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Neoadjuvant chemotherapy and targeted therapy: when pCR matters?
XII Michelangelo Foundation Seminar
when pCR matters? The NSABP Experience
N. Wolmark, Pittsburgh, USA
Neoadjuvant therapy in early BC: >50 Years
a hopeless heresy or a feasible paradigm shift?
MilanNorman Wolmark
Oct 12, 2012
Neoadjuvant TherapyTherapy
B-18Duration: 88 -93ACCRUAL: 1,523
B-27Duration: 95 -00ACCRUAL: 2,411ACCRUAL: 2,411
B-40Her2 Neg
BevpCR endpoint’’’’07-’’’’10; N=1206
B-41Her2 Pos
H and LapatanibpCR endpoint‘‘‘‘07-’’’’11; N=522
P E R S P E C T I V E
The FDA may grant accelerated approval on the basis of a surrogate end point …For neoadjuvant
June 2012: Tatiana Prowell and Richard Pazdur
basis of a surrogate end point …For neoadjuvant breast cancer we propose that the rate of pCR be used as this surrogate.
Patricia Cortazar , Meta-analysis: N=13,125Optimal def pCR; def N0; pCR correlation with outcome; ∆ pCR; enriched population; subtype def(molecular); pCR and targeted agents
Operable Breast CancerOperable Breast Cancer
StratificationStratification• Age• Age
NSABP BNSABP B --1818Neoadjuvant vs. Adjuvant ACNeoadjuvant vs. Adjuvant AC
•• Obj Clinical Response: Obj Clinical Response: 80%80%•• pCR: pCR: 13%13%•• Increase in lumpectomy Increase in lumpectomy
rate: rate: 68% vs. 60%68% vs. 60%
88-93; N=1523
• Clinical Tumor Size• Clinical Tumor Size• Clinical Nodal Status• Clinical Nodal Status
OperationOperation
AC x 4AC x 4 OperationOperation
AC x 4AC x 4
rate: rate: 68% vs. 60%68% vs. 60%•• Downstaging of (+) axillary Downstaging of (+) axillary
nodes: nodes: 58% vs. 40%58% vs. 40%•• No difference No difference inin DFS DFS andand SS**•• Significant Significant correlationcorrelation
between between pCR pCR andand survivalsurvival
Seq tam for women ≥≥≥≥50 yrs. only
Outcome: pre v postOutcome: pre v post
70
80
90
100N Ev HR PN Ev HR P
Post 751 311Post 751 311Pre 742 308Pre 742 308 .99 0.90 .99 0.90
% A
live
% A
live
NSABP BNSABP B --18: Overall Survival 18: Overall Survival
30
40
50
60
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
% A
live
% A
live
YearsYears
J Clin Oncol 2008J Clin Oncol 2008Goldie-Coldman Hypothesis Refuted
Treatment by AgeInteractionInteraction
SS
70
80
90
100
<50yrs<50yrs
70
80
90
100
≥≥50yrs50yrs
QualitativeTreatment by Age
Interaction
30
40
50
60
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
N Ev HR PPost 388 167
Pre 381 139 .81 0.06
30
40
50
60
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
N Ev HR PPost 363 148Pre 361 171 1.23 0.07
Interactionp=0.01
Should We Revisit the Concept of Should We Revisit the Concept of Neoadjuvant vs. Adjuvant Chemo?Neoadjuvant vs. Adjuvant Chemo?
OR OR
•• Are there subsets Are there subsets in in which one which one
•• Is neoadjuvant chemo = adjuvant Is neoadjuvant chemo = adjuvant chemo in all patient?chemo in all patient?
•• Are there subsets Are there subsets in in which one which one approach may be superior to the approach may be superior to the other?other?
NeoadjuvantNeoadjuvant >> AdjuvantAdjuvant : Triple Negative, : Triple Negative, HERHER--2 +, 2 +, HighHigh --Risk Risk ER + (<50) ER + (<50)
Adjuvant Adjuvant > > NeoadjuvantNeoadjuvant : : LowLow --Risk ER+ (Risk ER+ (>>50)50)
pCR and OutcomepCR = ypT0/is ypNx
Absence of invasive cancer in the breast ±±±± DCIS; ±±±± nodal involvement
70
80
90
100
Survival and pCRSurvival and pCR
86
66 ∆ 20%
30
40
50
60
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
N Ev HR No pCR 599 265pCR 86 14 .32 P <0.0001
OPERABLE BREAST CANCER
B-27
Age, T, cN12’’’’95-12’’’’00N=2411MTF=10 yrs
OPERATION
AC AC→→→→Txt*
OPERATION
AC
OPERATION
Txt*100mg/m² x 4; concom Tam for all
pCRpCR
Path Complete Response
40%
12.9
0%
20%
AC AC>T
pCR
JCO Nov ‘‘‘‘03
Path Complete Response
40%
12.9
26.1
0%
20%
AC AC>T
pCR
P < 0.001P < 0.001
JCO Nov ‘‘‘‘03
OutcomeOutcome
70
80
90
100
SurvivalSurvival
40
50
60
70
0 1 2 3 4 5 6 7 8
N Ev RR PAC 784 192AC→T 783 182 .93 0.46 ACSx→ T 777 189 .97 0.76
Doubling of pCR did not improve clinical outcome
15% 85%
AC arm
Extrapolation of B -18 and B -27 5 yr Survival
30% 70%
AC->T arm
pCR90% 5YS 75% 5YS
5YS = 77.25%
pCR90% 5YS 75% 5YS
5YS = 79.50%
pCR in B -27 was not a robust predictor for survival
pCR and OutcomepCR and Outcome
80
90
100
Survival and pCRSurvival and pCR
pCR93
80
40
50
60
70
0 1 2 3 4 5 6 7 8
No pCR
80
pCR v no pCRHR 0.36 P <.0001
Heterogeneous group includes subsets with good prognosis who may have ▼▼▼▼benefit from chemoRx
B-27 DFSno pCR and Nodes (1881)
0
1-3
#N %0 471-3 324-9 1610+ 5
4-9
10+
B-27 Affymetrix GeneChip analysis of FPET
50 gene Risk Prediction IndexNCI Reviewing the State of the Science Mar 2007
B-27 No pCR50 gene Risk Prediction Index
0.6
0.6
0.8
0.8
1.0
1.0
surv
ival
surv
ival highhigh --risk (n=163)risk (n=163)
lowlow--risk (n=163)risk (n=163)
00 2020 4040 6060 8080 100100
0.0
0.0
0.2
0.2
0.4
0.4
0.6
0.6
Time (months)Time (months)
surv
ival
surv
ival highhigh --risk (n=163)risk (n=163)
Paik NCI SOS Mar 2007
0.6
0.8
1.0
surv
ival
pCR (16)
No-pCR (147 )
B-27 pCR (50 gene)Low Risk
Time (months)
0.0
0.2
0.4
0.6
surv
ival
0 20 40 60 80 100
Paik NCI SOS Mar 2007
0.6
0.8
1.0
surv
ival
pCR (34)
no-pCR (125)
B-27 pCRHigh Risk
0.0
0.2
0.4su
rviv
al
0 20 40 60 80 100Time (months)
Ki67<10 (173 )
surv
ival
surv
ivalB-27 No pCR
Ki67
Ki67>10 (102)
HR 3.0; p=.0009
YearsYears
surv
ival
surv
ival
Paik, MD. Susan G Komen Award Lecture, SABCS 2010
E/PR+ N- patients(Paik, Wolmark: NEJM, 2004; JCO, 2006))
Oncotype DX
Preoperative Targeted Preoperative Targeted AgentsAgentsAgentsAgents
NOAH Trial: LABC Her2+NOAH Trial: LABC Her2+
EFS
Gianni L, et al; Lancet 2010
N Ev HR PT 117 36 .58 0.013
NoT 118 51
0 42 mo
Techno GBG N=217 JCO ‘‘‘‘11
NSABP BNSABP B --4141Her PosHer Pos
Paclitaxel/wk +Paclitaxel/wk +TrastuzumabTrastuzumab
SSuurr
AC X 4AC X 4
Paclitaxel/wk +Paclitaxel/wk +AC X 4AC X 4
OOppeerraa T T
uurrggeerryy
RPaclitaxel/wk +Paclitaxel/wk +
LapatinibAC X 4AC X 4aabbllee
BBCC
Paclitaxel/wk +Paclitaxel/wk +Lapatinib +
TrastuzumabTrastuzumabAC X 4AC X 4
T T mmaabb
pCR ∆ 22% (42→64%) ‘‘‘‘07-’’’’11; N=522 Tmab 2mg qW; Lnib 1250 qD; 750 w Tmab
NSABP B -41pCR Breast
P=0.095
P=0.99
ASCO 12
NSABP B -41pCR Breast by Hormone Receptor Status
P=0.23
P=0.96
P=0.49
P=0.71
N=100N=122 N=108 N=71N=55 N=63
HR+ HR–
P=0.96
NSABP/GBG/GNE B -5x (Her2+)
Neo-adjuvant Her2-directed Therapy
Residual Tumor
SURGERY N=1484 HR .753y IDFS
T-DM1
Residual Tumor
(Breast or Nodes)
H
3y IDFS