Transcript Cancer du sein & Herceptine

Leslie Willaume
Camille Freyburger
Thibaut Desquemack
Sandrine Couturier
Fouad Ziani
17 July, 2015
1
SUMMARY
I. What is Breast Cancer?
II. Her-2 Cancer
III. Efficacy of Trastuzumab
IV. Effectiveness of Trastuzumab
V. Cardiotoxicity
VI. Her-2 testing
VII.Cost-effectiveness analysis
VIII.Future perspectives
17 July, 2015
2
I. Breast cancer
A. Breast anatomy
B. Cancer genesis
C. Epidemiology
D. Risk factors
E. Screening
F. Therapeutic means
G. Prognosis factors
17 July, 2015
3
A. Breast anatomy
• 15 to 20 sections
called lobes, with
many smaller
sections called
lobules
• Each section is
connected by
thin tubes called
ducts
• Filled up with fat
tissue
17 July, 2015
4
B. Cancer genesis
17 July, 2015
5
C. Epidemiology
• The most common type of cancer in women
• 1 in 10 woman develops the disease in her lifetime
• Rare < 30, frequent between 60 & 65
• European Incidence in 2006: 3.2 M new casses.
• 1rst cause of mortality before 65
17 July, 2015
6
D. Risk factors
• Woman
• Age
• Hormonal factors:
• premature puberty
• late 1rst pregnancy
• late menopause…
• In-situ carcinoma
• Familial factors:
• personal or familial previous history of breast cancer
• gene mutation: BRCA1, BRCA2
• Environmental factors:
• high standard of living
• radioactivity exposure
• Histologic factors:
• atypic canalar hyperplasia
• intralobular neoplasia
17 July, 2015
7
E. Screening
• Breast self
examination
• visual checkout
• palpation (breast + axillary areas)
• Medical lookup
• interrogation
• physical examination
( bilateral, comparative)
17 July, 2015
8
E. Screening
• Mammography
-special x-ray picture of
the breast
-a large percentage of the
cancer is detected when
the tumors are 2
centimeters or smaller
17 July, 2015
9
E. Screening
• Ultrasound
-Determine whether a
lump is a cyst (containing
fluid) or a solid mass.
-Precisely locate the
position of a tumor
to guide the physician
during a biopsy or
aspiration
procedure
17 July, 2015
Ultrasound image showing
dark irregular mass
10
E. Screening
• Magnetic Resonance
Imaging
-Make a series of detailed
pictures of areas inside the
body
17 July, 2015
11
E. Screening
• Biopsy
-physical examination of
tissue extracted from the
breast (needle aspiration biopsy
a cross-section of a duct.
or surgical biopsy)
-examine it under a
microscope
breast tissue
becomes malignant
-check for cancerous cells
17 July, 2015
+ immunologic tests
12
a duct lined by cancer cells
E. Screening
• Galactography
(=ductography)
-mammographic
technique
-involves injection of a
contrast agent (dye) into a
milk duct
17 July, 2015
galactogram
13
F. Therapeutic means
• Selection of the appropriate therapeutic
approach depends on:
•
•
•
•
the location and size of the tumor
breast size, appearance on the mammogram
the extent of change in the tissues
the preference of the patient and treating doctor
• Surgery:
• The commonest modality of cancer treatment
• Lumpectomy
• Mastectomy
17 July, 2015
+Axillary lymph node dissection
14
F. Therapeutic means
• Radiotherapy:
• high-energy rays
• stop cancer cells from growing and dividing
• destroy any remaining breast cancer cells in the breast, chest
wall, or axilla area after surgery
• occasionally, before surgery to shrink the size of a tumor
• Chemotherapy:
• destroy cancer cells by stopping them from growing or
multiplying
• monotherapy / polytherapy
17 July, 2015
15
F. Therapeutic means
• Hormone therapy:
• cancer that is hormone-receptor-positive
• cancer treatment that removes hormones or blocks their action
and stops cancer cells from growing
• Targeted therapy:
• Anti-HER2 (ex: Herceptin®)
17 July, 2015
16
G. Prognosis factors
•
•
•
•
•
•
•
Age
Size of tumor (>2cm)
Oestrogen receptor-negative status of the tumor
Positive axillary node status
Presence of undifferentiated cells in the tumor
Presentation with metastasis
HER2+
17 July, 2015
17
II. HER2 cancer
A. Definition of HER2
B. Oncogenesis mechanism
C. Forecast / predictive factors
D. Characterisation test to show HER2
presence
E. Potential therapeutic target
17 July, 2015
18
HER2 = c-erbB-2
A. Definition
• Proto oncogène HER : gene of epidermal
growth factor's human receptor (HER2 ou cerbB-2)
• Allow the development and regulation of the
growth mammaire
• Presence: breast, ovary, endometer
• An important forecast and predictive factor for
breast cancer
17 July, 2015
19
HER 2 = c-erbB-2
A. Definition
• Schéma page 8
17 July, 2015
20
HER 2 = c-erbB-2
A. Definition
• Schéma page 11, expliquer
17 July, 2015
21
B. oncogenesis mechanism
17 July, 2015
22
B. oncogenesis mechanism
Consequences about the
amplification of HER2 on human
celles with breast cancer
Healthy human cells ( HER2 -)
gene (become HER2 +) =>
transfection by HER2
- increase of ADN's production: 50 to 75%
- increase of cell's growth: 30 to 50%
- increase of growth in Agar: 225%
- increase of metastasic potential: 220%
17 July, 2015
23
C. Forecast and predictive farctor
• Forecast factor: connection
- amplification of HER 2
- ganglionic attack
- shortening of survival without relapse or of gloabal
survival
• Predictive factor:
- About the answer of hormone treatment and
chemotherapy
- Predictive association for HER 2:
hormonotherapy: résistance
anthracyclines: increase in chemosensibility
other chemotherapy: no conclusion
17 July, 2015
24
D. Characterisation to show
HER2 presence
• ICH: Immunochemohistology
-Goal : identify, locate, +/-quantify, a tissular constituant in situ with
immunologic reaction like Ac/ Ag
- Advantage: -a good sensitivity
- practice in laboratory's hospital
- several applications
- Failing : - decrease in positivity with the time
- chirurgical taking
- should have some quality inspections
-sensitivity: O,92
17 July, 2015
25
17 July, 2015
26
D. Characterisation to show HER2
presence
17 July, 2015
27
D. Characterisation to show HER2
presence: kit DAKO
Score
0
Evaluation
Negative
Type of detection
No detection
1+
Negative
Slightly or rare
2+ Slightly positive
3+
Hightly positif
17 July, 2015
Slightly to moderate
Intense, complete
of all the membrane 28
D. Characterisation to show HER2 presence
Herceptest® DAKO: 2 Mabs / internal domain of the HER2
Protein
“0” Score negative
“1+” : neg
“2+” Score positive
17 July, 2015
“3+” Score positive
29
D. Characterisation to show HER2
presence
• Fish: Fluorescence In Situ Hibridization:
- Goal: detection of nucleotidic sequence on ADN, by an
hybridization of ADN's known sequence ( characterized
by probe ) with ADN target.
- 3 stages:
-> Hybridization
-> Revelation
-> Observation
- Several applications
- Sensitivity: 0,98
17 July, 2015
30
D. Characterisation to show HER2
presence
17 July, 2015
31
D. Characterisation to show HER2
presence
- Revelation: Ab with fluorescent molecular places
recognize the probes
17 July, 2015
32
17 July, 2015
33
C/ Characterisation test to show
HER2 presence
• CISH:Chromogenic in situ hybridization
- Goal: detection of nucléotidic sequence on ADN,by an
hybridization of ADN's known sequence ( caracterize by
probe ) with ADN target.
- Same mechanism of the FISH method
- Amplification's characterisation with peroxydase reaction
- Failing: long and difficult protocol
- Sensitivity: 0,85
17 July, 2015
34
C/ Characterisation test to show
HER2 presence: CISH
17 July, 2015
35
D. Characterisation to show HER2
presence
• Elisa ( Enzyme-Linked Immunosorption
Assay)
- Plasmatic screening
- immunoenzymatic dosage on solid support
- Goal: detect the presence of Ab or Ag in a sample
- Advantages: - Easy
- Cheap
- Several applications
- Blood samples
- Failings: - limited due to the disponibility of Ab
17 July, 2015
36
D. Characterisation to show HER2
presence
• Mechanism: sandwich method
17 July, 2015
37
E. Potential therapeutic target?
• Extracellular receptor = target for new
therapeutic of specific targeting
- with monoclonal Ab
17 July, 2015
38
II. HER2 cancer
A. Definition of HER2
B. Oncogenesis mechanism
C. Forecast / predictive factors
D. Characterisation test to show HER2
presence
E. Potential therapeutic target
17 July, 2015
39
HER2 = c-erbB-2
A. Definition
• Proto oncogène HER 2: gene of epidermal
growth factor's human receptor (HER2 ou cerbB-2)
• Allow the development and regulation of the
growth mammaire
• Presence: breast, ovary, endometer
• An important forecast and predictive factor for
breast cancer
17 July, 2015
40
HER 2 = c-erbB-2
A. Definition
• Schéma page 8
17 July, 2015
41
HER 2 = c-erbB-2
A. Definition
• Schéma page 11, expliquer
17 July, 2015
42
B. oncogenesis mechanism
17 July, 2015
43
B. oncogenesis mechanism
Consequences about the
amplification of HER2 on human
celles with breast cancer
Healthy human cells ( HER2 -)
gene (become HER2 +) =>
transfection by HER2
- increase of ADN's production: 50 to 75%
- increase of cell's growth: 30 to 50%
- increase of growth in Agar: 225%
- increase of metastasic potential: 220%
17 July, 2015
44
C. Forecast and predictive farctor
• Forecast factor: connection
- amplification of HER 2
- ganglionic attack
- shortening of survival without relapse or of gloabal
survival
• Predictive factor:
- About the answer of hormone treatment and
chemotherapy
- Predictive association for HER 2:
hormonotherapy: résistance
anthracyclines: increase of chemosensibility
other chemotherapy: non concluante studies
17 July, 2015
45
D. Characterisation to show
HER2 presence
• ICH: Immunochemohistology
-Goal : identify, locate, +/-quantify, a tissular constituant in situ with
immunologic reaction like Ac/ Ag
- Advantage: -a good sensitivity
- practice in laboratory's hospital
- several applications
- Failing : - decrease in positivity with the time
- chirurgical taking
- should have some quality inspections
-sensibility: O,92
17 July, 2015
46
17 July, 2015
47
D. Characterisation to show HER2
presence
17 July, 2015
48
D. Characterisation to show HER2
presence: kit DAKO
Score
0
Evaluation
Negative
Type of detection
No detection
1+
Negative
Slightly or rare
2+ Slightly positive
3+
Hardly positif
17 July, 2015
Slightly to moderate
Intense, complete
of all the membrane 49
D. Characterisation to show HER2 presence
Herceptest® DAKO: 2 Mabs / internal domain of the HER2
Protein
“0” Score negative
“1+” : neg
“2+” Score positive
17 July, 2015
“3+” Score positive
50
D. Characterisation to show HER2
presence
• Fish: Fluorescence In Situ Hibridization:
- Goal: detection of nucleotidic sequence on ADN, by an
hybridization of ADN's known sequence ( characterized
by probe ) with ADN target.
- 3 stages:
-> Hybridization
-> Revelation
-> Observation
- Several applications
- Sensitivity: 0,98
17 July, 2015
51
D. Characterisation to show HER2
presence
17 July, 2015
52
D. Characterisation to show HER2
presence
- Revelation: Ab with fluorescent molecular places
recognize the probes
17 July, 2015
53
17 July, 2015
54
C/ Characterisation test to show
HER2 presence
• CISH:Chromogenic in situ hybridization
- Goal: détection of nucléotidic sequence on ADN,by an
hybridization of ADN's famous sequence ( caracterize by
probe ) with ADN target.
- Same mechanism of the FISH method
- Amplification's caracterisation with peroxydase reaction
- Failing: long and difficult protocol
- Sensitivity: 0,85
17 July, 2015
55
C/ Characterisation test to show
HER2 presence: CISH
17 July, 2015
56
D. Characterisation to show HER2
presence
• Elisa ( Enzyme-Linked Immunosorption
Assay)
- Plasmatic screening
- immunoenzymatic dosage on solid support
- Goal: detect the presence of Ab or Ag in a sample
- Advantages: - Easy
- Cheap
- Several applications
- Blood samples
- Failings: - limited due to the disponibility of Ab
17 July, 2015
57
D. Characterisation to show HER2
presence
• Mechanism: sandwich method
17 July, 2015
58
E. Potential therapeutic target?
• Extracellular receptor = target for new
therapeutic of specific targeting
- with immunisation
- with monoclonal Ab
17 July, 2015
59
HERCEPTIN: In therapeutic arsenal
• Breast cancer HER2+
• Monotherapy, for patients who received a chemotherapy
with an Anthracyclin or a taxan.
• In association with placlitaxel for metastatic breast cancer
when a treatment by anthracyclin can’t be consider
• In association with docetaxel for metastatic breast cancer no
treated.
17 July, 2015
60
HERCEPTIN:
EFFICACY
17 July, 2015
61
HERCEPTIN: efficacy
• 2 studies.
.
• H0648g: evaluate HERCEPTIN+ chemotherapy Vs. chemotherapy
alone.
• M77001: compare HERCEPTIN+ docetaxel Vs. docetaxel alone.
17 July, 2015
62
Etude H0648g
• 449 women with no pretreated breast cancer by a chemotherapy.
• Compare herceptin + paclitaxel Vs. paclitaxel alone.
• Main criterion : time to recurrence.
• Secondary criterion : response rate, response median duration, time until
failure of the treatment, overall survival, quality of life.
17 July, 2015
63
Etude H0648g: results
Time to recurrence
Herceptin+paclitaxel
paclitaxel
6,9 Mois
2,7 Mois
HER2 3+
Time to recurrence
7,1 Mois
3 Mois
Response rate
49%
17%
Overall survival
24,8 Mois
17,9 Mois
17 July, 2015
64
Etude M77001
• HERCEPTIN +docetaxel Vs. Docetaxel for wom withen HER2 3+ metastatic
breast cancer who don’t receive chemotherapy .
•Main criterion: response rate (complete or partial)
•Second criterion: duration of response, time to recurrence, overallsurvival.
•Age median des patientes: 53 à 55 ans selon les groupes.
•186 patients: 92 for HERCEPTIN +docetaxel group, 94 for docetaxel group.
17 July, 2015
65
Etude M77001: results.
Herceptin + Docetaxel
Docetaxel
Response rate
61%
34%
Response median
duration
11,4 mois
5,1 mois
Time to recurrence
10,6 mois
5,7mois
Mediane de survie
30,5 mois
22,1 mois
17 July, 2015
66
Efficacy: conclusion.
•HERCEPTIN, is used alone after failure of other treatment or in association with
other drugs.
• Thanks to Herceptin, we can see:
- a longer free desease period until tumoral growth
- a increase of survival.
• No amelioration of quality of life..
17 July, 2015
67
SMR HERCEPTIN
SMR important
But:
Gentle impact on mortality.
Low impact of HERCEPTIN on public health.
17 July, 2015
68
ASMR HERCEPTIN
HERCEPTIN+ Taxane (Placlitaxel ou Docetaxel)  ASMR level II(important)
ASMR not determinated when used in 3rd intention in monotherapy.
17 July, 2015
69
HERCEPTIN: Effectiveness
17 July, 2015
70
HERA STUDIES
Observation
Studies
HERA
n= 5090
Any chemotherapy
Trastuzumab: q3w 1 year
Trastuzumab: q3w 2 year
•First endpoint: disease free survival
•1-year median follow-up
17 July, 2015
71
HERA studies
• 46% lower risk of a first
event than patients under
observation.
•The majority of first events
were distant metastases the
incidence of which was
significantly lower with
trastuzumab
17 July, 2015
72
Number of
event
17 July, 2015
Frequency of efficacy
end point events in the
Herceptin® Adjuvant (HERA)
73
NSABP B-31 and NCCTG
N9831 combined studies.
NSABP B-31
n=2030
Paclitaxel q3w X 12
Anthracyclines X 4
Paclitaxel q3w X 12 or P q1w X 12 +T 1w X 52
Studies
Paclitaxel q3w X 12
NCCTG N9831
n=3505
Anthracyclines X 4
Paclitaxel q3w X 12
Trastuzumab q1w X52
Paclitaxel q3w X 12 + T q1w X 52
• First endpoint: Deasease free survival.
• Second endpoint: survival to distant recurrence.
• 2 years median follow up.
17 July, 2015
74
•Risk of distant recurrence:
53% lower for patient who
received Trastuzumab+
Paclitaxel concurrently.
•Better DFS for patient who
received Trastuzumab and
paclitaxel concurrently than
sequentially.
Survie avant progression (%)
NSABP B-31 and NCCTG N9831: results.
AC  TH
87%
85%
ACT
78%
67%
HR=0.48
Années après randomisation
17 July, 2015
ACT
ACTH
N
1679
1672
Events
261
134
75
BCIRG STUDY
AC X 4
Studies
BCIRG
n=3222
AC X 4
Docetaxel q3w X 4
(Docetaxel q3w X 4) + (T q1w X 12)
(Docetaxel+ carboplatin q3w X 6)+( T q1w X 18)
T q3w X 13
T q3w X 13
•Median follow up: 2 years.
•Primary end point: DFS
•Secondary endpoints : overall survival, toxicity, marker for predicting efficacy:
analysis of coamplification of the topoisomerase-IIα gene.
17 July, 2015
76
BCIRG 006: study
•At a 2-year median follow-up,
significantly longer DFS compared
with the nontrastuzumab control
arm.
•Patients who received trastuzumab
concurrently with docetaxel
following treatment with AC
experienced a 51% lower risk of
relapse than those receiving
docetaxel alone
• These results suggest that it may be possible to omit adjuvant
anthracyclines in some women with HER-2-positive breast cancer without
17 July,
2015
loss
of efficacy.
77
FIN HER study
D q3w X3 or V q1w X 8
Studies
FINHER
n=232/1010(HER2+)
D q3w X3 or V q1w X 8 + T q1w X 9
CEF q3w X 3
CEF q3w X 3
•Median follow up: 3 years
•First end point: recurrence free survival
•Second end point: time to distant recurrence
adverse events
overall survival
17 July, 2015
79
FIN HER study: results
Recurrence free survival
significantly improved (58%)
No statistically significant
survival benefit yet
demonstrated.
17 July, 2015
80
Summary of
trastuzumab efficacy in
early breast cancer
17 July, 2015
81
Sensitivity Analysis
17 July, 2015
82
Cardiotoxicity
17 July, 2015
83
Therapy generally well tolerated
Phase III:
Elevated incidence of cardiotoxicity which was
not apparent in preclinical & early stage studies.
Generally reversible & manageable with standard medical
treatment.
17 July, 2015
84
Possible mechanism of trastuzumab
induced cardiac toxicity
Role of Neuregulin/ErbB
signalling network:
Cardiomyocytes survival
Cell differentiation
Protein Synthesis
Angiogenesis
Formation of heart valves
17 July, 2015
85
Anthracyclines + Trastuzumab :
The Forbidden Cocktail
Clinical studies:
“Trastuzumab acts as a molecular modifier of anthracyclin
induced cardiotoxicity and associated heart failure”
Loss of cardiac Cells
 of Left Ventricular Ejection
Fraction
17 July, 2015
86
Anthracyclines + Trastuzumab the
forbidden cocktail
Pathological stimuli  biomechanical stress,
Cardiomyocytes death pathways activation
Concomitant activation of cardiomyocytesurvival pathways
Trastuzumab: inhibition of ErbB2 receptor
loss of the neuregulin-dependent pathways
17 July, 2015
87
Cardiac data analysis
Pivotal trials
No cardiac
monitoring
Retrospective
analysis
Latest trials
Formal cardiac
monitoring
Prospective
analysis
17 July, 2015
88
Retrospective analysis
17 July, 2015
89
Retrospective Analysis of Cardiac Events
Study
H0650g
H0649g
Trastuzumab
1st line
monotherapy
Trastuzumab
2nd or 3rd
line
monotherapy
Trastuzumab
+
Paclitaxel
n=114
n = 222
Symptomatic
heart failure
2.6%
NYHA III-IV
< 1%
protocol
17 July, 2015
Prior chemotherapy
H0648g
No Prior chemotherapy
Paclitaxel
Trastuzumab
+
Anthracycline
Anthracycline
n=91
n=95
n=143
n=135
8.5%
8.8%
4.2%
28%
9.6%
5%
4%
1%
19%
3%
90
New York Heart Association classification
17 July, 2015
91
Retrospective Analysis of Cardiac Events
Study
H0650g
H0649g
protocol
Trastuzumab
1st line
monotherapy
Trastuzumab
2nd or 3rd
line
monotherapy
Trastuzumab
+
Paclitaxel
Paclitaxel
n=114
n = 222
n=91
Symptomatic
heart failure
2.6%
8.5%
NYHA III-IV
< 1%
5%
17 July, 2015
Prior chemotherapy
H0648g
No Prior chemotherapy
Trastuzumab
+
Anthracycline
Anthracycline
n=95
n=143
n=135
8.8%
4.2%
28%
9.6%
4%
1%
19%
3%
92
Retrospective analysis comment
Retrospective analysis
Unknown cardiac data quality
It is possible that:
Some case reports that appeared to demonstrate heart failure events
were misclassified
The baseline cardiac function was not routinely assessed in these
patients.
It is possible, therefore, that the incidence of cardiac dysfunction was
over or under reported in this analysis.
17 July, 2015
93
Prospective analysis
17 July, 2015
94
Cardiotoxicity Data
Trial
NSABP B-31
NCCTG N9831
BCIRG-006
17 July, 2015
Treatment
Asymptomatic
AC→Paclitaxel
≥10% LVEF
17%
AC→Paclitaxel +Herceptin
34%
4.1%
AC→Paclitaxel
6.7%
0.3%
AC→Paclitaxel +Herceptin
17.3%
3.5%
AC→Paclitaxel→Herceptin
14.2%
2.5%
AC→Docetaxel
8%
0.29%
AC→Docetaxel+Herceptin
17.3%
1.59%
Docetaxel+Carboplatin+Herceptin
9%
0.38%
Heart failure
class III/IV
0.8%
95
Cardiac safety:
impact on patient
management
17 July, 2015
96
Recommendations :
Prior to trastuzumab therapy
•
•
Risk factors evaluation  careful history and a physical examination
 LVEF > 55%: trastuzumab treatment can be started.
During trastuzumab therapy:
• Cardiac screening at least on every hospital visit.
• Any cardiac failure symptoms  Further diagnostic
Management of cardiac dysfunction when associated with use of trastuzumab
• Pharmacological treatment should be similar to that in patients with systolic
dysfunction of any other aetiology.
17 July, 2015
97
Should trastuzumab treatment be
continued?
Should be considered:
The prognosis for each patient on an individual basis and balance
potential cardiotoxicity against clinical benefit.
The median survival time:
Those with bone-only disease
Patients with visceral disease


18–30 months
6–13 months
The 1-year mortality
Patients with severe heart failure (III,IV)
Breast cancer patients with distant metastases


9 – 12 %
16 %.
Patients with metastatic disease  the overall benefit
outweighs the risk
17 July, 2015
98
VI. Testing HER 2- neu
status:
Sensitivity: avoiding false negative results
Specificity: eliminating false positive results
A.INTRODUCTION: What are the
differences between IHC and FISH?
B.EMEA guidelines
C.Study: Concordance between local,
central and reference laboratory
17 July, 2015
99
A. INTRODUCTION:
IHC or FISH?
17 July, 2015
100
Comparison of IHC & FISH
for HER2 Testing
IHC
FISH
Assay measures protein expression Assay measures gene amplification
using specific antibodies that precisely
localize site of expression
Test is highly sensitive
Test is highly sensitive
Specificity is moderately high (with
current methods)
Specificity is high
Frozen or paraffin-embedded tissue
can be used
Paraffin-embedded tissue can be used
Some of the necessary equipment is
Most of required equipment is
not commonly found in hospital
commonly found in hospital laboratory laboratory setting
setting
17 July, 2015
101
Current scheme
Breast cancer tissue
FISH
IHC
+
-
3+
2+
1+ / 0
TRASTUZUMAB
NO
TRASTUZUMAB
TRASTUZUMAB
FISH
NO
TRASTUZUMAB
17 July, 2015
+
-
TRASTUZUMAB
NO TRASTUZUMAB
102
B. EMEA GUIDANCE
• To date, two IHC assays, three FISH assays
and one CISH assay are commercially
available.
• Good agreement between the different
methodologies.
• In nearly all (24/25) studies the results of
IHC and FISH were comparable
17 July, 2015
103
B. Local vs cental and reference
laboratories HER-2 testing
concordance
Perez, JCO, July 2006
• Study NCCTG N9831
• Originally: Patients eligible = HER2+ by
IHC or FISH by either local labs.
• Modification 2002:
• Central lab. = testing mandatory
• Reference Lab. = additional testing of discordant
cases
17 July, 2015
104
2547-12=2535 cases
277 (8%)false positives
17 July, 2015
105
1. Local / Central
Test at local lab
HercepTest
Specimens
confimed by
central
testing
1803
Test in
central lab
Unconfirmed
cases by central
lab (%)
HercepTest
18,4
25
Non-HercepTest
636
HercepTest
FISH
813
FISH
11,9
• Considerable proportion of cases unconfirmed
• HercepTest/nonHT
standardisation IHC
17 July,
2015
scoring
criteria
106
17 July, 2015
107
2. Central / Reference
Test at central lab
HercepTest
FISH
Specimens Test in ref lab Unconfirmed
confimed by
cases by central
ref testing
lab (%)
300 HercepTest
5,7
271
FISH
4,8
• Discordant cases retested: high level of agreement
• Active quality assurance and control program =
better STANDARDIZATION
17 July, 2015
108
VII. Cost-effectiveness
analysis
A. NICE Recommendations
B. Cost-effectiveness of HER-2 testing
strategies
17 July, 2015
109
A. NICE RECOMMENDATIONS
Evidence
NICE was established
in April 1999 to:
Size of
Value of
• Reduce variation
in practice
effect
effect
• Improve quality
• Encourage innovation and accelerate uptake
Service
• Help make better use
of the budget
impact
17 July, 2015
Judgements
110
Manufacter’s data:
• Cost per additional QALY gained
= £ 2 400
Review group data:
QALY gained underestimated?
•Alteration of the proportion of
women receiving trastuzumab
•Shortened the duration of benefit
obtained from trastuzumab
•Cost QALY gained
= £ 18 000 [16 000 – 33 000]
17 July, 2015
111
HER-2 Testing strategies
Elkin, JCO, March 2004
IHC: $ 85
FISH: $ 400
Outcomes:
• QALYs
• Lifetime cost*
• ICER: Incremental Cost-Effectiveness
Ratio
* Cost : HER2 testing, chimiotherapy, travel, monitoring, oncologist…..
17 July, 2015
112
17 July, 2015
QALY
COST $ ICERQALY/$
1,28
43 300
1,37
79 180
1,37
54 700 145 400
1,34
51 230
1,36
57 460
1,36
54 060
1,36
53 700 125 100
113
ICER
Added cost to the added QALYs comparing each
strategy to the next less costly one
Exemple: $ / QALY
FISH alone
54738 - 43314
= 145000
1,37 – 1,28
17 July, 2015
114
Discussion
• The higher the false-positive rate of IHC, the
more cost-effective it is to use FISH alone
• Recent technological developments could
affect cost and accuracy of these tests
•If you are willing to spend the money to use
anything at all, even to use Herceptin in the
first place, you should probably be willing to
use the expensive test to be sure that you get
the drug to the right patients.
17 July, 2015
115
• High
cost-effectiveness
• High
pression by the ratio
media
compared to other therapies
•Increase of new drugs that are expensive
• <$5,000 : Beta-blockade post MI, high risk
• $5,000-10,000 : Statin therapy, prior heart disease
• $15,000-20,000 : AIDS drugs, Genotypic resistance testing for
treatment failures with HIV
• $50,000-100,000: Dialysis for end-stage renal disease
• >$100,000: Coronary angiography post MI, low risk , Cervical
cancer screening every year (vs. 2 yrs), FISH test and Herceptin
for Stage IV breast cancer
17 July, 2015
116
Future perspectives
17 July, 2015
117
• New studies are ongoing to:
 Incorporate anthracyclines associated with
lower cardiotoxicity, such as epirubicin and
liposomal doxorubicin.
 Shorten the duration of trastuzumab therapy.
 Testing other combinations
17 July, 2015
118
TYKERB® Lapatinib
A Novel Tyrosine Kinase Inhibitor
Targets both ErbB1 (EGFR) and ErbB2 (HER-2)
Small molecule, works inside the cell
Once-daily oral treatment for cancer
MAbs
Bind to extracellular receptor
May be inactive for truncated
receptors
IV
17 July, 2015
Small molecule TKIs
Inhibit intracellular kinase domain
Active for truncated receptor
Oral
119
Synergistic with Herceptin
33% response rate in monotherapy in Herceptin-naïve patients
Apparently low incidence of cardio toxicity, 1.5%
Potential benefit in patients with brain metastases
17 July, 2015
120
Rationale for Herceptin® + TYKERB®
Combination
Hypothesis:
• Achieve “total blockade” of ErbB2 signal transduction
• May overcome Herceptin resistance/failure
Preclinical data:
• Synergistic activity in ErbB2+breast cancer cell lines
Phase I data:
• Results showed a 26% response rate
17 July, 2015
121
Herceptin and ARIMIDEX™ combination
“Postmenopausal women with hormone-sensitive+HER2-positive* tumours:
 The addition of Herceptin to 'Arimidex' keeps cancer under control for
significantly longer than hormonal therapy alone”
17 July, 2015
122
Pending questions related to
HERCEPTIN®
1. Is there an optimal time to initiate trastuzumab?
2. Can we do as well with less trastuzumab or better with more trastuzumab
3. Who does not benefit from trastuzumab?
4. Can we design ‘softer’ and safer chemotherapy regimens?
5. Can we avoid chemotherapy in selected women?
6. Can we further improve results with other targeted therapies?
17 July, 2015
123
Merci pour votre
attention...
17 July, 2015
124