1. The Oncotype DX® Assay in the Contemporary Management of Invasive Early-stage Breast Cancer
GHI10006_1211

2. Cancer – The Biology Century
Understanding and treating the underlying tumor biology
Cancer genetic studies demonstrate the transition of basic research to clinical application (i.e. BRCA testing)
Targeted cancer therapies developed based on the unique tumor genetic characteristics (i.e. tamoxifen and trastuzumab)
Sequencing of the human genome
Gene  expression profiling shown to predict clinical outcome
Main point: We are in the Biology Century and have developed tools that reveal the molecular biology of cancer. We now know that understanding and treating the underlying biology will allow us to deliver better outcomes to the patients we serve. It is critical that we integrate genomic analysis into the clinical context and the continuum of healthcare.
Scientific breakthroughs making personalized medicine in cancer a reality

3. Evaluating Biomarkers for Clinical Use Key Principles
Does the test deliver what patients, physicians, regulators, and payers need?
Most importantly, tests must be “Fit for Purpose” with evidence relevant to that specific purpose
Consistent results across multiple well-designed studies are required to provide evidence for analytic performance, clinical validity, and clinical utility (see Roadmap to Establish Clinical Utility)
Test must be shown to have value beyond traditional measures
Has the test been brought to a standardized implementation? And has the evidence which supports its use been obtained in that standardized implementation?
Main point: Genomic assays must deliver the information patients, physicians and payers need. Assays must be fit for the purpose for which they are intended, substantiated with consistent results across multiple well-designed studies and show value beyond traditional measures.
History has taught us that methods matter and tests must be rigorously standardized.
Hayes DF. Am Soc Clin Oncol Ed Book. 2008:30-34.
Simon R. J Clin Oncol. 2005;23:

4. Key Questions When Evaluating Genomic Classifiers
Fit for purpose
Strongly prognostic?
Predictive of chemotherapy benefit?
What is the level of evidence?
Incorporated in treatment guidelines?
Accurate and reliable?
Oncotype DX® assays are rigorously validated and are “fit for purpose.”
Hayes DF. Am Soc Clin Oncol Ed Book. 2008:30-34.
Simon R. J Clin Oncol. 2005;23:

5. The Oncotype DX® Gene Panel Was Developed from Clinical Trial Evidence
250 cancer-related genes were selected based on extensive literature review (candidate-gene approach)
Genes were analyzed for expression and relapse-free interval correlations across 3 independent studies of 447 breast cancer 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%)
Main point: The Oncotype DX® gene panel was developed based on clinical trial evidence.
In the first step of the gene selection process (candidate-gene approach), 250 cancer-related candidate genes were selected from microarray data,1-4 genomic databases, cancer literature, and molecular and cell biology experiments.
The 250 cancer-related genes were selected from a variety of sources, including the scientific literature, microarray data and genomic databases were analyzed in a total of 447 patients from 3 separate studies:
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.5
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.6
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.7
The expression levels of these 250 genes where correlated with relapse-free interval using univariate models across 3 independent studies of 447 breast cancer patients with known clinical outcome data. In addition to the 5 references genes, obtained from these 3 studies, the 16 cancer related genes which correlated most strongly with relapse-free interval, consistently across the study populations, were selected and were used in the development of the 21-gene profile and an algorithm for calculating a Recurrence Score® result.
Gruvberger S, Ringner M, Chen Y, et al. Cancer Res. 2001;61(16):
Ramaswamy S, Ross KN, Lander ES, Golub TR. Nat Genet. 2003;33(1):49-54.
Sorlie T, Perou CM, Tibshirani R, et al. Proc Natl Acad Sci U S A. 2001;98(19):
van't Veer LJ, Dai H, van de Vijver MJ, et al. Nature. 2002;415(6871):
Paik S, Shak S, Tang G, et al. SABCS Abstract #16.
Cobleigh MA, Bitterman P, Baker J, et al. Proceedings of ASCO Abstract #3415.
Esteban J, Baker J, Cronin M, et al. Proceedings of ASCO Abstract #3416.
From these studies, 21 genes were selected
Paik S, et al. SABCS Abstract 16.
Cobleigh MA, et al. Clin Cancer Res. 2005;11:
Esteban J, et al. Proc Am Soc Clin Oncol. 2003;22: abstract 3416.

6. The Recurrence Score® Result Uses Key Genes Linked to Critical Molecular Pathways
16 Breast Cancer related genes
Estrogen
Proliferation
HER2
Invasion
Others ER PR
Bcl2
SCUBE2
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GRB7
HER2
Stromelysin 3
Cathepsin L2
CD68
GSTM1
BAG1
Main point: 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 3 clinical trials, which demonstrated a consistent statistical link between these genes and distant breast cancer recurrence and the most robust predictive power across the 3 studies.
Additional information on some of the 16 cancer related genes:
MYBL2: The protein encoded by this gene, a member of the MYB family of transcription factor genes, is a nuclear protein involved in cell cycle progression. The encoded protein is phosphorylated by cyclin A/cyclin-dependent kinase 2 during the S-phase of the cell cycle and possesses both activator and repressor activities. It has been shown to activate the cell division cycle 2, cyclin D1, and insulin-like growth factor-binding protein 5 genes. Transcript variants may exist for this gene, but their full-length natures have not been determined.
STK15: The protein encoded by this gene is a cell cycle-regulated kinase that appears to be involved in microtubule formation and/or stabilization at the spindle pole during chromosome segregation. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. This gene may play a role in tumor development and progression. A processed pseudogene of this gene has been found on chromosome 1, and an unprocessed pseudogene has been found on chromosome 10. Multiple transcript variants encoding the same protein have been found for this gene.
Scube2 can modulate the long-range action of Bmp-dependent Hedgehog signaling in the neural tube and somites.
STMY3 (MMP11): Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is activated intracellularly by furin within the constitutive secretory pathway. Also in contrast to other MMP's, this enzyme cleaves alpha 1-proteinase inhibitor but weakly degrades structural proteins of the extracellular matrix
CL2: The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that may play an important role in corneal physiology. This gene is expressed in colorectal and breast carcinomas but not in normal colon, mammary gland, or peritumoral tissues, suggesting a possible role for this gene in tumor processes.
GSTM1: Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens. Multiple protein isoforms are encoded by transcript variants of this gene.
BAG1: The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein encoded by this gene binds to BCL2 and is referred to as BCL2-associated athanogene. It enhances the anti-apoptotic effects of BCL2 and represents a link between growth factor receptors and anti-apoptotic mechanisms. At least three protein isoforms are encoded by this mRNA through the use of alternative translation initiation sites, including a non-AUG site
The Recurrence Score result ranges from 0 to 100.
Expression for each individual gene is measured on a scale from 0 to 15, where an increase of 1 unit generally reflects a 2-fold increase in RNA quantity.
Although the coefficients for each gene or gene group influence the Recurrence Score 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 result to a large degree.
Recurrence Score = × HER2 Group Score– 0.34 × Estrogen Group Score × Proliferation Group Score × Invasion Group Score × CD68– 0.08 × GSTM1– 0.07 × BAG1
Paik et al. N Engl J Med. 2004;351:
5 Reference genes
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Paik S, et al. N Engl J Med. 2004;351:

7. The Recurrence Score® Result Assesses Individual Tumor Biology for ER+ Breast Cancer
Continuous Biology 4 % 3 5 % 3 % 2 5 %
Distant recurrence at 10 years 2 % 1 5 % 1 % 5 % %
Main point: The Oncotype DX® Recurrence Score® is correlated with distant recurrence rate at 10 years, hormone therapy benefit, and chemotherapy benefit. There is a continuous biology of breast cancer that is revealed by the Recurrence Score. There are clear underlying phenotypes that correspond to Low Recurrence Score Disease and High Recurrence Score Disease.
Distant recurrence rate at 10 years with 5 years of tamoxifen treatment: the higher the score, the higher the risk of distant recurrence.
Hormone therapy benefit: the lower the score, the greater the impact of tamoxifen given for 5 years on proportion of patients recurrence-free at 10 years.
Chemotherapy benefit: the higher the score, the greater the proportion of patients distant recurrence-free at 10 years.
The precision of the Recurrence Score with a tight confidence interval in the lower Recurrence Score ranges, allows oncologists to confidently identify low Recurrence Score disease. Since a low Recurrence Score value is associated with low risk of distant recurrence and low benefit from adding chemotherapy to tamoxifen, many oncologists will choose to forego chemotherapy.
Conversely, a high Recurrence Score value is associated with a high risk of distant recurrence and significant benefit from adding chemotherapy to tamoxifen, prompting many oncologists to add chemotherapy.
Approximately 25% of patients will fall into the intermediate Recurrence Score range. Although the continuous nature of the assay results allows oncologists to ascertain distant recurrence risk for these patients, there are multiple ways to apply the information. Patients with a “high” intermediate Recurrence Score value may be considered differently from those with a “low” intermediate Recurrence Score value. Nonetheless, the information provided by the Recurrence Score result can be very helpful in making treatment decisions when viewed in the context of other patient-specific factors, including patient concern, age, tumor size and grade, and conditions that may increase the risk of chemotherapy-associated toxicity.
Paik S, et al. N Engl J Med. 2004;351:2817.
Habel LA, et al. Breast Cancer Res. 2006;8:R25.
Paik S, et al. J Clin Oncol. 2006;24:3726. 5 1 1 5 2 2 5 3 3 5 4 4 5 5
Recurrence Score value
LOW RECURRENCE SCORE DISEASE
Indolent
Hormone therapy-sensitive
Minimal, if any, chemotherapy benefit
HIGH RECURRENCE SCORE DISEASE
Aggressive
Less sensitive to hormone therapy
Large chemotherapy benefit
Paik S, et al. N Engl J Med. 2004;351:2817; Paik S, et al. J Clin Oncol. 2006;24:3726; Habel LA, et al. Breast Cancer Res. 2006;8:R25-R39.

8. Continuous Biology: ER and HER2 Expression as Measured by RT-PCR15
HER2+ 14 13 12 11
HER2 Expression (relative to ref genes; log2)
Triple-negative* 10 9
Main point: Unlike IHC, quantitative RT-PCR is able to identify a continuum of expression.
In this figure, ER expression is plotted against HER2 expression, both as determined by RT-PCR.
Unlike IHC, which assesses ER and HER2 status as positive or negative, quantitative RT-PCR is able to identify a continuum of expression.
Three groups are discernible: HER2+, ER+/HER2–, and a triple-negative group. Within each group is a continuous range of expression and considerable heterogeneity.
Biology (gene expression) is continuous - not dichotomous (i.e. on/off). Consequently, risk estimates should be continuous - not dichotomous.
Shak S, et al. Breast Cancer Res Treat. 2006;100 (suppl 1): Abstract 6118. 8 7
ER+ HER2– 6 2 3 4 5 6 7 8 9 10 11 12 13 14
ER Expression (relative to ref genes; log2)
*> 94% of these cases are PR–; rarely strongly PR+
Shak S, et al. Breast Cancer Res Treat. 2006;100(suppl 1): abstract 6118.

9. Clinical Validation of the Oncotype DX® Breast Cancer Assay in Node-Negative Disease
Main point: The clinical validation of the Oncotype DX® breast cancer assay was performed in ER+, node-negative patients in the NSABP B-14 study, a landmark study which served to establish the efficacy of tamoxifen.

10. Oncotype DX® Clinical Validation: NSABP B-14
Objective: Prospectively validate the Recurrence Score® result as a predictor of distant recurrence in node-negative, ER+ patients
Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan
Placebo—not eligible
Randomized
Tamoxifen—eligible
Registered
Tamoxifen—eligible
Main point: 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 node-negative, estrogen receptor–positive 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): 2800 N–, ER+ women 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, making 2617 tamoxifen-treated women available.1
Paik S, Shak S, Tang G, et al. Use of an RT-PCR assay to predict the likelihood of breast cancer recurrence in node-negative, estrogen receptor–positive, tamoxifen-treated patients. In preparation.
Paik S, et al. N Engl J Med. 2004;351:

11. Oncotype DX® Clinical Validation: NSABP B-14, Distant Recurrence
Distant recurrence over time
100%
10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6%
90%
80%
10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3%
70%
60%
10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4%
Proportion without distant recurrence
50%
40%
All Patients, n = 668
RS < 18, n = 338
30%
Main point: The Oncotype DX® assay is clinically validated to predict the risk of distant recurrence at 10 years in patients with ER+, node-negative breast cancer treated with tamoxifen.
The Recurrence Score® result 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).1
This graph demonstrates the difference in distant relapse-free survival (DRFS) over time for the different risk categories. The DRFS for the high- and low-risk groups were statistically significantly different; the 10-year distant relapse-free survival for the low-risk category was 93% compared to 69% for the high-risk category.1
Paik S, Shak S, Tang G, et al. Use of an RT-PCR assay to predict the likelihood of breast cancer recurrence in node-negative, estrogen receptor–positive, tamoxifen-treated patients. In preparation.
20%
RS 18-30, n = 149
10%
RS ≥ 31, n = 181
P < 0.001 0% 2 4 6 8 10 12 14 16
RS, Recurrence Score® result
Years
*10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001
Paik S, et al. N Engl J Med. 2004;351:

12. % Distant Recurrence-free at 10 Years
Oncotype DX® Clinical Validation: NSABP B-14, Subgroup Analysis by Tumor Grade
All patients N=668
All Patients
Low Risk (RS <18)
Int Risk (RS 18-30)
High Risk (RS ≥31)
Well
Moderate
Main point: In all subgroups of tumor grade, the Recurrence Score® result provides important additional information about the likelihood of recurrence.
This forest plot shows that for tumor grade, as determined by Pathologist A, the Recurrence Score result provides additional information that predicts the likelihood of recurrence.
For tumors characterized as well differentiated, some have high Recurrence Score results and higher rates of distant recurrence.
For tumors characterized as moderately differentiated, the Recurrence Score result provides additional information about the likelihood of recurrence.
For tumors characterized as poorly differentiated, these tumors tend to do worse, but again the Recurrence Score result provides important additional information.
These results indicate that the genomics of the tumor contain information that is not provided by standard measures such as tumor grade. They also indicate that the information provided by the standard measures should not be ignored.
Paik S, et al. N Engl J Med. 2004;351:
Poor 20 40 60 80
100
RS, Recurrence Score
% Distant Recurrence-free at 10 Years
Paik S, et al. N Engl J Med. 2004;351:

13. % Distant Recurrence-free at 10 Years
Oncotype DX® Clinical Validation: NSABP B-14, Subgroup Analysis by Tumor Size
All patients (N=668)
All Patients
Low Risk (RS <18)
Int Risk (RS 18-30)
High Risk (RS ≥31)
Size ≤1 cm
Size 1-2 cm
Size 2-4 cm
Analysis of clinical tumor size subgroups for all patients (as presented in the forest plot on this slide) shows that size alone is a modest predictor of the likelihood of distant recurrence.
The small number of tumors >4 cm for all patients were associated with a greater likelihood of recurrence at 10 years.
The forest plot presented in this slide demonstrates that Recurrence Score (RS) consistently predicted the likelihood of distant recurrence in all tumor size subgroups.
For all tumor size subgroups less than 4 cm, the rate of DRFS at 10 years was consistently high for patients categorized as low risk (RS <18), whereas the rate of DRFS at 10 years was consistently much lower for patients categorized as high risk (RS ≥31).
Thus, not all patients with small tumors (109 patients with tumor size ≤1 cm) are low risk; the Recurrence Score identified 42 of those patients with Recurrence Score ≥18 who had a 15%-20% distant recurrence risk at 10 years.
Paik S, et al. N Engl J Med. 2004;351:
Size >4 cm 20 40 60 80
100
RS, Recurrence Score
% Distant Recurrence-free at 10 Years
Paik S, et al. N Engl J Med. 2004;351:

14. Oncotype DX® Clinical Validation: NSABP B-14, Subgroup Analysis by Age
All patients (N=668)
All Patients
Low Risk (RS <18)
Int Risk (RS 18-30)
High Risk (RS ≥31)
Age <40
Age 40-50
Age 50-60
The forest plot presented in this slide demonstrates that patient age alone was generally only a modest predictor of recurrence.
Younger patients do somewhat more poorly, and older patients do somewhat better.
The forest plot presented in this slide demonstrates that the Recurrence Score (RS) was consistently a strong predictor of distant recurrence across all age subgroups.
For all patient age subgroups, the rate of distant recurrence-free survival (DRFS) at 10 years was consistently high for patients categorized as low risk (RS<18) based on the Oncotype DX™ assay. Thus, not all young patients (age <40) were at high risk for recurrence based on analysis of gene expression in the tumor tissue.
Conversely, for all subgroups of patient age, the rate of DRFS at 10 years was consistently much lower for patients categorized as high risk (RS ≥31).
Paik S, et al. N Engl J Med. 2004;351:
Age >60 40 60 80
100
% Distant Recurrence-free at 10 Years
RS, Recurrence Score
Paik S, et al. N Engl J Med. 2004;351:

15. Oncotype DX® Clinical Validation: NSABP B-20
Objective: Prospectively determine the relationship between Recurrence Score® result and chemotherapy benefit in node-negative, ER+ patients
Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan
Tam + MF
Randomized
Tam + CMF
Main point: The objective of this additional study of the NSABP B-20 patients was to determine the magnitude of the chemotherapy benefit with MF (methotrexate, and fluorouracil) or CMF (cyclophosphamide, methotrexate, and fluorouracil) as a function of the 21-gene Oncotype DX® 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 prespecified analyses, similar results were seen when the patients treated with CMF (insert) 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 Oncotype DX® 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 S, et al. J Clin Oncol. 2006;24:

16. High Recurrence Score® Result Correlates with Greater Benefit from Chemotherapy (NSABP B-20)
1.0
0.9
Patients with high RS
28% absolute benefit from tamoxifen + chemotherapy
0.8
0.7
0.6
Proportion without distant recurrence
0.5 N
Events N
Events
All patients
Tamoxifen + chemotherapy
Tamoxifen
424
227 33 31
P = 0.02
4.4% absolute benefit from tamoxifen + chemotherapy
0.4
0.3
RS < 18
Tamoxifen + chemotherapy
Tamoxifen
218
135 8 4
P = 0.61
0.2
RS 18-30
Tamoxifen + chemotherapy
Tamoxifen 89 45 9 4
P = 0.39
0.1
RS ≥ 31
Tamoxifen + chemotherapy
Tamoxifen
117 47 13 18
P < 0.001 2 4 6 8 10 12
Years
RS, Recurrence Score result
Paik S, et al. J Clin Oncol. 2006;24:

17. Node Negative, ER-Positive Breast Cancer Chemotherapy Benefit
High Recurrence Score® Disease Is Chemo-sensitive Whereas Low Recurrence Score Disease is Not (NSABP B-20)
Recurrence Score vs Distant Recurrence at 10 Years Tam vs Tam + CMF/MF
50%
45%
40%
30%
25%
20%
35%
10% 5% 0%
15% 5 10 15 20 25 30 35 40 45 50
Breast Cancer Recurrence Score
Rate: Tam 95% Cl: Tam Rate: Tam + CMF/MF 95% Cl: Tam + CMF/MF
Tam
Tam + CMF/MF
Average Rate of Distant Recurrence at 10 Years
Absolute Benefit of Chemotherapy (CMF/MF) at 10 Years by Recurrence Score Group
% Decrease in Distant Recurrence at 10 Years (mean ± SE)
-10%
Recurrence Score
< 18 (n = 353)
(n = 134)
≥ 31 (n = 164)
Node Negative, ER-Positive Breast Cancer Chemotherapy Benefit
The figures in this slide correspond to the second page of the Oncotype DX report. These are two graphical representations of the chemotherapy benefit data derived from NSABP B-20. The graph on the left represents the RS as a continuous variable. The graph on the right represents the RS as a categorical variable (i.e. risk groups).
Both graphs show that the highest benefit form chemotherapy is derived by the high RS disease group.

18. NSABP B-20: Many Small Tumors Have Intermediate to High Recurrence Score® Disease
100 80 60
Recurrence Score 40
16% % %
33%
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 Score® results. In addition, if one looks at patients with large tumors, > 4 cm, 46% of these patients had low Recurrence Score results. The P values are derived from a Cochran-Mantel-Haenszel chi-square test for determining whether there is a relationship between Recurrence Score result and clinical tumor size stratified by Recurrence Score risk group.
Paik S, et al. J Clin Oncol. 2006;24: 20
20% % %
21%
64% % %
46%
N = N = N = N = 24
≤1 cm cm cm >4 cm
Clinical tumor size
Paik S, et al. J Clin Oncol. 2006;24:

19. NSABP B-20: Many Younger Patients Have Low Recurrence Score® Disease
41% % % %
In the B-20 study, 44% of patients under 40 years old had low Recurrence Score® results. 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 result 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 result and age stratified by Recurrence Score risk group.
Paik S, et al. J Clin Oncol. 2006;24:
14% % % %
44% % % %
N = N = N = N = 196
Paik S, et al. J Clin Oncol. 2006;24:

20. NSABP B-20: Significant Proportion of High-Grade Tumors Have Low Recurrence Score® Disease
12% % %
5% % %
16% % %
12% % %
For the 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 Score® results.
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 result.
The P values are derived from a Cochran-Mantel-Haenszel chi-square test for determining whether there is a relationship between Recurrence Score result and grade stratified by Recurrence Score risk group.
Paik S, et al. J Clin Oncol. 2006;24:
73% % %
83% % %
N = N = N = 163
N = N = N = 190
Paik S, et al. J Clin Oncol. 2006;24:

21. Assessable B20 Patients (n = 651)
NSABP B-20: The Recurrence Score® Result Is the Strongest Predictor of Chemotherapy Benefit
Assessable B20 Patients (n = 651)
Variable HR
Lower 95%
Upper 95% P
Recurrence Score
0.32
0.11
0.94
.038
Age ≥50 yrs
2.02
0.75
5.47
.162
Tumor size >2 cm
1.34
0.49
3.68
.569
Quantitative ER ≥50
1.96
0.73
5.30
.183
Quantitative PR ≥50
1.87
0.70
4.97
.214
Grade site Poor Moderate
0.27
0.60
0.02
0.06
3.01
6.42
.284
.672
Grade, pathologist A Poor Moderate
1.04
0.19
0.23
2.89
4.58
.657
.963
Grade, pathologist B Poor Moderate
0.36
1.77
2.03
.192
.244
Main point: Only the Recurrence Score® result is a statistically significant predictor of chemotherapy benefit.
Paik S, et al. J Clin Oncol. 2006;24:

22. Oncotype DX® Node-Negative Clinical Experience

23. Clinical Experience Supports Findings from NSABP B-14 and NSABP B-20
RS Groups by Patient Age
<50 yrs (n=367)
RS Groups by Tumor Grade
Grade 1
(n=277)
≥50 yrs (n=1497)
Grade 2
(n=964)
RS Groups by Tumor Size
≤2 cm
(n=1447)
Grade 3
(n=289)
Main point: Real world experience with 1,864 node negative patients from the Clallit and Maccabi healthcare systems in Israel supports previous findings from the NSABP B-14 and B-20 studies. Mainly, across age, tumor size and tumor grade, one finds a wide distribution of Recurrence Score results.
>2 cm
(n=402)
Not all grade 1 tumors have low RS values.
Only 31% of grade 3 tumors have high RS values.
Small tumors have proportionately fewer high RS values.
However, there is a range of RS values across both categories of tumor size.
Liebermann N, et al. ASCO Abstract 632 (poster presentation).

24. Does the Recurrence Score® Impact Treatment Decisions
Does the Recurrence Score® Impact Treatment Decisions? Is the Oncotype DX® Assay Cost-Savings and Cost-Effective?

25. Meta-Analysis: The Recurrence Score® Result Changes Decisions Across 7 Independent Decision Impact Studies
Before RS
CT + HT HT
Total
After RS
Asad et al. 24 36 8 13 81
Henry et al. 6 7 2 14 29
Klang et al. 69
105 20
119
313
Liang et al.
125 85 3 47
260
Lo et al. 40 83
Oratz et al. 19 32 68
Thanasoulis et al. 30 38 78
This study analyzed 7 decision impact studies (6 from US, 1 from Israel), which, on the individual level, all showed a consistent finding in use of the Oncotype DX® Recurrence Score®: Half of patients initially recommended to chemohormonal therapy are changed to hormonal therapy alone, and some patients initially recommended hormonal therapy alone are recommended to chemotherapy following a high Recurrence Score result.
These 7 studies include:
Asad J, Jacobson A., Estabrook A., et al. Does Oncotype DX Recurrence Score affect the management of patients with early stage breast cancer? Am J Surg. 2008;196:527-9.
Henry L, Stojadinovic A, Swain S, et al. The influence of a gene expression profile on breast cancer decisions. J Surg Oncol. 2009;99:
Klang S, Hammerman A, Liebermann N, et al. Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli managed healthcare organization. Value in Health. 2010;13.
Liang H, Brufsky A, Lembersky B. A retrospective analysis of the impact of Oncotype DX low Recurrence Score results on treatment decisions in a single academic breast cancer cente [abstract]. 30th Annual San Antonio Breast Cancer Symposium. 2007; Abstract 2062.
Lo S, Norton J, Mumby P, et al. Prospective multi-center study of the impact of the 21-gene Recurrence Score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28:
Oratz R, Paul D, Cohn A, Sedlacek S. Impact of a commercial reference laboratory test Recurrence Score on decision making in early-stage breast can-cer. J Oncol Pract. 2007;3:182-6.
Thanasoulis T, Brown A., Frazier T. The role of Oncotype DX assay on appropriate treatment for estrogen positive, lymph node negative invasive breast cancer. In: American Society of Breast Surgeons Annual Meeting; 2008; New York, NY; 2008.
An additional decision impact study from Spain, not included in this meta-analysis, has since been presented at ESMO 2010: Albanell J, Colomer R, Ruiz-Borrego M, et al. Prospective TRANSGEICAM Study of Oncotype DX® in clinical decision making in estrogen receptor-positive node negative breast cancer women [abstract]. 35th European Society for Medical Oncology (ESMO) Congress. 2010; Abstract 222PD.
RS, Recurrence Score® result; CT, chemotherapy; HT, hormone therapy
N = 912 patients
Consistent, large impact of RS on treatment decisions in both directions:
Half of patients initially recommended CT+HT are changed to HT only
Some patients initially recommended HT alone have CT added upon being informed of “High RS Disease”
Asad J, et al. Am J Surg. 2008;196: ; Henry LR, et al. J Surg Oncol. 2009;99: ; Klang SH, et al. Value Health. 2010;13: ; Liang H, et al. SABCS 2007: Abstract 2061; Lo SS, et al. J Clin Oncol. 2010;28: ; Oratz R, et al. J Oncol Pract. 2007;3: ; Thanasoulis T, et al. Am Soc Br Surg Annual Meeting Hornberger J, et al. SABCS Poster P

26. Meta-Analysis: Overall Impact of Recurrence Score® on Treatment Decisions
Treatment plan prior to Oncotype DX®
Treatment plan after RS
Treatment plan after RS
This decision tree shows the breakdown of patients initially recommended to adjuvant chemo-hormonal therapy or hormonal therapy alone, and how the use of the Recurrence Score® result guided their treatment. Use of the Recurrence Score led to a 52% switch in patients recommended chemo-hormonal therapy to hormonal therapy alone and a 12% switch in patients recommended hormonal therapy alone to chemo-hormonal therapy.
Both arms combined, the Recurrence Score led to a treatment decision change in 37% of all patients studied: 33% from chemo-hormonal therapy to hormonal therapy alone and 4% from hormonal therapy alone to chemo-hormonal therapy.
Results from this meta-analysis underscore a consistent and large impact of Recurrence Score on treatment decisions by physicians. Physicians cannot reliably predict the Recurrence Score using traditional clinical, pathological, and biologic parameters; recommendations changed in more than a third of treatment decisions after integrating the Recurrence Score information with traditional measures.
33% of the overall population switched from CT + HT to HT only after Recurrence Score.
4% of the overall population switched from HT only to CT + HT (based on “high Recurrence Score disease”).
4% change
33% change
Overall, the RS led to a 37% change in treatment decisions
33% from CT + HT  HT
4% from HT  CT + HT
CT + HT HT
RS, Recurrence Score result
Hornberger J, et al. SABCS Poster P

27. Most Patients Were Positively Influenced by the Recurrence Score® Result
N= 89 patients *
* Those not satisfied noted a negative impact on QOL, treatment side effects including aches, hot flashes, pain, mood alteration, and negative impact on self image.
In addition, the Recurrence Score result helped reduce patients’ anxiety and decisional conflict
Lo SS, et al. SABCS Abstract [poster presentation]

28. The Oncotype DX® Assay Reduces Unnecessary Treatment and is Cost Saving
Studies show net savings up to $2,000 per patient tested with Oncotype DX1,2
Saves patients the negative health and QOL impact of unnecessary chemotherapy3
A reduction in chemotherapy use of approximately 30%, as observed in the Hornberger meta-analysis4, results in $195,000 savings per 100 patients tested annually5
1. Hornberger J, et al. Am J Manag Care. 2005;11: Horberger J, et al. J Oncol Pract 2011; 7: e38S-e45S.
3. Lo SS, et al. J Clin Oncol. 2010;28: Hornberger J, et al. SABCS Poster P
5. Data on file.

29. Oncotype DX® Testing in Node-Positive Disease
Main point: The Oncotype DX® assay was first validated and adopted in ER-positive, node-negative breast cancer. Can the Oncotype DX assay identify patients who are at low, intermediate and high risk of recurrence and predict differential chemotherapy benefit in node-positive patients—a group that has traditionally been thought to be at high risk and to unequivocally require chemotherapy?

30. Validity of the Oncotype DX® Assay Consistently Demonstrated in Node-Positive Patients
Study
Type
Nodal status
No. of patients
TransATAC1
Prospective Tam vs anastrozole
Node positive
Node negative
1231
SWOG 88142
Prospective Tam vs CAF → Tam
367
ECOG 21973
Prospective AC vs AT
465
When this assay was first commercially available in 2004, it was only validated for node-negative disease. Since then, 3 studies have been conducted to validate the ability of the Oncotype DX® assay to predict risk and response to therapy in patients with ER+, node-positive breast cancer.
The first was the ECOG 2197 study in which all patients received chemotherapy for patients with 0-3 positive nodes. The conclusion was that the Recurrence Score® result may potentially be used to distinguish between patients who do well with standard chemotherapy regimens and those who may be suitable candidates for clinical trials evaluating alternative chemotherapy regimens or other strategies.
The TransATAC study demonstrated the validity of the Recurrence Score result as a prognostic indicator in postmenopausal node-negative or node-positive patients treated with tamoxifen or an AI.
The SWOG 8814 study confirmed the prognostic value and establishes the predictive value of the Recurrence Score result in node-positive, postmenopausal patients.
Combined among these three studies, a total of 905 patients had 1 or more positive nodes.
It is estimated that 8.5% of the population has micrometastases, according to a population-based study in which 59,037 patients with infiltrating ductal or lobular breast cancer with ≤ 3 positive nodes (hormone receptor–positive or –negative) underwent sentinel lymph node biopsy from 1992 to The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies were conducted prior to the introduction of sentinel lymph node biopsy, so one may assume that a similar percentage of the patients in that study had micrometastases. The B-14 and B-20 studies validated the prognostic and predictive value of the Oncotype DX assay in patients with ER+, node-negative breast cancer.
In the next several slides, we will review the findings of these studies in node-positive patients.
Goldstein LJ, et al. J Clin Oncol. 2008;26:
Dowsett M, et al. J Clin Oncol. 2010; 28(11):
Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.
Chen SL, et al. Ann Surg Oncol. 2007;14(12):
Total N+ patients in all three studies =905
1. Dowsett M, et al. J Clin Oncol. 2010;28(11):
2. Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.
3. Goldstein LJ, et al. J Clin Oncol. 2008;26:

31. Trans ATAC Study Overview
ATAC study population (N = 9366)
Tamoxifen
Anastrozole
Tamoxifen + Anastrozole
(combination arm not examined)
Primary Analysis: To determine whether Oncotype DX® assay significantly adds to a proportional hazards model for time to distant recurrence (age, tumor size, grade, treatment) in node-negative, HR+, patients with no adjuvant chemotherapy
Main point: The primary analysis of this study sought to determine whether the addition of the continuous Recurrence Score® result added significantly to a statistical model that included age, tumor size, grade and treatment (tamoxifen or anastrozole).
Note that the tamoxifen and anastrozole arms were combined for the initial analysis, per the prospectively-specified analysis plan. They were subsequently broken out for separate analysis.
Since there was no added benefit to the addition of anastrozole to tamoxifen, this arm was discontinued early in the original ATAC trial and these patients were offered the opportunity to switch to anastrozole or tamoxifen monotherapy. Tumor blocks were not collected for patients in the combination arm.
Note that there were 1308 samples left with reportable Recurrence Score result that were ER+ and/or PgR+.
The “TransATAC” study eliminated from the ATAC study those patients that received the combination of tamoxifen and anastrozole or were ER–/PgR–. Another large group of patients were not included in this analysis because blocks were either not recoverable or insufficient tumor was present in the blocks for analysis.
Several secondary analyses were also performed. This included looking at the Recurrence Score result both as a continuous and as a categorical variable. Note that a comparison with Adjuvant! Online was also performed.
Dowsett M, et al. J Clin Oncol. 2010; 28(11):
Secondary analyses:
Determine whether the relationship between continuous Recurrence Score® result and time to distant recurrence differs by nodal status or treatment arm
Determine the relationship of predefined Recurrence Score groups with time to distant recurrence by nodal status and treatment arm
Evaluate whether Recurrence Score result adds to the Adjuvant! Online estimate of risk
Dowsett M, et al. J Clin Oncol. 2010;28(11):

32. Trans ATAC: The Recurrence Score® Value Is a Significant Predictors of Distant Recurrence (node-negative patients, both treatment arms)
Variable
HR (95% CI)*
P value
Recurrence Score / 50*
5.25 (2.84, 9.73)
< 0.001
Tumor Size: > 2 vs ≤ 2 cm
2.78 (1.70, 4.57)
Central grade
Moderate vs Well
Poor vs Well
1.70 (0.75, 3.86)
2.06 (0.82, 5.17)
0.270
Multivariate analysis adjusted for treatment arm and patient age
*Hazard Ratio for a 50-point increment in Recurrence Score value
Main point: The Recurrence Score® result as a continuous variable had a highly significant hazard ratio of 5.25 in this multivariate analysis.
This analysis is for node-negative patients with both tamoxifen-alone and anastrozole-alone treatment arms analyzed.
Tumor size had a statistically significant hazard ratio of 2.78 in this analysis.
Dowsett M, et al. J Clin Oncol. 2010; 28(11):
Multivariate analysis confirms that the Oncotype DX® Recurrence Score result as a continuous variable is a highly significant predictor of time to distant recurrence
Dowsett M, et al. J Clin Oncol. 2010;28(11):

33. Trans ATAC: Recurrence Score® Value Is Prognostic in Node-Positive Patients
Node+ (n = 306; both treatment arms)
1.0
0.9
0.8
83%
Log-rank P < 0.001
0.7
72%
0.6
Proportion distant recurrence-free
0.5
51%
0.4
0.3
N (%) Events
Low (52%)
Int (31%)
High (17%)
0.2
0.1
The TransATAC was designed to address the concerns that all the validation studies were done using tamoxifen, but in today’s world most postmenopausal women are given an AI.
In the original Anastrozole or Tamoxifen Alone in Combination (ATAC) study, patients with ER+, node-negative or node-positive breast cancer were randomized to receive tamoxifen, anastrozole, or both agents.
In the TransATAC study, 1231 tumor samples were available, of which 306 samples were from patients with node-positive tumors.
As shown here, the Recurrence Score® result predicts distant recurrence in node-positive patients treated with either tamoxifen or anastrozole.
Dowsett M, et al. J Clin Oncol. 2010;28(11):
0.0 1 2 3 4 5 6 7 8 9
Years
Recurrence Score group
Hazard ratio* (95% CI)
High vs Low
2.7 ( )
Int vs Low
1.8 ( )
Dowsett M, et al. J Clin Oncol. 2010;28(11):

34. 9-Year risk of distant recurrence (%)
Trans ATAC: Rate of Distant Recurrence Increases with Number of Positive Nodes for All Recurrence Score® Values
100
95% CI
Mean
≥ 4 Positive nodes
n = 63 90 80 70 60
9-Year risk of distant recurrence (%)
1-3 Positive nodes
n = 243 50 40 30
Node negative
n = 872
Main point: The risk of distant recurrence increases with the number of positive nodes for the Recurrence Score® result.
If we look at all patients with both node-negative and node-positive disease, we see that the 9-year risk of distant recurrence increases with the number of positive nodes.
Interestingly if we focus on just the lower end of the low Recurrence Score category we see that the confidence intervals overlap for 0 and 1-3 positive nodes suggesting their outcome is quite similar. A similar result was seen in the E21097 study when you looked specifically at 1 positive node vs node negative.
Dowsett M, et al. J Clin Oncol. 2010;28(11): 20 10 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Low Recurrence Score suggests a low risk of recurrence for patients with 1-3 positive nodes.
Dowsett M, et al. J Clin Oncol. 2010;28(11):

35. SWOG 8814:Oncotype DX® Clinical Validation in Node-Positive Patients
SUB ANALYSIS
Postmenopausal, node-positive, ER-positive breast cancer
N = 1477
Patients with samples (n = 666)
RT-PCR obtained (n = 601)
Tamoxifen alone (n = 148)
CAF + T (n = 243)
CAF  T (n = 219)
Sample for primary analysis
= 367 (40% of parent trial)
Tamoxifen × 5 yrs
n = 361
CAF × 6 + tamoxifen
n = 550
CAF × 6  tamoxifen
n = 566
Main point: The prognostic utility of the Oncotype DX® assay in node-positive patients was validated in several studies, including the SWOG 8814 study.
The sequential CAF–tamoxifen arm turned out to have superior disease-free survival and overall survival over 10 years.
Thus comparisons in this genomic study utilized this sequential arm rather than the concurrent arm, since it represents the most effective way to give CAF and tamoxifen.
Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.
Superior disease-free survival and overall survival over 10 years
Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

36. SWOG 8814: Recurrence Score® Result Is Prognostic for Node-Positive Patients (Tamoxifen Arm)
DFS by risk group (tamoxifen-alone arm)
OS by risk group (tamoxifen-alone arm)
1.00
0.75
0.50
0.25
0.00
1.00
0.75
0.50
0.25
0.00
Stratified log-rank P = at 10 years
Stratified log-rank P = at 10 years
RS < 18 (n = 55)
RS (n = 46)
RS ≥ 31 (n = 47)
RS < 18 (n = 55)
RS (n = 46)
RS ≥ 31 (n = 47)
Main point: The Recurrence Score® result was shown to be prognostic for patients with node-positive disease.
Among these node-positive patients, the Recurrence Score result was able to separate out a group with a better and a group with a worse prognosis.
These patients were treated with tamoxifen alone and thus these results are prognostic in the sense that they do not include any chemotherapy effect (though tamoxifen effect is included).
There was a wide gap between the 10-year disease-free survival (DFS) in those patients on this study with a low Recurrence Score result (40% 10-year DFS) and those with a high Recurrence Score result (57% 10-year DFS).
Here, DFS was used, as opposed to DRFS (distant recurrence-free survival) which was used in the NSABP B-14 and B-20 analyses with node-negative patients. Thus, the event rate would be expected to be higher here.
Albain KS, et al. Lancet Oncol. 2010; 11(1):55-65.
Years since registration
Years since registration
10-Year DFS: 60%, 49%, 43%
10-Year OS: 77%, 68%, 51%
RS, Recurrence Score result
Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

37. Breast cancer-specific survival by treatment
SWOG 8814: Breast Cancer-Specific Survival of Node-Positive Patients by Treatment and Recurrence Score® Group
Breast cancer-specific survival by treatment
10-yr BCSS
T: 92% vs CAFT: 87%
RS < 18 25 50 75
100 2 4 6 8 10
Years since registration
CAF  T (n = 91, 10 events)
Tamoxifen (n = 55, 4 events)
Stratified log-rank P = 0.56 at 10 years
10-yr BCSS
T: 70% vs CAFT: 81%
RS 18-30 25 50 75
100 2 4 6 8 10
Years since registration
CAF  T (n = 46, 10 events)
Tamoxifen (n = 57, 11 events)
Stratified log-rank P = 0.89 at 10 years
10-yr BCSS
T: 54% vs CAFT: 73%
RS ≥ 31 25 50 75
100 2 4 6 8 10
Years since registration
CAF  T (n = 47, 18 events)
Tamoxifen (n = 71, 20 events)
Stratified log-rank P = at 10 years
Breast Cancer specific survival (BCSS) was defined as the interval between random assignment and the date of death after breast cancer relapse.
Due to clinician feedback when the presented these results at San Antonio Breast conference a few years ago, they incorporated BCSS in their Lancet Oncology paper last year.
The results are the same with the chemo mostly benefiting the high-risk group.
Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.
No benefit to CAF over time for low Recurrence Score
Strong benefit to CAF over time for high Recurrence Score
Interaction P = 0.021
RS, Recurrence Score result
Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

38. Is the Oncotype DX® Assay Included in Treatment Guidelines?

39. Oncotype DX® Is the Only Multigene Expression Assay Incorporated into NCCN®, ASCO®, and St. Gallen’s Guidelines
Consider use in > 0.5 cm, HR+, HER2– disease
pT1, pT2, or pT3; pN0 and pN1mi
(≤ 2 mm axillary node metastasis)
NCCN GuidelinesTM
Newly diagnosed patients with node-negative, ER+ breast cancer who will receive tamoxifen
ASCO Guidelines
Oncotype DX has been shown to predict chemotherapy benefit among patients with HR+ disease
St. Gallen Consensus
Harris L, et al. J Clin Oncol. 2007;33(25):
Adapted from NCCN Practice Guidelines in Oncology – v
Goldhirsch A, et al. Ann Oncol. 2011;22:
ASCO is a trademark of the American Society of Clinical Oncology. NCCN and NCCN Guidelines are trademarks of the National Comprehensive Cancer Network. ASCO and NCCN do not endorse any therapy or product.

40. The Oncotype DX® Assay Provides Consistent Results in Over 4,000 Breast Cancer Patients Studied
Study
Design N
Nodal status
Prognostic
Predictive
NSABP B-141
Prospective; tam only
668
Neg
YES -
Kaiser Permanente2
Prospective; case-control
790 cases/controls
NSABP B-143
Prospective; placebo vs tam
645
Quantitative ER predicts tamoxifen benefit
NSABP B-204
Prospective; tam ± chemo
651
RS predicts chemotherapy benefit
ECOG 21975
Prospective;
AC vs AT
465
Neg/Pos
SWOG 88146
367
Pos
TransATAC7
Prospective; tam vs AI
1231
Main point: The Oncotype DX® assay provides reproducible results across a continuum of biology.
In ER+ early-stage breast cancer, the Oncotype DX assay has been validated in numerous clinical trials to be prognostic in patients with node-negative and node-positive disease. Archived samples used in these validation studies were obtained from randomized, controlled clinical trials, not from convenience samples.
In addition, the assay has been validated to predict tamoxifen and chemotherapy benefit in ER+ node-negative patients, and chemotherapy benefit in ER+ node-positive patients.
Taken together, the number of clinical studies, the stringent prospective study design of these studies, and the consistency of the results in ER+ node-negative and node-positive patient populations have fulfilled the criteria of level I evidence for tumor marker studies.
1. Paik S, et al. N Engl J Med. 2004;351:
2. Habel LA, et al. Breast Cancer Res. 2006;6:R25-R39.
3. Paik S, et al. J Clin Oncol. 2005;23(16S): abstract 510.
4. Paik S, et al. J Clin Oncol. 2006;24:
5. Goldstein LJ, et al. J Clin Oncol. 2008;26:
6. Albain KS, et al. Lancet Oncol. 2010;11:55-65.
7. Dowsett M, et al. J Clin Oncol. 2010;28:
1. Paik S, et al. N Engl J Med. 2004;351:
2. Habel LA, et al. Breast Cancer Res. 2006;6:R25-R Goldstein LJ, et al. J Clin Oncol. 2008;26:
3. Paik S, et al. J Clin Oncol. 2005;23(16S): abstract Albain KS, et al. Lancet Oncol. 2010;11:55-65.
4. Paik S, et al. J Clin Oncol. 2006;24: Dowsett M, et al. J Clin Oncol. 2010;28:

41. The Oncotype DX® Assay Fulfills Criteria for Level I Evidence
Level of evidence
Category
Study design
Validation studies available I A B
Prospective
Prospective using archived samples
None required
One or more with consistent results II C
Prospective / observational
None, or inconsistent results
Two or more with consistent results
III
None, or one with consistent results, or inconsistent results
IV-V D
Retrospective / observational
Not applicable*
Main point: Criteria for level of evidence in tumor marker studies has recently been revised by the National Cancer Institute.
In late 2009, Simon et al published recommendations regarding the use of “prospective retrospective” studies to clinically validate tumor biomarkers. Such prospective approaches involve the pre-specification of hypotheses and analytical study plans using archived tumor tissues collected from previously conducted clinical trials. When performed with requisite procedures and controls, these approaches can in fact generate Level I evidence.
In their newly revised criteria for level of evidence, Simon et al assign a Level I, category B, evidence to those tumor marker studies that demonstrate consistent results across clinical validation studies conducted with prospective study designs using archived tumor samples.
Biomarker studies conducted with convenience samples have no prospectively determined subject eligibility, power calculations, marker cut-point specification, or analytical plans.
These prospective retrospective methods represent a disciplined and pragmatic approach for validating tumor markers. They should clearly be distinguished from the much more common observational retrospective studies that are less rigorous, examine many variables without pre-specification, and yield only hypothesis-generating data.
Simon RM, et al. J Natl Cancer Inst. 2009;101:
*Level of evidence IV and V studies will never be satisfactory for determination of medical utility
Proper study design determines strength of results and level of evidence
Simon RM, et al. J Natl Cancer Inst. 2009;101:

42. Patient Cases

43. Can You Guess the Recurrence Score®?
68 & 69 year-old patients, small node-negative tumors, grade 2 & 3
PATIENT A
68-year-old patient with 1.1-cm tumor
Menopausal Status: Postmenopausal
Tumor Type: Infiltrating Ductal Carcinoma (IDC)
Tumor Size: 1.1 cm
ER Status (IHC): Positive
PR Status (IHC): Positive
HER2/neu Status: Negative
Histologic Grade: 2
Lymph Node Status: Negative
General Health: Fair
______________________________________
CASE SUBMITTED BY:
Victor G. Vogel, MD
PATIENT B
69-year-old patient with 1.3-cm tumor
Menopausal Status: Postmenopausal
Tumor Type: Infiltrating Ductal Carcinoma (IDC)
Tumor Size: 1.3 cm
ER Status (IHC): Positive (2)
PR Status (IHC): Positive (2)
HER2/neu Status: Negative (IHC)
Histologic Grade: 3
Lymph Node Status: Negative General Health: PS 0
______________________________________
CASE SUBMITTED BY:
Ella Tepper, MD

44. Can You Guess the Recurrence Score®?
68 & 69 year-old patients, small node-negative tumors, grade 2 & 3
PATIENT A RESULTS
Clinical Experience
Patients with a Recurrence Score of in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 23% (95% CI: 18%-28%).
PATIENT B RESULTS
Clinical Experience
Patients with a Recurrence Score of in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 7% (95% CI: 5%-10%).

45. Can You Guess the Recurrence Score®?
45 & 46 year-old patients, small node-negative tumors, grade 2 & 3
PATIENT A
45-year-old patient with 0.9-cm tumor
Menopausal Status: Premenopausal
Tumor Type: Infiltrating Ductal Carcinoma (IDC)
Tumor Size: 0.9 cm
ER Status (IHC): Positive (99%)
PR Status (IHC): Positive (13%)
HER2/neu Status: Negative (1.7 by FISH)
Ki-67: 38%
Histologic Grade: 2
Lymph Node Status: Negative (0/2 SLNs)
______________________________________
CASE SUBMITTED BY:
Barbara Schwartzberg, MD
PATIENT B
46-year-old patient with 0.7-cm tumor
Menopausal Status: Premenopausal
Tumor Type: Infiltrating Ductal Carcinoma (IDC)
Tumor Size: 0.7 cm
ER Status (IHC): Positive (91%)
PR Status (IHC): Positive (99%)
HER2/neu Status: Negative (0.7 by FISH)
Ki-67: 35%
Histologic Grade: 3
Lymph Node Status: Negative
______________________________________
CASE SUBMITTED BY:
Barbara Schwartzberg, MD

46. Can You Guess the Recurrence Score®?
45 & 46 year-old patients, small node-negative tumors, grade 2 & 3
PATIENT A RESULTS
Clinical Experience
Patients with a Recurrence Score of in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 10% (95% CI: 7%-12%).
PATIENT B RESULTS
Clinical Experience
Patients with a Recurrence Score of in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 24% (95% CI: 18%-30%).

47. Conclusions

48. The Oncotype DX® Report Provides Valuable Information Along a Continuum of ER+ Breast Cancer
The Oncotype DX report provides valuable information on:
Node-negative prognosis
Node-negative predicted chemotherapy benefit
Quantitative data on ER/PR/HER2
Node-positive report contains an additional page with prognosis and predicted chemo benefit information specific to node-positive patients
As such the report has a separate page for node-positive disease based on the SWOG 8814 study. This page allows you to combine the burden of nodal disease with the Recurrence Score® result and see the potential benefit of adjuvant chemotherapy.
Main point: The Oncotype DX® report provides valuable information along a continuum of ER+ breast cancer.
Genomic Health, Inc, has pursued an extensive process to develop the Oncotype DX assay and demonstrate its prognostic and predictive value in determining optimal therapy for women along a continuum of ER+ breast cancer, from node-negative to newly diagnosed node-positive disease.
The Oncotype DX assay is helpful in predicting which patients will benefit most and least from chemotherapy.
Shown in this slide is a sample report illustrating the types of valuable information that is provided by the Oncotype DX assay.
Page 1 contains prognostic information for node-negative patients; the Recurrence Score result as a measure of risk of 10-year distant recurrence, validated in the B-14 study.
Page 2 contains predictive information concerning chemotherapy benefit for node- negative patients, validated in the B-20 study.
Page 3 contains both predictive and prognostic information for newly diagnosed node-positive patients, as validated in the SWOG 8814 study.
Page 4 contains quantitative ER, PR, and HER2 single-gene results.

49. The Oncotype DX® Breast Cancer Assay
Quantitatively predicts the likelihood of breast cancer recurrence and assesses the benefit from both hormonal therapy and chemotherapy (Level I Evidence)
High and low Recurrence Score® results reflect different intrinsic tumor biology
You cannot predict the risk of distant recurrence or chemotherapy benefit by relying on clinical and pathological variables
Changes treatment decisions based on traditional measures 37% of time, sparing patients the negative health and QOL impact of unnecessary chemotherapy and resulting in cost savings
Only assay incorporated into ASCO®, NCCN® and St Gallen’s clinical practice guidelines
Longest history of commercial genomic assays with over 200,000 patients tested worldwide
Main point: The Oncotype DX® assay quantitatively predicts the likelihood of recurrence and assesses the likely benefit from both hormonal therapy and chemotherapy in women with newly diagnosed, early stage invasive breast cancer.
It is the only multi-parameter gene expression assay to show clinical utility in breast cancer, meaning that it has been shown to alter treatment decisions in a significant number of cases.
It is the only multivariate genomic classifier recommended in both ASCO, NCCN and St Gallen’s clinical practice guidelines.
Harris L, et al. J Clin Oncol. 2007;33(25):
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. v
ASCO is a trademark of the American Society of Clinical Oncology and NCCN is a trademark of the National Comprehensive Cancer Network. ASCO and NCCN do not endorse any therapy or product.