TAILORED ADJUVANT SYSTEMIC THERAPY FOR BREAST CANCER THERAPY FOR - - PowerPoint PPT Presentation

TAILORED ADJUVANT SYSTEMIC THERAPY FOR BREAST CANCER THERAPY FOR BREAST CANCER MYTH OR REALITY?

Presented by

• DR. KATHLEEN I. PRITCHARD

Senior Scientist, Sunnybrook Research Institute Sunnybrook Odette Cancer Centre Professor Department of Medicine Professor, Department of Medicine University of Toronto

CMF 6 cycles every 4 weeks R A N

• Cyclophosphamide 100 mg/m2 po

x 14 d

• Methotrexate 40 mg/m2 iv d 1& 8

NCIC-MA5

N D O M

• Methotrexate 40 mg/m iv d 1& 8
• 5FU 600 mg/m2 iv d 1& 8

Pre-menopausal node positive (n=710) M I Z CEF 6 cycles every 4 weeks (n 710) A T I CEF 6 cycles every 4 weeks

• Cyclophosphamide 75 mg/m2 po

x 14d

I O N

• Epirubicin 60 mg/m2 iv d 1 & 8
• 5FU 500 mg/m2 iv d 1 & 8

Cotrimoxazole or norfloxacin/ciprofloxacin

MA.5 Disease-Free Survival

100 Percent 60 80

CEF P=0.005

20 40

CMF

20 5 10 Time (years)

351 359

5

212 193

10

84 80 CEF CMF

At

359 193 80 CMF

Risk:

MA.5 Overall Survival

100 Percent 60 80

CEF

40

P=0.047 CMF

20 Time (years)

351 359 269 253 98 106 CEF CMF

At 5 10

359 253 106 CMF

At Risk:

Adverse Events

• 4 cases of CHF in the CEF group

compared to 1 in the CMF group p g p

• 5 patients in the CEF group experience
• 5 patients in the CEF group experience

acute leukemia (4 myeloid and 1 lymphoid) vs 1 in the CMF group vs 1 in the CMF group

DFS by treatment for those with HER2 amplification

HER2 as a

e 80 100

CEF

HER2 as a predictive factor

Percentage 20 40 60

HR = 0 52; p=0 003

DFS by treatment for those ith no HER2 amplification

CEF CMF

Time (years)

# At Risk(CEF) # At Ri k(CMF)

0.0

75 88

5.0

42 35

10.0

19 12

HR = 0.52; p=0.003

100

with no HER2 amplification

CEF CMF

( ) # At Risk(CMF)

P ercentage 40 60 80

CEF CMF

P e 20 0.0

237 228

5.0

145 138

10.0

59 60

HR = 0.91; p=0.49

CEF CMF

Time (years)

# At Risk(CEF) # At Risk(CMF) 228 138 60

OS by treatment for those ith HER2 lifi ti

HER2 as a

with HER2 amplification

100

HER2 as a predictive factor

ntage 60 80

CEF CMF

OS by treatment for

Percen 20 40

HR = 0.65; p=0.060

100

those not HER2 amp

Time (years)

# At Risk(CEF) # At Risk(CMF)

0.0

75 88

5.0

49 47

10.0

20 18

rcentage 40 60 80

CEF CMF

CEF CMF

# At Risk(CMF)

P er 20 40 0.0 5.0 10.0

HR = 1.06; p=0.91

CEF CMF

Time (years)

# At Risk(CEF) # At Risk(CMF)

0.0

237 228

5.0

184 175

10.0

71 78

Adjusted* Hazard Ratios by HER2 Status (CEF vs. CMF) CMF)

Overall Survival Disease Free Survival HER2 HR 95% CI p-value HR Overall Survival p-value Disease Free Survival 95% CI Amplified 0.52 0.34 - 0.80 p 0.003 0.65 p 0.06 0.42 – 1.02 Not Amplified 0.91 0.71 - 1.18 0.49 1.06 0.68 0.83 - 1.44

Test for interaction: p= 0 02 for DFS; p= 0 01 for OS

* adjusted for age, nodal status, grade, ER status, surgical procedure, tumor size

Pritchard et al, NEJM 2006

Test for interaction: p= 0.02 for DFS; p= 0.01 for OS

Her 2-neu amplification/overexpression is predictive of chemotherapy response

ANTHRACYCLINE vs NON-ANTHRACYCLINE CONTAINING TRIALS: HER 2-NEU

• 10 large studies
• Each suggests that HER 2-NEU overexpression is a

positive factor for response to anthracycline

• Each underpowered to test the question

Her 2 neu amplification/overexpression is Her 2-neu amplification/overexpression is predictive of chemotherapy response

• All from published data

All support interaction All support interaction

• DeLaurentis et al

between +Her2/neu status

• Gennari et al

and ad antage of

• Gennari et al

and advantage of

• Dhesy-Thind et al

anthracycline vs non- anthracycline containing regimen

Her 2-neu amplification/overexpression is predictive of chemotherapy response

T i 2 A (TOP 2A) Topoisomerase 2 A gene (TOP 2A)

• L

d l H 2/ h 17

• Located close to Her 2/neu on the 17q

chromosome

• Integrally involved in the antitumor action of
• Integrally involved in the antitumor action of

anthracyclines

• Topoisomerase IIα is essential for DNA
• Topoisomerase IIα is essential for DNA

replication and recombination

• Anthracyclines target topoisomerase IIα enzyme

y g p y

TOPO IIa (not HER2) Amplification as a Predictor of Anthrac cline Response in Breast Cancer as a Predictor of Anthracycline Response in Breast Cancer

Since 2002, at least 7 studies have been published d t ti th i ti b t t II l h

Study Yr N

demonstrating the association between topo II alpha amplification and improved anthracyline response.

Study Yr N Park et al. 2006 284 Tanner et al 2006 525 Tanner et al. 2006 525 Knoop at al. 2005 805 Park et al. 2003 188 Coon et al. 2002 35 Di Leo et al. 2002 354

TOP2A as a Predictive Factor

K l Knoop et al CEF vs CMF

• ti

t ith TOP 2A lifi ti patients with TOP 2A amplification or deletion had increased RFS (HR = 0.43; 0.63) and OS (HR = 0.57; HR = 0.56) if treated with and OS (HR 0.57; HR 0.56) if treated with CEF vs CMF TOP 2A vs treatment interaction was negative g

DFS Non Co-Amplified Topo II by Arm nd (2nd Interim Analysis)

e

1.0

91%

isease Free

0.9

91% 90% 85% 83%

% D

0.8

83% 78% 84% 81%

0.7

Patients Events

71%

0.6

Patients Events 643 146 AC->T 643 87 AC->TH 618 92 TCH P<0.001 P<0.001

0.5 1 2 3 4 5

Year from randomization

DFS Co-Amplified Topo II by Arm (2nd Interim Analysis) (2nd Interim Analysis)

e

1.0

95%

isease Free

0.9

92% 94% 87% 89% 87% 85%

% D

0.8

83% 83%

0.7

Patients Events

5 0.6

Patients Events 328 42 AC->T 357 35 AC->TH 359 42 TCH P=0.336 P=0.648

0. 1 2 3 4 5

Year from randomization

HER2 and TOPO II HER2 and TOPO II

17 q 12 17 q 21 17 q 12 17 q 21

HER2 Region TOP2A Region HER2 Region TOP2A Region

23 - 50% 23 - 50% 23 - 50% 13 - 43% 23 - 50%

Deletion Normal Amplified Deletion Normal Amplified

MA5 Clinical Trial

• TMAs constructed

– 480 patients (67% entire cohort) – 480 patients (67% entire cohort)

• TOP2A gene alterations (FISH)
• TOP2A gene alterations (FISH)

– FISH results available on 443/480

(92%) (92%)

TOP2A FISH Results

• Amplified:

48 (10.8%) p ( )

• Deleted:

27 (6.1%)

• Normal:

368 (83 2%)

• Normal:

368 (83.2%)

Baseline Characteristics for Patients with TOP2A FISH Measurements

TOP2A gene status Characteristic Amplified (n 48) Deletion (n 27) Normal (n=368) p* (n=48) (n=27) HER2/neu Amplified 28 (60%) 18 (67%) 73 (20%) <0.0001 Not amplified 19 (40%) 9 (33%) 288 (80%)

OS by TOP2A Status

TOP2A as a prognostic factor

TOP2A norm TOP2A amp/ del TOP2A amp/ del

Unadjusted p=0.01 Adj t d 0 46 Adjusted p=0.46

DFS by Treatment for patients with TOP2A amplified or deleted tumors p

CEF

DFS by

CEF

DFS by Treatment for patients with normal TOP2A

CMF

Unadjusted p=0.07 Adjusted p=0.01

normal TOP2A

e 80 100

CEF Time (years)

r cen t age 40 60

CEF CMF Time (years)

TOP2A as a Predictive

Pe r 20 40 Unadjusted p=0.75 Adjusted p=0.56

Factor

0.0 5.0 10.0

Time (years) p= 0.76

172 195 44 49 j p

OS by Treatment for patients with TOP2A amplified or deleted tumors

CEF CMF

OS by Treatment for patients with normal TOP2A

CMF

Unadjusted p=0.06 Adjusted p=0.01

80 100

CEF

normal TOP2A

Time (years)

c en t age 40 60 80

CMF

TOP2A as a predictive factor

Pe r 20 40

Unadjusted p=0.41 Adjusted p=0 60

0.0 5.0 10.0

Time (years)

Adjusted p 0.60 186 202 56 60

Hazard Ratios* by Treatment (CEF vs. CMF) and TOP2A Status

S OS DFS OS HR 95%CI P HR 95%CI P Amp/del 0.42 0.21-0.83 0.01 0.38 0.18-0.80 0.01 p Norm 0.93 0.68-1.25 0.56 1.10 0.77-1.56 0.60

*Adjusting for age, nodal status, grade, ER status, surgical procedure, tumor i HER2 t t size, HER2 status

Test for interaction: (adjusted) p=0.09 for DFS; p=0.04 for OS

T t i IHC Topo protein IHC:

• 1. No. positive cells/500;

expressed as a percentage

• 2. Initial analysis used

topo protein as a continuous variable

• 3. Final analysis used

y 13% as a cut-off

(28.5% over-expression) ( p )

TOPO II Status by FISH and IHC TOPO II Status by FISH and IHC

FISH TOP2A gene status Deleted (n=23) Amplified (n=44) Normal (n=351) p-value* IHC Topo protein status Over-expression 13 (30%) 7 (30%) 97 (28%) 0.93 Normal 31 (71%)

* CHI Square test for association

16 (70%) 254 (72%)

* CHI-Square test for association

Earlier work has also shown that topo protein expression and TOP2A gene amplification status O ge e a p cat o status are not correlated

Mueller, Parkes, Andrulis, O’Malley Genes, Chromosomes & Cancer, 2004

PROGNOSIS Disease Free Survival by topo protein expression Disease Free Survival by topo protein expression

100 Normal 60 80 Over-expression 40 60

Probability

(%) HR= 1 03 95% CI (0 78 1 36) p-value= 0 85 20 HR= 1.03 95% CI (0.78, 1.36) p-value= 0.85 10 5 Time (years) # at Risk Over-expression Normal 136 342 75 199 27 86 Time (years) # at Risk

PROGNOSIS Overall Survival by topo protein expression Overall Survival by topo protein expression

N l 100 Over-expression Normal 60 80 Over expression 40 60

Probability

(%) HR= 0 90 95% CI (0 66 1 22) p-value= 0 48 20 HR= 0.90 95% CI (0.66, 1.22) p value= 0.48 10 5 Time (years) # at Risk 89 253 32 106 Over-expression Normal 136 342 Time (years) # at Risk

Disease Free Survival by Treatment

CEF

Probability

80 100 Over-expression of topo protein p-value= 0.01 CMF

Probability

(%)

40 60 100 N l i f t t i 5 10 CEF

Probability

(%)

60 80 100 Normal expression of topo protein p-value= 0.6 CEF CMF

(%)

40 60 10 5 Time (years)

Overall Survival by Treatment

CEF 80 100 Over-expression of topo protein p-value= 0.02

Probability

CEF CMF 40 60

Probability

(%)

100 N l i f t t i 5 10 CEF CMF 60 80 100 Normal expression of topo protein p-value= 0.8

Probability

(%)

CMF 40 60

(%)

5 10 Time (years)

Adjusted* Hazard Ratios by Topo protein over- expression p (CEF vs. CMF)

Overall Survival Disease Free Survival Topo protein HR 95% CI p-value HR Overall Survival p-value Disease Free Survival 95% CI p p 0.49 0.28 - 0.85 p 0.01 0.51 p 0.03 0.28 – 0.93 Over- expression Normal 0.90 0.66 - 1.23 0.50 0.98 0.91 0.68 - 1.41 expression

* adjusted for age, nodal status, grade, ER status, surgical procedure, tumor size, HER2 status

Test for interaction: p= 0.04 for DFS; p= 0.03 for OS

SABCS 2006

WHICH IS THE BEST PREDICTIVE FACTOR FOR CEF CMF IN MA 5 ? FACTOR FOR CEF vs CMF IN MA.5 ?

• Regression adjustment is not an appropriate

technique (R. Simon, JNCI 2006)

• Needs new statistical methodology

gy

• Can use “ranked” p value as a rough estimate

Can use ranked p value as a rough estimate

WHICH IS THE BEST PREDICTIVE FACTOR FOR CEF vs CMF IN MA 5 ? FACTOR FOR CEF vs CMF IN MA.5 ?

DFS OS p value p value Her2 neu 0.01 0.02 T t i * 0 04 0 03 Topo protein * 0.04 0.03 Topo gene 0 09 0 04 Topo gene 0.09 0.04 * Exploratory analysis p y y

CONCLUSIONS (I) ( )

St th ti l d i i f TOP 2A d

• Strong theoretical underpining for TOP 2A gene and

TOPO 2 α protein and anthracycline efficacy

• More robust data supporting role of Her 2/neu and

anthracycline efficacy

• TOP 2A and TOPO 2 α not routinely available
• HER 2/neu available in most centres, qualty assured

CONCLUSIONS (II) ( )

• Individual trials and three meta-analyses support

HER 2/ lifi i di f HER 2/neu amplification as a predictor of response to anthracycline vs non-anthracycline chemotherapy

• Her 2/neu amplified or overexpressed: candidates for

anthracycline

• Her 2/neu non-amplified or non-overexpressed may

d ll ll ith th li bi ti do equally well with non-anthracycline combinations such as CMF

CONCLUSIONS (III) CONCLUSIONS (III)

• TOP 2A or TOPO 2 α may be better predictors but

more data and more robust and widely used testing is i d b f hi b l d d required before this can be concluded or

• perationalized