taxenes in breast cancer (sharm).ppt

Do we need a Taxane in the Do we need a Taxane in the treatment of breast cancertreatment of breast cancer

Yes

But not yet

NoI’m not convinced

Do we need a TaxaneDo we need a Taxanein breast cancerin breast cancer

Single agentSingle agentWith AnthracyclineWith AnthracyclineWith other drugsWith other drugsWith biological therapyWith biological therapy

Do we need a Taxane Do we need a Taxane in breast cancer in breast cancer

Adjuvant ? Adjuvant ?

Neoadjuvant ?Neoadjuvant ?

Metastatic ?Metastatic ?

Drug Year of publication

CR + PR (%)

Taxotere (75-100mg/ m²) 1993 - 95 48 - 68 Taxol (175 - 250 mg/ m² : 3-24hr) 1991 - 95 29 - 63 Doxorubicin (60-75mg/ m²) 1974 - 94 43 - 54 Capecitabine 1995 - 99 35 - 50 Navelbine 1992 - 94 30 - 41 Gemcitabine 1995 - 97 25 - 37 Carboplatin 1985 - 93 7 - 35 Cisplatin 1978 -88 9 - 50 Cyclophosphamide 1959 - 68 36 Fluorouracil 1961 - 81 28 Methotrexate 1952 - 81 26 Mitomycin C 1976 - 85 32

Single agents in Breast Cancer (First-line)

Vogel CL, Nabholtz Oncologist 1999; 4: 17-33.Nabholtz et al. Exp. Opin Pharmacother 2000;

1: 187-206.

TAX 306 AT vs ACTAX 306 AT vs ACEfficacy: Response RateEfficacy: Response Rate

All Randomized AT AC

Overall* 60% 47%

Visceral 59% 42%

Liver 62% 43%

Lung 59% 36%

3 organs 60% 41%

Adjuvant CT 54% 41%

Nabholtz et al 10/00 update of ASCO 99 abstract 485.

P = .012

*Odds ratio AT/AC 1.7 [95%CI 1.1 -2.5]

TAX306: AT vs AC: Overall TAX306: AT vs AC: Overall SurvivalSurvival

40 months median follow-up40 months median follow-up

Survival Time (months)Cut-off date: 22 Feb 01

Cu

mu

lativ

e P

rob

ab

ility

AT AC

[70,81][70,81][74,85][74,85] [95% CI][95% CI]75%75%79%79%1-yr survival1-yr survival

[19.8,25.2][19.8,25.2][19.0, 26.4][19.0, 26.4] [95% CI][95% CI]21.7 mos21.7 mos22.5 mos22.5 mosMedian survivalMedian survival48 (22%)48 (22%)59 (28%)59 (28%)CensoredCensored

167 (78%)167 (78%)155 (72%)155 (72%)DeathDeath215215214214No Of ptsNo Of ptsACACATAT

Log-rank p-value=0.2432

Nabholtz, May, 2001

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

PROC, July 11, 2001

AT(N=134)AT(N=134) FAC(N=133) FAC(N=133)Response rateResponse rate 87 (68%)87 (68%) 72 (5572 (55C.RC.R 24 (19%)24 (19%) 11 (8%)11 (8%)Early toxic deathEarly toxic death 11 0 0TTPTTP 8.3 m 8.3 m 6.2 m 6.2 m P=0.034P=0.034

MSTMST 23.3 m23.3 m 18.3 m18.3 m P=0.013P=0.013

At median followAt median follow 42 % alive42 % alive 26 % alive26 % aliveUp period of 29 mUp period of 29 m

Jassem et al, JCO 2001

East-Central Europe East-Central Europe studystudy

Metastatic Breast Metastatic Breast CancerCancer

Taxanes As Adjuvant Taxanes As Adjuvant TherapyTherapy

First Generation Of First Generation Of RandomizedRandomized

Clinical TrialsClinical Trials

Benefit of sequential Taxanes

Benefit of substituting taxanes with Anthracyclines

Benefit of combining Taxanes with Anthracyclines

Do we need a taxane?Do we need a taxane?

Taxanes As Adjuvant TherapyTaxanes As Adjuvant TherapySecond Generation of Clinical TrialsSecond Generation of Clinical Trials

Ok we’d better use a Taxane, Ok we’d better use a Taxane, BUTBUT we need to know:we need to know:

• Optimal taxane administration: sequence? combinationOptimal taxane administration: sequence? combination

• Optimal taxane dose-density/dose-intensityOptimal taxane dose-density/dose-intensity

• Docetaxel versus PaclitaxelDocetaxel versus Paclitaxel

• Benefit of combining taxanes with HerceptinBenefit of combining taxanes with Herceptin®®

Taxanes in adj. Taxanes in adj. treatmenttreatment

N 55200Paclitaxel 21700Docetaxel 34500

N 55200Paclitaxel 21700Docetaxel 34500

Sequentialtaxanes

N19000A-T

combinationsN10000

TC p53N1016

N1400

Sequencevs

combination

BestTaxane

Dose&

schedule

N9300

N8700

N5000

N2250

Taxane± Herceptin®

11stst Generation Generation11stst Generation Generation 22ndnd Generation Generation22ndnd Generation Generation

CALGB 9344 Adjuvant StudyCALGB 9344 Adjuvant StudyUpdate 11/00: Henderson et alUpdate 11/00: Henderson et al

NIH Consensus Conference: Adjuvant Therapy for Breast Cancer, November 1-3, 2000, Bethesda, MD .

ER+ or PR+ patients received Tamoxifen 5 y

No therapy

A75 C 4

A60 C 4N=3,170

• Node+

Statification:

• Premenopausal and post- menopausal

TXL 4RANDOMIZE

A90+G-CSF C 4

A=DxoribicinC=cyclophosphaneP=Pclitaxel

CALGB 9344

Median FU (mos)Median FU (mos) 21 52 69

Number of eventsNumber of events•RecurrencesRecurrences 453 901 1054•DeathsDeaths 200 589 742

Reduction inReduction in•Hazard of recurrenceHazard of recurrence 22%* 13%* 17%*•Hazard of deathHazard of death 26%* 14% 18%*

ASCO (98) NIH (2000)JCO (2003)

CALGB

Add Taxol to AC (median follow up: 69%)

Reduced odds of recurrenceReduced odds of recurrence 17% 17% (p=0.0023)(p=0.0023)

Reduced MortalityReduced Mortality 18% 18% (p=0.0064)(p=0.0064)

5-years DFS5-years DFS 70% (vs 65%)70% (vs 65%)

OASOAS 80% (vs 77%)80% (vs 77%)

RECENT UPDATERECENT UPDATE

Henderson et al. JCO; 2003

Comparative Efficacy of Adjuvant Comparative Efficacy of Adjuvant ChemotherapyChemotherapy

EBCTCG Meta-AnalysisEBCTCG Meta-Analysis

TheraTherapypy

Reduction in Annual Odds, %

RecurrenRecurrencece

DeatDeathh

Polychemotherapy vsPolychemotherapy vs 23.5 15no chemotherapy (1995)no chemotherapy (1995)(P < .00001)(P < .00001)

Anthracyclines vsAnthracyclines vs 12 11CMF (1995)CMF (1995) (P = .006) (P = .02)

Anthracyclines vsAnthracyclines vs 10.8 15.7 CMF (2000)CMF (2000) (P = .0005) (P < .00001)

Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;352:930-942.

CALGB 9344:CALGB 9344:Disease Free Survival by Disease Free Survival by

Subgroup Subgroup Receptor Status

Positive

Receptor Status Negative / Unknown

0.50

0

Pro

po

rtio

n D

ise

as

e-F

ree

AC TXL

AC

Years

AC TXL

AC

Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer.

0.75

1.00

0.50

0.75

1.00

1 2 3 4 5 6

Lessons from CALGB 9344 (N=3121)

MORE IS NOT ALWAYS BETTERMORE IS NOT ALWAYS BETTER

Increase ADRIAMYCINE dose Increase ADRIAMYCINE dose from 60mg/m2 from 60mg/m2

90mg/m2 didn’t improve 90mg/m2 didn’t improve treatment outcome in any treatment outcome in any

subsetsubset


Better outcome may be Better outcome may be achieved using achieved using

PACLITAXEL x 4 PACLITAXEL x 4 following AC x 4 or following AC x 4 or simply by using 8 simply by using 8

cyclescycles


Do we need Do we need molecular molecular

selection for selection for adjuvant adjuvant cases ??cases ??

ER +ve NO benefit

TXL 4

NSABP B-28: Study DesignNSABP B-28: Study Design

NIH Consensus Conference: Adjuvant Therapy for Breast Cancer, November 1-3, 2000, Bethesda, MD.

A=Doxorubicin

C=Cyclophosphamide

P=Paclitaxel

All patients 50 years and those <50 with ER+ or PR+ tumorsreceived Tamoxifen 5 y

RANDOMIZE

N=3,060

• Node+

Stratification:

• Premenopausal and post- menopausal

AC 4

AC 4

NSABP-B28 EARLY RESULTSNSABP-B28 EARLY RESULTS

Disease-Free SurvivalDisease-Free Survival

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48

•AC→ T 1528 pts, 269 events

•AC 1525 pts, 282 events

RR = 0.93 p= 0.38

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48

•ACAC→→TT 1528 pts, 136 deaths1528 pts, 136 deaths

•ACAC 1525 pts, 133 deaths1525 pts, 133 deaths

RR = 1.00 p= 0.98RR = 1.00 p= 0.98

Overall SurvivalOverall Survival

NSAPB B-28 CALGB 9344

F/U 40 mos 69 mos

1-3 (+) LN 70% 46%

4 (+) LN 30% 54%

Tamox 85% 67%

< 50 51% 60%

Recur/Death 561 / 269 1054/742

Hazard Ratio for Relapse:

No Tamoxifen .86 (.62-1.19) 0.69 (.57-.84)

Tamoxifen .96 (.78-1.16) 0.92 (.79-1.08)

MD Anderson Adjuvant Trialn=524 (67% post-op)

Est. 4 yr DFS:

86%

83%

p=0.09

Buzdar, et al, Clin Cancer Res, 2002. 8(5): p. 1073-9.

#

265

259

(No Impact By Receptor Status)

FAC

P

FAC

BCIRG 001: TAC vs FACBCIRG 001: TAC vs FAC3 Year F/U: Adjuvant Rx for Node (+) BC3 Year F/U: Adjuvant Rx for Node (+) BC

n

745

746

DFS

82%

74%

0.680.0011

OS

92%

87%

0.760.11

Nabholtz et al Proc ASCO 2002 abs # 141

RRp

ACD

ACF

Disease Free Survival by Nodal Disease Free Survival by Nodal StatusStatus

RRRR p-valuep-value

1-3 Nodes1-3 Nodes 0.500.50 0.00020.0002

TAC

FAC

0 6 12 18 24 30 36 42 48Months

Number at RiskTACFAC

463 462 452 437 427 250 103 14 1459 454 438 417 393 224 98 26 0

50

60

70

80

90

100

% A

live

an

d D

ise

ase

Fre

e

1-3

1-3

90%

79%

TACFAC

0 6 12 18 24 30 36 42 48

4+ TACFAC

282 274 258 241 227 123 49 9 0287 275 261 239 212 110 52 5 0

50

60

70

80

90

100

0.330.330.860.864+ Nodes4+ Nodes

4+

69%

67%

Nabholtz et al. ASCO 2002 (Abs 141).

TAC

FAC

0 6 12 18 24 30 36 42 48MonthsNumber at Risk

TACFAC

463 462 459 453 449 261 112 14 1459 457 453 444 422 243 107 28 1

50

60

70

80

90

100

% A

live

Overall Survival by Nodal Overall Survival by Nodal StatusStatus

96%

89%

RRRR p-valuep-value

1-3 Nodes1-3 Nodes 0.460.46 0.0060.006

1-3

1-3

TAC

0 6 12 18 24 30 36 42 48

4+ TACFAC

282 279 273 265 251 132 59 10 0287 281 275 269 256 132 64 5 0

50

60

70

80

90

100

0.750.751.081.084+ Nodes4+ Nodes

4+

86%84%


Disease Free Survival by Disease Free Survival by Hormonal StatusHormonal Status

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

231 217 188 47 0228 202 158 34 0

50

60

70

80

90

100

% A

live

an

d D

ise

ase

Fre

e

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

514 493 466 105 1518 497 447 116 0

50

60

70

80

90

100

Negative Positive

RR = 0.62p = 0.005

RR = 0.68p = 0.02


Pre vs Post Operative ACNSABP B-18

Fisher et al, JCO 1997 15:2483

S

S -More Breast ConservationMore Breast Conservation-Response Predicts OutcomeResponse Predicts Outcome

No Difference in DFS or OS through 5 years f/u

B-18B-18Disease-Free and Overall Disease-Free and Overall

SurvivalSurvivalAccording to ResponseAccording to Response

00

20%20%

40%40%

60%60%

80%80%

100%100%

22 44 66 88YearYear

P=0.00005P=0.00005pINVpINVcPRcPRcNRcNR

pCRpCR

22 44 66 88

pINVpINVcPRcPRcNRcNR

pCRpCR

P=0.0008P=0.0008

Wolmark N: CDC, 2000Wolmark N: CDC, 2000

NSABP B-27NSABP B-27

1492

718

9.8

19.7

?

?

n pCR DFS/OS

Bear et al, SABC Proceedings 12/2001 69:210. Abstract 5

AC

T

All Patients

4 cycles of CVAP

4 cycles of docetaxel4 cycles of docetaxel

4 cycles of docetaxel4 cycles of docetaxel

4 cycles of CVAP4 cycles of CVAP

No Response

Response

Ran

do

mise

First First PhasePhase

Second Second PhasePhase F

inal A

ssessmen

t / Su

rgery

Tax 301 StudyConducted by the Aberdeen

Breast Group

Fin

al Assessm

ent / S

urg

ery

N= 47

N= 50

N= 167

Tax 301 StudyTax 301 StudySurvivalSurvival

Patients whoPatients who responded to responded to CVAP CVAP

Randomized Randomized to: to: docetaxel docetaxel x4x4 or or CVAP x 4CVAP x 4

Survival Survival increased in increased in docetaxel docetaxel groupgroupTime (months)

6050403020100

Sur

viva

l pro

babi

lity

1.0

.9

.8

.7

docetaxel

CVAP

p=0.05

Log Rank Test

Taxanes as Adjuvant or Neo-Adj. Rx:

Available Randomized Trials

Study Design ResultCALGB 9344 AC +/-P POSITIVENSABP B-28 AC +/-P NEG. / EARLYMD Anderson P->FAC vs FAC Too Small...?POS.BCIRG 001 TAC vs FAC POSITIVENSABP B-27 AC +/-D POSITIVEAberdeen CAVp +/D POSITIVE

P = paclitaxelD = docetaxel

Taxanes in Breast Cancer

1.1. Better schedulingBetter scheduling

2.2. Dose – Dense programsDose – Dense programs

3.3. Synergy with other drugsSynergy with other drugs

4.4. Synergy with biological therapySynergy with biological therapy

5.5. Predict benefitPredict benefit

6.6. Newer generation of Taxanes Newer generation of Taxanes

How to Improve Outcome ??How to Improve Outcome ??

Scheduling of TaxolScheduling of Taxol

Advantages:Advantages:

1- Better toxicity profile- Less alopecia- Less neuropathy- Less myelosuppression

Perez et.al.Proc. ASCO, 1998 Abs #480

Weekly TaxolWeekly Taxol

Advantages:Advantages:Weekly TaxolWeekly Taxol

2- Better Tumour cell kill- More frequent drug exposure

Dose dense (Seidman et.al., JCO, 1998)

- Enhancement of Anti Angiogenic propertyof Taxol (Belotti et.al., Cancer Res.,1998)

- Enhancement of Apoptosis induction by Taxol (Milross et.al., JNCI, 1996)

Dose-dense Paclitaxel Via Dose-dense Paclitaxel Via Weekly 1-hour Infusion: Lack Weekly 1-hour Infusion: Lack Of Cumulative NeutropeniaOf Cumulative Neutropenia

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10111213141516171819202122

AN

C (

1000

/µL

)

WeekSeidman et al: JCO16:3353-61, 1998

Weekly vs q 3 Week PaclitaxelWeekly vs q 3 Week PaclitaxelMD Anderson Neo-Adjuvant MD Anderson Neo-Adjuvant

TrialTrial

225/24h

80mg/m2

Green MC, et al, Proc ASCO 2002 abs # 135

225/24h

150 (3/4 wks)

Node Neg.

Node Pos.

N= 258 patients

Weekly vs q 3 Week PaclitaxelWeekly vs q 3 Week PaclitaxelMD Anderson Neo-Adjuvant MD Anderson Neo-Adjuvant

TrialTrial

225/24h

80

mg/m2

Green MC, et al, Proc ASCO 2002 abs # 135

225/24h

150 (3/4 wks)

Path CR

29%29%

13%13%

28%28%

14%14%

Node Neg

Node Pos

1012

108

104

100

0 20 40 60

WeeksWeeks

Cel

l Num

ber

Cel

l Num

ber

Why conventional sequential therapy may fail?Why conventional sequential therapy may fail?

Dose dense sequential therapy… Why it might succeed?

q 2 wk (w/G-CSF)q 2 wk (w/G-CSF) q 3 wkq 3 wk

24 weeks

16 weeks 24 weeks

36 weeks

Radiation therapy and tamoxifen follow as appropriateClosed March 31, 1999 with n~2005

doxorubicin 60 mg/m2

cyclophosphamide 600 mg/m2

paclitaxel 175 mg/m2 over 3 hours

CALGB 9741

Intergroup Node (+) Trial

Citron et al: SABCC 12/02 abs # 15

Disease-Free Survival by Disease-Free Survival by DensityDensity

Years From Study Entry

Pro

po

rtio

n D

ise

ase

-Fre

e

0 1 2 3 4

0.0

0.2

0.4

0.6

0.8

1.0

q 2 wksq 3 wks

N= 988N= 985

Events= 136Events= 179

p=0.0072


Overall Survival by Overall Survival by DensityDensity

Years From Study Entry

Pro

po

rtio

n S

urv

ivin

g

0 1 2 3 4

0.0

0.2

0.4

0.6

0.8

1.0

Overall Survival By Density

q 2 wksq 3 wks

N= 988N= 985

Events= 75Events= 107

p=0.013


4.5%4.5%3.9%3.9%1.9%1.9%1.9%1.9%Neurologic: Severe Sensory Neurologic: Severe Sensory Loss or Motor WeaknessLoss or Motor Weakness

0%0%0%0%0%0%0%0%Platelet TransfusionPlatelet Transfusion

13%13%3%3%2%2%0%0%Red Cell TransfusionRed Cell Transfusion

2%2%5%5%2%2%3%3%Febrile Neutropenia Febrile Neutropenia HospitalizedHospitalized

9%9%43%43%3%3%24%24%Granulocytes < 0.5/ulGranulocytes < 0.5/ul

10110110110196969999No. DataNo. Data

495495501501493493488488No. TreatedNo. Treated

IVIVCon q 2Con q 2

IIIIIICon q 3Con q 3

IIIISeq q 2Seq q 2

IISeq q 3Seq q 3


Capecitabine

TPupregulation1

Bcl-2downregulation2

Taxane

Potential mechanisms Potential mechanisms underlying underlying

Capecitabine plus Taxane Capecitabine plus Taxane synergysynergy

1Sawada N et al. Clin Cancer Res 1998;4:1013–92Fujimoto-Ouchi K et al. Proc Am Assoc Cancer Res 2001 (Abst 463)

Taxotere/Cap Taxotere

42% PR + CR 30%

6.1 mons TTP 4.2 mons

13.7 mons OAS (median) 11.1 mons

32% IRC (PR+ CR) 23%

O’Shaughnessy et al. Proc San Antonio; Abs#381, 2000

Previous treatment by Anthracycline in 100%of patients for adjuvant/metastatic disease

N=255 N=256

Lessons From The Past 5 YearsLessons From The Past 5 Years Novel Combinations in Metastatic Breast Novel Combinations in Metastatic Breast

CancerCancer

Rationale for capecitabine in Rationale for capecitabine in combination: combination:

TP upregulationTP upregulation

PaclitaxelPaclitaxel 100100

DocetaxelDocetaxel 1515

VinblastineVinblastine 33

VindesineVindesine 55

Mitomycin CMitomycin C 55

DoxorubicinDoxorubicin 7.57.5

CisplatinCisplatin 1010

CyclophosphamideCyclophosphamide 200200

GemcitabineGemcitabine 9090

VinorelbineVinorelbine 1212

0 1 2 3 4 5 6 7 8 9 10

*

*

*

*

*

*

*†

*p<0.05†p value not available

TP upregulation (x control activity)

Ishitsuka H. Invest New Drugs 2000;18:343–54Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388)

(mg/kg)

Addition of Herceptin to chemotherapy Addition of Herceptin to chemotherapy improves:improves:

Response rate 54% Response duration 58% TTP 65% OAS (at 30 months) 25%

Slamon Proc ICAT; Abs # 24, 2002

Pivotal study Pivotal study (H0648g)

Herceptin in Combination with Chemotherapy as First Line in Metastatic Breast Cancer

Lessons From The Past 5 Lessons From The Past 5 YearsYears

Metastatic Breast CancerMetastatic Breast Cancer

Mean Combination Index Values for Mean Combination Index Values for Chemotherapeutic Drugs / Herceptin Chemotherapeutic Drugs / Herceptin

Combinations in-vitroCombinations in-vitro Drug Combination Interaction index

Vinorelbine 0.34 SynergyCisplatin 0.56 ± 0.15 SynergyEtoposide 0.54 ± 0.15 SynergyThiotepa 0.67 ± 0.12 SynergyDocetaxel/Platinum 0.34 SynergyPaclitaxel/carboplatin 0.64 SynergyDoxorubicin 1.16 ± 0.18 AdditionPaclitaxel 0.91 ± 0.23 AdditionMethotrexate 1.36 ± 0.17 AdditionVinblastine 1.09 ± 0.19 Addition5-fluorouracil 2.87 Antagonism

Pegram et al. Seminar Oncology, 2000

Advanced Breast CancerFirst Line

HER2 +HER2 +

TP Paclitaxel 175 mg/m2 q 21d

TPC Paclitaxel 175 mg/m2/Carboplatin (AUC 6) q 21d

Trastuzumab until progression

Trastuzumab until progression

Roberts et al; SABCC 2002

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Pro

gres

sion

Fre

e

P=0.007

Estimated Progression-Free Estimated Progression-Free Survival by Treatment ArmSurvival by Treatment Arm

TPC (% Progression Free)

TP (% Progession Free)

4533

2511

18 8

TPC TPPatients 96 95Median TTP (Mos) 11.2 6.9Range 1.2 - 36 1.2 - 43

Roberts et al; SABCC 2002

ConclusionsConclusions• The addition of Carboplatin to TP significantly

increases the overall response and time to progression

RRRR

TTPTTP

TP3+TP3+TPCTPC TPC3+TPC3+

37%52% 57%

7.2 mo11.2 mo 13.5 mo

TPTP

36%

6.9 mo

Herceptin Platinum Combination(s) in HER2 +ve Metastatic Breast

Cancer (prior exposure to Anthracyclines)

Herceptin Platinum Combination(s) in HER2 +ve Metastatic Breast

Cancer (prior exposure to Anthracyclines)

Ongoing study Ongoing study

CAIRO University Oncology CAIRO University Oncology CentreCentre

Herceptin 4mg/kg/week or 2mg/kg/weekCisplatinum 25 mg/m2 D1+D8+D15Navelbine 25 mg/m2 D1+D8+D15 Recycle D28 x 6 then maintain on weekly Herceptin till progression

Herceptin 4mg/kg/week or 2 mg/kg/weekCisplatinum 25 mg/m2 D1+D8+D15Taxol 60 mg/m2 D1+D8+D15Recycle D28 x 6 then maintain on weekly Herceptin till progress

patients previously treated By a Taxane

patients previously treated By a Taxane

patients not treatedBy a Taxane

patients not treatedBy a Taxane

Herceptin Platinum Herceptin Platinum Combination(s) in HER2 +ve Combination(s) in HER2 +ve

Metastatic Breast CancerMetastatic Breast Cancer

Herceptin Platinum Herceptin Platinum Combination(s) in HER2 +ve Combination(s) in HER2 +ve

Metastatic Breast CancerMetastatic Breast CancerOngoing study Ongoing study

CAIRO University Oncology CAIRO University Oncology CentreCentre

CR CR : 2: 2 PR PR : 7: 7 OAROAR : 9 (60%): 9 (60%) SD SD : 4: 4 DP DP : 2 (1 case HER2 +3): 2 (1 case HER2 +3) Response duration Response duration : 10 months: 10 months TTP TTP : 8.5 months: 8.5 months ttt>1yearttt>1year : 4 cases: 4 cases

Breast Cancer International Breast Cancer International Research Group [BCIRG]Research Group [BCIRG]

Node-/+HER2+

AC x 4 docetaxel x 4

C+T [carboplatin + docetaxel] x 6

Herceptin x 1 Year

AC x 4 docetaxel x 4

Herceptin x 1 Year

N=3,000Activated 2002

FISH +

Design of Design of Treatment Treatment

According to According to Molecular Profile Molecular Profile

of the Diseaseof the Disease

FUTUR PROMISES

Design of treatment according to molecular profile of the disease

CHANGINGCONCEPTS

• ? Need for adequate doses of Anthracycline • ? Need for a Taxane

• Need for Herceptin in metastatic phase ?adjuvant phase

• Herceptin synergy with other drugs

HER2/neu+ve

SurvivalSurvivalHER2 negative (n = 170)

ET 82 (95%CI 51-112) EC 90 (95%CI 79-101)

Median Survival in Weeks

200150100500

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Log rank p = 0.8999

ET 31 / 91events

EC 29 / 79 events

Weeks

Cu

m S

urv

ival

Konecny et al., Proc ASCO 2001

200150100500

HER2 positive (n =102)

ET 103 (95%CI 64-142) EC 56 (95%CI 41-71)

Median Survival in Weeks

SurvivalSurvival

ET 14 / 49 events

EC 27 / 53 events

Log rank p = 0.035

Weeks

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Cu

m S

urv

ival

Konecny et al. Proc ASCO, 2001

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

485 467 433 102 1478 455 402 108 0

40

50

60

70

80

90

100

% A

live

an

d D

ise

ase

Fre

e

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

138 131 118 32 0148 135 107 26 0

40

50

60

70

80

90

100

Disease Free Survival by Disease Free Survival by HER2 StatusHER2 Status

Negative (FISH) Positive (FISH)

RR = 0.74p = 0.06

RR = 0.59p = 0.02


CHANGINGCHANGINGCONCEPTSCONCEPTS


• ?? Resistance to Anthracycline

• ?? Sensitivity to Taxanes

Mutant P53

Taxol induced rapid onset of P53Independent apoptotic pathway

Taxanes may induce tumor cell apoptosis independent on P53 status

Lanni et cell biology;1997

Wood et al Mol Med;1995

A potential for Predictive A potential for Predictive Value of P53Value of P53

Patients with P53 deficient tumors may benefit

from Paclitaxel

Kandiokr-Eckersberger Clin CancerRes;2000

Anthracycline and radiation therapy requireIntact P53 for efficient tumor cell death

P53 mutations are associated with de novo resistance to Anthracyclines

In breast cancer patients

Lawe et cell biology;1993

Aas et al Nat Med;1996

CHANGINGCHANGINGCONCEPTSCONCEPTS


• SensitivityTo

Anthracycline

Overexpression of Topo II







6.6. Newer generation of TaxanesNewer generation of Taxanes


Taxane resistant Pat-21 breast cancerTaxane resistant Pat-21 breast cancer

Novel epothilone BMS-Novel epothilone BMS-247550: 247550:

Activity against clinical taxane Activity against clinical taxane resistanceresistance

Rx

Time post tumor implantation (days)

Rx

ControlPaclitaxel (36 mpk x5)

BMS-247550 (10 mpk x3)

Me

dia

n t

um

or

we

igh

(m

g)

10

100

1000

40 50 60 70 80

Years0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

Pat-21(Breast)

Biopsied

ADR + CMF (10 cycles)TAXOL + Dexverapamil

(4 cycles)

Microtubule stabilization is a clinically Microtubule stabilization is a clinically validated biological target validated biological target

Epothilone (BMS-247550) is active in vitro Epothilone (BMS-247550) is active in vitro and and in vivo against taxane-resistant tumor modelsin vivo against taxane-resistant tumor models

Activity demonstrated in taxane-refractory Activity demonstrated in taxane-refractory patients in Phase I and IIpatients in Phase I and II

Phase 2 studies are in progress, in a broad Phase 2 studies are in progress, in a broad program program via BMS and NCI via BMS and NCI

Novel epothilone BMS-Novel epothilone BMS-247550: Summary247550: Summary

HN

O

O

O H

O H

S

N

O

BMS-247550

Do We Really Need Anthracycline Do We Really Need Anthracycline For All Patients?For All Patients?

Do We Really Need Anthracycline Do We Really Need Anthracycline For All Patients?For All Patients?

Some tumorsmay not besensitive to

anthracycline

Some patientsmight not tolerate

anthracycline

Some Combinationsmay be moreeffective but

also more toxic •Herceptin

Do we need a Taxane in Do we need a Taxane in the treatment of breast the treatment of breast

cancercancer

CostCost BenefitBenefit

-Acute &-Acute & ch.ch. toxicitytoxicity-Q.O-Q.O..LL

Survival gainSurvival gain

How to minimizeHow to minimizeAdverse events? Adverse events?

How to predictHow to predictTherapeutic benefit?Therapeutic benefit?

BudgetBudget

How to improveHow to improveTreatment outcome? Treatment outcome?

taxenes in breast cancer (sharm).ppt

Documents

breast cancer adjuvant

adjuvant studyupdate

ac median

treatment of breast

rank pvalue

optimal taxane administration

treatment n

median follow42