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When to consider mid-course changes of therapy based on
early response?
Gunter von Minckwitz, M.D., Ph.D., German Breast Group
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Topics
Early response:
• As predictor of pathologic response• As predictor of long-term outcome• As a decision aid to switch therapy• To identify patients who might (not)
benefit from a switch
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Royal Marsden Hospitaln = 198 pts. with operable b.c.
Predictors of pCR/pINV univariateafter a variety of therapies p-value
T1/T2 tumors 0.004Young age 0.008Response after 2nd cycle 0.001*
*best predictor in multi-variate analysis
Verrill MV et al. Breat Cancer Res Treat 50:328 1998
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Prediction of pCR by response evaluation after 2-4 cycles
Study Treatment N pts. pCR (%)R NR R NR
• GeparDuo ddAT 350 348 17 3• GeparDuo AC-T 300 148 17 7• GeparTrio TAC 1390 622 21 5
Total 2040 1118 19.6 4.6(65%) (35%) p<0.001
R=Responder (cCR or cPR); NR=Non-responder (cNC); dd=dose-dense; T=Docetaxel
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Multivariate analysis for pCR in GeparTrio(N=2190)
* Odds ration against group with lowest pCR rate
group with highest Odds ratio*
chance for pathCR All Responder Non-Responder
< 40 yrs 2.0 - 6.3
High grade 2.7 2.2 -
ductal 2.2 2.1 -
ER/PR neg 3.7 4.3 2.5
Complete Response 10.4 2.3 n.a.
after 2 cycles
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Predictors of pCR in GeparTrio% pCR ER/PR
(P<0.00000)
0
10
20
30
40
- / -(N=629)
+ / -(N=266)
+ / +(N=900)
0
10
20
30
40Response after 2 cycles
(P<0.00000)% pCR
CR(N=108)
PR(N=1257)
PD(N=12)
NC(N=627)
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GeparQuattro
OPN=1500
Stratified acc. to Early Response
R OP
OP
Cyclophosphamide600 mg/m²
Docetaxel100 mg/m² (A)75 mg/m² (B,C)
Capecitabine1800 mg/m²
A G OA G O
Epirubicin90 mg/m²
If Her2 pos:Trastuzumab6 mg/kg q3w 1y
If endocrineresponsiveTam/AIs
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Topics
Early response:
• As predictor of pathologic response• As predictor of long-term outcome• As a decision aid to switch therapy• To identify patients who might (not)
benefit from a switch
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Long Term Prognosis according to Early Response to 4xAC(+Tam)
Response to N Pts. Event rate 4x AC(+Tam) at 78 months
(after nil or Docetaxelx4)
cCR 906 24.7%
cPR 1079 35.1%
cNC 324 49.1%
p<0.0001
Bear D, NSABP B-27, JCO 2006
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GeparDuo 425 Pts. receiving AC-DocD
isea
se-fr
eeSu
rviv
al
2 4 6 yrs
N=61N=62
N=282
Logrank p=0.00981st measurement after 4xAC2nd measurement after 4xDoc
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Topics
Early response:
• As predictor of pathologic response• As predictor of long-term outcome• As a decision aid to switch therapy• To identify patients who might (not)
benefit from a switch
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02SR 86 French Phase II Trialn = 272 Patients Stage I-IIIB
VTMFA x 3
EvaluationcCR/cPR cNC
VTMAP PEFM±A
82% 67%5yrs OS
VTMFA:VinblastinThiotepaMTX5-FuDoxorubicin
PEFM±ACisplatinEpoposide5-FuMitomycin CDoxorubicin
D. Khayat, ASCO 2001 Educational Book
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02SR 86 French Phase II Trialn = 272 Patients Stage I-IIIB
survival
NR/R
NR/NR
R
100
50
50 100Time (months) 150
D. Khayat, ASCO 2001 Educational Book
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Aberdeen Trialn = 133 Patients T>3cm or IIIB
CVAP x 4
EvaluationcCR/cPR (n=97) cNC (n=45)
R
CVAP x 4 T x 4 T x 4
16% 34% 2%pCR
Eremin O et al. Breast Cancer Res Treat 57:29 1999
CVAP:CyclophospamideVincristineDoxorubicinPrednisolone
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Progression-free Survival in the Aberdeen-Study (median F-up: 104 wks)
Prop
ortio
n Su
rviv
ing
Prog
ress
ion
Free
Time (Weeks)
Initial Response Randomised to Docetaxel
No Initial Response Non Randomised to Docetaxel
Initial Response Randomised to CVAP
P=0.022
Heys SD, Clin Breast Cancer 2002
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Gepartrio
OP
OP
CoreCore biopsy:biopsy:uni/bilateral uni/bilateral cT2cT2--44cN0cN0--33size size ≥≥ 2 cm2 cm
DocetaxelDocetaxelAdriamycinAdriamycinCyclophosphamideCyclophosphamide+G+G--CSFCSF
NCNC
CR/CR/PRPR
OP
OP
TAC
Pal
patio
n /
Pal
patio
n /
sono
grap
hyso
nogr
aphy
NX
TAC
TAC x 8
TAC x 6
RR
RR
Von Minckwitz, SABCS 2006Von Minckwitz, SABCS 2006
VinorelbineVinorelbineCapecitabineCapecitabine
NX
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pCR Rates in GeparTrio Study
6.06.023.523.5
Non-ResponderN=604
2121.0.0
ResponderN=1344
9.79.77.67.6
5.85.8 1.71.7
P=0.08 P=0.17P=0.73P=0.27
P<0.0001
5.35.3
40%40%
20%20%
00
TACTAC--NXNXTAC x 6TAC x 6TAC x 6TAC x 6 TAC x 8TAC x 8ypTis or ypT0, ypN+path CR
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Topics
Early response:
• As predictor of pathologic response• As predictor of long-term outcome• As a decision aid to switch therapy• To identify patients who might (not)
benefit from a switch
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Predictive Factors in GeparTrio for pCR by Therapy
%path CR Responder Non-Responder
TACx6 TACx8 TACx6 TAC/Nx
ER+ and PR+ 11.7 18.3 9.5 2.5
P=0.03 P=0.01
Partial Response
after 2 cycles 25.5 31.4 n.a.
P=0.02
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Adding a Taxan to FAC(Experience from 7 MD Anderson Trials)
N=1079 pCR (%)- Taxane + Taxane
ER neg 15 29
ER pos 2 9
Mazouni C, Ann Oncol 2007
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Patients with a Partial Response after AC might benefit from Preop Doc
Response after AC(+Tam)
cCR
cPR
cNCall
cCR
cPR
cNCall
Doc better Doc worse
Doc preop.
Doc postop.
Bear D, NSABP B-27, JCO 2006
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Her2 negative –Non-Responding Patients
Pw
NCNC
CR/CR/PRPR
Son
ogra
phy
Son
ogra
phy
Rep
eat
Rep
eat C
ore
Cor
e
Cor
eC
ore
biop
sybi
opsy EC+/-B
N=540 Her 2 neg. Non-responderPw = weekly PaclitaxelR = Rad 001
Pw + R
RRSurgery
Surgery
continue responder part
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Decision Tree
N=2500
In/Exclusion criteria fulfilled noNo participation possible
yes
Her-2 Status positive no Her2- Setting:EC vs EC + BevacizumabN=1900
yes N=600
Non-ResponderSetting:Pw +/- RAD 001
Her2+ Setting:EC-Doc/CapTrastuzumab vs.Lapatinib
noResponse after 4xEC+/-B N=540
yesN=1360
Continue Doc/Cap +/- Bev.
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Conclusion• Early response is an independent predictor of pCR and
long term outcome (CR>PR>NC>PD).
• Benefit of a late response after switching of treatment is unclear
• Patients with an early cCR might not need further treatment intensification
• Patients with an early cPR (incomplete chemoresistancedue to e.g. ER+) might benefit from more intense treatment.
• Patients with an early cNC or cPD are at high medical need for new treatment options.