Clinical Dilemma:

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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
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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

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Decision Making in Adjuvant Therapy
Tumour characteristics T, N, Grade, ER, PgR,
HER2, LVI
Patient Characteristics Age, Comorbidities Prior
Therapy Performance Status
Patient Preference Work/Family/Self
Molecular Profile
Clinical Trials, Guidelines Recent Reports
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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
Negative
Positive HER2-targeted therapy
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Breast Cancer is not ONE Disease
Luminal B
Normal
HER-2
Basal-like
Luminal A
Sorlie T et al, PNAS 2001
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ER 65-75
All Breast Cancer
HER2 15-20
Basaloid 15
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Molecular Classifications of Breast Tumors
Luminal A ER high Prolif - P53 mutations 16
Luminal B ER low 71
Basal -like ER - 75, also BRCA1
ERBB2 ER-/ -/ 86
Normal-like ER - -
Sorlie 2007
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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

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Adapted by Dr. Maureen E. Trudeau, MD
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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 gt FEC50 (FASG) ? ?
• FEC50 ? CMF (ICCG) -- --
• (4) CAF (SWOG) ? ?
• (5) E ? CMF (NEAT/SCTBG) ? ?
• AV CF (MISSET) ? ?
• (7) TC (Jones) ? --

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Taxane Regimens Superior To AC-type Regimens

• Regimen Trials Group DFS / OS
• (1) AC ? P (CALGB) ? ?
• (2) AC ? P (NSABP) ? --
• (3) P ? FAC (MDACC) -- --
• DAC (BCIRG) ? ?
• FEC ? D (PACS 01) ? ?
• (6) A(C) ? D ? CMF (BIG 2-98) ? --
• Regimens superior to AC ? P
• (1) dd AC ? P (CALGB) ? ?
• or dd A ? P ? C
• (2) CEF or dd (EC) ? P ? - -

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Adjuvant Chemotherapy Options A Growing List
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 (EC) ? Taxol (AC ? Taxol)
CEF (AC ? Taxol)
1998 Options CMF (1970s)
(F) AC (1980s)
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TAXANES AS ADJUVANT THERAPY SECOND GENERATION OF
CLINICAL TRIALS
Best taxane
ECOG 1199 (intergroup trial)
P x 4
AC x 4
N?5000
AC x 4
P weekly x 12
2800 pts
AC x 4
D x 4
AC x 4
D weekly x 12
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Are There Factors that May Predict Response or
Suggest which Therapy to Use?
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TAXANES AS ADJUVANT THERAPY SECOND GENERATION OF
CLINICAL TRIALS

• Taxane Herceptin
• 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

N?8700
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Trastuzumab DFS
Piccart-Gebhart et al 2005 Romond et al
2005Slamon et al 2005 Joensuu et al 2005
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Adjusted for pos nodes, T size, menopausal status
Courtesy Berry et al SABCS 2004
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PACS 01DFS by Age, ITT
Age lt 50 yrs
Age ? 50 yrs
1.00
1.00
3FEC100-3D
3FEC100-3D
0.75
0.75
6FEC100
6FEC100
Kaplan-Meier Estimate
Kaplan-Meier Estimate
0.50
0.50
Log-rank P-Value 0.690 HR (Cox model) 0.98
0.77-1.25
Log-rank P-Value 0.001 HR (Cox model) 0.67
0.51-0.88
0.25
0.25
Multivariate Interaction Test HR 0.66
0.46-0.95 P-value 0.026
0.00
0.00
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
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Survival Time (years)
Survival Time (years)
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TAC vs FACDFS by HER2 Status
(Centrally reviewed, FISH centrally reviewed)
100
Alive and Disease-Free
Time to First Event
Time to First Event
NEJM 2005
Ratio of HRs 0.85 p 0.4122
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Topoisomerase II

• Topoisomerase II? is essential for DNA
  replication and recombination
• Anthracyclines target topoisomerase II?
• Increased sensitivity to HER2 due to
  co-amplification of TOP2A?

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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
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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)
Total (available/randomised) 5.088/6.216 (82)
SABCS 2006
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Disease Free Survival
HER2 positive HER2 negative
non anthra better
Study
HR
95 CI
anthra better
NSABP B11
0.44 - 0.82 0.75 - 1.23
0.60 0.96
0.65 - 1.08 0.86 - 1.20
NSABP B15
0.84 1.02
0.34 - 1.27 0.93 - 1.97
0.65 1.35
Brussels
0.46 - 1.49 0.91 - 1.64
0.83 1.22
Milan
0.53 - 1.06 0.60 - 1.05
0.75 0.79
DBCCG-89-D
0.34 - 0.80 0.71 - 1.17
0.52 0.91
NCIC MA-5
0.82 - 0.98
0.90
Total
p 0.01
p lt 0.0001
0.61 - 0.83 0.90 - 1.11
0.71 1.00
Overall
p 1.0
heterogeneity ?25 5.3, p 0.38 heterogeneity
?25 7.6, p 0.18
0.6
1
2
5
0.4
0.9
Test for interaction ?2 13.7 p lt 0.001
SABCS 2006
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Efficacy summary
HER2 negative
HER2 positive

• Risk of relapse
• anthra non anthra
• HR 1.00 (0.90-1.11)
• (p 1,0)
• Risk of death
• anthra non anthra
• HR 1.03 (0.92-1.16)
• (p lt 0,86)

• Risk of relapse
• 29
• HR 0.71 (0.61-0.83)
• (p lt 0,0001)
• Risk of death
• 27
• HR 0.73 (0.62-0.85)
• (p lt 0,0001)

SABCS 2006
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Hierarchy of Chemotherapy Regimens
Appropriate high riskpopulation 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
is better than
Moderate risk FEC 100 CEF (MA 5) AC?P AC?P AC?D
is better than
Low Risk FEC 50 CMF AC DC AD
CAF
FAC
No Therapy
P paclitaxel D docetaxel
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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

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Cost of common regimens

• Regimen N Study Total Treatment Costs USD
• (drug acquisition incidental
  administration)
• DAC BCIRG001 8,226
• AC -gtP CALGB9344 4,340
• AC-gtP CALGB9741 11,741
• CE120F MA-5 4,852
• FE100C FASG-5 3,557
• FE100C-gtD PACS-01 6,200

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Convenience of common regimens

• Regimen N Study Visits Chair time (h)
• TAC BCIRG001 6 14
• AC -gtT CALGB9344 8 21.6
• AC-gtT CALGB9741 8 21.6
• CE120F MA-5 12 5.4
• FE100C FASG-5 6 9
• FE100C-gtD PACS-01 6 8

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Where are we going?
Adapted by Dr. Maureen E. Trudeau, MD
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Cases
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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

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A 68-year old woman presents with an invasive
ductal carcinoma
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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

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A 59-year old postmenopausal women with invasive
ductal carcinoma
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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

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A 49-year old premenopausal woman with invasive
lobular carcinoma
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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

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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

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