HER2-neu status en adjuvante chemotherapie bij het mammacarcinoom

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HER2-neu status en adjuvante chemotherapie bij
het mammacarcinoom

• M. Bontenbal
• Erasmus MC - Daniel den Hoed Kliniek
• 19 november 2004

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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
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Challenge
Select the best drug(s) for a particular patiënt
with a biologically specific tumor
Cardoso, Int J Oncol 2004, 24, 201
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HER2 in breast cancer
HER2 oncogeneamplification
Shortened median survival HER2 overexpressing 3
yearsHER2 normal 67 years
HER2 oncoprotein overexpression
Slamon D et al. Science 1987
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Methods of detection of HER-2/neu status in
breast cancer
Method Target FDA-approved Silde-based IHC Protein
Yesa Yes FISH Gene Yesa Yes CISH Gene No Yes Sout
hern 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
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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

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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
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HER2 positivity correlates with

• a poor prognosis

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HER2 as a predictor of response to chemotherapy
in MBC
Author Pt. HER2 Test Therapy Outcome
(n) () HER2 HER2- Stender
97 319 23 EIA APP equal Gianni
97 (49) 35 FISH AP 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
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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
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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 R
R, DFS (3yr) equal FISH Gonzalez
04 71 28 FISH P/D pCR 10 HER- 16
HER OS (5yr) equal
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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
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HER2 positivity correlates with

• a poor prognosis
• relative resistance to alkylating agents

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HER2 as a predictor of response to adjuvant
anthracyclines
Author Pt HER2 Therapy Conclusions (n) () Anth
ra 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
better CMF Pritchard 02 602 20 (IHC) CMF DFS,
OS better 24 (FISH) CEF Di Leo 02 354 21
(FISH) CMF EFS better EC hEC Moliterni
03 506 19 CMFA DFS, OS better CMF
significant
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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
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HER2 positivity correlates with

• a poor prognosis
• relative resistance to alkylating agents
• slightly higher anthracycline sensitivity

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BCIRG 001 - Design
5-FU 500 mg/m2Doxorubicin 50
mg/m2 Cyclophosphamide 500 mg/m2
R
Every 3 weeks x 6 cycles

• Stratification
• Nodes 1-3 4
• Center
• N 1491

Docetaxel 75 mg/m2 Doxorubicin 50
mg/m2 Cyclophosphamide 500 mg/m2
Dexamethasone premedication, 8 mg bid, 3 days
Prophylactic Cipro 500 mg bid, day 5-14
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BCIRG 001 - Disease-Free Survival (ITT)
1.0
TAC
75
0.8
FAC
68
0.6
Cumulative probability

0.4
N Events HR P-value Stratified Log
Rank TAC 745 172 0.72 .0010 FAC 746
227
0.2
0.0
0
6
12
18
24
30
36
42
48
54
60
66
DFS Time(months)

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BCIRG 001 - Overall Survival (ITT)
1.0
87
TAC
0.8
FAC
81
0.6
Cumulative Probability

0.4
N Events HR P-value Stratified
Log-Rank TAC 745 91 0.70 .0080 FAC 746
130

0.2
0.0
0
6
12
18
24
30
36
42
48
54
60
66
Survival Time (months)
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BCIRG 001 - DFS by HER2 Status
(FISH performed centrally)
100
Negative
90
80
TAC
Alive and Disease-Free
FAC
70
60
HR 0.76 P 0.046
50
0
6
12
18
24
30
36
42
48
54
60
66
Time to First Event
Ratio of HRs 0.85 P 0.4122
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HER2 positivity correlates with

• a poor prognosis
• relative resistance to alkylating agents
• slightly higher anthracycline sensitivity
• probably slightly higher taxane sensitivity

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First-line Anthracycline Paclitaxel in
MBCPhase III studies

• 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

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First-line Anthracycline Docetaxel in MBC
Phase III studies
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Taxane-based adjuvant therapy Phase III studies

• Med.
• Trial Design Nodes Pt FU
  Outcome (n) (mo)
  (of taxane)
• CALGB 4AC?4P N 3170 69 DFS and OS
  9344 4AC better
• NSABP 4AC?4P N 3060 64 DFS better,
  B28 4AC OS equal
• BCIRG 6TAC N 1491 55 DFS and OS
  001 6FAC better

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Tabel II Richtlijn adjuvante systemische
therapie bij een N mammacarcinoom met HER2-neu
overexpressie
Hormoon
(N)
Leeftijd / Menopauzale status / Aantal positieve
klieren
Receptoren
Postmenopauzaal
Premenopauzaal
50-59 jaar
60-69 jaar
gt
70 jaar
N
gt
1
N
gt
1
N1-3
N
gt
1
ER en/of
6 TAC 5 jr
5 FEC 5 jr
5 jr aromatase-
5 jr
PgR
tam. of LHRH of
aromataseremmer
remmer
aromataseremmer
tam. LHRH
N 4
5 FEC 5 jr
aromataseremmer
N
gt
1
N
gt
1
N
gt
1
N
gt
1
ER- en PgR-
6 TAC
5 FEC
5 FEC
Geen advies
mogelijk
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Incidence of neutropenic complications
Geicam-9805 study (adjuvant TAC for N0)
No. of patients TAC
FAC pre- post-
pre- post- amendm.
amendm. amendm. amendm.
(n109) (n115) (n111)
(n113) 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 (gt38.5ºC) with grade 4 neutropenia
and requiering I.V. antibiotics and/or
hospitalisation in the some cycle