Neoadjuvante systemische therapie Een goed begin'''

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(Neo-)adjuvante systemische therapieEen goed
begin...

• Marijke Bontenbal
• Erasmus Medisch Centrum - Daniel den Hoed
• Rotterdam

2
Questions

• ? Taxanes for all
• ? Adjuvant or Neo- (chemo)
• ? Trastuzumab ASAP
• ? Anthras are out

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TACT Trial Design
CONTROL
Centres choose control arm... FEC OR E-CMF
RANDOMIZE
FEC 600/60/600 mg/m2 q3wk x 8
Epirubicin 100mg/m2 q3wk x 4
CMF Classical Bonnadonna or Classical IV regimen
x4
EXPERIMENTAL
For all centres... FEC-T
Docetaxel 100 mg/m2 q3wk x 4
FEC 600/60/600 mg/m2 q3wk x 4
Eligibility N or high risk N0, completely
excised invasive BC
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Disease Free Survival
100
FEC-T 473/2073 5yr DFS 74.7 (95 CI
72.576.8)
75
Control 484/2089 5yr DFS 73.9 (95 CI 71.7
76.0)
surviving Disease-Free
50
25
HR 0.97 (95 CI 0.86 1.10) Stratified log
rank test p0.62
0
0
1
2
3
4
5
Time from randomization (Years)
Number of events / number at risk Control 0/2089
81/2002 154/1837
119/1660 86/1079
40(4)/338 FEC-T 0/2073 62/2006
145/1858 142/1668 84/1127
33(7)/363
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Trial Design
Doxorubicin 60 mg/m2 IV Day
1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21
days X 4 Cycles
AC
Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide
600 mg/m2 IV Day 1 Every 21 days X 4 Cycles
TC
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DFS for HER2-negative Patients
Jones et al. SABCS 2007. Abstract 12.
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DFS for HER2-positive Patients
Jones et al. SABCS 2007. Abstract 12.
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Disease-free Survival by Treatmentand Age Group
Jones et al. SABCS 2007. Abstract 12.
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First generation taxane trialsTaxane timing
schedule
6 negative trials
10 positive trials
DFS
Combination strategy
Sequencing strategy
Sequencing strategy
Combination strategy
BCRIG-001 ECTO USO-9735
TACT NSABP-B27 NCIC-MA.21 Taxit-216 HeCOG-1
097
ECOG-2197
CALGB-9344 NSABP-B28 BIG 2-98 PACS-01 GEICAM-9
906 FinHER MDACC
ONLY ONE TRIAL WITH TAXANE UPFRONT !
Trials using weekly or dose-dense paclitaxel,
Piccart, EBCC, 2008
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Lower strength control trials
Standard strength control trials
Negative trials
Negative trials
Positive trials
Positive trials
DFS
DFS
ECOG- 197 NSABP-B27
BIG 2-98 PACS-01 ECTO GEICAM-9906
CALGB-9344 NSABP-B28 BCRIG-001 USO-9735 FinHER
MDACC
TACT NCIC-MA.21 HeCOG-1097 Taxit-216
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Taxanes improve BC mortalityPreliminary results
from 11 trials
Taxanes gt Anthra gt CMF gt No Chemo
50
Control36.4
Anthra 31.0
CMF31.3
40
4.2
4.3
5.1
30
CMF32.2
20.5
19.9
Anthra27.0
20
15.3
Taxane25.9
SE
17.8
16.5
10
12.8
Years
Years
Years
0
0
0
0
EBCTCG 2005-06 Overview Peto SABCS 2007
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Conclusions

• Taxane research in BC has suffered from
  fragmentation
• EBCTCG investigators are examining the possible
  role of the anthracycline reference arm and of
  the BC molecular subtypes
• There are no predictive biomarkers that are ready
  for clinical use
• The relationship between HER-2 and taxane
  sensitivity is not clear
• First generation of taxane trials (16,000 women,
  "N") suggests an absolute survival gain of 5 at
  10y. Additional data on 30.000 women expected
  for 2010
• Piccart, EBCC, 2008

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Preoperative systemic therapy

• - No inherent reason to believe that a regimen
  that works post-op will not work pre-op.
• - An acceptable adjuvant regimen is an acceptable
  preoperative regimen
• Gralow, Summary NCI State of the Science
  Conference on preoperative therapy.
• EBCC 2008

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Can early response assessment guide neoadjuvant
systemic therapy in early stage breast cancer?
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Is there any advantage to using early response to
chemotherapy to guide subsequent therapy?

• - Early responders have better outcome
• - Trials have not shown improvement in outcome
  with mid-course switch based on response
• Gralow, Summary NCI State of the Science
  Conference on preoperative therapy.
• EBCC 2008

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Trastuzumab for women with HER2-positive breast
cancer
EBC
MBC
Surgery
Relapse
Progression
Adjuvant
1st line
2nd lines
Neo
HERA NSABP-B31 NCCTG N9831 BCIRG
006 FinHer PACS-04
HO648g M77001 US Oncology BCIRG
007 CHAT TAnDEM RHEA
NOAH MDACC GeparQuattro Numerous Phase II studies
GBG-26 Numerous Phase II studies
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PACS04 Trial
Trastuzumab started after chemotherapy and RT
RT was delivered within 4 weeks after the last
chemotherapy cycle
Spielmann et al. Breast Cancer Res Treat
2007106(suppl 1)S19. Abstract 72.
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PACS 04 DFS and OS (ITT)
Median follow-up 48 months
OS
DFS
Spielmann et al. Breast Cancer Res Treat.
2007106(suppl 1)S19. Abstract 72.
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Adjuvant Treatment of Early BC Concomitant Chemo
Trastuzumab vs. Sequential Chemo And
Trastuzumab
Concomitant chemo T Sequential chemo
T HR
HR NSABP B31 0.48 HERA 1-yr
FU 0.54 NCCTG9831 0.48
HERA 2-yr FU 0.64 BCIRG 006
0.61 NCCTG9831seq 0.87 FinHer
0.42 PACS-04
0.87
-ve (p0.29) -ve (p0.41)
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Trastuzumab for women with HER2-positive breast
cancer
EBC
MBC
Relapse
Surgery
Progression
Adjuvant
1st line
2nd lines
Neo
HERA NSABP-B31 NCCTG N9831 BCIRG
006 FinHer PACS-04
HO648g M77001 US Oncology BCIRG
007 CHAT TAnDEM RHEA
NOAH MDACC GeparQuattro Numerous Phase II studies
GBG-26 Numerous Phase II studies
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Neoadjuvant treatment of HER2 breast cancer. The
key issues

• Is it better to start trastuzumab before surgery?
• If so, what is the best way to combine with
  chemotherapy to maximize efficacy and minimize
  cardiotoxicity?

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Neoadjuvant Trastuzumab for HER2-positive breast
cancer investigated by the NOAH trial
HER2-positive LABC(IHC 3 and / or FISH)
HER2-negative LABC(IHC 0/1)
n113
n115
n99
H AP q3w x 3
APq3w x 3
APq3w x 3
H Pq3w x 4
Pq3w x 4
Pq3w x 4
H q3w x 4 CMF q4w x 3
CMFq4w x 3
CMFq4w x 3
Surgery followed by radiotherapya
Surgery followed by radiotherapya
Surgery followed by radiotherapya
H continued q3w to Week 52
aHormone receptor-positive patients receive
adjuvant tamoxifen AP, doxorubicin 60 mg/m2,
paclitaxel 150 mg/m2 H, Herceptin 8 mg/kg
loading then 6 mg/kg LABC, locally advanced
breast cancer P, paclitaxel 175 mg/m2 q3w,
every 3 weeks q4w, every 4 weeks
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Significant improvement of pCR in IBC by adding
trastuzumab
p0.004
p0.002
Patients()
17 (55)
15 (48)
p0.49
p0.20
4 (29)
4 (29)
6 (19)
4 (13)
H
-H
HER2negative
H
HER2negative
-H
HER2 positive
HER2 positive
tpCR
pCR
eradication of invasive cancer in the breast
plus axillary nodes
eradication of invasive cancer in the breast
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pCR rate in context HER2-positive disease
Study
Pernas et al 2006, n16
T ? FEC H
Buzdar et al 2007, n64
T ? FEC H
Coudert et al 2005, n33
D H
Lybaert et al 2006, n89
X D H
Gianni et al 2007, n115
AT ? T ? CMF H
Limentani et al 2007, n31
D V T (including IBC)
Griggs et al 2005, n18
D H
Trastuzumab
NOAH, all patients
D cisplatin H (including IBC)
Hurley et al 2002, n48
NOAH, IBC only
Harris et al 2003, n40
V H (including IBC)
Lapatinib
Kelly et al 2006, n37
AC ? T H (including IBC)
Burstein et al 2003, n40
T H (including IBC)
D H
Bines et al 2003, n32
AT ? T ? CMF H (IBC only)
Baselga et al 2007, n31
Christofanilli et al 2006, n30
T L (IBC only)
0
10
20
30
40
50
60
70
80
90
100
pCR ()
L, lapatinib V, vinorelbine X, capecitabine
FEC, 5-fluorouracil, epirubicin, cyclophosphamide
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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
NSABP B15
0.65 - 1.08 0.86 - 1.20
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
Total
0.90
p 0.01
p lt 0.0001
0.61 - 0.83 0.90 - 1.11
0.71 1.00
Overall
p 1.0
heterogeneity c25 5.3, p 0.38 heterogeneity
c25 7.6, p 0.18
0.6
2
5
0.4
0.9
1
Test for interaction chi2 13.7 p lt 0.001
A.Gennari, et.al. JNCI, 2008, 100
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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)
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BCIRG 006
4 x Docetaxel 100 mg/m2
4 x AC60/600 mg/m2
AC?T
Her 2 (Central FISH) N or high risk N-
4 x Docetaxel 100 mg/m2
4 x AC60/600 mg/m2
AC?TH
1 Year Trastuzumab
6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6
N3,222
TCH
Stratified by Nodes and Hormonal Receptor Status
1 Year Trastuzumab
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DFS Non Co-Amplified Topo II by Arm (2nd Interim
Analysis)
1.0
91
0.9
90
Disease Free
85
83
84
83
0.8
81
78
71
0.7
Patients
Events
0.6
643
146
AC-gtT
643
87
AC-gtTH
Plt0.001
618
92
TCH
Plt0.001
0.5
0
1
2
3
4
5
Year from randomization
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DFS Co-Amplified Topo II by Arm (2nd Interim
Analysis)
1.0
95
94
89
0.9
92
87
Disease Free
87
85
83
0.8
83
0.7
Patients
Events
0.6
328
42
AC-gtT
357
35
AC-gtTH
P0.336
359
42
TCH
P0.648
0.5
0
1
2
3
4
5
Year from randomization
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Implications for HER2 negative and HER2 positive
Breast Cancers

• The superior efficacy benefits for anthracyclines
  (when present) derives from their effects on topo
  IIa amplification/overexpression.
• Given that thus far topo IIa amplification occurs
  ONLY in 35 of the 25 of breast cancer patients
  with HER2 amplification,
• What data supports their preferential use in a
  HER-2 negative breast cancer population which is
  75 of all breasts cancers
• Moreover, for HER-2 positive breast cancers we
  now have trastuzumab and lapatinib which appears
  to replace the gained efficacy of anthracyclines
  in the 1/3 of patients with co-amplification of
  HER2 and Topo IIa without risking their known and
  well established toxicities
• Slamon,EBCC,2008

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Critical Question

• Considering
• BCIRG 006 update in HER2 breast cancer
• - the difference in DFS/OS in favor of ACTH is
  statistically insignificant and is now exceeded
  by the number of critical adverse events
  including grade III/IV CHF and AC related
  leukemia as well as a significant AND sustained
  loss of LVEF for 18 (189 pts) both of which are
  highly statistically significant and..
• The recently published data from US Oncology
  shows a highly statistically significant DFS
  superiority of 4 TC over 4 AC.

What is the role of anthracyclines in the
adjuvant treatment of breast cancer? Slamon,EBCC,
2008
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Her2 ve - relevance of topo II

• No data on non-anthracycline, non-trastuzumab
  use
• If amplified (1/5 1/3 of Her2 ve patients)
• AC-TH looks the best, but only by a small margin
  anthracyclines or trastuzumab needed
  (anthracyclines are cheaper)
• If not amplified (60 of Her2 ve patients)
• Need trastuzumab
• If deleted (5 of patients)
• - No data
• Cameron, EBCC, 2008

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Conclusions

• Taxane-based chemo 10y survival gain 5
• Unknown best strategy
• which patients
• relationschip with HER2
• An acceptable adjuvant regimen is an acceptable
  preoperative regimen
• No proof of better outcome by mid-course chemo
  switch based on response
• Neo-adjuvant trastuzumab improves pCR rate
• Anthras are still in

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2007 Taxane Global Scene DFS
Hazard Ratio 0.72 (0.59 - 0.88) 0.93 (0.76 -
1.12) 0.72 (0.54 - 0.96) 0.93 (0.75 -
1.14) 0.83 (0.73 - 0.94) 0.83 (0.72 -
0.95) 0.91 (0.77 - 1.08) 0.79 (0.64 - 0.98) 0.66
(0.48 - 0.91) 0.78 (0.61 - 1.01) 0.93 (0.69 -
1.24) 0.80 (0.67 - 0.95) 1.49 (1.12 -
1.99) 0.97 (0.86 - 1.10) 0.85 (0.80 -
0.89) 0.87 (0.82 - 0.91)
Combination Treatment
BCIRG 001
E2197
US Oncology
BIG 2-98 (AT v AC)

Sequential Treatment (unequal duration)
CALGB 9344
NSABP B-28
NSABP B-27
BIG 2-98 (A-T v A)
ECTO
Taxit 216
HeCOG
Sequential Treatment (equal duration)
PACS 01
MA21 (AC-T v CEF)

TACT
OVERALL OVERALL inc. TACT
0.4
1
1.5
Favors Taxanes Favors Control
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pCR rate in context IBC irrespective of HER2
status
Study
FAC ? mitoxantrone C melphalan SCT
D carboplatin (including non-IBC)
ET
E ?T
Chemotherapy
NOAH (trastuzumab)
ET
FAC or FAC T
FEC-HD
CAF or CEF
AT ? T ? CMF H
Baselga et al 2007, n31
pCR ()
A, doxorubicin C, cyclophosphamide D,
docetaxel E, epirubicin F, 5-fluorouracil HD,
high-dose 5-fluorouracil (750 mg/m2) SCT, stem
cell transplantation
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