her2-neu status en adjuvante chemotherapie bij het mammacarcinoom m. bontenbal erasmus mc - daniel...
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HER2-neu status en adjuvante HER2-neu status en adjuvante chemotherapie bij het mammacarcinoomchemotherapie bij het mammacarcinoom
M. Bontenbal
Erasmus MC - Daniel den Hoed Kliniek
19 november 2004
Chemotherapy in breast cancer
Emperical, based on conclusions of studies
Extrapolated for the individual patiënt
Leads to inefficient and potentially toxic treatment for
many to benefit a few
Cardoso, Int J Oncol 2004, 24, 201
Challenge
Select the best drug(s)
for a particular patiënt
with a biologically specific tumor
Cardoso, Int J Oncol 2004, 24, 201
16-10-2001
HER2 in breast cancer
Slamon D et al. Science 1987
HER2 oncoprotein overexpression
HER2 oncogeneamplification Shortened median survival
HER2 overexpressing 3 yearsHER2 normal 6–7 years
Method Target FDA-approved Silde-based
IHC Protein Yesa Yes
FISH Gene Yesa Yes
CISH Gene No Yes
Southern blot Gene No No
RT-PCR mRNA No No
Microarray TPb mRNA No No
Tumor ELISA Protein No No
Serum ELISA Protein Yesc No
a For prognosis and prediction of response and eligibility to receive trastuzumab therapy. b TP, transcriptional profiling. c For monitoring response of breast cancer to treatment.
Ross, Molecular and Cellular Proteomics 2004, 3, 379
Methods of detection of HER-2/neu status in breast cancer
HER2-neu gene and protein and the prognosis in breast cancer
Correlation status Number of Number of
studies (%) cases (%)
All cases
None 8 (10%) 1995 (8%)
Univariate or 73 (90%) 25.166 (92%)
multivariate significance
Independent on 52 (71%) NA
multivariate analysis
Totals 81 (%) 27.161 (100%)
Ross, The Oncologist 2003, 8, 307
HER2-neu gene and protein and the prognosis in breast cancer
Cases with no correlation: Number of Number of
studies (%) cases (%)
Immunohistochemistry 5 (63%)
Southern blot 2 (25%)
RT-PCR 1 (12%)
Totals 8 (100%) 1995 (100%)
Ross, The Oncologist 2003, 8, 307
HER2 positivity correlates with:
a poor prognosis
HER2 as a predictor of response to chemotherapy in MBC
Author Pt. HER2+ Test Therapy Outcome
(n) (%) HER2+ HER2-
Stender ‘97 319 23 EIA A+P;P equal
Gianni ‘97 (49) 35 FISH A+P CR: 50% vs 17%
Niskanen ‘97 173 31 IHC FEC q 1 equal
or 4 wk
Sjöström ‘02 283 42 IHC MF vs D equal
Poznak ‘02 188 25/15 IHC Phase II equal
P or D
P, paclitaxel; D, docetaxel
HER2 as a predictor of response to chemotherapy in MBC
Author Pt. HER2+ Test Therapy Outcome (RR)
(n) (%) HER2+ HER2-
Kònecny ‘04 275 35 FISH EP 76%* 50%
vs
EC 46% 33%
Di Leo ‘04 176 20 FISH A 27% 35%
vs
D 67% 40%
D, docetaxel; P, paclitaxel; *difference significant
HER2 as a predictor of response to neo-adjuvant chemotherapy
Author Pt. HER2+ Test Therapy Outcome
(n) (%)
Rozan ‘98 329 19 IHC FAC cCR 20% HER-
31% HER+
S (5yr) : equal
Colleoni ‘99 73 10 IHC FUFAv RR 56% HER-
86% HER+
Zhang ‘03 79 28 IHC/ FAC RR, DFS (3yr): equal
FISH
Gonzalez ‘04 71 28 FISH P/D pCR 10% HER-
16% HER+
OS (5yr): equal
HER2 as a predictor of response to adjuvant CMF
Author Pt HER2+ Therapy Conclusions(n) (%) DFS and OS
Allred ‘92 613 14 CMFp Adv. better in HER2--
Gusterson ‘93 1506 16-19 CMF (1) Adv. better in HER2-CMFp (6)
Miles ‘99 274 30 CMF Adv. better in HER2- -
Menard ‘01 386 16 CMF Adv. “equal” -
Adv.: advantage
HER2 positivity correlates with:
a poor prognosis
relative resistance to alkylating agents
HER2 as a predictor of response to adjuvant anthracyclinesAuthor Pt HER2+ Therapy Conclusions
(n) (%) Anthra in HER2+
Paik ‘98 638 38 PF DFS, RFS, OS better*PAF
Ravdin ‘98 595 16 CAFT DFS better*T
Paik ‘00 2034 29 AC DFS, RFS, OS betterCMF
Pritchard ‘02 602 20 (IHC) CMF DFS, OS better24 (FISH) CEF
Di Leo ‘02 354 21 (FISH) CMF EFS better EChEC
Moliterni ‘03 506 19 CMF+A DFS, OS* better CMF
* significant
Dose-response effect of (neo-)adjuvant anthracyclines in HER2 positive tumors
Author Pt. HER2+ Therapy Conclusion
(n) (%) HER2+
Thor ‘98 992 27 FISH CAF PFS, OS related
(3 dose levels) to dose
Petit ‘01 79 26/30 FEC 50 or OR HER2-: equal
FEC 100 OR HER2+:
FEC 50: 12%
FEC 100: 100%
HER2 positivity correlates with:
a poor prognosis
relative resistance to alkylating agents
slightly higher anthracycline sensitivity
BCIRG 001 - Design
Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2
Cyclophosphamide 500 mg/m2
5-FU 500 mg/m2
Doxorubicin 50 mg/m2
Cyclophosphamide 500 mg/m2
FAC
TAC
R
Dexamethasone premedication, 8 mg bid, 3 days Prophylactic Cipro 500 mg bid, day 5-14
Every 3 weeks x 6 cycles
Stratification:• Nodes:
1-3 4+
• Center
N= 1491
BCIRG 001 - Disease-Free Survival (ITT)
75%
N Events HR P-value
Stratified Log Rank
TAC 745 172 0.72 .0010
FAC 746 227
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60 66
FAC
TAC
Cu
mu
lati
ve p
rob
abil
ity
68%
DFS Time(months)
BCIRG 001 - Overall Survival (ITT)
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60 66
FAC
TAC
Cu
mu
lati
ve P
rob
abil
ity
87%
81%
N Events HR P-value
Stratified Log-Rank
TAC 745 91 0.70 .0080
FAC 746 130
Survival Time (months)
HR = 0.60 P = 0.0088
Positive
0 6 12 18 24 30 36 42 48 54 60 66
90
80
70
60
50
FAC
TAC
Time to First Event
100
BCIRG 001 - DFS by HER2 Status
0 6 12 18 24 30 36 42 48 54 60 66
100
90
80
70
60
50
FAC
TAC
HR = 0.76 P = 0.046
Negative
Time to First Event
% A
live
and
Dis
ease
-Fre
e
(FISH performed centrally)
Ratio of HRs 0.85 P = 0.4122
HER2 positivity correlates with:
a poor prognosis
relative resistance to alkylating agents
slightly higher anthracycline sensitivity
probably slightly higher taxane sensitivity
Author N Scheme RR TTP OS (%) (mo) (mo)
Lück ‘00 541 EP 60/175 46 9.4 NS
EC 60/600 40 7.4
Carmichel ‘01 705 EP 75/200 40 6.5 NS
EC 75/600 37 6.8
Jassem ‘01 267 AP 50/220 68 8.3 23.3
FAC 500/50/500 55 6.2 18.3
Biganzoli ‘02 271 AP 60/175 58 5.9 20.6
AC 60/600 54 6.0 20.5
First-line Anthracycline + Paclitaxel in MBCPhase III studies
First-line Anthracycline + Docetaxel in MBC Phase III studies
22.6
16.1
8.1
6.6
64
41
AT 50/75
FAC 500/50/500
216Bontenbal ‘03
34
28
7.8
5.9
63
34
ET 75/75
FEC 500/75/500
142Tubiana ‘03
21
22
7.1
6.7
55
44
TAC 75/50/500
FAC 500/50/500
484Mackey ‘02
22.5
21.7
8.6
7.3
59
47
AT 50/75
AC 60/600
429Nabholtz ‘03
OS
(mo)
TTP
(mo)
RR
(%)
SchemeNAuthor
Taxane-based adjuvant therapy Phase III studies
Med.
Trial Design Nodes Pt FU Outcome
(n) (mo) (of taxane)
CALGB 4AC4P N+ 3170 69 DFS and OS
9344 4AC better
NSABP 4AC4P N+ 3060 64 DFS better,
B28 4AC OS equal
BCIRG 6TAC N+ 1491 55 DFS and OS
001 6FAC better
HormoonReceptoren
ER+ en/ofPgR+
ER- en PgR-
Leeftijd / Menopauzale status / Aantal positieve klieren (N)PostmenopauzaalPremenopauzaal
50-59 jaar 60-69 jaar > 70 jaarN > 1: 6 TAC + 5 jrtam. of LHRH oftam. + LHRH
N > 1: 6 TAC
N > 1: 5 FEC + 5 jraromataseremmer
N > 1: 5 FEC
N1-3: 5 jr aromatase-remmer
N 4: 5 FEC + 5 jraromataseremmerN > 1: 5 FEC
N > 1: 5 jraromataseremmer
N > 1: Geen adviesmogelijk
Tabel II: Richtlijn adjuvante systemische therapie bij een N+ mammacarcinoom met HER2-neu overexpressie
Incidence of neutropenic complications Geicam-9805 study (adjuvant TAC for N0)
No. of patients %
TAC FAC
pre- post- pre- post- amendm. amendm. amendm. amendm. (n=109) (n=115) (n=111) (n=113)
Neutropenia (all grades) 105 (96.3) 86 (74.8) 86 (86.5) 88(77.9)
Neutropenia (grade 3-4) 102 (93.6) 47 (40.9) 47 (42.3) 44(38.9)
Febrile neutropenia* 26 (23.9) 4 (3.5) 1 (0.9) 2 (1.8)
Fever during 39 (35.8) 12 (10.4) 3 (2.7) 4 (3.5)
* grade 2 fever (>38.5ºC) with grade 4 neutropenia and requiering I.V. antibiotics and/or hospitalisation in the some cycle
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