1. Oncotype DX® Breast Cancer Assay

2. Agenda Introduction Development of Oncotype DX® Clinical Studies
Validation studies
Hormonal therapy benefit study (NSABP B-14)
Chemotherapy benefit study (NSABP B-20)
Node + study (SWOG 8814)
Decision Impact Studies
TAILORx
Genomic Health Clinical Laboratory Experience
Clinical Summary

3. 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
Likelihood of distant recurrence for node-negative (N–), estrogen receptor–positive (ER+) breast cancer is important for determining which women will benefit most from treatment and what will be the most appropriate treatment strategy.1
Generally, patients diagnosed with early breast cancer (defined as tumor size <5 cm, with no node involvement or metastasis) receive surgery (breast-conserving or mastectomy), radiotherapy with or without adjuvant hormonal therapy (dependent on their ER status), and/or chemotherapy.
Clinical and histological prognostic factors in general use include tumor size, stage, and grade, and patient age.1
Clinicians often select patients for chemotherapy over and above tamoxifen based on clinical characteristics that have limited predictive prognostic power, such as tumor size and patient age, or are subjective and not reproducible, such as tumor grade.
While many biological markers, such as markers of proliferation (e.g., Ki-67), have some prognostic value,1 the lack of standardized methods and poor reproducibility make their use problematic.1
1. Bundred NJ. Prognostic and predictive factors in breast cancer. Cancer Treat Rev. 2001;27:
Bundred. Cancer Treat Rev. 2001;27:

4. Breast Cancer Treatment Planning: Not Optimized
Chemotherapy treatment for N–, ER+ disease
Many women are offered chemotherapy, knowing that few benefit
Prior to 2007, guidelines assumed all patients benefit equally
Some patients are under-treated, many others are over-treated
The major challenge in current management of women with N–, ER+ breast cancer is the selection of patients for adjuvant chemotherapy.

5. What Would Your Treatment Strategy Be For This Patient?
Age: 61
ER: 95%
PR: 95%
Tumor Type: IDC
Tumor Size: 0.6 cm*
Tumor Grade: 2
HER-2 neu Neg (FISH)
*Additional 6 mm on re-excision
Standard version 8.0. Accessed 8/07 5

6. Recurrence Score: 36 Average Rate of Distant Recurrence at 10 Yrs: 25%

7. Oncotype DX®: Unmet Clinical Need for Better Markers
High risk/ Large chemo benefit
Optimize chemotherapy + local therapy + hormonal therapy
Biopsy
or Resection
Robust markers
A robust assay that could characterize an individual’s risk of recurrence and benefit from treatment would enable physicians to better tailor therapeutic intervention.
This type of assay can help inform decisions about patient management. For example, patients at high risk of recurrence and/or with large chemotherapy benefit may decide, together with their physicians, to receive appropriate chemotherapy, while those at low risk and/or with little chemotherapy benefit may decide, together with their physicians, to avoid the unwanted toxicities associated with chemotherapy.
Optimize local therapy and hormonal therapy
Low risk/ Little chemo benefit

8. Development and Validation of a 21-Gene Assay for N–, ER+, Tam+ Patients
YEAR
Develop real-time RT-PCR method for paraffin block
2001
Select candidate genes (250 genes)
2002
Model building studies (N = 447, including 233 from NSABP B-20)
2002
The Oncotype DX™ assay was developed in three steps:
Optimization of assay methods for quantifying gene expression in fixed, paraffin-embedded tissue (FPET) and development of a high-throughput real-time RT-PCR assay for this particular purpose.
Selection of 250 candidate genes from the human genome using microarray data as well as other information sources. In the first step of the gene selection process, 250 cancer-related candidate genes were selected from microarray data,1-4 genomic databases, cancer literature, and molecular and cell biology experiments.
3. Selection of a 21-gene panel based on three independent breast cancer studies of the candidate genes.
The following two factors synergistically contribute to success in using gene expression by RT-PCR to predict recurrence and/or benefit from treatment in breast cancer:
The measurement of expression of each gene is highly quantitative over a large dynamic range
The use of multiple genes to capture the independent pathways that are biologically important
The Oncotype DX™ assay was validated in two studies:
A large, independent, multicenter clinical trial, NSABP B-14
A large population-based case-control study in breast cancer patients at Northern California Kaiser Permanente
The prespecified Oncotype DX™ test was validated in these clinical studies with prospectively defined endpoints. this approach to assay development and validation is consistent with that outlined in a review article published in J Clin Oncol in 2005 by Richard Simon, DSc, National Cancer Institute.5
1. Gruvberger S, Ringner M, Chen Y, et al. Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res. 2001; 61(16):
2. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003;33(1):49-54.
3. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):
4. van't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):
5. Simon R. Roadmap for developing and validating therapeutically relevant genomic classifiers. J Clin Oncol. 2005;23(29):
Commit to a single 21-gene assay
2003
Validation studies in NSABP B-14 and Kaiser Permanente
2003
Paik et al. N Engl J Med. 2004;351:

9. Oncotype DX® Technology: Final Gene Set Selection
Objective
Gene expression and relapse-free interval correlations across three independent studies – testing 250 genes in 447 patients
Study Site N
Node Status
ER 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+/–
Tamoxifen (41%) Chemotherapy (39%)
21 genes and Recurrence
Score (RS)
algorithm
The 250 candidate genes were analyzed in a total of 447 patients from three separate studies, which eventually led to the 21-gene profile and an algorithm for calculating a Recurrence Score.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 study: A multicenter study in which tissue was analyzed from 233 patients in a homogeneous patient cohort characterized by having histologically negative nodes, estrogen receptor–positive tumors, and treatment with tamoxifen and no other intervention.1
Rush Presbyterian-St. Luke’s Hospital: A single-site study in which tissue was analyzed from 78 patients, all characterized by having >10 positive nodes and treatment predominantly with chemotherapy and/or tamoxifen.2
Providence St. Joseph’s Hospital: A single-site study in which tissue was analyzed from 136 patients who were either node positive or negative, ER positive or negative, and treated with tamoxifen or chemotherapy or not treated.3
Paik S, Shak S, Tang G, et al. Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients – NSABP studies, B-20 and B-14. SABCS Abstract #16.
Cobleigh MA, Tabesh B, Bitterman P, et al. Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res. 2005;11(24 Pt 1):
Esteban J, Baker J, Cronin M, et al. Tumor gene expression and prognosis in breast cancer: multi-gene RT-PCR assay of paraffin-embedded tissue. Proc ASCO Abstract #3416.
Paik et al. SABCS Abstract #16.
Cobleigh et al. Clin Cancer Res. 2005;11(24 Pt 1):
Esteban et al. Proc ASCO Abstract #3416.

10. Oncotype DX® 21-Gene Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN ER PR
Bcl2
SCUBE2
RS =
x HER2 Group Score
x ER Group Score
x Proliferation Group Score
x Invasion Group Score
x CD68
x GSTM1
x BAG1
GSTM1
BAG1
INVASION
Stromelysin 3
Cathepsin L2
The final gene set used for the Oncotype DX™ assay includes the 16 cancer genes identified in the clinical trials: 5 genes are in the proliferation group, 2 in the HER2 group, 4 in the estrogen receptor group, 2 in the invasion group, and 3 are unaligned. Some of the genes are well known in the breast cancer literature; others are relatively new.
The 5 reference genes are used for normalizing the expression of the cancer-related genes.
As was previously stated, it is important to note that there are other genes linked to breast cancer (eg, the 250 candidate genes from which the 16 genes were selected). The 16 genes presented in this slide were selected for the Oncotype DX™ assay based on the three clinical trials, which demonstrated a consistent statistical link between these genes and distant breast cancer recurrence and the most robust predictive power across the three studies.
The Recurrence Score is calculated from the expression results for each of the 16 cancer-related genes by the equation shown in this slide.
The Recurrence Score (RS) ranges from 0 to 100.
Although the coefficients for each gene or gene group influence the RS result, the quantitative expression for each gene can have a dominant effect. For example, there is a 200-fold range of expression of ER in the quantitative RT-PCR assay. For individual tumors, the expression of any one gene can affect the Recurrence Score to a large degree.
Cut-off points for Recurrence Score risk groups were defined prior to the initiation of the validation study:
A low-risk group with an RS of <18
An intermediate-risk group with an RS between 18 and 30
A high-risk group with an RS of 31
If the right number of genes to address these questions had been 6 or 60, we would have designed the assay accordingly. As it turned out, the assay was designed to include expression of 16 genes because the development studies indicated these genes provided the most robust predictive score.
CD68
Category
RS (0 -100)
Low risk
RS <18
Int risk RS
High risk
RS ≥ 31
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
HER2
GRB7
Paik et al. N Engl J Med. 2004;351:

11. Oncotype DX® Clinical Validation: RS as Continuous Predictor
My RS is 30. What is the chance of recurrence within 10 years?
The likelihood of distant recurrence at 10 years increases continuously with increase in Recurrence Score.
Patients with a Recurrence Score of 3 have a much lower risk of distant recurrence than patients with a Recurrence Score of 17, even though both have scores in the “low risk” group. The use of the Recurrence Score as a continuous predictor provides an estimate of the likelihood of distant recurrence at 10 years (mean and 95% CI) that is accurate and precise.
In the example presented in this slide, the patient has a Recurrence Score of 30; therefore, the risk of a distant recurrence at 10 years for this patient is 20% [95% confidence interval (CI): 15%, 24%]
95% CI

12. Oncotype DX® Clinical Validation: The NSABP B-14 Study*
*Paik et al. N Engl J Med. 2004;351:

13. Oncotype DX® Clinical Validation: Genomic Health – NSABP B-14
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
Randomized
Registered
Placebo—not eligible
Tamoxifen—eligible
A study was performed to clinically validate the prespecified 21-gene RT-PCR assay and Recurrence Score algorithm as a predictor of the prospectively defined primary endpoint of distant recurrence-free survival in N–, ER+ patients treated with tamoxifen from the large multicenter NSABP Study B-14.1
The study protocol also defined the prespecified endpoints and analysis plan. The laboratory was blinded to the clinical outcomes.
NSABP B-14 trial (original): 2828 N–, ER+ patients were randomized 1:1 to tamoxifen or placebo in double-blind fashion between 1982 and An additional 1235 patients were registered to tamoxifen in the 10-month period following closure of the trial in 1988, yielding 2617 clinically eligible tamoxifen-treated patients.
Patients who were treated with tamoxifen in the randomized portion or the registered portion of the trial were eligible for the Genomic Health study.
1. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:
Paik et al. N Engl J Med. 2004;351:

14. Oncotype DX® Clinical Validation: B-14 Results – Distant Recurrence
Distant Recurrence Over Time – All 668 Patients
100%
90%
80%
70%
60%
Proportion Without Distant Recurrence at 10 years = 85%
Proportion without Distant Recurrence
50%
40%
The overall distant recurrence-free survival at 10 years was 85%; 15% of the cohort had a distant recurrence at 10 years.
From the 2617 tamoxifen-treated patients in the study, 675 paraffin blocks were available in the NSABP tumor library (for the others, the blocks were never obtained or were depleted by prior study). The NSABP provided Genomic Health with FPET tissue from 675 patients who met clinical eligibility and pathology eligibility criteria. Of these 675 cases, 2 (0.3%) cases had insufficient RNA (< 275 ng), 2 (0.3%) failed assay quality control, and 3 (0.4%) failed sample quality control. These cases were excluded from analysis resulting in 668 (99%) cases with evaluable RT-PCR profiles.
The 668 evaluable patients were similar to all 2617 tamoxifen-treated patients.
30%
20%
10% 0% 2 4 6 8 10 12 14 16
Years
Paik et al. N Engl J Med. 2004;351:

15. Oncotype DX® Clinical Validation: B-14 Results – Distant Recurrence
Distant Recurrence for the three distinct cohorts identified 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100% 2 4 6 8 10 12 14 16
Years
P <0.001
Proportion without Distant Recurrence
The Recurrence Score was calculated for each patient: 51% of the patient population fell into the low-risk group (n = 338), 22% fell into the intermediate-risk group (n = 149), and 27% fell into the high-risk group (n = 181).
The Kaplan-Meier plot shows DRFS over time for the different risk categories. The distant recurrence-free survival percentages for the high- and low-risk groups were statistically significantly different; the 10-year distant recurrence-free survival for the low-risk group was 93% compared to 69% for the high-risk group.
RS <18 n = 338
RS n = 149
RS 31 n = 181
Paik et al. N Engl J Med. 2004;351:

16. Oncotype DX® Clinical Validation: B-14 Results – Distant Recurrence
Risk Group % of yr Rate of
Patients Recurrence % CI
Low (RS <18) 51% % 4.0%, 9.6%
Intermediate (RS 18-30) 22% % 8.3%, 20.3%
High (RS ≥31) % % 23.6%, 37.4%
The table presented in this slide indicates that the proportion of patients in the low-risk group who were distant-recurrence-free at 10 years was significantly greater than the proportion of patients in the high-risk group (P < ).
The risk of distant recurrence in the high-risk group is similar to that observed in node-positive patients.
For each risk-based cohort, the 95% confidence interval error bands have little or no overlap.
Test for the 10-year Distant Recurrence comparison between the low-and high-risk groups: P <0.001
Paik et al. N Engl J Med. 2004;351:

17. Multivariate Cox Models: Age, Size + RS
Oncotype DX® Clinical Validation: B-14 Results Multivariate Analysis Confirms Power of RS
Multivariate Cox Models: Age, Size + RS
Variable
Hazard Ratio
95% CI
P value
Age ≥50
0.71
(0.48, 1.05)
0.084
Size >2.0 cm
1.26
(0.86, 1.85)
0.231
Recurrence Score
3.21
(2.23, 4.61)
<0.001
If the multivariate Cox proportional hazards model is applied to the DRFS data using standard criteria such as age and clinical tumor size, age 50 is a statistically significant factor, with a hazard ratio of 0.57.
With addition of the Recurrence Score to the model, the Recurrence Score provides significant (P <0.001) predictive power that goes beyond age and clinical tumor size.
Overall, there is a significant (P <0.001) difference between the Cox proportional hazards model for DRFS based only on age and clinical tumor size and the proportional hazards model based on the Recurrence Score, age, and clinical tumor size.
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.
Paik et al. N Engl J Med. 2004;351:

18. Oncotype DX® Clinical Validation: The Kaiser Permanente Study
Habel et al. Breast Cancer Res. 2006;May 31;8(3):R25.

19. The Kaiser Permanente Study: Methods
Study Design
Study Population
Data Sources
Matched Case-Control
Kaiser Permanente patients <75 yr in 14 Northern California hospitals diagnosed with node-negative BC , 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
This study was performed using a case control study design. Of the population of almost 5000 patients with node-negative breast cancer, 220 cases with death due to breast cancer and 570 matched controls were studied. Of those 220 cases, 55 were treated with tamoxifen, and 150 tamoxifen-treated matched controls were studied.
This was a good test of the robustness of the assay, as it involved largely a community hospital–based patient population from multiple sites and many treating physicians. (albeit the study was conducted in one region of the country with physicians practicing in the same large multi-specialty group).
Habel et al. Breast Cancer Res. May 2006.

20. The Kaiser Permanente Study: Risk of BC Death at 10 Years: ER+, Tam+ Patients
10-yr 10-yr
Absolute Absolute
Risk Classifier Risk1 Risk Kaiser NSABP B14
Recurrence Score
Low (<18) % 3.1%
Intermediate (18-30) % 12.2%
High (>31) % 27.0%
Results indicate that the Oncotype DX™ Recurrence Score assay is predictive of breast cancer survival in the Kaiser Permanente population. Note the very low rate of breast cancer death, 2.8%, in the low-risk group at 10 years.
This result is similar to the result in NSABP B-14, where 3% of low-risk patients died from breast cancer at 10 years.
Also, as in NSABP B-14, more than half of the Kaiser Permanente population is in the low-risk group with a Recurrence Score <18.
No formal statistical analyses were performed to compare the results of Kaiser and NSABP B-14. The primary reason was the difference in study designs (randomized trial versus case-cohort design) and the resulting differences in analysis approaches (Cox proportional hazards model versus conditional logistic regression modeling).
1Based on methods by Langholz and Borgan, Biometrics 1997;53:
Habel et al. Breast Cancer Res. May 2006.

21. 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.”
The Kaiser study further validates the Oncotype DX™ breast cancer assay by showing that Recurrence Score is strongly associated with risk of breast cancer death among LN–, ER+ patients in a community setting and confirms the data from the NSABP B-14 study.
The Recurrence Score should be used in conjunction with traditional factors to best make treatment decisions for patients.
Habel et al. Breast Cancer Res. May 2006.

22. Oncotype DX® Prediction of Tam Benefit:
NSABP B-14 Placebo and Tamoxifen Arms*
*Paik et al. ASCO Abstract #510.

23. Tamoxifen Benefit and Oncotype DX™
NSABP B-14 Tam Benefit Study in N–, ER+ Patients
Design
Objective: Determine whether the 21-gene RS assay provides predictive information for patients who were treated with tamoxifen (likelihood of recurrence)
Placebo-Eligible
Randomized
Tam-Eligible
The objective of this additional study of the NSABP B-14 placebo arm was to determine whether the 21-gene Recurrence Score assay provides information on prognosis (likelihood of recurrence), response to tamoxifen (change in likelihood of recurrence with tamoxifen), or both.
Patients who were randomized in NSABP B-14 to placebo or to tamoxifen treatment were eligible.
From the 2817 clinically eligible randomized patients in the study, 645 paraffin blocks were identified and underwent successful evaluation with RT-PCR. As in the other studies, the loss of cases was principally because the blocks were never collected.
The 645 evaluable patients were similar to all 2817 randomized patients.
Paik et al. ASCO Abstract #510.

24. B-14 Overall Benefit of Tamoxifen
All Patients (N = 645)
1.0
0.9
0.8
0.7
0.6
0.5
Proportion without Distant Recurrence
0.4
Shown here is the overall benefit of tamoxifen in the 645 evaluable patients.
0.3
0.2
0.1
Placebo
Tamoxifen
0.0 2 4 6 8 10 12 14 16
Years
Paik et al. ASCO Abstract #510.

25. B-14 Benefit of Tamoxifen By Recurrence Score Risk Category2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
Placebo
Tamoxifen 12 10 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
Placebo
Tamoxifen 12 10
Proportion without Distant Recurrence
Proportion without Distant Recurrence
Low Risk (RS<18)
Int Risk (RS 18-30) N
171
142 N 85 69 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
Placebo
Tamoxifen 12 10
Interaction P = 0.06
The magnitude of the benefit of tamoxifen was then examined for each of the RS groups.
The patients in the low-risk group and in the intermediate-risk group as defined by the Recurrence Score had a large benefit from tamoxifen.
The apparent benefit from tamoxifen in patients in the high-risk group, as defined by a Recurrence Score 31, was smaller.
The P value for the interaction between tamoxifen treatment and the Recurrence Score is 0.06 which is suggestive that the recurrence score is predictive of tamoxifen benefit. These results suggest that the Recurrence Score provides information on both prognosis and benefit from tamoxifen. In addition, none of the individual genes alone was shown to predict both prognosis and benefit from tamoxifen as accurately as the Recurrence Score (based on multiple genes).
The results should not be used to indicate that tamoxifen should not be given to the high-risk group. First, we cannot exclude a small but clinically important benefit of tamoxifen with regard to DRFS. Second, tamoxifen has benefits in these patients with regard to prevention of contralateral breast cancer or second primaries. Nevertheless, these results indicate that one cannot expect large benefits from tamoxifen alone in the high-risk group.
Proportion without Distant Recurrence
High Risk (RS≥31)1
1 The results should not be used to conclude that tamoxifen should not be given to the high-risk group N 99 79
Paik et al. ASCO Abstract #510.

26. Analysis of Placebo and Tam-Treated Patients in NSABP B-14
Results
Subset of Oncotype DX® genes is prognostic
5 proliferation genes
Cyclin B1, Ki-67, MYBL2, Survivin, STK15 PR
Quantitative measurement of the ER gene expression by the Oncotype DX® assay predicts the benefit of tamoxifen
Quantitative ER and Recurrence Score are only modestly correlated
The key findings from the analysis of both the placebo and tamoxifen arms of NSABP B-14 are shown on this slide.
A subset of the Oncotype DX™ genes is prognostic.
The second major observation was that the quantitative measurement of the ER gene expression by the Oncotype DX™ assay predicts the benefit of tamoxifen. In other words, the Recurrence Score assay combines both prognosis and prediction of tamoxifen benefit into a single assay.
Third, quantitative ER expression measured by RT-PCR and the RS are only modestly correlated. No single gene provides all the information that is contained in the 21-gene assay.
Paik et al. ASCO Abstract #510.

27. 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
The Recurrence Score combines both prognostic and predictive features into one assay report.
The Recurrence Score’s performance is derived from measurement of the expression of each of the 21 genes, on a continuous scale with high precision and reproducibility.
Paik et al. ASCO Abstract #510.

28. Oncotype DX® Prediction of Chemo Benefit: NSABP B-20 Study*
*Paik et al. J Clin Oncol. 2006;24:

29. Chemotherapy Benefit and Oncotype DX®
NSABP B-20 Chemo Benefit Study in N–, ER+ Pts
Design
Objective: Determine the magnitude of the chemo benefit as a function of the 21-gene RS assay
Tam + MF
Randomized
Tam + CMF
The objective of this additional study of the NSABP B-20 patients was to determine the magnitude of the chemotherapy benefit (with MF or CMF) as a function of the 21-gene Recurrence Score assay.
Patients who were randomized in NSABP B-20 to tamoxifen or to tamoxifen plus either CMF or MF chemotherapy were eligible. The primary analysis was prespecified to compare the tamoxifen-treated patients with both chemotherapy arms combined.
In secondary pre-specified analyses, similar results were seen when the patients treated with CMF or with MF were examined separately.
The analysis by NSABP shows the B-20 study subjects included in this study were similar to all B-20 patients in the cohort and the loss of cases was principally due to blocks never being collected.
Fisher B, Dignam J, Wolmark N, et al. J Natl Cancer Inst.1997;89:
Paik S, Shak S, Tang G. Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. SABCS Abstract #24.
Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:
Tam
Paik et al. J Clin Oncol. 2006;24:

30. B-20 Results Tam vs Tam + Chemo – All 651 Patients Years
1.0
0.9
0.8
0.7
4.4% absolute benefit from tam + chemo at 10 years
0.6
Proportion without Distant Recurrence
0.5
Shown here is the overall benefit of chemotherapy in the 651 evaluable patients.
These results recapitulate the seminal findings from the original B-20 study (Fisher B, Dignam J, Wolmark N, et al. J Natl Cancer Inst.1997;89: ), which supported the widespread use of adjuvant cytotoxic therapy for this population.
The absolute benefit of chemotherapy at 10 years is 4.4%. Is this small overall benefit due to a little benefit in many or most of the patients, or is this small benefit due to a large benefit in a subset of the patients?
To address this question, the magnitude of the chemotherapy benefit was examined for each of the Recurrence Score risk groups.
0.4
0.3
All Patients
0.2
N Events
0.1
Tam + Chemo
P = 0.02
Tam
0.0 2 4 6 8 10 12
Years
Paik et al. J Clin Oncol

31. B-20 Results: Tam vs Tam + Chemo
Low RS
p = 0.61
Int RS
p = 0.39
Proportion without Distant Recurrence
Low Risk Patients (RS<18) N Events
TAM + Chemo TAM
Int Risk Patients (RS 18-30) N Events
TAM + Chemo TAM
28% absolute benefit from
tam + chemo
These results indicate that not all women benefit equally from chemotherapy.
The results in patients in the high-risk group (Recurrence Score >31) are shown here. It appears that much of the benefit associated with CMF therapy in the B-20 study was a function of the risk reduction experienced by this high-risk cohort, which represents approximately 25% of the population. The high-risk patients have a large benefit (28% absolute) from the addition of chemotherapy.
The results in patients in the low-risk group (Recurrence Score <18) are shown here. These patients have a very low likelihood of distant recurrence. The difference between the tamoxifen alone and tamoxifen plus chemotherapy groups is not statistically significant, so the benefit of chemotherapy appears to be minimal, if any.
The results in patients in the intermediate-risk group (Recurrence Score 18-30) are shown here. The patients in the intermediate-risk group, as expected, had a higher risk of distant recurrence than those in the low-risk group. The benefit of chemotherapy in the intermediate-risk patients does not appear to be large.
High RS
p < 0.001
High Risk Patients (RS≥31) N Events
TAM + Chemo TAM
Paik et al. J Clin Oncol

32. % Increase in Proportion Distant Recurrence-Free at 10 Yrs (mean ± SE)
B-20 Results: Absolute % Increase in Proportion Distant Recurrence-Free at 10 Years
n = 353
Low
RS <18
n = 134
Int
RS 18-30
Shown here is the absolute increase in distant recurrence-free survival provided by the addition of chemotherapy in each of the Recurrence Score risk groups.
The high-risk patients gain a large benefit from chemotherapy, with the absolute risk of recurrence decreased by 28%. This amounts to a 74% relative risk reduction in this group!
The low-risk patients have minimal, if any, benefit.
The intermediate-risk patients may gain as much as a 4% absolute benefit from chemotherapy. Consideration of chemotherapy treatment in the intermediate-risk patients should take into account all factors, such as the individual Recurrence Score (an RS of 19 is different from 30), tumor size, age, grade, patient preference, etc.
n = 164
High
RS ≥31
% % % %
% Increase in Proportion Distant Recurrence-Free at 10 Yrs (mean ± SE)
Paik et al. J Clin Oncol

33. Summary of Treatment Benefit Related to RS and Breast Cancer Death in NSABP B-14 and B-20
Shown here are the Kaplan-Meier estimates of the risk of breast cancer death at 10 years for the NSABP B-14 and B-20 studies
The results on top are for patients in the B-14 arm with no systemic therapy.
The results in the middle are the patients treated with hormonal therapy, both in B-14 tam and in B-20 tam.
The results at the bottom are for patients treated with hormonal therapy plus chemotherapy in NSABP B-20.
The Recurrence Score is optimized for hormonal therapy-treated patients and you can see in the middle the greatest discrimination, and that low-risk patients are low risk; intermediate-risk patients are intermediate; and high-risk patients are high risk.

34. Largest Tamoxifen Benefit Observed in Low- and Intermediate-Risk Recurrence Score Groups
This slide indicates important trends. The largest benefits of tamoxifen are observed in the low-risk and the intermediate-risk patients. One should not expect a large benefit of tamoxifen for patients in the high-risk group.

35. Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group
This slide indicates important trends. The largest benefits of chemotherapy are observed in the high-risk patients.
In ER-positive breast cancer (also known as luminal breast cancer), molecular expression can discriminate a continuous distribution of tumor types.
Tumors with low Recurrence Scores are less likely to recur, tend to benefit from hormonal therapy, and benefit little, if any, from chemotherapy.
Breast cancers with high Recurrence Scores are likely to recur, have less benefit from hormonal therapy, but actually benefit the most from chemotherapy.

36. Standardized Quantitative Oncotype DX Assay
Recurrence Score in N-, ER+ patients
The Recurrence Score has been correlated with
Distant recurrence rate at 10 years assuming 5 years of tamoxifen treatment (the higher the score, the higher the distant recurrence rate)
Hormone therapy benefit (the lower the score, the greater the impact of tamoxifen given for 5 years on 10 year distant recurrence-free survival)
Chemotherapy benefit (the higher the score, the greater the impact of chemotherapy on 10 year distant recurrence-free survival)
Lower RS’s
Lower likelihood of recurrence
Greater magnitude of TAM benefit
Minimal, if any, chemotherapy benefit
Higher RS’s
Greater likelihood of recurrence
Lower magnitude of TAM benefit
Clear chemotherapy benefit
1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research ) Paik et al JCO 2006, 4) Gianni et al JCO 2005

37. Results from NSABP B20 Results
Correlation of RS with traditional prognostic factors including age, tumor size, and tumor grade
Results from NSABP B20 Results

38. NSABP B20 Results: Many Younger Patients Have Low Recurrence Scores
In the B-20 study, 44% of patients under 40 years old had low Recurrence Scores. While overall, younger patients do worse and are probably more likely to benefit from chemotherapy, there is a large fraction of younger patients for whom the Recurrence Score is low and benefits of chemotherapy may be minimal. The P values are derived from a Cochran-Mantel-Haenszel chi-square test for determining whether there is a relationship between Recurrence Score and age stratified by RS risk group.
Paik et al. J Clin Oncol

39. NSABP B20 Results: Many Small Tumors Have Intermediate to High RS
If one looks at tumor size in the B-20 study, there are a number of patients with small tumors who have intermediate and high Recurrence Scores. In addition, if one looks at patients with large tumors, >4 cm, 46% of these patients had low Recurrence Scores. The P values are derived from a Cochran-Mantel-Haenszel Cochran-Mantel-Haenszel chi-square test for determining whether there is a relationship between Recurrence Score and clinical tumor size stratified by RS risk group.
Paik et al. J Clin Oncol

40. NSABP B20 Results: Significant Proportion of High-Grade Tumors Have Low RS
Grading by pathologist at local clinical trial site
Grading by pathologist at central lab
For the top left figure, grade for B-20 reflects original assessment by local pathologists – not NSABP central lab as was reported for B-20. This reflects the kind of grading normally provided in community practice. These figures show that even for the poorly differentiated tumors, 36% of these patients had low Recurrence Scores.
In this example, while grading done at a central lab is more highly correlated with outcomes, 19% of poorly differentiated tumors still had a low Recurrence Score.
The P values are derived from a Cochran-Mantel-Haenszel chi-square test for determining whether there is a relationship between Recurrence Score and grade stratified by RS risk group.
Paik et al. J Clin Oncol

41. 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
This abstract was sponsored by Genomic Health
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, Ann Arbor MI, 3Edward Hospital, Naperville IL, 4UC Davis, Sacramento CA, 5Mount Sinai Medical Center, New York NY
ASCO 2007, Abstract #577

42. Background
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 can affect MO and pt adjuvant treatment selection.
The Recurrence Score is validated as a prognostic and predictive marker, but there are still questions as to how physicians and patients use the test. This study was designed to help answer these questions.
ASCO 2007, Abstract #577

43. Methods
17 MOs at 1 community and 3 academic practices participated. Each participating MO consecutively offered enrollment to eligible women with N-, ER+ BC.
Each participating MO and consenting patient completed pre- and post-RS assay questionnaires.
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.
This is the first prospective study looking at the impact of the Recurrence Score on patients and patient decision-making
ASCO 2007, Abstract #577

44. Change in MO Treatment Recommendation by RS
Pre-RS
Post- 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%)
In a side by side comparison, we see that the % of patients offered chemotherapy pre- and post-RS information dropped from 47.2% to 25.8%.
Also, note that there appears to be little difference in RS in those patients classified for treatment before knowledge of the RS was known, suggesting that doctors can’t predict well what the RS will be.
ASCO 2007, Abstract #577

45. 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)
In one of the most important conclusions of the abstract/poster, the chemotherapy recommendation changed 31.5% of the time after the M.D. found out the R.S.
In 22.5% of the cases, the recommendation switched from chemotherapy (plus hormone therapy) to hormone therapy alone
This is consistent with other studies (Kamal et al Proc. ASCO 2007, Oratz et al J. Oncology Practice July 2007) suggesting that the direction of change is more likely to be away from chemotherapy administration
Treatment recommendation changed for 28 (31.5%) cases after results of RS Assay known.
The most common change was from a recommendation of CHT to HT in 22.5% of cases
ASCO 2007, Abstract #577

46. Other Findings
Confidence was increased in 76% of the MO recommendations.
RS Assay impacted patient adjuvant treatment decisions
95% of patients were glad they had the test performed
12 (13.5%) patient treatment decisions did not match their MO treatment recommendation. This may be due to:
Patients choosing different treatment option than that recommended
Inadequate communication between MOs and pts
Patient misunderstanding of survey question
ASCO 2007, Abstract #577

47. Conclusions
RS Assay changed physician adjuvant treatment recommendation 31.5% of the time
Results from the RS assay were associated with less adjuvant chemotherapy administration
The most common treatment recommendation change for MO was changing recommendation from CHT to HT in 22.5% of cases
Of the 6 pts whose physicians thought their RS represented equipoise, 1 pt chose chemotherapy, 3 chose HT, 1 chose observation, and 1 understood the concept of equipoise.
Results of the RS Assay increased physician confidence in treatment recommendation
ASCO 2007, Abstract #577

48. TAILORx (PACCT-1 Trial) Sponsored by NCI Administered by ECOG
The TAILORx study – Trial Assigning IndividuaLized Options for Treatment (Rx) – opened in April PACCT-1 is the first study that is part of the NCI PACCT (Program for the Assessment of Clinical Cancer Tests) program.
This trial is sponsored by the National Cancer Institute and administered by ECOG. All the North American breast cancer cooperative groups are participating in this study.
The PACCT program was established by the NCI in 2000 to integrate clinical cancer tests into clinical practice. One of the first questions that the NCI wanted to address with this program was the overtreatment of ER+, N– women. They wanted to utilize tests that would determine the risk of recurrence and tailor treatment to these patients. Other tests were considered, such as Ki67, uPA/PAI-1; however, the Oncotype DX™ breast cancer assay was selected as the most appropriate marker for the first PACCT trial based on the number and quality of the trials that tested the prognostic and predictive value of this assay.
Participating cooperative groups include ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP

49. Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx)
Premise
Integration of a molecular profiling test (Oncotype DX®) into the clinical decision-making process
Potential Implications
Reduce chemotherapy overtreatment in those likely to be appropriately 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
The premise of the trial is that the Oncotype DX™ assay is able to identify women who are expected to benefit from chemotherapy and women who are expected to have little or no benefit . The potential implications are that many women are currently being overtreated with chemotherapy and could benefit from hormonal therapy alone without loss of treatment benefit and other patients are getting inadequate treatment and could benefit from chemotherapy.
In this trial, patients will be treated based upon their risk of recurrence and likelihood of chemotherapy benefit.  There are some women for whom uncertainty still exists about the likelihood of benefit from chemotherapy in addition to hormonal therapy, and these women will be randomized to determine whether they could benefit from hormonal therapy alone without loss of treatment benefit.

50. TAILORx: Scientific Rationale for NCI and Breast Intergroup Selecting Oncotype DX® Assay for First PACCT trial
Validated prognostic test for tamoxifen-treated patients
Predictive of distant recurrence
May be used as categorical or continuous variable
Paik et al. NEJM, 2004
Also validated in population-based Kaiser study
Habel et al. Breast Cancer Research, May 2006
Lower RS predictive of tamoxifen benefit
Paik et al. ASCO 2005, abstr 510
Higher RS predictive of chemotherapy benefit
Paik et al. JCO, August 2006
Correlates more strongly with outcome than Adjuvant!
Bryant et al. St. Gallen, 2005
Predictive of local recurrence in tam-treated patients
Mamounas, SABCS 2005, abstr 29
The Oncotype DX™ breast cancer assay was validated in two independent prospectively defined studies.
There is a correlation of the Recurrence Score with tamoxifen benefit and the Recurrence Score with chemotherapy benefit.
The results of the Oncotype DX™ assay correlate more strongly with outcomes than Adjuvant! Online based on a study presented by Bryant et al at the 2005 St. Gallen meeting.
In addition, the Oncotype DX™ assay is predictive of loco-regional recurrence in tamoxifen-treated patients.
Sparano, Clinical Breast Cancer, 2006 Sparano, ASCO Educational Book 2007

51. TAILORx Primary Study Group
This slide shows how the Recurrence Score is reported, and the intermediate group has a score between 18 and 31. The low-risk, intermediate-risk, and high-risk cutoffs were prospectively defined for the purposes of the validation trial, but these do not represent true cutoffs in risk of recurrence among the 3 groups.
For the TAILORx trial, the middle-range cutoffs are 11 and 25 because these scores correlate roughly with a 10%-20% risk of distance recurrence at 10 years when looking at the upper 95% confidence intervals. These cutoffs were selected by the TAILORx study designers to define stratification groups in whom, in addition to hormone therapy, (a) chemotherapy does not improve outcomes (RS <11); (b) chemotherapy does improve outcomes (RS >25); and (c) there is a legitimate question whether chemotherapy improves outcomes (RS between 11 and 25).

52. Node-Neg, ER-Pos Breast Cancer Chemotherapy + Hormone Rx
Schema: TAILORx
Node-Neg, ER-Pos Breast Cancer
Register
Specimen banking
Oncotype DX® Assay
RS 11-25
Randomize
Hormone Rx vs
Chemotherapy Hormone Rx
RS <10
Hormone
Therapy
Registry
This is the schema of the TAILORx trial. The eligible patients for this trial are N–, ER+ and are candidates for chemotherapy (ie, patients who do not have comorbid conditions that would preclude them from receiving chemotherapy and who are willing to take it if recommended).
The fact that the Breast Cancer Intergroup is stratifying patients for the TAILORx trial by the Oncotype DX™ assay demonstrates that this assay is widely accepted and validated in the study population. Treatment will be based on the results of the assay.
Patients will be stratified as follows:
Patients with a Recurrence Score below 11 will receive hormonal therapy alone.
Patients with a Recurrence Score between 11 and 25 will be randomized to either hormonal therapy alone or hormonal therapy + chemotherapy. This is the primary study group. This corresponds approximately to a risk of recurrence at 10 years of 10%-20%. "(at upper bound of 95% CI)
Patients with a Recurrence Score greater than 25 will receive chemotherapy + hormonal therapy.
Since this trial has a dealer’s choice–type design, individual investigators can select the type of hormonal therapy and chemotherapy from a list included in the protocol.
The groups in this trial do not correspond to the low-, intermediate-, and high-risk cutoffs found on the Oncotype DX™ report. The treatment groups for the TAILORx trial were selected for different purposes from those involved with the selection of cutoffs for the validation trial and the Oncotype DX report.  The treatment groups for the TAILORx study were selected to correspond with specific levels of risk of recurrence and likelihood of chemotherapy benefit.  The TAILORx investigators felt it would not be ethical to withhold chemotherapy from women who have a 20% risk of recurrence
RS >25
Chemotherapy +
Hormone Rx
Primary study group

53. 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
This study has a non-inferiority design. The hypothesis is that patients in this middle-range Recurrence Score risk group will do no worse with hormonal therapy alone than they would with hormonal therapy plus from chemotherapy.
Note: The study does not assess the validity of the Oncotype DX™ assay. This trial design is predicated on the assessment that the assay is fully validated. For a patient with a RS <11, chemo will not be given. For a patient with a RS >25, chemo will be given. The risk generated from the RS is felt to be validated and is actionable, based on the references below.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):
Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol Aug 10;24(23) [Epub ahead of print May 23, 2006].
Habel L, Shak S, Jacobs M, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;May 31;8(3):R25 [Epub ahead of print].
Simon R. Roadmap for developing and validating therapeutically relevant genomic classifiers. J Clin Oncol. 2005;23(29):

54. TAILORx: Key Points Participating groups Adjuvant therapy Other trials
ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP
Adjuvant therapy
Choice of hormonal and/or chemotherapy regimen is at discretion of treating physician
Other trials
May enroll on other CTSU or other cooperative group studies if treatment assignment on other trial is consistent
Payment for the Oncotype DX Assay
Genomic Health will assist in securing reimbursement for patients who have health insurance
By agreement with NCI to avoid bias in enrollment in the trial, patients who are uninsured or who have copayments or deductibles will not be responsible for the cost of the Oncotype DX®
Financial Considerations
Costs associated with treating the patient and any supportive care will be billed by local treating providers in the customary manner.
Genomic Health will submit claims to relevant health plans for the Oncotype DX™ assay – just as they do for patients outside this study.
In those cases where specific claims for this test are denied, Genomic Health will facilitate appeals.
If, after pursuing appeals, any patient is left with an outstanding balance for the test, and for those patients who are uninsured or who have copayments or deductibles, Genomic Health will waive all rights to seek payment from the patient.
This policy ensures that out-of-pocket costs for patients enrolled in this study will be $0, eliminating the sample bias that might occur if insurance coverage or financial status affected enrollment decisions.

55. Oncotype DX® Extensively Studied: Study Experience in >3300 Patients
No. Pts
Providence
Exploratory
136
Rush* 78
NSABP B-20
233
NSABP B-14*
Prospective
668
MD Anderson*
149
Kaiser Permanente*
Prospective Case-Control
790 Cases/Controls
NSABP B-14
Prospective Placebo vs Tam
645
Milan* 89
NSABP B-20*
Prospective Tam vs Tam+Chemo
651
ECOG 2197*
Exploratory and Prospective
776
SWOG 8814
367
Although this assay has emerged for clinical use over the last few years, there is evidence supporting its utility in multiple studies involving over 3000 patients.
References from top to bottom for the studies shown including both published studies and abstracts
Esteban J, Baker J, Cronin M, et al. Tumor gene expression and prognosis in breast cancer: Multi-gene RT-PCR assay of paraffin-embedded tissue. Proc Am Soc Clin Oncol 22: 2003 (abstr 3416).
Cobleigh MA, Tabesh B, Bitterman P, et al. Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res. 2005;11(24 Pt 1):
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):
Esteva FJ, Sahin AA, Cristofanilli M, et al. Prognostic role of a multigene reverse transcriptase-PCR assay in patients with node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res. 2005;11(9):
Habel L, Shak S, Jacobs M, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;May 31;8(3):R25 [Epub ahead of print].
Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol.2005;23(29):
Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:
L. J. Goldstein, R. Gray, B. H. Childs, et al. Prognostic Utility of 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. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 526
*Published studies

56. Recurrence Score in N-, ER+ patients
Conclusions
Recurrence Score in N-, ER+ patients
The Recurrence Score has been correlated with
Distant recurrence rate at 10 years with 5 years of tamoxifen treatment (the higher the score, the higher the distant recurrence rate)
Hormone therapy benefit (the lower the score, the greater the impact of tamoxifen (given for 5) years on 10 year distant recurrence-free survival)
Chemotherapy benefit (the higher the score, the greater the impact of chemotherapy on 10 year distant recurrence-free survival)
Lower RS’s
Lower likelihood of recurrence
Greater magnitude of TAM benefit
Minimal, if any, chemotherapy benefit
Higher RS’s
Greater likelihood of recurrence
Lower magnitude of TAM benefit
Clear chemotherapy benefit
1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research ) Paik et al JCO 2006, 4) Gianni et al JCO 2005

57. Physician Usage and Adoption
Genomic Health Today
Physician Usage and Adoption
65,000+ Oncotype DX® test results delivered*
>7,500 physicians have ordered the test*
Reimbursement for Oncotype DX
Coverage for Medicare patients
Coverage >90% of privately insured lives
*As of August 5, 2008

58. Conclusions
The Oncotype DX® Recurrence Score assay predicts the likelihood of adjuvant chemotherapy benefit
It also is a prognostic assay for the risk of distant recurrence at ten years assuming five years of adjuvant tamoxifen treatment
Oncotype DX® Recurrence Score assay shows consistent results across multiple independent studies