Up-to-Date Review

A Review of 2007 Breast Cancer Highlights

Harold J. Burstein, MD, PhDAssistant Professor of Medicine

Dana Farber Cancer InstituteBreast Oncology centerHarvard Medical School

Boston, MA

Highlights

• New agents for refractory disease

– Ixabepilone

– Lapatinib

• Chemotherapy in node-positive disease?

– CALGB 9344

– Oncotype DX®

Ixabepilone: Epothilone B Analog

• A new class of antineoplastics: the epothilones

• Epothilones bind to microtubules resulting in polymerization and apoptosis

• Novel microtubule-stabilizing agent with tubulin-binding mode distinct from other agents

S.cellulosum Epothilone B Ixabepilone

Lee JJ, Swain SM. Semin Oncol. 2005;32(suppl 7):S22-S26Kamath K et al. J Biol Chem. 2005;280:12902-12907Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.

Ixabepilone: Preclinical Activity

Days Post-Tumor Implant

Pat-21 Xenograft

Lee FY et al. Clin Cancer Res. 2001;7:1429-1437.

Control

Paclitaxel

Ixabepilone

1000

40 70 100 130 160

Med

ian

Tu

mo

r W

eig

ht

(mg

)

Paclitaxel Rx (36 mg/kg/inj)

Ixabepilone Rx (10 mg/kg/inj)

100

10

N = 8

Ixabepilone: Combination Preclinical Activity

(P=0.0001)

Days post-tumor implantGEO Human Colon Carcinoma

Me

dia

n t

um

or

we

igh

t (m

g)

Control IxabepiloneCapecitabine Combination

0

500

1000

1500

2000

2500

10 30 50

250 mg/kg (MTD)

10 mg/kg (MTD)

Capecitabine Synergy

Bevacizumab Synergy

Rx

20 40 601

10

100

1000

10000

Me

dia

n t

um

or

we

igh

t (m

g)

Control

Trastuzumab

Ixabepilone

Combined

Trastuzumab Synergy

Days Post-Tumor ImplantHER2 receptor positive KPL4

Human breast Carcinoma Xenografts

Data on file. Bristol Myers Squibb Company; Princeton, NJ

0

500

1000

1500

2000

2500

10 20 30 40 50 60 70

control

Ixabepilone, 6mg/kg

bevacizumab, 4mg/kg

Ixabepilone, 6mg/kg+

bevacizumab, 4mg/kg

Med

ian

tu

mo

r w

eig

ht

(mg

)

0

500

1000

1500

2000

2500

10 20 30 40 50 60 70

controlpaclitaxel24mg/kg

bevacizumab 4mg/kg

paclitaxel 24mg/kg+

bevacizumab 4mg/kg

Med

ian

tu

mo

r w

eig

ht

(mg

)

Days post-tumor implantGEO Human Colon Carcinoma

Days post-tumor implantGEO Human Colon Carcinoma

Trastuzumab, 10 mg/kgIxabepilone 4 mg/kg

Trastuzumab, 10 mg/kg+

Ixabepilone, 4 mg/kg

Ixabepilone in MBC: Summary of Single-agent Phase II Trials

1. Roche H et al. J Clin Oncol. 2007;23:3415-3420.

2. Denduluri N et al. J Clin Oncol. 2007;23:3421-3427.

3. Low et al. J Clin Oncol 2005;23:2726–2734

4. Thomas E et al. J Clin Oncol. 2007;23:3399-3406

7783

5753

4257

22 12

35

26

3541

0

10

20

30

40

50

60

70

80

90

100

After Adjuvant Anthracycline1 (40 mg/m2 q3w)

Taxane Naïve MBC2

(6 mg/m2 daily X 5)

Taxane Pretreated MBC3

(6 mg/m2 daily X 5)Taxane Resistant MBC4

(40 mg/m2 q3w)

Per

cen

tag

e (%

)

SD

RR

N=65 N=23 N=37 N=49

Ixabepilone(40 mg/m2 IV over 3 hr d1 q3wk)

+Capecitabine

(2000 mg/m2/day PO 2 divided doses d1-d14 q3wk)

N = 375

Capecitabine(2500 mg/m2/day PO 2 divided doses

d1-d14 q3wk)N = 377

Metastatic or locally advanced breast cancer

RESISTANT to anthracyclines

and taxanesN = 752

Stratification •Visceral metastases•Prior chemotherapy for MBC

Study Design: International, Randomized, Open-label, Phase III Trial

•Anthracycline resistance•Study site

Resistance to Prior Therapy

Strict definition: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes

Setting Anthracycline Taxane

Metastatic ≤3 months of last dose ≤4 months of last dose

Neo/adjuvant ≤6 months of last dose ≤12 months of last dose

Any

Minimum cumulative dose

Doxorubicin: 240 mg/m2

Epirubicin: 360 mg/m2

Phase III Study 046: Key Baseline Patient Demographics

Characteristic

Patients, no. (%)

Ixabepilone + Capecitabine

(N=375)

Capecitabine

(N=377)

Median age (min-max) in years 53 (25-76) 52 (25-79)

Visceral disease (liver and/or lung) 316 (84) 315 (84)

No. of disease sites: < 2 sites ≥ 2 sites

43 (11)

332 (89)

36 (10)

341 (90)

ER-, PR-, HER2- 91 (24) 96 (26)

Prior neoadjuvant/adjuvant chemotherapy 282 (75) 285 (76)

No. of prior chemotherapy regimens for metastatic disease

0

1

2

3

27 (7)

179 (48)

152 (41)

17 (5)

33 (9)

184 (49)

138 (37)

22 (6)

Anthracycline resistance 164 (44) 165 (44)

Taxane resistance

Neoadjuvant/adjuvant setting

Metastatic setting

PD as best response to prior taxanes

40 (11)

327 (87)

144 (38)

44 (12)

319 (85)

130 (35)

Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006; Data on file. Bristol Myers Squibb Company; Princeton, NJ; (ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.

Phase III Study 046: Progression-free SurvivalP

RO

PO

RT

ION

NO

T P

RO

GR

ES

SE

D

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 4 8 12 16 20 24 28 32

Median 95% CI

Ixabepilone + Capecitabine 5.7 mo (4.8–6.7)

Capecitabine 4.1 mo (3.1–4.3)

HR: 0.69 (0.58–0.83)

P<0.0001

(ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.

Phase III Study 046:Non-hematologic Toxicities

Adverse Events

Ixabepilone + Capecitabine, % (N=369)

Capecitabine, % (N=368)

Total G3 G4 Total G3 G4

Non-Hematologic Toxicities

Peripheral sensory neuropathy a,b,c 65 20 <1 16 0 0

Hand-foot syndrome 64 18 0 63 17 0

Fatigue/asthenia 60 15 <1 29 4 <1

Diarrhea 44 6 0 39 8 0.5

Myalgia/arthralgia 39 8 0 5 <1 0

Stomatitis/mucositis 31 4 0.5 20 3 0

a Grade 3/4 Peripheral Neuropathy 23% (21% sensory and/or 5% motor)bMedian time to improvement of Grade 3/4 neuropathy is 6.0 weekscImprovement was defined as a return of symptoms to baseline levels or to grade 1

Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006

Data on file. Bristol Myers Squibb Company; Princeton, NJ; (ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.

Ixabepilone Grade 3/4 Neuropathy Rates in Breast Cancer

3

0

3

20

12

21

14

0

5

10

15

20

25

Prior Therapy Neoadjuvant Taxane Naïve MBC

Taxane Pretreated

MBC

Anthracycline Pretreated

MBC

Taxane Resistant

MBC

Anthracycline and Taxane

resistant MBC

Anthracycline, Taxane, and Capecitabine

resistant MBC

Treatment schedule

40 mg/m2 q3w x 4 cycles

6 mg/m2 daily x 5

6 mg/m2 daily x 5

40 mg/m2 q3w 40 mg/m2 q3w 40 mg/m2 q3w

+ capecitabine

40 mg/m2 q3w

Median # of cycles

4 8 4 6 3 5 4

Roche H et al. J Clin Oncol. 2007;23:3415-3420; Denduluri N et al. J Clin Oncol. 2007;23:3421-3427; Low et al. J Clin Oncol 2005;23:2726–2734; Thomas E et al. J Clin Oncol. 2007;23:3399-3406; Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305; Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006; Perez E, et

al. J Clin Oncol. 2007;23: 3407-3414.

Gra

de

3/4

Neu

rop

ath

y R

ates

(%

)

Phase III Study 046:Hematologic Toxicities

Adverse Events

Ixabepilone + Capecitabine, % (N=369)

Capecitabine, % (N=368)

Total G3 G4 Total G3 G4

Hematologic Toxicities

Neutropenia 79 32 36 31 9 2

Febrile Neutropenia 5 4 1 1 0.5 0.5

Leukopenia 90 41 16 36 5 1

Anemia 84 8 2 6 4 1

Thrombocytopenia 44 5 3 6 2 2

Vahdat L, et al. Proc ASCO. 2007;25:18s Abstract 1006; Data on file. Bristol Myers Squibb Company; Princeton, NJ; (ixabepilone) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ; 2007.

Highlights

• New agents for refractory disease

– Ixabepilone

– Lapatinib

• Chemotherapy in node-positive disease?

– CALGB 9344

– Oncotype DX®

Burstein, H. J. N Engl J Med 2005;353:1652-1654

Interactions Between Trastuzumab and Tumor Cells

Lapatinib Targets HER2

Konecny et al, Cancer Res 2006; 66(3): 1630-9)

Phase I Results Summary

• Steady-state achieved in 6-7 days in cancer patients (Studies EGF10003 and EGF10004)1,2

• Serum concentrations were 90% of the in vitro IC503

• Dose proportionality at steady state (500 – 1600 mg/day)1

– Tmax = 3 – 6 hours post-dose

– Cmax = 1.02 – 2.13 g/mL

– AUC = 13.9 – 29.4 g/mL-h

• Effective half-life = 24 hours, once-daily dosing should be possible1,2

1. Burris HA et al. Journal of Clinical Oncology. 2005;23(23):5305-5313.

2. Burris HA et al. Oncologist. 2004;(9 suppl 3):10-15.

3. Kim TE, Murren JR. Drugs. 2003;6:886-893.

Phase I Results Summary

• Clinical activity observed in heavily pretreated patients in EGF10003 (43 patients)1

– 1 CR in head and neck cancer

– 1 minor response

– Stable disease for up to 13 months in remainder

• Clinical activity observed in heavily pretreated patients in EGF100042

– 4 PR in trastuzumab-resistant breast cancer

– Prolonged SD in 10 patients

• Well tolerated: most common AEs were rash, diarrhea, nausea, and fatigue1,2

1. Burris HA et al. Oncologist. 2004;(9 suppl 3):10-15.

2. Burris HA et al. Journal of Clinical Oncology. 2005;23(23):5305-5313.

EGF20002/EGF20008: Designs

EGF20002 EGF20008

Location North America Global

Planned Accrual 80200

A = 120, B = 80

Status Completed Completed

Treatment 1500 mg QD* 1500 mg QD

Tumor HER2 Status

3+ or FISH A: 3+ or FISH

B: negative

Prior Therapy

Trastuzumab Yes Yes: cohort A

Chemo 1-2 Prior A, T, & C

*first 13 patients treated at 1250 mg QD

Phase II Trial of Lapatinib for Brain Metastases in Patients with HER2-positive

Breast Cancer

NU Lin, LA Carey, MC Liu, J Younger, SE Come, M Ewend, E Bullitt, A van den Abbeele, JT Yap, G Harris, X Li, R Gelman, A Crawford, E Kasparian, HJ Burstein, D

Kirsch, F Hochberg, EP Winer

Dana-Farber/Harvard Cancer Center, University of North Carolina at Chapel Hill, Georgetown University

Best CNS Response (RECIST)(N=39)

Complete Response (CR) 0Partial Response (PR) 1 (2.5%)

Baseline Week 8

Taxane +Trastuzumab

Disease Progression

MD Anderson, 2001 SWOG, 2003

Caveat:trastuzumab t1/2

1-4 weeks

Test of Principle: Should Trastuzumab be Continued

After Disease Progression?

Vinorelbine

Vinorelbine +Trastuzumab

Study Design

• Progressive, HER2+ MBC or LABC

• Previously treated with anthracycline, taxane and trastuzumab*

• No prior capecitabine

Lapatinib 1250 mg po qd continuously +

Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

Patients on treatment until progression or unacceptable toxicity, then followed for survival

Stratification:• Disease sites• Stage of disease

RANDOMIZE

*Trastuzumab must have been administered for metastatic disease

N=528

Geyer CE et al. N Engl J Med 2006;355:2733-2743

Independent Radiology Review Investigator Reported Outcomes

Progression-free Survival

Geyer CE et al. N Engl J Med 2006;355:2733-2743

Overall Survival

Geyer CE et al. N Engl J Med 2006;355:2733-2743

Efficacy End Points in the Intention-to-Treat Population

Geyer CE et al. N Engl J Med 2006;355:2733-2743

Adverse Events

San Antonio Breast Cancer Symposium 2007

• German collaborative group study (Gunter von Minckwitz)

RANDOMIZED

Capecitabine

Capecitabine +

Trastuzumab

Trastuzumab-treated patients

Higher response rate and longer TTP resulted with ongoing anti-HER2 therapy

with trastuzumab

Highlights

• New agents for refractory disease

– Ixabepilone

– Lapatinib

• Chemotherapy in node-positive disease?

– CALGB 9344

– Oncotype DX®

Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer

ER + ER -

HER2+

trastuzumab

chemo

endocrine

trastuzumab

chemo

HER2 - endocrine

± chemochemo

In the Beginning, There Was ACAnd Then There Was CALGB 9344

CALGB 9344

A dose Sequential T

DFS

OS

De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008

Meta-analysis of Disease-free Survival (DFS)

De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008

Meta-analysis of Disease-free Survival (DFS) According To Estrogen Receptor (ER) Status

De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008

Meta-analysis of Disease-free Survival (DFS) According to HER-2 Status

De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008

Pooled DFS (A) and OS (B) Curves for Studies Included in the Meta-analysis

Hayes D et al. N Engl J Med 2007;357:1496-1506

Disease-free Survival Among Patients Treated with or without Paclitaxel According to Estrogen-Receptor

Status and HER2 Expression

Sorlie, et al. PNAS 2001

ER neg ER pos

HER2+Basaloid

2 3 4 5 6 7 8 9 10 11 12 13 14

E R E xpression (re la tive to re f genes; log2)

6

7

8

9

10

11

12

13

14

15

HE

R2

Exp

ress

ion

(re

lativ

e to

re

f ge

nes;

log2

) HER2+

ER+HER2-(luminal?)

Triple Neg*

*>94% of these cases are PR-;rarely strongly PR+

• First Cohort - n = 10,618

Oncotype DX® Results:Distribution of Quantitative ER and HER2

Current Recommendations for Chemotherapy for ER+ Breast Cancer• NIH Consensus Conference 2000

– LN+

– LN – if T > 1 cm

• NCCN 2006

– LN+

– LN – if T > 1cm

– Consider for LN – if 0.6 to 1.0 cm

• St. Gallen 2005 (endocrine responsive)

– LN + (> 4 LN if HER2 negative, any if HER2+)

– Consider for LN – if: T > 2 cm, or grade 2-3, or LVI+, or HER2+, or age < 35 years

Candidate Gene SelectionFrom ~40,000 genes

*Sources include: 1) Sotiriou et al., Breast Cancer Res Treat 4:R3, 20022) Scherf et al., Nat Genetics 24:236-44, 20003) Lamendola et al., Cancer Res 63:2200-5, 20034) Chang et al., Lancet 362:362-9, 20035) Staunton et al., Proc Natl Acad Sci U S A 98:10787-92, 2001

Cancer Literature

Microarray

Data*

Gen

omic

Dat

abas

e

s

384 cancer-related genes*

Molecu

lar

Biology

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromolysin 3Cathepsin L2HER2

GRB7HER2

BAG1

GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

• Best RT-PCR performance and most robust predictions

16 Cancer and 5 Reference Genes

Genomic Health-NSABP B-14 Prospective Clinical Validation Study

• Objective

– Validate Recurrence Score as predictor of distant recurrence in N-, ER+, Tamoxifen-treated patients

• Design

– Pre-specified 21 gene assay, algorithm, endpoints, analysis plan

– Blinded laboratory analysis of three 10 micron tumor block sections

Randomized

Registered

Placebo--Not Eligible

Tamoxifen--Eligible

Tamoxifen--Eligible

B-14

10 year DRFS = 85%

DRFS - All 668 Patients

B14-Results

0 2 4 6 8 10 12 14 16

Years

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DR

FS

Oncotype DX®

Validation Study B-14

Paik et al. NEJM 2004;351:2817

Low Risk (RS<18)N

171142

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

Int Risk (RS 18-30)N8569

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

High Risk (RS≥31)N9979

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

Benefit from Tamoxifen in the NSABP B14by Oncotype DX® Recurrence Score

Chemotherapy Response and Oncotype DX®

Design

Objective: Determine the magnitude of the chemotherapy benefit as a function of 21 gene Recurrence Score assay

Randomized

Tam + MF

Tam + CMF

Tam

NSABP Study B-20

B-20 Results

• Tam vs Tam + Chemo – All

All Patients N Events

Tam + Chemo 424 33

Tam 227 31

P = 0.02

0 2 4 6 8 10 12Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

RS < 18 “low”

RS 18-30 “int”

RS > 30 “high”0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0D

RF

S

High Risk Patients (RS 31) Tam + Chemo Tam

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

Int Risk (RS 18 - 30) Tam + Chemo Tam

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

Low Risk Patients (RS < 18) Tam + Chemo Tam

Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+

N = 1477

tam x 5 yrs CAF x 6, then tam

CAF x 6, with concurrent tam

Albain, et al. Breast Cancer Res Treat 2005

(N = 361)(N= 550) (N = 566)

RANDOMIZE

Superior Disease-Free Survival (DFS) and Overall Survival (OS) over 10 Years

0.0

00

.25

0.5

00

.75

1.0

0

Dis

ea

se

-fre

e s

urv

iva

l

0 2 4 6 8 10

Years since registration

Tamoxifen (N=148, 63 events)CAF-T (N=219, 74 events)

Stratified log-rank P-value = 0.054 at 10 years (adjusted for nodal status)

Disease-Free Survival

Outcomes in RS Subset Mirror Those Reported in Main Trial: Superiority of CAF-T

SWOG 8814/TBCI 0100 21-Gene Recurrence Score is Prognostic for DFS and

OS in Tamoxifen Arm

0.00

0.25

0.50

0.75

1.00

Ove

rall

Su

rviv

al

0 2 4 6 8 10

Years since registration

Low RS <18 (N=55)Intermediate RS 18-30 (N=46)

High RS ≥31 (N=47)

Stratified log-rank P = 0.003 at 10 years

(tamoxifen alone)Overall Survival by Risk Group

0.00

0.25

0.50

0.75

1.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Low RS <18 (N=55)Intermediate RS 18-30 (N=46)

High RS ≥31 (N=47)

Stratified log-rank P = 0.017 at 10 years

(tamoxifen alone)Disease-Free Survival by Risk Group

10-yr: 60%, 49%, 43% 10-yr: 77%, 68%, 51%

No benefit to CAF over time if low RS

Strong benefit if high RS

0.00

0.25

0.50

0.75

1.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (N=55, 15 events)CAF-T (N=91, 26 events)

Stratified log-rank P = 0.97 at 10 years

Low risk (RS < 18)

Disease-Free Survival by Treatment0

.00

0.2

50

.50

0.7

51

.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (N=47, 26 events)CAF-T (N=71, 28 events)

Stratified log-rank P = 0.033 at 10 years

High risk (RS ≥31)

Disease-Free Survival by Treatment

0.0

00

.25

0.5

00

.75

1.0

0

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (N=46, 22 events)CAF-T (N=57, 20 events)

Stratified log-rank P = 0.48 at 10 years

Intermediate risk (RS 18-30)

Disease-Free Survival by Treatment

Summary

• New treatment options available for refractory breast cancer

– Ixabepilone

– Lapatinib

• Ongoing refinement for:

– Patients who need chemotherapy

– Which types of chemotherapy