1. Oncotype DX® Breast Cancer Assay Clinical Data Review
Post-SABCS 2011 Update
GHI10102_0112

2. Agenda SABCS 2011 Meeting Overview
Clinical Validation of the Oncotype DX® Breast Cancer Assay for DCIS Patients
ECOG 5194 Podium Presentation
New Data for Patients with Invasive Breast Cancer
Oncotype DX reveals underlying biology in the neoadjuvant setting
Traditional clinical pathologic measures cannot predict the Recurrence Score®
Assay quality assurance is critical
Oncotype DX Changes Treatment Decision in Node Negative and Node Positive Breast Cancer
Advances in New Technology: Next Generation Sequencing
Closing Remarks

3. SABCS 2011 Meeting Overview
Understanding and treating the underlying biology
Quantifying recurrence risk in DCIS
New therapeutic regimens in ER-positive breast cancer
Combination antibody therapy for HER-2 positive disease
Continual advances in basic research and technology

4. Clinical Validation of the Oncotype DX® Breast Cancer Assay for DCIS Patients

5. A QUANTITATIVE MULTIGENE RT-PCR ASSAY FOR PREDICTING RECURRENCE RISK AFTER SURGICAL EXCISION ALONE WITHOUT IRRADIATION FOR DUCTAL CARCINOMA IN SITU (DCIS): A PROSPECTIVE VALIDATION STUDY OF THE DCIS SCORE FROM ECOG E Solin LJ, Gray R, Baehner FL, Butler S, Badve S, Yoshizawa C, Shak S, Hughes L, Sledge G, Davidson N, Perez EA, Ingle J, Sparano J, Wood W Eastern Cooperative Oncology Group (ECOG) North Central Cancer Treatment Group (NCCTG) Genomic Health, Inc (GHI) San Antonio Breast Cancer Symposium
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.

6. PRESPECIFIED STUDY OBJECTIVES
Primary: To determine whether there is a significant
association between the DCIS Score and the risk of
an ipsilateral breast event (IBE)
Secondary: To determine whether the DCIS Score provides value beyond standard clinical and pathologic factors
Conditional (if DCIS Score validated):
To evaluate the Recurrence Score as a predictor of risk of an ipsilateral breast event (IBE)
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.

7. DCIS SCORE: 10-YEAR IPSILATERAL BREAST EVENTS (IBE) BY RISK GROUP
ANY IBE
INVASIVE IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.

8. DCIS SCORE: 10-YEAR RISK OF AN IPSILATERAL BREAST EVENT (IBE)
ANY IBE
INVASIVE IBE
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.

9. SUMMARY: DCIS SCORE
Present study validates the DCIS Score as a predictor of an ipsilateral breast event (IBE) and invasive IBE
DCIS Score quantifies 10-year risk of IBE - Continuous variable or 3 risk groups
DCIS Score provides independent information on IBE risk beyond clinical and pathologic variables - Including tamoxifen, grade, and negative margin width - Identifies underlying tumor biology
DCIS Score provides a new clinical tool to guide treatment selection for patients with newly diagnosed DCIS
Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.

10. Oncotype DX® Reveals Underlying Biology in the Neoadjuvant Setting

11. Previous Studies Evaluating the Recurrence Score as a Predictor of Neoadjuvant Chemotherapy Response
Neoadjuvant Anthracyline-Taxane Treatment1
(N=89)
Neoadjuvant Docetaxel Treatment2 (N=72)
P=0.005
P=0.0079
1Gianni L, et al. J Clin Oncol Chang JC, et al. Breast Cancer Res Treat

12. Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER2-Negative Breast Cancer with Exploratory Oncotype DX® Assessments: A Sarah Cannon Research Institute Phase II Trial
Yardley DA,1,2 Peacock NW,1,2 Hendricks C,3 Huh SY,4 Ketchum S,5 Chao C,6 Yoshizawa C,6 Burris HA,1,2 Hainsworth JD1,2
1Sarah Cannon Research Institute, Nashville, TN; 2Tennessee Oncology, PLLC, Nashville, TN; 3Center for Cancer and Blood Disorders, Bethesda, MD; 4Providence Medical Group, Terre Haute, IN; 5Mercy Hospital, Portland, ME; 6Genomic Health, Inc.®, Redwood City, CA
Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P

13. Study Objectives
To correlate the baseline Oncotype DX® Recurrence Score® with
pCR rate to neoadjuvant ixabepilone/cyclophosphamide
Clinical response rate to neoadjuvant ixabepilone/cyclophosphamide
To compare Recurrence Score results determined at baseline to those determined after completion of neoadjuvant ixabepilone/cyclophosphamide
Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P

14. Clinical Characteristics and Neoadjuvant Treatment Results in Patients with Baseline Recurrence Score® Results
Characteristic (N=138)
Number of Patients
Median age, years (range)
51 (30-79)
Hormone receptor status
ER+ 75 (54%)
PR+ 61 (44%)
ER-/PR- 62 (45%)
Baseline Oncotype DX Recurrence Score
Low (<18) 20 (14%)
Intermediate (18-30) 23 (17%)
High (≥31) 95 (69%)
Completed 6 cycles of neoadjuvant chemotherapy
112
Definitive surgery performed
108
Clinical response to neoadjuvant treatment (N=112)
CR 30 (27%)
CR + PR 70 (63%)
Pathologic Complete Response (N=108)
19 (18%)
Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P

15. Baseline Recurrence Score (N=108) Logistic Regression of Continuous RS
Correlation of Pathologic Complete Responses and Baseline Recurrence Score® Results
Baseline Recurrence Score (N=108)
Baseline RS Group
Low
(RS<18)
Intermediate
(RS 18-30)
High
(RS≥31)
Proportion (%) with pCR
0/19 (0%)
0/17 (0%)
19/72 (26%)
Mantel-Haenszel Chi-square p=0.002
Logistic Regression of Continuous RS
Variable
Odds Ratio
95% CI
P-value
Continuous RS
57.9
(9.5,583)
<0.001
There were NO pCRs in tumors with either “Low” or “Intermediate” baseline Recurrence Scores (RS≤30).
A high Oncotype DX® Recurrence Score, analyzed either by RS group or as a continuous variable, was strongly associated with a pCR to neoadjuvant chemotherapy.
Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P

16. Paired Baseline and Post-treatment Recurrence Score® Results
o ER+ by IHC (n=44)
o ER- by IHC (n=28)
Spearman correlation
Overall: 0.82 (95% CI )
ER+: 0.60 (95% CI )
ER-: 0.55 (95% CI )
Lin’s concordance: correlation Overall: 0.76
ER+: 0.72
ER-: 0.44
N=72 samples
Paired baseline and post-treatment Recurrence Scores demonstrated concordance.
ER negative tumors demonstrated higher Recurrence Scores at baseline and after neoadjuvant chemotherapy.
13 of 40 tumors (33%) with a high RS at baseline had residual tumor with low or intermediate RS after neoadjuvant chemotherapy. No tumors with initial low or intermediate RS had high risk RS after neoadjuvant chemotherapy.
Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P

17. Summary and Conclusions
Baseline Oncotype DX® Recurrence Score ® Results were highly predictive of the likelihood of achieving a pCR with neoadjuvant ixabepilone/cyclophosphamide.
All pCRs occurred in patients with baseline high risk Recurrence Scores (≥31).
There was high concordance (Spearman coefficient = 0.82) and agreement (Lin’s concordance correlation = 0.76) in Recurrence Scores determined at baseline and after neoadjuvant chemotherapy, suggesting that most tumors retain the same molecular characteristics.
Further follow-up is necessary to confirm that Oncotype DX Recurrence Scores correlate with survival endpoints in addition to pCR rate.
Oncotype DX Recurrence Scores may provide important prognostic information in patients who are candidates for neoadjuvant chemotherapy. Identification of patients unlikely to achieve pCR with current regimens may be useful in the design of future clinical trials.
Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P

18. Traditional Clinical Pathologic Measures Cannot Predict the Recurrence Score®

19. Prospective Comparison of Risk Assessment Tools in Early Breast Cancer (Recurrence Score®, uPA/PAI-1, Central Grade, and Luminal Subtypes): Final Correlation Analysis from the Phase III WSG planB Trial
Gluz O,1,2 Kreipe HH,³ Degenhardt T,1 Christgen M,³ Kates R,1
Liedtke C, 1,4 Shak S,5 Clemens M,6 Markmann S,7 Uleer C,8
Augustin D,9 Thomssen C,10 Nitz U,1,2 and Harbeck N 1,11
on behalf of the planB investigators
1West German Study Group, Moenchengladbach, Germany; 2Bethesda Hospital, Moenchengladbach, Germany; ³Institut of Pathology, Medical College, Hanover, Germany; 4University Hospital Muenster, Muenster, Germany; 5 Genomic Health, Redwood City, CA.; 6Hospital Mutterhaus, Trier, Germany; 7University Hospital Suedstadt, Rostock, Germany; 8Gynecological Practice, Hildesheim, Germany; 9Hospital Deggendorf, Deggendorf, Germany; 10University Halle, Halle, Germany; 11 Breast Center, University of Cologne, Cologne, Germany
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.

20. Plan B Trial Design HER2-negative Primary Breast Cancer
HR-
RANDOMIZATION
T75C600 x 6*
pT1-4
free margins
pN+
pN0 high risk RE
CURRENCE
SCORE
0-3 LN and
RS>11
or ≥ 4 LN
E90C600x4 Doc100 x4*
pT>2cm
G2-3
uPA/PAI-1↑
HR-
age <35 years
HR+
0-3 LN and
RS<11
Endocrine therapy*
* Endocrine therapy and RT according to national guidelines
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.

21. Patient Characteristics
Recurrence Score® population
n=2549*
Central tumor bank population
n=3033
Age
< 50
> 50
Median
33%
67%
56 years
Nodal status
pN0
pN1
pN2/3
62% 5%
Tumor size
< 20 mm
> 20 mm
55%
45%
Central grade G1 G2 G3
63%
32%
57%
39%
*Baseline data not available for two patients
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.

22. Risk Distribution by Recurrence Score®
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.

23. Recurrence Score ® by Ki-67 Plan B Cut-offs
high risk
high risk
(>25)
(>25)
intermediate
intermediate
risk (12-25)
risk (12-25)
low risk
low risk
(0-11)
(0-11) 9%
67%
24%
32%
55%
13%
11%
68%
22%
41%
48%
11%
Ki-67 <14
Ki-67 14
Ki-67 <20
Ki-67 20
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..

24. Recurrence Score ® by Ki-67 Standard Cut-offs
high risk
high risk
(≥31)
(≥31)
intermediate
intermediate
risk (18-30)
risk (18-30)
low risk
low risk
(<18)
(<18) 3%
36%
61%
19%
43%
38% 3%
38%
59%
26%
44%
30%
Ki-67 <14
Ki-67 14
Ki-67 <20
Ki-67 20
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..

25. Recurrence Score® by Central Grade Plan B Cut-offs
high risk
(>25)
intermediate
Concordance is limited
If the RS is high it is quite likely that central grade is high.
However, the converse is not true.
risk (12-25)
low risk
(0-11) 4%
72%
24%
12%
67%
21%
43%
46%
11% 1 2 3
Central grade
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..

26. Recurrence Score® by Central Grade Standard Cut-offs
high risk
(≥31)
intermediate
Concordance is limited
If the RS is high it is quite likely that central grade is high.
However, the converse is not true.
risk (18-30)
low risk
(<18)
37%
63% 5%
39%
56%
30%
39%
31% 1 2 3
Central grade
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..

27. Conclusions
Large phase III prospective study comparing two CT regimens. Data presented: correlation between RS and uPA/PAI-1, central grade, and Ki-67in patients with HR+, N+/- early stage breast cancer at baseline.
RS data available in large cohort of 2,549 patients.
This study demonstrated only a moderate correlation between RS and Ki-67 and RS and central grade. Weak concordance was observed between RS and uPA/PAI-1.
As previously demonstrated in multiple studies, Oncotype DX® provides an individualized RS result that cannot be predicted by traditional clinicopathologic measures.
Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.

28. Assay Quality Assurance is Critical

29. Consistency and Control in Clinical Assay Technology over Time: The Oncotype DX® Recurrence Score® and Assessment of Single Gene Expression Levels Baehner FL,1,2 Butler S,1 Anderson J,1 Ballard J,1 Tan V,1 Tharayanil A,1 Shak S1 1Genomic Health, Inc., Redwood City, CA; 2University of California, San Francisco, San Francisco, CA
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

30. Background
The American Society of Clinical Oncology® and College of American Pathology® have highlighted the importance of consistency and control in clinical assay technology.1-2
The Genomic Health clinical laboratory quality assurance and quality control programs and biannual proficiency testing ensures consistency and reproducibility for the RS and quantitative single gene results for ER, PR, and HER2.
1Wolff A et al, J Clin Oncol Hammonds E et al, J Clin Oncol 2010.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

31. Methods
All tumors successfully analyzed in the Genomic Health laboratory from January 1, 2005 to March 31, 2011 were included.
Descriptive statistics for the Recurrence Score® value, the average reference gene expression level, and expression levels for quantitative single genes ER, PR and HER2 were calculated for each calendar year.
Single gene reporting (ER, PR, HER2) began in 2008.
The associations by year between HER2 and GRB7, ER and HER2, and ER and PR expression levels were characterized using scatterplots and correlation statistics.
Subgroup analyses were conducted by histological tumor type, core biopsy versus excision, and whether micro-dissection was done.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

32. Recurrence Score® Distribution Over Time
RS distribution is consistent over time.
The average and median RSs are 19.5 and 17, respectively.
Approximately 50% of cases have a RS between 12 and 24.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

33. Reference Gene Distributions
The distribution of the average non-normalized level of expression for the five reference genes remained consistent over time, with non-systematic variation in the median value within approximately 0.5 units.
The middle 50% of cases were within one unit, indicating consistently low variation in reference gene expression levels.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

34. ER Quantitative Gene Distributions
The distribution of quantitative ER and PR expression was consistent over time.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

35. HER2 Quantitative Gene Distributions
% HER2 positive: % % % %
The distribution of quantitative HER2 expression was consistent over time, with a wide range of HER2 expression noted.
The majority of cases show HER2 expression levels consistent with HER2 normal status.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

36. HER2 and GRB7 Quantitative Gene Distributions
Year
Pearson Correlation, Regression Slope
2008
0.80, 0.76
2009
0.79, 0.75
2010
0.77, 0.74
2011
HER2 and GRB7 gene expression are highly correlated
High degree of similarity over time in the distributions of HER2 and GRB7
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

37. Conclusions
This study evaluated consistency of RS and single gene expression levels for ER, PR, and HER2 over a 6 year period (2005 to 2011) in 207,691 patient cases.
Multiple quality control and quality assurance processes have resulted in consistent performance of the Oncotype DX® Breast Cancer Assay.
A high degree of consistency and no systematic change in expression level for reference genes, RS, ER, PR, or HER2 was observed.
Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P

38. Oncotype DX® Changes Treatment Decision in Node Negative and Node Positive Breast Cancer

39. Impact of the Recurrence Score® on Adjuvant Decision-Making in ER-positive Early Breast Cancer - Results of a Large Prospective Multicentre Decision Impact Study in Node-negative and Node-positive Disease
Rezai M,1 Eiermann W,2 Kümmel S,3 Kühne T,4 Warm M,5 Friedrichs K,6 Schneeweiss A,7 Markmann S,8 Eggemann H,9 Hilfrich J,10 Jackisch C,11 Witzel I,12 Eidtmann H,13 Kaufmann M,14 Blohmer J15
1 Luisenkrankenhaus, Düsseldorf, 2Rotkreuzkrankenhaus, München, 3Kliniken Essen Mitte, Essen, 4Klinikum, Esslingen, 5Krankenhaus Holweide, Köln, 6Mammazentrum, Hamburg, 7Nationales Tumorcentrum, Universität Heidelberg,, 8Universitätsklinikum, Rostock , 9Universitätsklinikum, Magdeburg ,10Eilenriedeklinik, Hannover, 11Klinikum, Offenbach, 12Universitätsklinikum, Hamburg , 13Universitätsklinikum, Kiel 14Universitätsklinikum, Frankfurt, 15Sankt Gertrauden-Krankenhaus, Berlin
Rezai M et al, San Antonio Breast Cancer Symposium 2011; Abstract P

40. Changes in Treatment Recommendations Based on the Oncotype DX® Results
Patients N
Overall Change Rate
Pre- to Post-Oncotype DX
CHT to HT
HT to CHT
Other
All evaluable
366
121
33.1% (95% CI 28.3 – 38.1) 79
21.6% 39
10.7% 3
0.8%
Node-negative
244 74
30.3% (95% CI 24.6 – 36.5) 45
18.4% 28
11.5% 1+
0.4%
Node-positive
122 47
38.5% (95% CI 29.9 – 47.8) 34
27.9% 11
9.0% 2*
1.6%
95% confidence intervals calculated using Clopper-Pearson method
+Observation to CHT *Observation to HT, CT to CHT
Rezai M et al, San Antonio Breast Cancer Symposium 2011; Abstract P

41. de Boer RH,1 Baker C,2 Speakman D,3 and Mann GB4
Australian Decision Impact Study: The impact of Oncotype DX® Recurrence Score® (RS) on Adjuvant Treatment Decisions in Hormone Receptor Positive (HR+), Node-negative (N0) and Node-positive (N+) Early Stage Breast Cancer (ESBC) in the Multidisciplinary Clinic (MDC)
de Boer RH,1 Baker C,2 Speakman D,3 and Mann GB4
1Royal Melbourne Hospital, Melbourne, Victoria, Australia; 2Austin Hospital, Melbourne, Victoria, Australia; 3Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; 4Royal Melbourne and Royal Women’s Hospital, Melbourne, Victoria, Australia
de Boer RH et al, San Antonio Breast Cancer Symposium 2011; Abstract P

42. Changes in Treatment Recommendations Based on the Oncotype DX® Results
Patients N
Overall Change Rate
Pre- to Post-Oncotype DX
CHT to HT
HT to CHT
All evaluable
151 36
24% 24
15.9% 12
7.9%
Node-negative
101 23
22.8%
11.9% 11
10.9%
Node-positive 51 13
26% 1 2%
de Boer RH et al, San Antonio Breast Cancer Symposium  2011; Abstract P

43. Conclusions
There were multiple decision impact studies presented at SABCS in both node-positive and node-negative patients.1-3
Changes in treatment decisions ranged from 23.8% to 33.1%.
These results are consistent with previous studies performed worldwide showing that the RS changes treatment decisions approximately a third of the time.4
1Rezai M et al, San Antonio Breast Cancer Symposium 2011; 2de Boer RH et al, San Antonio Breast Cancer Symposium 2011; 3Holt S et al, San Antonio Breast Cancer Symposium 2011; 4 Hornberger J et al, St Gallen International Breast Cancer Conference 2011

44. Advances in New Technology: Next Generation Sequencing

45. Breast Cancer Recurrence Risk Probed by Whole Transcriptome Next Generation Sequencing in 136 Patients
Baker J,1 Liu ML,1 Crager M,1 Stephans J,1 Pho M,1 Jeong J,1 Scott A,1 Ambannavar R,1 Morlan J,1 Pelham R,1 Qu K,1 Mena R,2 Esteban J,2 Collin F,1 and Sinicropi D1
1Genomic Health, Inc.®, Redwood City, CA; 2Providence Saint Joseph Medical Center, Burbank, CA
Baker J et al, San Antonio Breast Cancer Symposium 2011; Abstract PD 45

46. Summary and Conclusions
Genomic Health reported on the technical performance of whole transcriptome next generation sequencing compared to the 21-gene RT-PCR Oncotype DX® Breast Cancer Assay.
Whole transcriptome RNA-Seq identified more than 1800 new coding, intronic, and intergenic transcripts that were strongly associated with breast cancer recurrence risk.
This technology has sensitivity and selectivity comparable to RT-PCR, can provide a vast increase in the number of interrogated transcripts, can reveal new biological relationships, and has excellent performance suitable for the discovery of RNA biomarkers.
Baker J et al, San Antonio Breast Cancer Symposium 2011; Abstract PD

47. Closing Remarks
These studies support the importance of understanding cancer biology to advance the treatment of breast cancer patients.
Oncotype DX® is the first clinically validated commercial genomic assay quantifying the risk for local recurrence in DCIS patients.
Data from a large phase III prospective study confirms that the Recurrence Score® cannot be predicted by clinical and pathological variables.
A growing body of evidence suggests that the Recurrence Score may help guide neoadjuvant treatment decisions.

48. Closing Remarks
Genomic Health’s quality assurance and quality control programs ensure consistency and reproducibility for the Recurrence Score® and quantitative single gene results for ER, PR, and HER2.
Multiple decision impact studies demonstrate that the Recurrence Score changes treatment decisions in node negative and node positive breast cancer.
Genomic Health is committed to performing cutting edge research to better serve the oncology community (physicians and patients).

49. Thank You