selection
Comorbidities
Toxicities
Tumor characteristics:
ER, PR, HER-2
Adjuvant!
• Validated computer-based model
– Estimates 10-year DFS and OS[1-3]
• Used to estimate individual risk for breast cancer recurrence
– Began development 15 years ago
– Can be used for other malignancies
• Prognostic estimates based on
– Nodal involvement, Tumor size
– Histological grade
– ER, PgR, and HER2 receptor status
– Options Include additional information
• Efficacy estimates based on
– Type of adjuvant therapy
– Age, ER status, Her2 status (only for trastuzumab)
1. Ravdin PM, et al. J Clin Oncol. 2001;19:980-991. 2. Olivotto IA, et al.
J Clin Oncol. 2005;23:2716-2725. 3. http://www.adjuvantonline.com.
Adjuvant! Background
• San Antonio tumor bank originally designed to help physicians assess
patient prognosis
• Evidence-based estimates of benefit for diverse adjuvant treatment
options
• 2 major changes since 1998
– Use of more complete data from SEER database
– Addition of more current adjuvant therapies
• Provides baseline prognostic estimate of recurrence with adjuvant
therapy
– Applies data from meta-analyses and individual trials to estimate
net benefit
• More than 50,000 users; applied to > 100,000 cases/year
http://www.adjuvantonline.com.
Adjuvant! Validation
90
Adjuvant! Online
Breast Cancer Outcomes
Unit database
80
Percentage
• Validated using the BCCA’s
Breast Cancer Outcomes Unit
database
– Outcome estimates made
in a blinded fashion
– Estimates to the BCCA
actual patient outcomes
• Results statistically similar
70
60
50
40
30
20
10-Yr OS
Olivotto IA, et al. J Clin Oncol. 2005;23:2716-2725.
10-Yr
BCSS
10-Yr
EFS
HER2 and Adjuvant!
• Benefit estimates for use of trastuzumab available in
Adjuvant! Version 9.0 (not yet available)
– HER2 included as a variable
• HER2 expression prognostic for breast cancer
– Modest independent relative risk of 1.5
• Trastuzumab now included as adjuvant therapy option
– Projections of benefit for trastuzumab only for 3 years
because of short follow-up on current trials
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
Gene expression array-identified
subtypes of Breast Cancer
Unsupervised Hierarchical Clustering of Primary Breast Cancers
Perou et al. Nature 2000;406:747-52.
PERSONALIZED MOLECULAR MEDICINE BREAST CANCER
LUMINAL
Hormonal
Manipulation
HER2
Trastuzumab
Lapatinib
BASAL
Chemotherapy
Rich Neve
Breast Cancer Subtypes according to race
and menopausal status
Carey LA et al, JAMA 2006
Breast Cancer Specific Survival by Subtype
in the Carolina Breast Cancer Study (n=496)
Carey LA, et al. JAMA 295:2492-502, 2006
Management of ER+/HER2Breast Cancer
Choice of Modalities
Highly
Incompletely
Endocrine
Endocrine
Responsive Responsive
Her2
neg
ET
ET
(consider adding CT
according to risk)
(consider adding CT
according to risk)
Endocrine
NonResponsive
CT
Inhibition of
Estrogen-Dependent Growth
Antiestrogens
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis
Aromatase
inhibitors
Tumor cell
Inhibition of
cell
proliferation
Endocrine Treatment Schema
Adjuvant or
First-line Therapy
Premenopausal
Postmenopausal
SERM
Aromatase Inhibitor
or SERM
Recurrent Disease
Ovarian Ablation
Aromatase Inhibitor
or Antiestrogen
Third-line Therapy
Aromatase Inhibitor
(only following ablation
of ovarian function)
Progestins or
SERD
Fourth-line Therapy
Progestin / Androgens
Androgens
Second-line Therapy
Comparative Efficacy of Adjuvant
Hormonal Therapies
Therapies
% Reduction in Annual Odds of
Recurrence
Death
50
P<0.00001
33
P<0.00001
Anastrozole vs. Tamoxifen
(ATAC)
22
P=0.007
12
P=0.2
Letrozole + Tamoxifen vs.
Tamoxifen (BIG98, MA-17)
19-43
P=0.003-0.00008
14-24
P=0.25->0.05
Anastrozole + Tamoxifen
vs. Tamoxifen (ITA)
64
P=0.006
82
P=0.07
Exemestane + Tamoxifen
vs. Tamoxifen (IES)
26
P<0.0001
17
P=0.04
Tamoxifen vs. no Tamoxifen
(5 years)
Adjuvant Hormonal Therapy for
Premenopausal Women with ER-Positive
Breast Cancer
• LHRHa appears equivalent to adjuvant
CMF for ER+ breast cancer.
• Is LHRHa + tamoxifen better than each
component?
• Should LHRHa be added to best
chemotherapy + tamoxifen?
• Or only to those who remain
premenopausal after chemotherapy?
Effect of Combined Adjuvant Hormone and
Chemotherapy for Primary Breast Cancer
Patient Group
<50 Years of Age
CT vs CT + T(5)
Annual Reduction in
Odds of (% + SD)
Recurrence
Death
40 + 19
39 + 22
T vs T + CT
21 + 13
25 + 14
CT vs CT + Ov
10 + 9
8 + 10
54 + 8
49 + 10
19 + 3
11 + 4
> 50 Years of Age
CT vs CT + T(5)
T vs T + CT
EBCTCG 1996 & 1998
Management of HER2+
Breast Cancer
Choice of Modalities
Highly
Incompletely Endocrine
Endocrine
Endocrine
NonResponsive Responsive Responsive
Her2 pos
ET +
ET +
CT +
Tratuzumab Trastuzumab
Trastuzumab
+ CT
+ CT
HER2+ tumors treatment selection
• Chemotherapy
– Anthra vs non-Anthra regimens
– Low risk/endocrine-responsive tumors
• Endocrine therapy
– Tam vs aromatase inhibitors
• Trastuzumab
– Concomitant vs sequential
– Duration
HER2 and Responsiveness of Breast
Cancer
to Adjuvant Chemotherapy
Overall Survival According to the Type of
Adjuvant Chemotherapy in Women
with HER2 Amplification on FISH
Overall Survival According to the Type of
Adjuvant Chemotherapy in Women
without HER2 Amplification on FISH
Pritchard KI, et al. N Engl J Med 2006;354:2103-11
HER-2 as a Surrogate Marker of
Anthracycline Efficacy
HER-2 amplified
Di Leo et al. Clin Cancer Res 2003; 8:1107-16
Benefit from Anthracyclines by HER2
Status - Disease-Free Survival
Study
HR
95% CI
NSABP B11
0.60
0.96
0.44-0.82
0.75-1.23
NSABP B15
0.84
1.02
0.65-1.08
0.86-1.20
Belgian
0.65
1.35
0.34-1.27
0.93-1.97
Milan
0.83
1.22
0.46-1.49
0.91-1.64
Danish
0.75
0.79
0.53-1.06
0.60-1.05
NCIC MA.5
0.52
0.91
0.34-0.80
0.71-1.18
Overall
0.90
0.82-0.98
HER2 specific
0.71
1.00
0.61-0.83
0.90-1.11
Heterogeneity 25=5.3, p=.38
Heterogeneity 25=7.6, p=.18
Anthracycline
Better
Nonanthracycline
Better
p=.01
0.4
0.6
0.9 1
HER2+
HER22
Test for interaction 2=13.2, p<.001
Gennari A, et al. Presented at: 29th Annual SABCS; Dec 14-17, 2006; San Antonio, Tex.
5
Benefit from Anthracyclines by HER2
Status - Overall Survival
Study
HR
95% CI
NSABP B11
0.66
0.90
0.47-0.92
0.69-1.19
NSABP B15
0.82
1.07
0.63-1.06
0.89-1.28
GUN 3
0.85
1.64
0.27-2.71
0.85-3.14
Milan
0.61
1.26
0.32-1.16
0.89-1.79
Danish
0.73
0.82
0.50-1.05
0.59-1.13
NCIC MA.5
0.65
1.06
0.42-1.02
0.83-1.44
Overall
0.91
0.83-1.00
HER2 specific
0.73
1.03
0.62-0.85
0.92-1.16
Heterogeneity 25=5.2, p=.39
Heterogeneity 25=5.5, p=.36
Anthracycline
Better
Nonanthracycline
Better
p=.056
0.4
0.6
0.9 1
Test for interaction 2=12.2, p<.001
HER2+
HER22
Gennari A, et al. Presented at: 29th Annual SABCS; Dec 14-17, 2006; San Antonio, Tex.
5
Trastuzumab in early breast cancer: studies
designs of the adjuvant trials
Baselga at al., The Oncologist, 2006
Similarities in patient characteristics
from adjuvant trials
• The median age of patients in all trials was
virtually identical (49 years)
• 40% of patients in all of the trials had T1
tumors
• The percentage of patients with hormone
receptor-positive tumors was
approximately 50%
Differences in patient characteristics
from adjuvant trials
• Node negative disease (29% in BCIRC, 32 % in
HERA, 6%in the joint analysis of B31 and
N9831)
• Only in HERA trial random assignment occurred
after completion of adjuvant chemotherapy and
radiation
• The central confirmation of tumor HER2
positivity was required only in HERA and BCIRG
trials
Trastuzumab Adjuvant Trials: Efficacy
Results
Trial and
arm
N° pts
N° events
3-year DFS
(%)
HR
95% CI
AC-TH
1.672
133
87
0.48
0.39-0.59
AC-T
1.679
261
75
AC-DH
1.074
128
87
0.61
0.48-0.76
DCarboH
1.075
142
86
0.67
0.54-0.83
AC-D
1.073
192
81
H
1.703
218
81
0.64
0.54-0.76
Control
1.698
321
74
CT+H
115
12
89
0.42
0.21-0.83
CT alone
116
27
78
B31/N9831
BCIRG 006
HERA
FinHer
Summary of Trastuzumab efficacy in early
breast cancer: Disease free-survival
a. Recurrence-free survival
Baselga at al., The Oncologist, 2006
Open Questions
• Cardiotoxicity
• Treatment duration
• Concomitant or sequential
• Timing of Hormonotherapy
• Role of lapatinib in the adjuvant setting
Management of TripleNegative Breast Cancer
Basal-like Breast Cancer
• 10-20% of tumors
HER2
Basal
• Low HER2
expression
• Low ER (and related
genes)
• Common in BRCA1
carriers
Luminal
• 50% are p53 mutant
Proliferation
• Very proliferative
Basal-like Breast Cancer
Frequent, early relapses
N= 311
p < 0.0000001
Triple-negative breast cancers
• Respond well to “standard chemotherapy” but
relapse early and with greater frequency
• Most BRCA1-mutated breast cancers belong
to this group; they represent 20%-25% of
triple negatives.
• Many triple-negative BC have mutated p53
• Many
triple-negative
breast
cancers
(especially the pure squamous tumors) have
EGFR overexpression
EGFR-directed Therapy for TripleNegative Breast Cancer
• Cetuximab alone has negligible activity
• Gefitinib and Erlotinib alone have marginal
activity
• The activity of platinum salts is currently
under evaluation, usually in combination of
chemotherapy or EGFR-directed therapy
• The state-of-the-art remains anthracyclines
+ taxanes, although taxane + platinum
combinations are used by some
Treatment by Molecular Class
Class
Treatment
Additional
Therapies
± chemotherapy
ER and/or PRexpressors
Aromatase inhibitors
SERMs
HER2-amplified
Trastuzumab, lapatinib ± chemotherapy,
hormone therapy
Triple-negative
(ER, PR, HER2)
Chemotherapy
(Platinum salts [?])
± bevacizumab
Basaloid
EGFR-inhibitors (?)
Platinum salts (?)
Courtesy of Hortobagyi GN
OUR STUDIES IN EARLY
BREAST CANCER
SEQUENTIAL EPIRUBICIN-DOCETAXEL-CMF AS
ADJUVANT THERAPY FOR NODE-POSITIVE EARLY
STAGE BREAST CANCER: UPDATED RESULTS OF THE
TAXit216 RANDOMIZED TRIAL
F. Cognetti, M. De Laurentiis, A. De Matteis, L. Manzione, C.
Boni, S. Palazzo, M. Di Palma, P. Papaldo, S. De Placido, A.R.
Bianco
On Behalf of the Taxit 216 Investigators
PRESENTED AT ESMO MEETING, SEPTEMBER 2008
TAXit 216 Original Study Design
Epi
N+
Pre/Post
 65 yrs
Epi
CMF
TXT
CMF
n=997
ddEpi
ddEpi: Epirubicin 120 mg/m2 d1 q14
ddTXT: Docetaxel 100 mg/m2 d1 q14
hd-CTX: Cyclophosphamide 3000 mg/m2 q21
ddTXT
hd-CTX
Feasibility Arm: closed after 25 pts
Objectives
• Primary objective:
– Disease-Free Survival (DFS), defined as time to
BC recurrence, contralateral BC, second non-BC
malignancy, or death
• Secondary objectives
– Overall Survival (OS)
– Safety
– Recurrence-free survival (RFS), defined as DFS
but excluding contralateral cancer and non-breast
second malignancy
– Subgroup analysis according to:
–
–
–
–
age (≤50 vs >50)
menopausal status
ER status (positive vs negative)
nodal status (N1-3 vs N4+)
Disease Free Survival
E→T→CMF
E→CMF
HR= 0.82 (95%CI: 0.64–1.03; P=0.1337)
P=0.1337)
Relapse Free Survival
E→T→CMF
E→CMF
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0.8
E→CMF
0.7
Probability of survival
0.9
1.0
Overall Survival
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0.6
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0.5
HR=0.67( 95%CI: 0.48–0.94; P=0.0168).
months
0
12
24
36
48
60
72
84
96
E-CMF
E-T-CMF
486
0
458
438
406
370
247
81
21
3
486
458
436
403
377
256
87
20
2
Subgroups analysis
DFS
Arm B better Arm A better
RFS
OS
Arm B better Arm A better
Arm
ArmBBbetter
better Arm
ArmAAbetter
better
Age,y
≤<5050
>>
5050
Menopausal status
Pre
Post
ER
Negative
Positive
Unknown
Nodes
1-3
>4

All
0.30
0.50
0.83 1.00
1.40
2.00
0.30
0.50
0.77
1.00
1.40
2.00
0.30
0.50
0.67
1.00
1.40
2.00
Conclusions
• Incorporating docetaxel into a block-sequential E-CMF
regimen was associated with
– Improved DFS (HR 0.82; 95%CI 0.64–1.03; P=0.1337)
– Significantly improved RFS (HR 0.75; 95%CI 0.59–0.96; P=
0.0394)
– Significant improved OS (HR 0.67; 95%CI 0.48–0.94;
P=0.0168)
• The observed treatment benefit is independent of age,
ER status, menopausal status, and nodal status
• This advantage comes at the cost of an increased, but
manageable toxicity
Clinical trials in breast cancer in Italy: the
Gruppo Italiano Mammella (GIM)
•Intergroup: GONO-GOCSI-GOIRC-GOL
•Participating centers: 100 italian centers
•Main focus: phase III study in early breast
cancer
–Chemotherapy
–Endocrine therapy
–Supportive care
A phase III randomized study of sequential Epidoxorubicin plus
Cyclophospamide followed by Docetaxel (ECD) versus the
combination of 5-Fluorouracil, Epidoxorubicin and
Cyclophospamide (FEC) as adjuvant treatment of node-negative
early breast cancer patients
GIM 1: phase III randomized study
EC 90/600 q21 x 4
DOCETAXEL 100 q21 x 4
FEC 600/75/600 q21 x 6
Study objectives and details
• Primary objective:
 to compare Disease
Free Survival (DFS)
between treatment
groups
• Secondary objective:
 to compare Overall
Survival (OS)
 to compare Safety
• Start date:
13/11/2003
• Protocol status
ongoing
• Participating
centers:
98
• Total randomized
patients: 1289
Protocol GIM 2
A phase III randomized study of EC followed by Paclitaxel versus
FEC followed by Paclitaxel, all given either every 3 weeks or 2
weeks supported by Pegfilgrastim, for node positive breast
cancer patients
• Primary objective:
 to compare Disease Free Survival (DFS) from adding of
5-Fluorouracil to EC followed by Paclitaxel
 to compare Disease Free Survival (DFS) of schedule
every 2 weeks versus 3 weeks
• Secondary objective:
 to compare Safety
GIM-2: study design and objectives
ARM A
ARM C
EC x 4  T x 4 q. 3 w
EC x 4  T x 4 q. 2 w +
Pegfilgrastim
ARM B
ARM D
FEC x 4  T x 4 q. 3 w
FEC x 4  T x 4 q. 2 w +
Pegfilgrastim
Factorial study aimed at assessing two separate hypothesis:
• Factor 1: A+C vs B+D = the efficacy and safety of 5-FU in
addition to ECT
• Factor 2: A+B vs C+D = the efficacy and safety of a 50%
increase in dose-density
Study details
•
•
•
•
Start date:
20/03/2003
Protocol status:
closed 03/07/2006
Participating centers:
91
Total randomized patients:
2091
PROTOCOL GIM4
LETROZOLE ADJUVANT THERAPY
DURATION STUDY (LEAD): STANDARD
VERSUS LONG TREATMENT with
AROMATASE INHIBITORS
A PHASE III STUDY IN POSTMENOPAUSAL
WOMEN WITH EARLY BREAST CANCER
Study design
Phase III randomized study
• Postmenopausal
• TAM 2-3 yrs
R
LETROZOLE 5 YRS
LETROZOLE 3-2 YRS
Study objectives and details
• Primary objective: • Start date:
to compare Disease 27/07/05
Free Survival (DFS)
between treatment • Protocol status:
groups
ongoing
• Secondary
objectives: to
compare Overall
Survival (OS)
to compare Safety
• Participating centers:
100
• Total randomized patients:
1508
PROTOCOL GIM-5
CYPLEC STUDY: CYP19 LETROZOLE
CORRELATION STUDY
Letrozole Extended-Adjuvant Therapy
After Tamoxifen
Study of Gene CYP19 Correlation with
Letrozole Efficacy in Postmenopausal Early
Breast Cancer Patients
CYPLEC – GIM 5
Multicenter, not comparative, prospective,
phase IIIb study of GIM group
Postmenopausal
Tamoxifen
pts
4,5-6 yrs.
ER and/or PgR +
Registration
Letrozole
5 years
Total Patients: 2400 during a 3-year period
Primary objective: correlation between a Single Nucleotide
Polymorphism (SNP) of CYP19 and Disease Free Survival (DFS)
Hypothesis: 86% of power to detect a relative reduction of relapse
of 46%: 4-yrs DFS for TC genotype = 91%
4-yrs DFS for CC or TT genotype = 95%
Study objectives and details
• PRIMARY OBJECTIVE • Start date:
Correlation DFS - SNP of
27/07/05
CYP19 gene
• Protocol status:
ongoing
• SECONDARY
OBJECTIVES
• Participating centers:
Correlation SNP of CYP19 gene
100
and:
1) letrozole plasma
• Total enrolled patients:
concentration
478
2) aromatase inhibition by
plasma estrone-S
3) OS
4) Safety
PROMISE (GIM-6)
Prevention of chemotherapy – induced menopause by temporary
ovarian suppression with Triptorelin vs control in young breast
cancer patients.
A randomized phase III multicenter study
Randomized phase III study
 Age <45 yrs
 Stage I-II-III
 Candidate for chemotherapy
Only CT
CT + Triptorelin
Study Objectives and details
• Primary objective:
•
– to evaluate efficacy of
Triptorelin to prevent •
chemotherapy-induced
amennorreha
•
Start date:
29/05/2003
Protocol status:
closed
Participating Centers:
30
• Total randomized patients:
• Secondary objective:
282
– to compare safety of
chemotherapy associated
to Triptorelin vs only
chemotherapy
21-Gene RS Assay
 16 cancer and 5 reference genes from 3 studies
Proliferation
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
Estrogen
ER
PgR
Bcl2
SCUBE2
GSTM1
Invasion
Stromolysin 3
Cathepsin L2
HER2
GRB7
HER2
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
BAG1
- 0.07 x BAG1
CD68
Reference
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Category
RS (0-100)
Low risk
RS < 18
Int risk
High risk
RS ≥ 18 and < 31
RS ≥ 31
Paik S, NEJM 351(27):2817, 2004
Recurrence Score as a Continuous Predictor
40%
Intermediate
Risk Group
Distant Recurrence at 10 Years
Low Risk Group
35%
High Risk Group
My RS is 30, What is the chance
of recurrence within 10 yrs?
30%
25%
20%
15%
10%
5%
95% CI
0%
0
5
10
15
20
25
30
Recurrence Score
35
40
45
50
Tamoxifen Benefit and 21-Gene RS Assay
NSABP B-14 Tamoxifen Benefit Study in N-, ER+ Patients
Design
Placebo—Eligible
N-, ER+
Tamoxifen—Eligible
Objective
Determine whether the 21-gene RS assay captures
• Prognosis
• Response to tamoxifen
• Both
Paik et al SABCS 2005. Abstract 510.
NSABP B-14 Results: DRFS—Low,
Intermediate, & High RS Groups
Risk Group, %
Patients
10-Yr Rate
Recurrenc
e
95% CI
51
22
27
6.8
14.3
30.5
4.0-9.6
8.3-20.3
23.637.4
Low (RS < 18)
Intermediate (RS 18-30)
High (RS ≥ 31)
Test for the 10-year DRFS comparison between the low and high risk groups: P < .00001
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
NSABP B-14 Results: DRFS—Low,
Intermediate, & High RS Groups (cont’d)
DRFS, %
100
90
338 patients
80
149 patients
70
181 patients
60
50
40
30
Low risk (RS < 18)
Intermediate risk (RS 18- 30)
High risk (RS ≥ 31)
20
10
0
0
2
4
6
8
10
Years
12
14
Paik S, et al. N Engl J Med. 2004;351:2817-2826. Copyright © 2004. Massachusetts Medical
Society. All rights reserved.
16
1.0
1.0
0.8
0.8
DRFS
DRFS
NSABP B-14 Benefit of Tamoxifen
By RS Risk Category
0.6
Low Risk (RS < 18)
0.4
N
Placebo 171
Tamoxifen 142
0.2
0
0
2
4
6
0.6
Intermediate Risk (RS 18-30)
0.4
N
Placebo 85
Tamoxifen 69
0.2
0
8 10 12 14 16
Years
1.0
0
2
4
6
8 10 12 14 16
Years
DRFS
0.8
0.6
0.4
0.2
0
Paik S, et al. ASCO 2005. Abstract 510. 0
Permission granted to print.
High Risk (RS ≥ 31)
N
Placebo 99
Tamoxifen 79
2
4
6
8 10 12 14 16
Years
Interaction P = .06
Chemotherapy Benefit and 21-Gene
RS Assay
NSABP B-20 Chemo Benefit Study in N-, ER+ Patients
Design
Tamoxifen + MF
N-, ER+
Tamoxifen + CMF
Tamoxifen
Objective
Determine the magnitude of the chemotherapy benefit as a
function of 21-gene RS assay
Paik S, et al. ASCO 2005. Abstract 510.
Benefit of Chemotherapy Based on RS
10 yr
96%
95%
1.0
Low Risk (RS < 18)
0.6
0.4
Tam + Chemo
Tam
0.2
N
218
135
0
2
4
6
Years
8
Events
11
5
P = .76
10
0.8
10 yr
89%
90%
0.6
Intermediate Risk (RS 18-30)
0.4
Tam + Chemo
Tam
0.2
0
2
4
0.8
10yr
88%
0.6
60%
High Risk (RS≥31)
0.4
0.2
Tam + Chemo
Tam
N
117
47
0
0
Paik S, et al. ASCO 2005.
Abstract 510. Permission granted to print.
N
89
45
0
12
1.0
DRFS
0
DRFS
DRFS
0.8
1.0
2
4
6
Years
8
Events
13
18
P = .001
10
12
6
Years
8
Events
9
8
P = .71
10
12
ASCO Guidelines
“The Oncotype DX tumor marker test is recommended for
patients with node-negative breast cancer that is ER positive
and/or PgR positive, which is the case for 50 percent of
breast cancer patients. The test measures multiple genes at
once to estimate the risk of breast cancer recurrence.
Patients with a low recurrence score may be able to receive
only hormone therapy and avoid chemotherapy. Sparing
patients from unnecessary treatment may not only improve
their quality of life, but it also will reduce overall health care
costs”
Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology
2007 Update of Recommendations for the Use of Tumor Markers in Breast
Cancer. J Clin Oncol. 2007;25:5287-5312.
Oncotype DX™ - TAILORx - Study Design
Oncotype DX™ Assay
No Minimal Chemotherapy
Benefit Group
Recurrence Score <11
(~29% of Population)
Uncertain Chemotherapy
Benefit Group
Recurrence Score 11-25
(~44% of Population)
Established Chemotherapy
Benefit Group
Recurrence Score >25
(~27% of Population)
Stratify
 Tumor Size ≤2.0 cm vs. ≥ 2.1 cm
 Post menopausal vs. Pre-or Peri-menopausal
 Planned chemotherapy: Taxane-containing (i.e. paclitaxel, docetaxel) vs.
Non-taxane-containing
Randomize
Arm A
Hormonal Therapy
Arm B
Hormonal Therapy
Arm C
Chemotherapy Plus
Hormonal Therapy
Arm D
Chemotherapy Plus
Hormonal Therapy
MINDACT Design
(Microarray in Node-Negative Disease May
Avoid Chemotherapy Trial)
Evaluate clinico-pathological risk (Adjuvant!) AND 70-gene signature risk
32%
N=3300
55%
N=780
Discordant cases
Clinical pathological
AND
70-gene signature
HIGH risk
13%
Clinical pathological
AND
70-gene signature
Clin-Path HIGH risk
LOW risk 70-gene
LOW risk
Clin-Path LOW risk
70-gene HIGH risk
n=1920
Use Clin-Path risk to
decide on adjuvant
chemotherapy or not
chemotherapy
R
Use 70-gene risk to
decide on adjuvant
chemotherapy or not
No chemotherapy
All hormone responsive patients receive endocrine therapy
Buyse M et al, JNCI 2006
WHAT’S NEW IN METASTATIC BREAST
CANCER
• HER-2 POSITIVE DISEASELAPATINIB
• HER-2 NEGATIVE DISEASEBEVACIZUMAB
Geyer C et al. N Engl J Med 2006;355:2733-2743
Geyer C et al. N Engl J Med 2006;355:2733-2743
Geyer C et al. N Engl J Med 2006;355:2733-2743
ECOG 2100
Bevacizumab added to weekly paclitaxel in first line
Metastatic Breast Cancer
R
A
N
D
O
M
I
Z
E
Paclitaxel +
Bevacizumab
Paclitaxel
28-day cycle:
Paclitaxel 90 mg/m2 D1, 8 and 15
Bevacizumab 10 mg/kg D1 and 15
Miller et al. SABCS 2005
Improved Progression-Free Survival
with Bevacizumab Added to Paclitaxel
Pac. + Bev. 11.4 months
1.0
Paclitaxel
6.11 months
PFS Probability
0.8
0.6
HR = 0.51 (0.43-0.62)
0.4
Log Rank Test
p<0.0001
0.2
0.0
0
Miller K, SABCS 05
6
12
18
Months
24
30
484 events reported
Bevacizumab in Clinical Subsets
Group
ER+, PR+
ER+, PRER-, PRNo adj chemo
Non-taxane
Taxane
Age 27 - 49
Age 50 - 64
Age 65 - 85
DFI 0 - 24 mos.
DFI > 24 mos.
< 3 sites
3 or more sites
Overall
Miller K, SABCS 05
Ratio 95% Conf Int N
0.39 (0.29, 0.53) 200
80
0.86 (0.52, 1.43)
0.47 (0.35, 0.63) 184
0.60 (0.44, 0.82) 178
0.51 (0.39, 0.67) 234
0.38 (0.25, 0.59)
86
0.45 (0.32, 0.63) 155
0.44 (0.33, 0.58) 232
0.79 (0.53, 1.17) 111
0.57 (0.43, 0.75) 204
0.47 (0.37, 0.60) 294
0.48 (0.37, 0.61) 252
0.54 (0.41, 0.71) 245
0.51 (0.43, 0.62) 680
0.0
0.5
1.0
1.5
HAZARD RATIOS FOR DISEASE
PROGRESSION
Conclusions
• Chemotherapy, endocrine therapy, and targeted therapy
improve prognosis in breast cancer
• There is a rationale for combination targeted therapies
• Evolving technology will lead to better selection of
patients and treatments, resulting in enhanced
therapeutic ratio and reduced mortality from breast
cancer
• Cooperation between centers in planning and conducting
clinical trials is fundamental in the fight against cancer