Treatment Options for Women with HER2 Positive Breast Cancer

1
Treatment Options for Women with HER2 Positive
Breast Cancer
The Herceptin Story
Roanne Segal MD FRCPC Medical Oncologist The
Ottawa Hospital Regional Cancer Centre May 4, 2006
2
The Herceptin Story In the beginning
3
Objectives

• Introduction
• review terminology
• pathophysiology of HER-2 family of proteins
• diagnostic testing
• Treatment options for women with HER-2
• advanced disease
• early stage disease
• Toxicity
• acute and long term settings
• Economics
• The future and its questions

4
HER-2 Terminology

• Human Epidermal Growth Factor Receptor-2
• HER2/neu-2
• oncogene encoding production
• HER2 receptor
• Also known
• neu (rat gene)
• c-erbB-2

5
The EGFR/HER Family
erb-b1 EGFR HER1
6
TrastuzumabHumanized Anti-HER2 Antibody

• Targets HER2 protein
• High affinity (Kd 0.1 nM)
• High specificity
• 95 human, 5 murine
• Decreases potential for immunogenicity

HER2 epitopes recognized by hyper variable murine
antibody fragment
Human IgG-1
7
Transmembrane Structure of HER2 Receptor
Extracellular domain (632 amino
acids) Ligand-binding site
Transmembrane domain (22 amino acids)
Plasma membrane
Intracellular domain (580 amino acids) Tyrosine
kinase activity
Cytoplasm
8
HER2 Receptor Transmembrane Signal Transduction
Pathway
Growth factor
Binding site
Plasma membrane
Tyrosine kinase activity
Signal transduction to nucleus
Cytoplasm
Nucleus
CELL DIVISION
Gene activation
9
Role of HER2 in Breast Cancer

• A HER2-positive status
• predictor of poor prognosis
• multivariate analysis
• HER2 was a strong independent predictor
• relapse (p0.001)
• overall survival (p0.02)
• The HER2 receptor provides
• Extracellular target specific anticancer
  treatment
• Herceptin

Slamon DJ et al. Science 198723517782
10
Indicators of Increased HER2 Production
Normal
Amplification/overexpression
3
Cytoplasm
C
2
B
1
4
Nucleus
A
Cytoplasmic membrane
1 gene copy number 2 mRNA transcription 3
cell surface receptor protein expression 4
release of receptor extracellular domain
A HER2 DNA B HER2 mRNA C HER2 receptor
protein
11
The HER2 Alteration
Southern
Northern
Western
IHC
Slamon et al. Science 1987,1989
12
HER2-Evaluation

• IHC Immuno-histochemical test
• HER-2 protein/receptor
• Graded 1-2-3
• FISH (Fluorescence In Situ Hybridization)
• copies of gene
• Positive IHC 3

Slamon DJ et al. Science 1987
13
From bench to bedside
Role of Herceptin in MBCThe Middle.
14
Herceptin TrialsMetastatic Breast Cancer

• Slamon 2001
• Chemotherapy vs. Chemotherapy Herceptin
• Established benefit Herceptin
• Additional Chemotherapy Trials
• Robert Trial
• Taxol/Herceptin vs Taxol/Carbo/Herceptin
• BCIRG (101/102)
• Taxotere/Carbo/Herceptin
• Taxotere/Cisplatin/Herceptin

15
Pivotal TrialSlamon et al. 2001
R A N D O M I Z E
CHEMOTHERAPY (96)
1st line MBC
PACLITAXEL HERCEPTIN (92)

• Doxorubicin or Epirubicin plus cyclophosphamide
  patients.
• Paclitaxel for patients who had received adjuvant
  anthracycline.

16
Slamon et.al. 2001

• Results

17
Platinum/Herceptin Mechanism of action
Pt
Herceptin
Pt
Pt
DNA repair/platinum resistance
Pt
Pt
Herceptin
Pt
Pt
Pt
Pt
Pt
Pt
DNA repair, reversal of resistance
18
Robert Trial - Advanced Breast Cancer First Line
(2002)
TP Paclitaxel 175 mg/m2 q 21d
HER2 IHC N191
Trastuzumab until progression
TPC Paclitaxel 175 mg/m2/Carboplatin (AUC 6) q 21d
Trastuzumab until progression
Robert N, D, et al. San Antonio Breast Cancer
Symposium 2002
19
Estimated Progression-Free Survival
1.0
0.9
0.8
0.7
0.6
0.5
P0.007
Progression Free
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
18 8
45 33
25 11
TPC ( Progression Free) TP ( Progression
Free)
20
Summary of Herceptin Trials -Taxol
21
Marty Trial M77001
HER2-Positive MBC (IHC 3/FISH) n188
Two patients did notreceive study medication
Docetaxel100mg/m2 q3w x6
Docetaxel100mg/m2 q3w x6

Herceptin 4mg/kg i.v. then 2mg/kg/week until
disease progression
22
Response Rates M77001
23
Time to Disease ProgressionM77001
1.0 0.8 0.6 0.4 0.2 0
Herceptin Docetaxel Docetaxel alone
Estimated probability
p0.0001
6.1
10.6
0 3 6 9 12 15 18 21 24 27 30
Months
24
Overall Survival M77001
Herceptin docetaxel (n92) Docetaxel
alone/crossover (n45) Docetaxel alone (n49)
1.0 0.8 0.6 0.4 0.2 0
Estimated probability
19.1
30.5
24.5
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
25
Pilot Trials BCIRG 101/102
26
Metastatic Breast Cancer BCIRG 007
TH Docetaxel 100 mg/m2
Trastuzumab until progression
HER2 FISH
TCH Docetaxel 75 mg/m2 and Carboplatin AUC 6
N250 (160 accrued)
Trastuzumab until progression
27
Summary Herceptin Trials Taxotere
28
Advanced Breast CancerSummary

• Herceptin when added to chemotherapy
• Increase DFS
• Overall Survival
• Several chemotherapy agents
• Taxotere
• Taxol
• Vinorelbine
• Remaining questions
• Mechanisms of resistance
• Is H useful after progression
• Is H.CT as effective as H CT

29
Future ResearchHerceptin and Pertuzumab

• An IgG1 (k) humanized monoclonal antibody
• 95 human, 5 murine
• Produced in CHO (Chinese Hamster Ovary)
• Targets the HER2 receptor extra-cellular domain

30
Pertuzumab and Herceptin
Pertuzumab
Pertuzumab

• Protects against receptor shedding
• Has no effect on role of HER2 as a co receptor
• Inhibits HER2-mediated signaling pathways
• Applicable to breast cancer tumors thatover
  express HER2

• Does not prevent receptor shedding
• Has a major effect on role of HER2 as a co
  receptor
• Inhibits multiple HER-mediated signaling pathways
• Potentially applicable across a wide range of
  tumor types

31
Treatment Options for Women with HER2 Positive
Early Stage Breast Cancer

• The beginning the middle
• BUT certainly not the end

32
Benefits of Herceptin in Early Stage Breast
Cancer

• Evaluate if Herceptin adds benefit
• Chemotherapy in HER-2 positive Breast Cancer
• Evaluate the impact of Herceptin
• schedule (Sequential/Concurrent)
• different chemotherapy combinations
• Duration of Herceptin (1-2 years)
• Evaluate cardiac safety

33
NSABP B-31
Control AC?T
Arm 1
Arm 2
NCCTG N9831
Arm A
Investigational AC?TH
Arm B
Arm C
doxorubicin/cyclophosphamide (AC) 60/600 mg/m2
q 3 wk x 4
paclitaxel (T) 175 mg/m2 q 3 wk x 4
paclitaxel (T) 80 mg/m2/wk x 12
trastuzumab (H) 4mg/kg LD 2 mg/kg/wk x 51
34
Statistical Analysis

• Median follow-up 2.0 years
  (2.4 years on B-31/1.5 years on
  N9831)
• Primary endpoint DFS
• analyzed by intent-to-treat
• Secondary endpoints
• OS and Time to 1st Distant Recurrence
• Definitive analysis after 710 DFS events
• First interim analysis after 355 DFS events
• Stop trials only if equivalence is rejected at
  p0.0005 (2p0.001)

35
Disease-Free Survival
AC?TH
87
85
AC?T
75

67
N Events AC?T 1679 261 AC?TH 1672 134
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831
36
Forest Plot For Disease-Free Survival
ALL DATA
Age
60 50-59 40-49 39
Positive Negative
Hormone Receptor
4.1cm 2.1- 4.0 cm lt2.0 cm
Tumor Size
No. Positive Nodes
10 4-9 1-3 0
Protocol
N9831 NSABP B-31
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Hazard Ratio
37
Disease-Free Survival
B-31
N9831
AC?TH
AC?TH
87
87
AC?T
85
86
AC?T
78
74

66
68
N Events
N Events
AC?T 807 90
AC?T 872 171
AC?TH 808 51
AC?TH 864 83
HR0.45, 2P1x10-9
HR0.55, 2P0.0005
Years From Randomization
38
Time to First Distant Recurrence
100
AC?TH
AC-gtTH
90
90
90
90
90
90
90
AC?T
AC-gtT
80
81
81
81

74
74
74
70
N Events
N Events
AC?TH 1672 96 AC?T 1679 194
AC-gtT 1679 194
60
AC-gtTH 1672 96
HR0.47, 2P8x10-10
HR0.47, 2P8x10-10
50
0
1
2
3
4
5
B31/N9831
Years From Randomization
39
B-31/N9831 Survival
AC?TH
94
91
AC?T
92
87
N Deaths AC?T 1679 92 AC?TH 1672 62
HR0.67, 2P0.015
Years From Randomization
B31/N9831
40
Conclusions

• 52 decreased recurrence with concurrent vs.
  control treatment (P3X10-12) (joint analysis
  finding)
• 13 decreased recurrence with sequential vs.
  control treatment (P0.2936)
• 36 decreased recurrence with concurrent vs.
  sequential treatment (P0.0114)
• More follow up required

41
HERA Trial

• A randomized three-arm multi centre comparison
  of
• 1 year Herceptin
• 2 years Herceptin
• or no Herceptin
• in women with HER-2 positive primary breast
  cancer who have completed adjuvant chemotherapy

Martine J. Piccart-Gebhart, MD, PhD
42
HERA Trial
Women with HER-2 POSITIVE invasive breast cancer
IHC3 or FISH centrally confirmed
Surgery (neo)adjuvant chemotherapy (CT) ?
radiotherapy
Stratification
Nodal status, adjuvant CT regimen, hormone
receptor status and endocrine therapy, age, region
Randomization
Trastuzumab 8 mg/kg ? 6 mg/kg 3 weekly x 2 years
Trastuzumab 8 mg/kg ? 6 mg/kg 3 weekly x 1 year
Observation
43
Disease Free Survival
alive and disease free
44
DFS Subgroups
Hazard
Hazard
ratio
ratio
n
n
All
All
3387
0.54
3387
0.54
Nodal
status
Nodal
status
Any, neo
-
adjuvant chemotherapy
358
0.53
Any, neo
-
adjuvant chemotherapy
358
0.53
0 pos, no neo
-
adjuvant chemotherapy
1100
0.52
0 pos, no neo
-
adjuvant chemotherapy
1100
0.52
1
-
3 pos, no neo
-
adjuvant chemotherapy
1
-
3 pos, no neo
-
adjuvant chemotherapy
972
0.51
972
0.51
³
4 pos, no neo
-
adjuvant chemotherapy
953
0.53
³
4 pos, no neo
-
adjuvant chemotherapy
953
0.53
Adjuvant chemotherapy regimen
Adjuvant chemotherapy regimen
203
0.64
No anthracycline or taxane
203
0.64
No anthracycline or taxane
2307
0.43
Anthracycline, no taxane
2307
0.43
Anthracycline, no taxane
872
0.77
Anthracycline taxane
872
0.77
Anthracycline taxane
Receptor status/endocrine therapy
Receptor status/endocrine therapy
Negative
Negative
1674
0.51
1674
0.51
Pos no endocrine therapy
467
0.49
Pos no endocrine therapy
467
0.49
1234
0.68
1234
0.68
Pos endocrine therapy
Pos endocrine therapy
Age group
Age group
lt35 yrs
251
0.47
lt35 yrs
251
0.47
35
-
49 yrs
35
-
49 yrs
1490
0.52
1490
0.52
50
-
59 yrs
50
-
59 yrs
1091
0.53
1091
0.53
³
60 yrs
³
60 yrs
549
0.70
549
0.70
Region
Region
Europe, Nordic, Canada, SA, Aus, NZ
Europe, Nordic, Canada, SA, Aus, NZ
2430
0.58
2430
0.58
Asia Pacific, Japan
405
0.42
Asia Pacific, Japan
405
0.42
Eastern Europe
364
0.31
Eastern Europe
364
0.31
Central South America
188
0.90
Central South America
188
0.90
Favors
Favors
Favors
Favors
0
1
2
0
1
2
trastuzumab
observation
trastuzumab
observation
45
Secondary Efficacy Points
RFS
DDFS
OS
No of events
209
113
179
98
37
29
95 CI p value (logrank) 2y outcome ()
0.40-0.63 lt 0.0001 78.6 vs 87.2
0.40-0.66 lt 0.0001 81.8 vs 89.7
0.47-1.23 lt0.26 95.0 vs 96.0
46
Conclusions

• At one year median follow-up
• Trastuzumab given every 3 weeks
• prolongs DFS and RFS
• Trastuzumab significantly reduces the risk of
  distant metastases
• Trastuzumabs clinical benefits are independent
• patients baseline characteristics
• type of adjuvant chemotherapy

47
ConclusionsCardiac Toxicity
48
Questions to be addressed

• Should we deliver the Herceptin with the
  chemotherapy or sequentially ?
• What is the appropriate duration of Herceptin
  therapy?
• What is the price of Herceptin therapy?
• Cardiac toxicity
• Financial considerations

49
Timing of Herceptin Therapy
Concurrent
Sequential

• Preclinical data suggests Trastuzumab may amplify
  chemotherapys pro-apoptotic effects
• Concurrent chemotherapy plus Trastuzumab may be
  superior to sequential therapy (N9831)
• Cardiotoxicity concerns when Trastuzumab given in
  proximity to anthracyclines

• Preclinical data suggests Trastuzumab may amplify
  chemotherapys pro-apoptotic effects
• Trastuzumab following chemotherapy improves DFS
  and DDFS (HERA)
• Concurrent therapy a la N9831 associated with
  greater cardiotoxicity

50
Disease-Free Survival Control vs Sequential
AC -gt T -gt HEvents103
100 90 80 70 60 50 40 30 20 10 0
AC ? TEvents117

Hazard ratio0.87 Stratified logrank 2P0.2936
0 1 2 3 4 Years
51
Disease-Free Survival Concurrent vs. Sequential
AC -gtT H -gt H Events 53
100 90 80 70 60 50 40 30 20 10 0
AC -gtT -gtH events84

Stratified logrank P0.0114
0 1 2 3 4 months
52
Duration of Therapy

• Should we deliver the Herceptin with the
  chemotherapy or sequentially ?
• What is the appropriate duration of Herceptin
  therapy?
• What is the price of Herceptin therapy?
• Cardiac toxicity
• Financial considerations

53
Duration of Herceptin Therapy

• Unknown (HERA 1 vs. 2y pending)
• Current data supports one year of therapy
• Current data supports initiation of therapy
• up to six months following completion of therapy
• Could we get by with less Trastuzumab
• 6 months?
• Concurrently with chemotherapy ?

54
The Footnotes of JusticeThe costs of our
success
55
Price of Success

• Should we deliver the Herceptin with the
  chemotherapy or sequentially ?
• What is the appropriate duration of Herceptin
  therapy?
• What is the price of Herceptin therapy?
• Cardiac toxicity
• Financial considerations

56
Toxicity of Therapy

• Cardiac toxicity (CHF) can be a consequence of
  using Trastuzumab close to doxorubicin
• Rate
• 0-0.5 for AC-gtT
• 3.3-4.3 for AC-gtTH (N9831/B-31)
• 0.5-2.2 post-chemotherapy (HERA/N9831)
• Degree of reversibility is uncertain
• While benefits far outweigh the risk, the price
  is real and should be discussed with patients.

57
BCIRG 006 Optimal Chemotherapy
BCIRG 006
AC-T
AC-TH
HER2 FISH
N3150
TCH
58
Conclusions-Efficacy Results

• Both AC-TH and THC arms have statistically
  significantly improved DFS in comparison to
  standard treatment
• AC-T (HR .49 p 0.00000048)
• TCH ( HR .61 p 0.00015)
• At this point in time there is no difference for
  OS
• AC-TH and TCH
• At this analysis there is insufficient
  information to evaluate OS.

59
HER2 and TOPO II in BCIRG 006 2120 of 3222
patients analyzed
17 q 12
17 q 21.1
17 q 21.2
HER2 Core region
N2120
1285 pts (60)
91 pts (4)
60
DFS Topo II Co-Amplified vs Non Co-Amplified
1.0
0.9
Co-Amplified
0.8
Disease Free
Non Co-amplified
0.7
Patients
Events
Topo II
744
57
Co-Amplified
Logrank Plt0.001
1376
191
Non Co-amplified
0.6
0.5
1
2
3
4
5
0
Year from randomization
61
DFS Co-Amplified Topo II
1.0
AC-gtTH
AC-gtT
0.8
Disease Free
TCH
Patients
Events
Treatment
AC-gtT
227
23
Logrank P 0.24
265
13
AC-gtTH
252
21
TCH
0.6
0.5
0
6
12
18
24
30
36
42
48
54
Months
62
DFS Non Co-Amplified Topo II
1.0
0.8
Disease Free
AC-gtTH
TCH
Patients
Events
Treatment
0.6
458
92
AC-gtT
472
45
AC-gtTH
Logrank P lt0.001
AC-gtT
446
54
TCH
0.0
0
6
12
18
24
30
36
42
48
54
Months
63
LVEF Declines by NYHA Class
Implication Trastuzumab per se is not
cardiotoxic it becomes so when it keeps company
with DOX
64
SummaryCardiac Concerns

• Adjuvant Trastuzmab after anthracyclines leads to
  an approximate 3-year cumulative incidence rate
  of 2.5-3.5 of significant cardiac concerns.
• The cardiac function in the majority of patients
  who developed CHF improved following medial
  therapy.
• There is a trend towards increased risk of
  cardiac toxicity with increased patient age.
• There appears to be NO correlation between
  radiation therapy and risk of cardiac toxicity.

65
Financial ConcernsClinical Implications

• Who should be tested for HER2 ?
• What test should be used ?
• Who should we treat ?
• How long should we treat with herceptin ?
• What are the future implications ?

66
Who should be tested?Clinical Impact

• Metastatic disease
• Must request original blocks for testing
• Blocks may be from another institution
• Inadequate or poorly prepared sample
• Lost blocks or inadequate material
• Delay in discussion of treatment options
• Influences systemic
• Clinical trials options

67
Who should be tested?

• Initial testing
• Approximately 20 of tumors Her2 positive
• Risk of recurrence of 30 or greater
• node positive breast cancer
• high risk node negative breast cancer
• LABC/inflammatory breast cancer
• (core biopsy)

68
What test should be used ?

• IHC for screening
• Consistency between labs
• PPV (3 ) 91.6 NPV (0/1) 97.2
• 2 should be confirmed with FISH
• FISH
• Confirmation of HER 2
• Reagent cost 140 vs. 10
• Longer testing time 36 hours
• Interpretation 7 minutes vs 45 minutes
• CISH (Chromogenic In Situ Hybridization)

69
Current Implications

• Reimbursement to hospitals through the NDFP
• For Herceptin
• ??Supportive services RNs/pathology
• 2005/06
• 17 million dollars provincially
• 2006/07
• 53 million dollars provincially
• Assuming Herceptin given for one year

70
Conclusions

• Human epidermal growth factor receptor 2 (HER2)
  is a key contributor to normal cell growth and
  differentiation.
• When overexpressed it is associated with
  neoplastic transformation of cells.
• HER-2 positive malignancies have a more
  aggressive disease course and a worse clinical
  outcome.
• Herceptin a monoclonal antibody binds
  specifically to the extracellular domain of the
  HER2 protein and results in improved DFS and OS
  in the adjuvant as well as metastatic settings.