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Clinical Dilemma:
Which Adjuvant
Chemotherapy is Just Right?
Dr. Maureen Trudeau
Head, Division of Medical Oncology/Hematology
Toronto Sunnybrook Regional Cancer Centre
Associate Professor, University of Toronto
June 15, 2007
Systemic Therapy - Chemotherapy
• Overall survival improvement in clinical trials
both for standard and newer treatments
• Choice – for patients, for physicians
(anthracycline +/- taxanes)
• Better decision making aids
– www.adjuvantonline.com
• Molecular profiles – Oncotype Dx, MammoPrint
• Improved supportive care
Decision Making in Adjuvant
Therapy
Tumour characteristics
T, N, Grade, ER, PgR, Patient Characteristics
HER2, LVI
Age, Comorbidities
Prior Therapy
Performance Status
Patient Preference
Work/Family/Self
Molecular
Profile
Clinical Trials,
Guidelines
Recent Reports
Select Breast Cancer Treatments
Based on Tumor Phenotype
• Tumor phenotype defines treatment options
Hormone receptor
Positive
Hormonal therapy
Negative
Chemotherapy
HER2
HER2
Positive
HER2-targeted
therapy
Negative
Positive
HER2-targeted
therapy
Negative
IMPROVED RISK ASSESSMENT OF EARLY
BREAST CANCER THROUGH GENE
EXPRESSION PROFILING
Gene-expression profile
Good signature
Poor signature
microarray
N Engl J Med, Vol 347 (25), Dec. 2002
March 2005 - Confidential
BIGBIG-TRANSBIG Secretariat–
Secretariat– Used with permission
Breast Cancer is not ONE Disease
Basal-like
HER-2
“Normal”
Luminal B
Luminal A
Sorlie T et al, PNAS 2001
Gene Expression Patterns of
Breast Carcinomas
ER
Gene
expression
ER
Gene
expression
O.S.
A
B
C
D
E
Basal-like HER2 Normal Luminal Luminal
Subgroup Subgroup breast Subtype Subtype
=E
=D
like
C
B
Adapted from PNAS, 2001, vol 98 no. 19
Luminal
Subtype
A
months
ER+
65-75%
All Breast Cancer
HER2+
15-20%
Basaloid
15%
Molecular Classifications of
Breast Tumors
Luminal A
ER +
high
Prolif
-
Luminal B
+
Basal -like
ER +
low
ER -
ERBB2 +
Normal-like
ER-/+
ER -
-/+
-
+
P53
mutations
16%
71%
75%, also
BRCA1
86%
Sorlie 2007
The “Triple Negative” Breast Cancer
Estrogen Receptor (ER) negative
Progesterone receptor (PR) negative
Her2neu (HER2) negative
ER/PR/HER2 -
Up to 90% of Triple Negative Breast
Cancers are Basal-Like Breast Cancers
Basal like Breast Cancers (BLC)
• BLCs comprise 15% of all invasive cancers
• More common in:
– Younger pts
– African Americans (40% premenopausal women)
– BRCA1 mutation carriers
• BLC are associated with:
– high grade
– p53 mutations
– Increased expression of EGFR
– CK5/6
(recent studies in 2006…Vimentin, cKIT, SRC)
Sample
• From the HBBC database, 1601 (80%) of
patients had details on hormone
receptors/HER2 and were eligible for the study
• 180 (12%) of the 1601 patients were defined as
basal-like breast cancers
• Mean follow up was 8.1 years
Characteristics of Basal-like versus Non basal-like
Breast Cancers
Characteristic
Non Basal
(N=1421)
number (percent)
Basal-like
(N=180)
number (percent)
Significance
p value *
57.7
53
p < 0.0001
2.1 cm
3.0 cm
p < 0.0001
Mean Age at Diagnosis (yrs)
Mean Tumor Size
Tumor Size
T1 (? 2 cm)
T2 (>2cm to ? 5cm)
T3 (>5cm)
Missing
880
461
64
16
(62.7)
(32.8)
(4.6)
65
99
14
2
(36.5)
(55.6)
(7.9)
p < 0.0001
Lymph Node Status
Positive
Negative
Missing or Not Tested
510
609
302
(45.6)
(54.4)
87
70
23
(54.4)
(44.6)
p = 0.02
237
616
336
(19.9)
(51.8)
(28.3)
15
37
101
(9.8)
(24.2)
(66.0)
p < 0.0001
Tumor Grade
I
II
III
Missing
* p values were calculated with the use of the chi-square test
Hazard Rate of Distant Recurrence
Survival
Novel Therapies for TN
• BRCA1 involved in repair of double stranded DNA breaks
– Mutations implicated in breast/ovarian susceptibility
• BRCA1 cancers appear to closely resemble sporadic triple negative
breast cancers on molecular level
• in vitro chemo-sensitivity studies have found that basal-like breast
cancers may be particularly sensitive to cisplatin and to other drugs
that cause double-strand breaks in DNA
• Agents such as cisplatin and carboplatin may be more effective
treatment than other types of chemotherapy for the basal like group
Oncotype DX
• A multigene assay to predict recurrence of
Tamoxifen-treated, node-negative breast cancer
(Paik NEJM 204)
• 21 genes - proliferation (5), invasion (2), HER 2
(2), Estrogen (4) , 3 others and 5 reference genes
with a Recurrence Score (RS) algorithm
• For node negative, tam treated (JCO 2007):
–Luminal A = low risk oncotype DX
–Luminal B = mod/high risk
Program for the Assessment of Clinical
Cancer Tests (PACCT-1):
Trial Assigning IndividuaLized Options for
TReatment (TAILORx)
TAILORx
Participating Groups:
ECOG, North American Breast Cancer Intergroup
(CALBG, SWOG, NCCTG, NCIC, & ACOSOG)
& NSABP
Background:
Management of ER-Positive, LymphNode Negative Breast Cancer
• ~ 137,000 diagnosed annually in North America
• ~ 80-85% are adequately treated with
• surgery +/- irradiation
• hormonal therapy
• Adding chemotherapy  recurrence by ~ 25%
• absolute benefit is small (~3-5% or less)
• Current practice guidelines
• chemotherapy recommended for most
Background:
Practical Considerations for Selecting
Oncotype DX Assay
• Approved diagnostic test by regulatory agencies in
the United States (CLIA)
• No special processing required - may be performed
on routinely collected and processed formalin-fixed,
paraffin embedded tissue
• Extensive post-marketing experience and familiarity
in U.S. oncology community
• Increasing precedent for third party reimbursement
• Prior successful collaboration between NCIsponsored groups and industry partner
Background:
Scientific Rationale for Selecting Oncotype DX
Assay
1. Validated prognostic test for tamoxifen treated patients
–
–
–
2.
predictive of distant recurrence
may be used as dichotomous or continuous variable
(Paik et al. NEJM, 2004)
Also validated in population based Kaiser study
–
(Habel et al. SABCS 2004, abstr 3109)
3. Lower RS predictive of tamoxifen benefit
–
(Paik et al. ASCO 2005, abstr 510)
4. Higher RS predictive of chemotherapy benefit
–
(Paik et al. SABCS 2004, abstr 21)
5. Correlates more strongly with outcome than Adjuvant!
–
(Bryant et al. St. Gallen, 2005)
6. Predictive of local recurrence in tam treated patients
–
(Mamounas, SABCS 2005, abstr 29)
Pre-REGISTER
TAILORx
Study Design
ONCOTYPEDXASSAY
REGISTER
SpecimenBanking
SecondaryStudy Group1
RS <11
~29%of Population
PrimaryStudyGroup
RS11-25
~44%of Population
SecondaryStudy Group 2
RS>25
~27%of Population
ARMA
Hormonal Therapy
Alone
RANDOMIZE
StratificationFactors:
Tumor Size, Menopausal Status,
PlannedChemo, PlannedRadiation
ARMD
ChemotherapyPlus
Hormonal Therapy
ARMB
ARMC
Hormonal Therapy ChemotherapyPlus
Alone
Hormonal Therapy
Background:
Definition of Risk Groups for TAILORx
•
•
•
•
Risk groups originally defined as (NEJM, 2004):
– < 18 “Low Risk”
– 18-30 “Intermediate Risk”
– > 30 “High Risk”
Definitions modified for TAILORx:
– 11-25 “Primary Study Group”
– < 11 “Secondary Study Group 1”
– > 25 “Secondary Study Group 2”
Rationale for selecting RS 11 as the lower bound for Primary Stu dy Group:
– RS predicts distant and local recurrence
– RS 11: ~ 10% local & distant recurrence rate at 10 years
– 10% threshold is typically used for recommending adjuvant chemotherapy
Rationale for selecting 25 as upper bound for Primary Study Group:
– RS 30 associated with 20% risk of distant recurrence
– Lowering threshold to 25 reduces risk for undertreatment
– When viewing chemotherapy and tamoxifen benefit as a continuous
variables, 95% Confidence Intervals overlap in the 11-25 RS range (shown
in next slides)
Adapted by Dr. Maureen E. Trudeau, MD
Anthracycline-based Regimens
Superior To CMF/AC
Regimen
Trials Group
DFS / OS
(1)
CEF
(NCIC-CTG)


(2)
dd (EC)  CEF
(NCIC/EORTC/SAKK)
--
--
(3)
FEC100 > FEC50
(FASG)


FEC50  CMF
(ICCG)
--
--
(4)
CAF
(SWOG)


(5)
E  CMF
(NEAT/SCTBG)


(6)
AV CF
(MISSET)


(7)
TC
(Jones)

--
Taxane Regimens Superior To
AC-type Regimens
(1)
(2)
(3)
(4)
(5)
(6)
(1)
(2)
Regimen
AC  P
AC  P
P  FAC
DAC
FEC  D
A(C)  D  CMF
Trials Group
(CALGB)
(NSABP)
(MDACC)
(BCIRG)
(PACS 01)
(BIG 2-98)
Regimens superior to AC  P
dd AC  P
(CALGB)
or dd A  P  C
CEF or dd (EC)  P
DFS / OS
 
 --- - 
 
 --



--
Adjuvant Chemotherapy
Options – A Growing List
1998
CMF
Options
(F) AC
(1970’s)
(1980’s)
2007
Options
CEF
(CMF)
FEC 100
(FEC 50)
AC  Taxol
(AC)
TAC
(FAC)
FEC 100 
Docetaxel
(FEC 100)
Dose-dense
AC  Taxol
(AC  Taxol)
Dose-dense
(AC  Taxol)
(EC)  Taxol
CEF
(AC  Taxol)
TAXANES AS ADJUVANT THERAPY
SECOND GENERATION OF CLINICAL TRIALS
Best taxane
ECOG 1199 (intergroup trial)
Dose &
schedule
Sequence vs
combination
Best taxane
AC x 4
Px4
AC x 4
P weekly x 12
N5000
Taxane ±
Herceptin®
2800 pts
AC x 4
Dx4
AC x 4
D weekly x 12
Are There Factors that May
Predict Response or Suggest
which Therapy to Use?
TAXANES AS ADJUVANT THERAPY
SECOND GENERATION OF CLINICAL TRIALS
Taxane ± Herceptin®
Dose &
schedule
Sequence vs
combination
Best taxane
Taxane ±
Herceptin®
N8700
• HERA: any chemo 
Herceptin: 0 vs 1 vs 2 yr
• AC  D vs AC  D + H 1 yr vs
DCH x 6  H 1 yr
• AC  P vs AC  P + H 1 yr
• AC  P weekly x 12 vs AC 
P weekly x 12  H 1 yr vs AC
 P weekly x 12 + H 1 yr
Trastuzumab DFS
Median follow-up
HERA
1 year
Combined analysis
2 years
DH
2 years
BCIRG 006 DCarboH
2 years
BCIRG 006 AC
FinHER VH / DH
3 years
CEF
0
Favors
Trastuzumab
1
Favors no 2
Trastuzumab
HR
Piccart-Gebhart et al 2005; Romond et al 2005;
Slamon et al 2005; Joensuu et al 2005
Average hazard reduction
(Confidence interval)
ER
Neg
DFS
Pos
Neg
OS
Pos
8541
LoHi
9344
Tax
9741
q3q2
Overall
Loq2
36%
25%
23%
63%
(15 to 52%)
(11 to 36%)
(0 to 42%)
(43 to 76%)
14%
12%
10%
32%
(-18 to 37%)
(-4 to 25%)
(-19 to 33%)
(-7 to 56%)
29%
25%
22%
59%
(3 to 48%)
(11 to 37%)
(-5 to 43%)
(34 to 74%)
8%
10%
1%
18%
(-27 to 36%)
(-10 to 26%)
(-44 to 32%)
(-41 to 52%)
Adjusted for pos nodes, T size, menopausal status
Courtesy: Berry et al SABCS 2004
PACS 01
DFS by Age, ITT
Age  50 yrs
Age < 50 yrs
1.00
1.00
3FEC100-3D
0.75
0.75
Kaplan-Meier Estimate
Kaplan-Meier Estimate
3FEC100-3D
6FEC100
0.50
Log-rank P-Value = 0.690
HR (Cox model) = 0.98 [0.77-1.25]
0.25
6FEC100
0.50
Log-rank P-Value = 0.001
HR (Cox model) = 0.67 [0.51-0.88]
0.25
Multivariate Interaction Test
HR: 0.66 [0.46-0.95] P-value = 0.026
0.00
0
0.00
1
2
3
4
5
6
Survival Time (years)
7
8
0
1
2
3
4
5
Survival Time (years)
6
7
8
TAC vs FAC
DFS by HER2 Status
(Centrally reviewed, FISH centrally reviewed)
% Alive and Disease-Free
100
Negative
90
100
Positive
90
80
TAC
80
TAC
FAC
70
60
HR = 0.76
P = 0.046
50
70
60
HR = 0.60
P = 0.0088
FAC
50
0 6 12 18 24 30 36 42 48 54 60 66
0 6 12 18 24 30 36 42 48 54 60 66
Time to First Event
Time to First Event
Ratio of HRs 0.85 p= 0.4122
NEJM 2005
Topoisomerase II
• Topoisomerase II is essential for DNA
replication and recombination
• Anthracyclines target topoisomerase II
• Increased sensitivity to HER2 due to coamplification of TOP2A?
A pooled analysis on the interaction
between HER-2 expression and
responsiveness of breast cancer
to adjuvant chemotherapy
Alessandra Gennari, Maria Pia Sormani,
Matteo Puntoni and Paolo Bruzzi
National Cancer Research Institute - Genoa
and University of Genoa - Italy
SABCS 2006
Characteristics of studies - I
Study
Comparison
HER2 status
determined
(%)
NSABP B11
PF vs PAF
638/682
(94%)
NSABP B15
CMF vs AC
2.034/2.295
(89%)
GUN 3
CMF vs CMF/EV
123/220
(56%)
Brussels
CMF vs HEC/EC
354/777
(46%)
Milan
CMF vs CMF→ A
506/552
(92%)
DBCCG - 89 - D
CMF vs FEC
805/980
(82%)
NCIC MA5
CMF vs CEF
628/710
(88%)
5.088/6.216
(82%)
Total (available/randomised)
SABCS 2006
Disease Free Survival
HER2 positive
HER2 negative
Study
HR
95% CI
NSABP B11
0.60
0.96
0.84
1.02
0.65
1.35
0.83
1.22
0.75
0.79
0.52
0.91
0.44 - 0.82
0.75 - 1.23
0.65 - 1.08
0.86 - 1.20
0.34 - 1.27
0.93 - 1.97
0.46 - 1.49
0.91 - 1.64
0.53 - 1.06
0.60 - 1.05
0.34 - 0.80
0.71 - 1.17
Total
0.90
0.82 - 0.98
p = 0.01
Overall
0.71
1.00
0.61 - 0.83
0.90 - 1.11
p < 0.0001
p = 1.0
NSABP B15
Brussels
Milan
DBCCG-89-D
NCIC MA-5
heterogeneity 25 = 5.3, p = 0.38
heterogeneity 25 = 7.6, p = 0.18
anthra better
0.4
0.6
0.9
non anthra better
2
1
5
Test for interaction 2 = 13.7 p < 0.001
SABCS 2006
Efficacy summary
HER2 positive
• Risk of relapse
HER2 negative
• Risk of relapse
29%
anthra ≈ non anthra
HR 0.71 (0.61-0.83)
HR 1.00 (0.90-1.11)
(p < 0,0001)
(p = 1,0)
• Risk of death
• Risk of death
27%
anthra ≈ non anthra
HR 0.73 (0.62-0.85)
HR 1.03 (0.92-1.16)
(p < 0,0001)
(p < 0,86)
SABCS 2006
Hierarchy of Chemotherapy
Regimens
Appropriate high
risk
population
Older, no
GCSF
Younger,
+ GCSF
Younger,
+/- GCSF
Younger,
+ GCSF
Younger,
+ GCSF
# of cycles
6 cycles
10 cycles
6 cycles
(12 visits)
8 cycles
6 cycles
High risk
FECD
dd(EC)P
CEF
dd(AC)P
TAC
FEC 100
CEF
(MA 5)
FEC 50
CMF
is better than
Moderate risk
CAF
ACP
AC
P
AC
D
AC
DC
AD
is better than
Low Risk
P = paclitaxel
D = docetaxel
No Therapy
FAC
The choice of chemotherapy
Depends on the following:
• Tumour characteristics and risk of relapse
• Patient comorbidities
• Patient age
• Social determinants
• Drug availability / costs
• Physician or patient preference
Cost of common regimens
Regimen
N+ Study Total Treatment Costs USD
(drug acquisition + incidental + administration)
DAC
AC ->P
AC->P
CE120F
FE100C
FE100C->D
BCIRG001
CALGB9344
CALGB9741
MA-5
FASG-5
PACS-01
$8,226
$4,340
$11,741
$4,852
$3,557
~ $6,200
Convenience of common regimens
Regimen
N+ Study
TAC
BCIRG001
AC ->T
CALGB9344
AC->T
CALGB9741
CE120F
MA-5
FE100C
FASG-5
FE100C->D PACS-01
Visits
6
8
8
12
6
6
Chair time (h)
14
21.6
21.6
5.4
9
8
Where are we going?
Adapted by Dr. Maureen E. Trudeau, MD
Cases
A 68-year old woman presents with an
infiltrating duct carcinoma
• 1.2 cm in size
• ER 80% PR 60%
• HER 2 • Sentinel node negative
A 68-year old woman presents with
an invasive ductal carcinoma
A 59-year old postmenopausal woman
with invasive ductal carcinoma
• 1.9 cm in size
• ER 30% PR 0%
• HER 2+ (3+ by IHC)
• Grade 3
• Sentinel node negative
A 59-year old postmenopausal women
with invasive ductal carcinoma
A 49-year old premenopausal woman
with invasive lobular carcinoma
• 2.5 cm in size
• ER 70% PR 30%
• HER 2• Grade 2
• 2/10 positive lymph nodes
A 49-year old premenopausal woman
with invasive lobular carcinoma
A 39-year old premenopausal woman
with invasive ductal carcinoma
• 2.8 cm in size
• ER 0% PR 0%
• HER 2 • Grade 3
• 5 nodes positive
A 44-year old premenopausal woman
with invasive ductal carcinoma
• 2.0 cm in size
• ER 100% PR 100%
• HER 2 • Grade 2
• 1/17 nodes positive
• 2 other smaller lesions, grade 1