genomics in the treatment of early stage breast cancer oncotype dx ™ breast cancer assay rosemary...

Genomics in the Treatment of Genomics in the Treatment of Early Stage Breast CancerEarly Stage Breast Cancer

OncoOncotypetype DX DX™™

Breast Cancer AssayBreast Cancer Assay

ROSEMARY LEEMING, MD, FACSApril 11, 2008

22

Agenda

• Introduction• Development of Oncotype DX• Clinical Studies

– Validation studies– Hormonal therapy benefit study (B-14)– Chemotherapy benefit study (B-20)

• ASCO Data (6/07)– Clinical Utility Studies

• Exploratory Studies– RS and local recurrence (SABCS 12-06)– Node Positive Data (ASCO 6/07)

• Other Gene Profiles– MammaPrint– “Invasiveness” gene signature

• TAILORx• Clinical Summary

33

Breast Cancer Treatment Planning: History

• Treatment planning for N–, ER+ disease is based on: – Traditional prognostic factors with limited

predictive power (tumor size, patient age) or poor reproducibility (tumor grade)

– IHC markers (eg, Ki-67) lacking standardization and validation

– Limited insight into relative benefits of chemotherapy for different individuals

Bundred. Cancer Treat Rev. 2001;27:137-142.

44

Breast Cancer Treatment Planning: Not Optimized

• Chemotherapy treatment for N–, ER+ disease– Many women are offered chemotherapy,

knowing that few benefit

– Guidelines assume all patients benefit equally

– Some patients are under-treated, many others are over-treated

55

Oncotype DX™: Unmet Clinical Need for Better Markers

Biopsyor

Resection

Optimize chemotherapy + local therapy +

hormonal therapy

Optimize local therapy and hormonal therapy

Robust markers

High risk/Large chemo benefit

Low risk/Little chemo benefit

66

Development and Validation of a 21-Gene Assay for N–, ER+, Tam+ Patients

Develop real-time RT-PCR method for paraffin block

Select candidate genes (250 genes)

Model building studies (N = 447, including 233 from NSABP B-20)

Commit to a single 21-gene assay

Validation studies in NSABP B-14 and Kaiser Permanente

YEAR

2001

2002

2002

2003

2003

Paik et al. N Engl J Med. 2004;351:2817-2826.

77

Oncotype DX™ Technology: Final Gene Set Selection

Study Site NNode

StatusER

Status Treatment

NSABP B-20, Pittsburgh, PA

233 N– ER+ Tamoxifen (100%)

Rush University, Chicago, IL

78 >10 positive nodes

ER+/– Tamoxifen (54%)Chemotherapy

(80%)

Providence St. Joseph’s Hospital, Burbank, CA

136 N+/– ER+/– Tamoxifen (41%)Chemotherapy

(39%)

21 genes and Recurrence Score (RS)algorithm

Paik et al. SABCS 2003. Abstract #16. Cobleigh et al. Clin Cancer Res. 2005;11(24 Pt 1):8623-8631.

Esteban et al. Proc ASCO 2003. Abstract #3416.

ObjectiveGene expression and relapse-free survival correlations across three independent studies – testing 250 genes in 447 patients

88

Oncotype DX™ 21-Gene Recurrence Score (RS) Assay

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Category RS (0-100)Low risk RS <18

Int risk RS ≥18 and <31

High risk RS ≥31


RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score + 0.05 x CD68- 0.08 x GSTM1- 0.07 x BAG1


Clinical Validation:Clinical Validation:

The The NSABP B-14 Study*NSABP B-14 Study*

*Paik et al. N Engl J Med. 2004;351:2817-2826.

1010

• Objective: Prospectively validate RS as predictor of distant recurrence in N–, ER+ patients

• Design

– Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan

Oncotype DX™ Clinical Validation: Genomic Health – NSABP B-14

Randomized

Registered

Placebo—not eligible

Tamoxifen—eligible

Tamoxifen—eligible


1111

Oncotype DX™ Clinical Validation:B-14 Results – Distant Recurrence-Free

Survival (DRFS)

DRFS Over Time – All 668 Patients

10-year DRFS = 85%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16

Years

DR

FS


1212

Oncotype DX™ Clinical Validation: B-14 Study Objectives

• First primary objective– Validate that 10-year DRFS in the

low-risk group (RS <18) is larger than 10-year DRFS in the high-risk group (RS ≥31)

• Second primary objective– Determine whether Recurrence Score as a predictor of

DRFS is more significant than age and tumor size


1313

Oncotype DX™ Clinical Validation: B-14 Results – DRFS

DRFS for the three distinct cohorts identified

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16

Years

DR

FS

P <0.00001

Low Risk (RS <18) n = 338

Intermediate Risk (RS 18-30) n = 149

High Risk (RS 31) n = 181


1414

Oncotype DX™ Clinical Validation:B-14 Results – DRFS (cont.)

Risk Group % of 10-yr Rate of Patients Recurrence 95% CI

Low (RS <18) 51% 6.8% 4.0%, 9.6%

Intermediate (RS 18-30) 22% 14.3% 8.3%, 20.3%

High (RS ≥31) 27% 30.5% 23.6%, 37.4%

Test for the 10-year DRFS comparison between the low-and high-risk groups: P <0.00001


1515

Oncotype DX™ Clinical Validation: B-14 Results Multivariate Analysis Confirms Power of RS

Multivariate Cox Models: Age, Size Alone vs Age, Size + RS

0.058(0.99, 2.11)1.44Size >2.0 cm

0.004(0.39, 0.83)0.57Age ≥50

P value95% CIHazard RatioVariable

<0.00001(2.23, 4.61) 3.21Recurrence Score

0.231(0.86, 1.85)1.26Size >2.0 cm

0.084(0.48, 1.05)0.71Age ≥50 P <0.00001

Age at surgery used as a binary factor: 0 = <50 yr, 1 = ≥50 yr.Clinical tumor size (CTS) used as a binary factor: 0 = ≤2 cm, 1 = >2 cm.Recurrence Score used as a continuous variable, with HR relative to an increment of 50 RS units.


1616

Oncotype DX™ Clinical Validation:Conclusions – NSABP B-14

• RS validated as predictor of recurrence in N–, ER+ patients

• RS performance exceeds standard measures (age, size)

• 50% of patients are reclassified by RS when compared to NCCN criteria

• RS (based on tumor gene expression) more accurately quantifies the risk of distant recurrence than do the NCCN guidelines (based on age, tumor size, and tumor grade)


Clinical Validation:Clinical Validation:

The The Kaiser Permanente StudyKaiser Permanente Study

Habel et al. Breast Cancer Res. 2006;May 31;8(3):R25.

1818

The Kaiser Permanente Study: Methods

Study Design

Study Population

Data Sources

Case-control

Kaiser Permanente patients <75 yr in 14 Northern California hospitals diagnosed with node-negative BC 1985-94, no chemotherapy (N = 4964)

Cases: Deaths from BC (n = 220)

Controls: Randomly selected, matched on age, race, diagnosis year, KP facility, tamoxifen (n = 570)

Cancer registry, medical records, archived diagnostic slides, and tumor blocks

Habel et al. Breast Cancer Res. May 2006.

1919

The Kaiser Permanente Study: Risk of BC Death at 10 Years: ER+, Tam+ Patients

% of % of 10-yr Cases Controls Absolute

Risk Classifier (n = 55) (n = 150) Risk1

Recurrence Score Low (<18) 29% 63% 2.8%2

Intermediate (18-30) 40% 23% 10.7% High (>31) 31% 13% 15.5%

1Based on methods by Langholz and Borgan, Biometrics 1997;53:767-774.

2Consistent with 3.0% absolute risk of breast cancer death in similar population of tamoxifen-treated patients in NSABP B-14.


2020

The Kaiser Permanente Study: Conclusions

• “The RS has now been shown to be strongly associated with risk of breast cancer-specific mortality among LN–, ER+, tam-treated patients participating in a clinical trial and among similar patients from the community setting.”

• “Combining Recurrence Score, tumor grade, and tumor size provides better risk classification than any one of these factors alone.”



Prediction of Tam Benefit:Prediction of Tam Benefit:NSABP B-14 Placebo andNSABP B-14 Placebo and

Tamoxifen Arms* Tamoxifen Arms*

*Paik et al. ASCO 2004. Abstract #510.

2222

Design

Objective: Determine whether the 21-gene RS assay provides information on:

1) Prognosis (likelihood of recurrence)2) Response to tamoxifen (change in likelihood of

recurrence with tamoxifen)3) Both

Tamoxifen Benefit and Oncotype DX™

NSABP B-14 Tam Benefit Study in N–, ER+ Patients

Randomized

Placebo-Eligible

Tam-Eligible

Paik et al. ASCO 2004. Abstract #510.

2323

All Patients (N = 645)

0 2 4 6 8 14 16

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

PlaceboTamoxifen

1210

B-14 Overall Benefit of Tamoxifen


2424

B-14 Benefit of TamoxifenBy Recurrence Score Risk Category

Low Risk (RS<18)N

171142

Int Risk (RS 18-30)N8569

High Risk (RS≥31)N9979

Interaction P = 0.06

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210

0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210 0 2 4 6 8 14 16

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

PlaceboTamoxifen

1210


2525

Analysis of Placebo and Tam-Treated Patients in NSABP B-14

• Conclusions– RS combines prognostic and predictive

factors into one assay report

– RS performance is derived from measurement of expression of each of the 21 genes on a continuous scale with high precision and reproducibility



Prediction of Chemo Benefit:Prediction of Chemo Benefit:

NSABP B-20 StudyNSABP B-20 Study**

*Paik et al. J Clin Oncol. 2006;24:3726-3734

2727

Chemotherapy Benefit and Oncotype DX™

Design

Objective: Determine the magnitude of the chemo benefit as a function of the 21-gene RS assay

Randomized

Tam + MF

Tam + CMF

Tam

NSABP B-20 Chemo Benefit Study in N–, ER+ Pts

Paik et al. J Clin Oncol. 2006;24:3726-3734.

2828

B-20 Results

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

All Patients

Tam + ChemoTam P = 0.02

N Events 424 33 227 31

DR

FS

Tam vs Tam + Chemo – All 651 Patients

Paik et al. J Clin Oncol. 2006.

4.4% absolute

benefit from tam + chemo

2929

B-20 Results: Tam vs Tam + Chemo

28% absolute benefit from tam + chemo

Paik et al. J Clin Oncol. 2006.

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 R isk Patients (R S < 18) T am + C hemo T am

p = 0.61

N Events 218 11 135 5

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 + C hemo Tam

p = 0.39

N Events 89 9 45 8

Low RS

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

H igh R isk Patients (R S 31) T am + C hemo T am

p < 0.0001

N Events 117 13 47 18

Int RS

High RS

3030

LowRS <18

IntRS 18-30

HighRS ≥31

0 10% 20% 30% 40%

B-20 Results: Absolute % Increase in DRFS at 10 Years

n = 353

n = 134

n = 164

% Increase in DRFS at 10 Yrs (mean ± SE)Paik et al. J Clin Oncol. 2006.

3131

• Benefits of adjuvant treatment differ by Recurrence Score risk category

– Benefits of tamoxifen are greater in patients with low-risk or intermediate-risk tumors

– Benefits of chemotherapy are greater in patients with high-risk tumors

RS and Breast Cancer Death in NSABP B-14 and B-20

3232

ASCO ABSTRACTS JUNE 2007

• CLINICAL UTILITY OF ONCOTYPE DX

– ABSTRACT #577: LOYOLA UNIVERSITY

– ABSTRACT #576: MAYO CLINIC

Prospective multi-center study of the impact of the 21-gene Recurrence Score (RS) assay on medical oncologist (MO) and patient

(pt) adjuvant breast cancer (BC) treatment selection.

Shelly S. Lo1, John Norton1, Patricia B. Mumby1, Jeffrey Smerage2, Joseph Kash3, Helen K. Chew4, Daniel Hayes2,

Andrew Epstein5, Kathy S. Albain1

1Loyola University, Maywood IL, 2University of Michigan, AnnArbor MI, 3Edward Hospital, Naperville IL, 4UC Davis,

Sacramento CA, 5Mount Sinai Medical Center, New York NY

3434

Background

• The 21-gene Recurrence Score (RS) assay (Oncotype DXTM) has been validated to quantify the risk of distant recurrence in tamoxifen treated patients in lymph node negative, estrogen receptor (ER) positive breast cancer. The RS also predicts benefit from adjuvant chemotherapy.

• There is little data regarding the impact of the RS on medical oncologist (MO) and patient (pt) decision making. A multi-center study was designed to prospectively examine whether the RS affects MO and pt adjuvant treatment selection.

ASCO 2007, Abstract #577

3535

Methods

• 17 MOs at 1 community and 3 academic practices participated in this study. Each participating MO consecutively offered enrollment to eligible women with node negative, ER positive breast cancer.

• Each participating MO and consenting patient completed pre- and post-RS assay questionnaires specifically developed for the study.

• MOs stated their adjuvant treatment recommendation and confidence in it pre and post RS assay.

• Pts indicated treatment choice pre and post RS assay. In addition, patients completed measures for quality of life, anxiety, and decisional conflict pre and post assay.

• RS assay results were returned to MO and shared with pt for routine clinical care.

• Frequency distributions and co-frequency tables are used to display categorical distributions of nominal variables; means and standard deviations are used to summarize continuous variables.

3636

Medical Oncologist Characteristics

• 17 medical oncologists from 4 institutions

– University of Michigan: 6

– LUMC: 6

– Edward: 3

– UC Davis: 2

• Length of time in practice <5 yrs: 29%

• Length of time in practice>5 yrs: 71%


3737

Change in Treatment Recommendation by RS

Treatment Recomm.

Pre-RS Post- RS

Number (%) Mean RS Number (%)

Mean RS

CHT 42 (47.2%) 21 23 (25.8%) 29

HT alone 46 (51.7%) 18 60 (67.4%) 16

Equipoise 1 (1.1%) 19 6 (6.7%) 19


3838

MO Treatment Recommendations Changed 31.5% of the Time

MO Pre to Post-RS Assay Treatment Recommendation

Number of Cases(%)

CHT to HT 20 (22.5)

HT to CHT 3 (3.4)

CHT or HT to Equipoise 5 (5.6)

Treatment plan did not change 61 (68.5)

Total 89 (100)

Treatment recommendation changed in 28 (31.5%) after results of RS Assay known. The largest change was from a recommendation of CHT to HT in 22.5% of cases.

3939

Conclusions

• RS Assay changed physician adjuvant treatment recommendations in 31.5% of the cases

• RS Assay is used by patients in their adjuvant treatment decisions

• Results from the RS assay was associated with less adjuvant chemotherapy administration– The largest treatment recommendation change for

MO was changing recommendation from CHT to HT

4040

How Well Do Standard Prognostic Criteria Predict Oncotype DX Scores?

Kamal AH, Loprinzi CL, Reynolds C,

Dueck AC, Geiger XJ, Ingle JN,

Carlson RW, Hobday TJ, Winer EP,

Perez EA, Goetz MP

Mayo Clinic, Rochester, MN; Mayo Clinic, Jacksonville, FL; Stanford Comprehensive

Cancer Center, Palo Alto, CA; Dana-Farber Cancer Institute, Boston, MA

4242

Mayo Clinic Study

Methods:

31 patients with Oncotype DX scores available

Slides reviewed for path, receptors and her-2

Cases presented to 6 “academic” oncologists, blinded to RS

asked to predict RS and to recommend chemo

given RS and asked chemo question again

4343

Mayo Clinic Study

Results:

RS: low – 18, int – 10, high – 3

Concordance between predicted and actual RS low/int vs. high >87%

Easier to pick out high risk

More important to identify low risk than low/int

4444

Mayo Clinic Study

Results:

Most frequent discrepancies:

actual low RS predicted as intermed

(31/80 discordant 39%)

actual intermed RS predicted as low

(29/80 discordant 36%)

Treatment recommendations following Oncotype DX changed about 18.2%

most frequent change from CHT to HT

4545

Mayo Clinic Study

Conclusions:

“Proper evaluation and interpretation of traditional prognostic criteria will identify most node negative, ER+ patients at high risk of recurrence (as predicted by RS), but poorly discriminate low vs. intermediate risk.”

Recommendation for treatment was changed in about 20% of cases

This study used expert pathologists and nationally known breast oncologists.

4646

Conclusions of clinical utility studies

• Oncotype DXTM directly changes treatment recommendations approx. 20 – 30+% of the time

• Physicians and patients alike find the RS useful

• Even when treatment decisions are not altered, the RS can increase confidence in the decision

4747

ONCOTYPE DX

EXPLORATORY STUDIES:

ONCOTYPE DX AND LOCAL RECURRENCE

ONCOTYPE DX AND NODE POSITIVE PATIENTS

ONCOTYPE DX AND NEO-ADJUVANT CHEMOTHERAPY

4848

48

Association Between Recurrence Score

and Risk of Local-regional Failure

in N─, ER+ Breast Cancer:

Results from NSABP B-14 and NSABP B-20

E. Mamounas, G. Tang, J. Bryant, S Paik, S Shak, E. Mamounas, G. Tang, J. Bryant, S Paik, S Shak,

J Costantino, D Watson, D. L Wickerham, and N Wolmark J Costantino, D Watson, D. L Wickerham, and N Wolmark

4949

Study ObjectivesStudy Objectives

• To examine the relationship between RS To examine the relationship between RS and and Risk of Loco-Regional Failure (LRF)Risk of Loco-Regional Failure (LRF) in Node-Negative, ER-Positive, Patients in Node-Negative, ER-Positive, Patients from NSABP B-14 and NSABP B-20: from NSABP B-14 and NSABP B-20:

–Placebo treated patients from B-14Placebo treated patients from B-14

–Tamoxifen treated patients from B-14, B-20Tamoxifen treated patients from B-14, B-20

–Chemo-TAM treated patients from B-20Chemo-TAM treated patients from B-20

5050

Study PopulationStudy Population

• Patients with RS Assay from NSABP node-Patients with RS Assay from NSABP node-negative, ER-positive adjuvant trials:negative, ER-positive adjuvant trials:

– B-14 Placebo: 355 pts B-14 Placebo: 355 pts

– B-14/B-20 Tamoxifen: 895 ptsB-14/B-20 Tamoxifen: 895 pts• B-14: 668 B-14: 668

• B-20: 227 B-20: 227

– B-20 Chemo + Tamoxifen: 424 ptsB-20 Chemo + Tamoxifen: 424 pts

5151

SurgerySurgery

TypeType

B-14B-14

PlaceboPlacebo

(n=355)(n=355)

B-14B-14

TAMTAM

(n=668)(n=668)

B-20B-20

TAMTAM

(n=227)(n=227)

B-20B-20

TAM+ChemTAM+Chem

(n=424)(n=424)LumpectomyLumpectomy 32%32% 42%42% 48%48% 39%39%MastectomyMastectomy 68%68% 58%58% 52%52% 61%61%

Patient CharacteristicsPatient CharacteristicsSurgery TypeSurgery Type

• All lumpectomy patients received breast XRTAll lumpectomy patients received breast XRT

• Post-mastectomy chest wall XRT was not allowedPost-mastectomy chest wall XRT was not allowed

• Regional nodal XRT was not allowed irrespective of surgical Regional nodal XRT was not allowed irrespective of surgical procedureprocedure

5252

1.6 2.7

7.8

Chemo + TAM Chemo + TAM n=424n=424

P=0.028P=0.028

4.37.2

15.8

TAM n=895TAM n=895

P<0.0001P<0.0001

10.8

2018.4

Placebo Placebo n=355n=355

P=0.022P=0.022

00101

0202

0303

0404

0%%

10 Year LR Failure Rates According to 10 Year LR Failure Rates According to Treatment and RS CategoryTreatment and RS Category

RS < 18RS < 18

RS RS >>3131RS 18-30RS 18-30

5353

VariableVariable P-value P-value HRHR HRHR 95% CI for95% CI for

Recurrence ScoreRecurrence Score 0.0050.005 2.162.16 (1.26, 3.68)(1.26, 3.68)

Age (Age (>> 50 vs. < 50) 50 vs. < 50) 0.00020.0002 0.400.40 (0.25, 0.65)(0.25, 0.65)

Mastectomy vs. Mastectomy vs. Lumpectomy + Lumpectomy +

XRTXRT0.0470.047 0.620.62 (0.39, 0.99)(0.39, 0.99)

CTS ( >2 cm vs. CTS ( >2 cm vs. << 2 cm)2 cm) 0.9330.933 0.980.98 (0.61, 1.59)(0.61, 1.59)

Grade (Mod vs. Grade (Mod vs. Well)Well) 0.9660.966 1.101.10 (0.54, 1.92)(0.54, 1.92)

Grade (Poor vs. Grade (Poor vs. Well)Well) 0.1050.105 1.761.76 (0.89, 3.48)(0.89, 3.48)

Multivariate Cox Proportional Hazard ModelsMultivariate Cox Proportional Hazard Models TAM-Treated Pts (n=895)TAM-Treated Pts (n=895)

5454

AgeAge RSRS LRF LRF RateRate 95% CI95% CI P-P-

valuevalue EventsEvents

<50<50 < 18< 18 1.5%1.5% (0, 4.5%)(0, 4.5%) 0.0010.001 2/732/7318 - 3018 - 30 7.6%7.6% (0, 17.6%)(0, 17.6%) 2/312/31

≥ ≥ 3131 23.8%23.8% (9.4%, (9.4%, 38.1%)38.1%) 9/499/49

≥ ≥ 5050 < 18< 18 2.6%2.6% (0.1%, 5%)(0.1%, 5%)0.0050.005 6/1896/18918 - 3018 - 30 3.8%3.8% (0, 8.1%)(0, 8.1%) 3/823/82

≥ ≥ 3131 12.8%12.8% (4.3%, (4.3%, 21.3%)21.3%) 9/819/81

10-Year Loco-Regional Failure Rates 10-Year Loco-Regional Failure Rates TAM-Treated PtsTAM-Treated Pts with with MastectomyMastectomy (n=505) (n=505)

5555

55

Exploratory Analysis10-Year Loco-Regional Failure Rates

TAM-Treated Pts with Mastectomy (n=505)

• RS correlated with 10-year LRF rates in patients

< 50 and > 50

– High (23.8%) LRF rate in pts <50 with a high RS

– However, small sample size of pts <50 who had

high RS and mastectomy (49 pts)

• Subset analysis - hypothesis-generating ONLY

5656

AgeAge RSRS LRF RateLRF Rate 95% CI95% CI P-P-valuevalue EventsEvents

<50<50 < 18< 18 12.5%12.5% (4.4%, 20.7%)(4.4%, 20.7%) 0.0570.057 10/7210/72

18 - 3018 - 30 27.7%27.7% (8.8%, 46.6%)(8.8%, 46.6%) 7/237/23

≥ ≥ 3131 26.5%26.5% (12.2%, (12.2%, 40.8%)40.8%) 12/4512/45

≥ ≥ 5050 < 18< 18 3.6%3.6% (0.1%, 7.1%)(0.1%, 7.1%) 0.6630.663 6/1396/139

18 -18 - 3030 3.7%3.7% (0, 8.7%)(0, 8.7%) 4/584/58

≥ ≥ 3131 4.8%4.8% (0, 11.2%)(0, 11.2%) 3/533/53

10-Year Loco-Regional Failure Rates 10-Year Loco-Regional Failure Rates TAM-Treated Pts with TAM-Treated Pts with Lumpectomy/XRTLumpectomy/XRT (n=390) (n=390)

5757

57

Exploratory Analysis Summary

10-Year Loco-Regional Failure Rates

TAM-Treated Pts with Lumpectomy/XRT (n=390)

• Women < 50: RS associated with LRF (p = 0.057)

– LRF is high with intermediate/high RS

• Women > 50: RS NOT associated with LRF (p = 0.663)

• However, as a subset analysis these findings should be

hypothesis-generating ONLY

5858

SummarySummary

• The 21-Gene Recurrence Score was found to predict risk of The 21-Gene Recurrence Score was found to predict risk of LRF in node-negative, ER-positive, pts treated with LRF in node-negative, ER-positive, pts treated with tamoxifen.tamoxifen.

• In this group of pts, RS was an independent predictor of In this group of pts, RS was an independent predictor of LRF along with age and surgery type.LRF along with age and surgery type.

• RS also predicted risk of LRF in node-negative, ER-positive RS also predicted risk of LRF in node-negative, ER-positive pts treated with chemotherapy + tamoxifen and to a lesser pts treated with chemotherapy + tamoxifen and to a lesser extent in those treated without adjuvant therapyextent in those treated without adjuvant therapy

5959

ConclusionsConclusions

• The present study demonstrates a similar association between The present study demonstrates a similar association between RS and risk for LRF as the one previously shown for RS and RS and risk for LRF as the one previously shown for RS and risk of distant failure. risk of distant failure.

• This information has biologic implications and may have This information has biologic implications and may have clinical implications relative to loco-regional therapy decisions clinical implications relative to loco-regional therapy decisions

in patients within patients with node-negative, ER-positive breast cancer.node-negative, ER-positive breast cancer.

6060

60

Can Oncotype DX be used for

node positive patients?

Prognostic Utility of the 21-Gene Assay in Hormone Receptor (HR) Positive Operable Breast Cancer and 0-3 Positive Axillary Nodes Treated with

Adjuvant Chemohormonal Therapy (CHT): An Analysis of Intergroup Trial E2197

Goldstein LJ1, Gray R1, Childs B2, Watson D3, Yoshizawa C3, Rowley S2, Shak S3, Badve S1,

Davidson NE1, Sledge GW1, Sparano JA1

From the Eastern Cooperative Oncology GroupFrom the Eastern Cooperative Oncology Group11, , sanofi aventissanofi aventis22, & Genomic Health, Inc., & Genomic Health, Inc.33

6262

62

ASCO 2007 - Abstract #526

6363

ObjectivesObjectives

Specific:1. To evaluate the prognostic utility of Oncotype DX

Recurrence Score (RS) in patients with HR-Pos treated with adjuvant chemotherapy

2. To perform an exploratory analysis for individual genes associated with prognosis in patients with HR-Pos and HR-Neg disease treated with adjuvant chemotherapy (analysis ongoing)

3. To perform an exploratory analysis to identify individual genes associated with differential sensitivity to AC versus AT (analysis ongoing)

6464

Outcomes by Nodal Status

6565

Outcomes by Recurrence Score

6666

66

5-Year Event Rates by Nodal Status & RS Recurrence Rates Are Very Low (Recurrence Rates Are Very Low (<< 5%) if the RS < 18 Irrespective of 5%) if the RS < 18 Irrespective of

Axillary Lymph Node StatusAxillary Lymph Node Status

RS Nodes RFI (%) DFS (%) OS (%)

Low <18Neg 96 93 95

Pos 95 91 97

Int 18-30

Neg 86 87 97

Pos 87 77 86

High ≥ 31

Neg 87 80 92

Pos 75 61 72ASCO - Abstract #526

6767

67

Conclusions

For HR-Pos Disease with 0-3 Pos Axillary Lymph NodesFor HR-Pos Disease with 0-3 Pos Axillary Lymph Nodes

• Low RS (< 18) predictive of excellent Low RS (< 18) predictive of excellent

outcomes at 5 yrsoutcomes at 5 yrs

• including patients with 1-3 positive axillary lymph nodes

• when adjusted for centrally determined tumor grade

• Low RS (< 18) commonLow RS (< 18) common

• ~ 46% of patients with HR-positive disease in this study,

of whom 49% had 1-3 positive axillary lymph nodes

ASCO - Abstract #526

6868

Prognostic and Predictive Value of the Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in 21-Gene Recurrence Score Assay in

Postmenopausal, Node-Positive (N+), ER-Postmenopausal, Node-Positive (N+), ER-Positive (ER+) Breast Cancer Positive (ER+) Breast Cancer

SWOG 8814, TBCI 0100SWOG 8814, TBCI 0100Oral Presentation #10Oral Presentation #10

K. Albain, W. Barlow, S. Shak, G. Hortobagyi, R. K. Albain, W. Barlow, S. Shak, G. Hortobagyi, R. Livingston, I. Yeh, P. Ravdin, C. Yoshizawa, F. Livingston, I. Yeh, P. Ravdin, C. Yoshizawa, F. Baehner, N. Davidson, G. Sledge, E. Winer, C. Baehner, N. Davidson, G. Sledge, E. Winer, C.

Hudis, J. Ingle, E. Perez, K. Pritchard, L. Hudis, J. Ingle, E. Perez, K. Pritchard, L. Shepherd, C. Allred, K. Osborne, and D. Hayes for Shepherd, C. Allred, K. Osborne, and D. Hayes for

The Breast Cancer Intergroup of North AmericaThe Breast Cancer Intergroup of North America

6969

SWOG 8814/TBCI 0100 Correlative Science Rationale

• The 21-gene Recurrence Score assay (RS) is prognostic for women with node(-), ER+ breast cancer on 5 years of tamoxifen*

• A high RS predicts large benefit from chemotherapy in node(-) disease, but no improvement if the RS is low**

• There are no RS data in a N+ population with a tamoxifen-alone control

• SWOG 8814 is an ideal trial to explore this question Albain, SABCS 2007, Abstract #10

*Paik, et al. NEJM, 2004**Paik, et al. J Clin Oncol, 2006

7070

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

RANDOMIZEn = 1477

tamoxifen x 5 yrs CAF x 6, then tamoxifen

CAF x 6, with concurrent tam

Superior Disease-Free Survival (DFS) and Overall Survival (OS)

over 10 Years

(n = 361)(n = 550) (n = 566)

Albain, SABCS 2007, Abstract #10Albain, et al. Breast Cancer Res Treat 2005

7171

SWOG 8814/TBCI 0100 Correlative Science Study

1) Provides prognostic information for women with N+ disease treated only with tamoxifen, and

2) Allows prediction of a N+ group that does not derive benefit from chemotherapy

Two co-primary objectives were to determine if the RS:

Albain, SABCS 2007, Abstract #10

7272

0.0

00.

25

0.5

00.

75

1.0

0

Dis

eas

e-f

ree

surv

ival

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 Survival0.

00

0.2

50.

50

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00

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ree

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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


7373

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

and OS in Tamoxifen Arm

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

0.0

00

.25

0.5

00

.75

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0 2 4 6 8 10


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

0.0

00

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0.5

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High RS ≥31 (n=47)


(tamoxifen alone)Overall Survival by Risk Group

0.0

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High RS ≥31 (n=47)


(tamoxifen alone)Disease-Free Survival by Risk Group

0.0

00

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High RS ≥31 (n=47)


(tamoxifen alone)Disease-Free Survival by Risk Group


7474

0.0

00

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0.5

00

.75

1.0

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isea

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ree

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0 2 4 6 8 10




Low risk (RS < 18)

Disease-Free Survival by TreatmentNo 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

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0 2 4 6 8 10




High risk (RS ≥31)

Disease-Free Survival by Treatment

0.00

0.25

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ease

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Intermediate risk (RS 18-30)

Disease-Free Survival by Treatment


7575

CAF Benefit Greatest in Higher RS for Both Nodal Subsets,

with No Benefit in Lower RS

Recurrence Score

0.2

.4.6

.81

Fiv

e Y

ear

Pro

bab

ility

of

an E

ven

t

0 20 40 60 80 100

Tam, 4+ nodes (n=54)

CAF-T, 4+ nodes (n=86)Tam, 1-3 nodes (n=94)CAF-T, 1-3 nodes (n=133)

Linear model for Recurrence Score and interactions with treatmentFive-Year Probability of Death or Disease Recurrence

Chemo benefit 4+ nodes

Chemo benefit 1-3 nodes


7676

NEOADJUVANT DATA

Milan and Baylor Studies

7777

Chemotherapy Response: Exploratory Studies in Stage 3 neoadjuvant setting confirm the

findings from NSABP B20 StudyMilan Study Baylor Study

– Independent & Exploratory Studies in Stage 3 patients

– Nearly identical trends with neoadjuvant & CR rates

– Consistent with B20

Neoadjuvant anthracyline-taxane treatmentNeoadjuvant anthracyline-taxane treatment Neoadjuvant docetaxel therapy Neoadjuvant docetaxel therapy

Gene Expression Profiles in Paraffin-Embedded Core Biopsy Tissue Predict Response to

Chemotherapy in Women With Locally Advanced Breast Cancer

L. Gianni, M. Zambetti, K. Clark, J. Baker, M. Cronin, J. Wu, G. Mariani, J. Rodriguez, M. Carcangiu,

D. Watson, P. Valagussa, R. Rouzier, W. Symmans, J. Ross, G. Hortobagyi, L. Pusztai, and S. Shak

Gianni et al. J Clin Oncol. 2005;23(29):7265-7277.

7979

Study Design Istituto Nazionale Tumori – Milan

Core biopsy

Primary chemotherapyDOX/TAX 3 w TAX 12

Surgery

Adjuvant chemotherapyIV CMF q 4 wks 4

RT TAM

for RT-PCRanalysis

for pathologydetermination

of pCR

Nonrandomized in women with LABC

89 evaluable patients


8080

Results – Chemotherapy Response

• 89 evaluable patients– 11 patients with pathologic complete response (pCR)

• 4 pts ER+ by IHC

– pCR rate in ER+ pts = 8% (95% CI 1%-15%)

• 7 pts ER– by IHC

– pCR rate in ER– pts = 23% (95% CI 8%-37%)

– Overall pCR rate = 12%


8181

Higher Recurrence Score Associated With Higher Likelihood of pCR (P = 0.005) to neoadjuvant

anthracyline-taxane treatment

Gianni et al. J Clin Oncol. 2005;23(29):7265-7277. N=89

P=0.005

Milan Study

Gene expression profiles in paraffin-embedded core biopsies

predict docetaxel chemosensitivity

J. Chang, A. Makris, SG. Hilsenbeck, J. Hackett, J Jeong, M Liu, J Baker, K Sexton,

K Osborne, S Shak

8383

Methods

Patients identified from 3 phase II clinical trials who received neoadjuvant docetaxel (100 mg/m2 q3wks) for 4 cycles before surgery

Diagnostic biopsies: 10-micron sections x 3

98 clinically eligible patients

81 (83%) of 98 with adequate tumor tissue (≥5% tumor)

80 (99%) of 81 with adequate RNA and expression signal

72 (90%) of 80 with response data (RECIST)

Chang, ASCO 2006, Abstract #538

8484

Correlation between RS and clinical complete response

Likelihood of correlation between RS and clinical complete response (CR) is not significant among all 3 categories (P = 0.3792)

Recurrence Category Complete Response

Yes No

Low Risk 0 (0%) 8 (100%)

Intermediate Risk 3 (13.6%) 19 (86.4%)

High Risk 9 (21.4%) 33 (78.6%)

Chang, ASCO 2006, Abstract #538

8585

≥1.7-fold increase in the odds of CR to neoadjuvant docetaxel therapy for

high vs. low RS

Chang, ASCO 2006, Abstract #538N=72

Baylor Study

8686

Exploratory Studies Summary

• RS is associated with LRF

• Associated with response to modern

Neoadjuvant Chemotherapy

• Prognostic in Node Positive Disease

86

8787

Other Gene Profiles

• MammaPrint– 70-gene signature

– Netherlands–based Agendia

• “Invasiveness” Gene Signature– 186-gene signature

– University of Michigan, Ann Arbor

• Wound Response Signature

8888

MammaPrint and Oncotype DX Distinctions

MammaPrint• Fresh Tissue by Microarray• 81% Microarray success rate

for RNA extraction• Binary result (low risk vs. high

risk) • Patients all <61 years old• 302 untreated patients (LN-,

ER+, ER-)• Clinical Utility Not Yet

Established–Patients not representative

of those diagnosed and treated today

• Insurance Coverage TBD

Oncotype DX• FPET by RT-PCR• 99% FPET success rate for

RNA extraction• Continuous Predictor Curve

(Individual Recurrence Score)

• No age barriers• Multiple, reproducible studies in

>2,600 treated patients with ER+, LN- disease

• Provides Clinical Utility for adjuvant treatment decisions–>20,000 patients, 4,500

physicians• Over 100 million lives insured

TAILORxTAILORx(PACCT-1 Trial)(PACCT-1 Trial)

Sponsored by NCISponsored by NCI Administered by ECOG Administered by ECOG

Participating cooperative groups include ECOG, SWOG, NCCTG, CALGB, NCIC,

ACOSOG, and NSABP

9090

Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx)

• Premise– Integration of a molecular profiling test (Oncotype DX™)

into the clinical decision-making process

• Implications– Reduce chemotherapy overtreatment in those likely to

be optimally treated with hormonal therapy alone– Reduce inadequate treatment by identifying individuals

who derive great benefit from chemotherapy– Evaluate benefit of chemotherapy where uncertainty

still exists about its utility

9191

Schema: TAILORx

Node-Neg, ER-Pos Breast CancerNode-Neg, ER-Pos Breast Cancer

RS <10HormoneTherapyRegistry

RS <10HormoneTherapyRegistry

RS 11-25Randomize

Hormone Rxvs

Chemotherapy + Hormone Rx

RS 11-25Randomize

Hormone Rxvs

Chemotherapy + Hormone Rx

RS >25Chemotherapy

+Hormone Rx

RS >25Chemotherapy

+Hormone Rx

Oncotype DX™ AssayOncotype DX™ AssayRegister

Specimen banking

Primary study group

9292

Study Design: Primary Objectives

• To determine whether adjuvant hormonal therapy (ie, experimental arm) is not inferior to adjuvant chemohormonal (standard arm) for patients in the “primary study group” (Oncotype DX™ RS 11-25)

• To create a tissue and specimen bank for patients enrolled in this trial to learn more about breast cancer

9393

Study Design: Secondary Objectives

• Low RS group (<11)– To determine risk of recurrence with hormonal therapy prospectively

• Comparison with clinical models (Adjuvant! Online)

• Refine estimates of Oncotype DX™ RS in contemporary practice

• Evaluate individual gene groups – Proliferation gene group

– HER2 gene group

– ER gene group

– Invasion gene group

– Other genes

9494

0%

5%

10%

15%

20%

25%

30%

35%

40%

0 5 10 15 20 25 30 35 40 45 50

Recurrence Score

Dis

tant

Rec

urre

nce

at 1

0 Ye

ars

Low Risk Group High Risk Group Intermediate Risk Group

genomics in the treatment of early stage breast cancer oncotype dx ™ breast cancer assay rosemary...

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