1. Genomics in Breast Cancer: An Overview for Nurses
Today we are going to discuss the role genomics is currently playing in breast cancer clinical practice

2. Learning Objectives
Provide background on breast cancer, its staging and current adjuvant treatments
Distinguish between role of Genomics and Genetics in clinical practice
Understand the clinical utility of new genomic tests, such as the Oncotype DX® Breast Cancer Assay
Explain the Oncotype DX Recurrence Score ® result and its association with risk of recurrence and prediction of chemotherapy benefit
Identify the patients for whom the Oncotype DX assay has been clinically validated
Describe the mechanism to obtain assistance regarding ordering and reimbursement of the Oncotype DX assay

3. Breast Cancer Figures
1 in 8 women in the United States will develop breast cancer, most occurring by age 70
Incidence: 180,000 people in the United States will be diagnosed in 2007 with invasive breast cancer including 2,000 men
Over 40,000 women and men will die from the disease in 2007
Over 77% of breast cancer cases are diagnosed in people over the age of 50
Statistics from 2007
Source: American Cancer Society and National Cancer Institute

4. Breast Cancer Progress Report
Breast Cancer mortality rates have decreased by 2.3% annually since 1990
The decline in mortality is primarily due to early detection and new treatment methods
Source: Breast Cancer Facts and Figures
National Center for Health Statistics data as analyzed by NCI

5. The Stages of Breast Cancer
Breast Cancer is diagnosed according to stages (stages 0 through IV) under the TNM classification.
Factors used in staging of Breast Cancer:
Tumor Size
Size of primary tumor
Nodal status Indicates presence or absence of cancer cells in lymph nodes
Metastasis Indicates if cancer cells have spread from the affected breast to other areas of the body (i.e. skin, liver, lungs, bone)
Source: National Cancer Institute

6. Early Stage Breast Cancer
Stage 0 Ductal carcinoma in situ (DCIS) is very early breast cancer that has not spread beyond the duct. Stage I Tumor is < 2 cm and has not spread outside the breast. Stage IIA No tumor is found in the breast, but cancer is found in the axillary lymph nodes, or tumor is ≤ 2 cm and has spread to the axillary lymph nodes, or tumor is 2-5 cm but has not spread to the axillary lymph nodes. Stage IIB Tumor is 2-5 cm and has spread to the axillary lymph nodes or is > 5 cm but still confined to the breast.
Source: National Cancer Institute

7. Advanced Breast Cancer
Stage IIIA The tumor in the breast is smaller than 5 centimeters and the cancer has spread to underarm lymph nodes that are attached to each other or to other structures, OR the tumor is more than 5 centimeters across and the cancer has spread to the underarm lymph nodes. Stage IIIB Tumor has spread to tissue near the breast (i.e. the skin or chest wall) and may have spread to lymph nodes within the breast area or under the arm. Stage IIIC Tumor has spread to the lymph nodes beneath the collarbone and near the neck, and may have spread to the lymph nodes within the breast area or under the arm and to the tissues near the breast.
Stage IV Tumor has spread to other organs of the body (i.e. lungs, liver, or brain).
Source: National Cancer Institute

8. Genetics and Genomics

9. Genetics Help us Identify Patients at High Risk of Developing Breast Cancer
Genetics is the study of heredity
While genetics influence genomics, genetics is responsible for only 5-10% of breast cancer
Genetics focuses primarily on the likelihood of developing cancer
Genetic tests find mutations, not disease
Genetics is the study of genes and heredity.
Genomics is the study of genes, their functions, and related techniques.
The main difference between genomics and genetics is that genetics studies how inherited traits are passed from one generation to the next, as well as how traits appear by means of mutations. Genomics studies a group of genes and their inter-relationships in order to identify their combined influence on the growth and development of the organism.
Source: Understanding Cancer Series: Gene Testing,
National Cancer Institute

10. Genomics Help us Look at the Patients Individual Tumor Biology
Genomics is the study of how genes interact and are expressed as a whole
Genomics and gene expression profiling tools focus on the cancer itself and can help determine
How aggressive is the cancer (prognosis)
What is the likely benefit from treatment (prediction)

11. Examples of Genetic and Genomic Tests
Genetic Test
BRCA1 and BRCA2
The genetic make up of patients is tested for BRCA1 and BRCA2 mutations. Patients with those mutations have higher chances of developing breast cancer.
Genomic Test
Oncotype DX® Breast Cancer Assay
The expression level of 21 genes is measured in tumor tissue from patients that have already been diagnosed with breast cancer. This assay evaluates if a patient is going to recur (prognostic) and predicts benefit from chemotherapy and hormonal therapy (predictive).
Example of Genetic test: BRCA1 and BRCA2 look at specific gene mutations on the patient’s genetic make up that make them more susceptible to developing breast cancer in their lifetime.
Example of Genomic test: Oncotype DX looks at the expression level of 21 different genes on the patient’s tumor tissue and correlates that information with the likelihood of distant recurrence in 10 years and the magnitude of chemotherapy benefit.

12. Adjuvant Treatment for Early Stage Breast Cancer Today

13. Hormonal Therapy
Based on the Landmark NSABP B-14 Study using Tamoxifen
If 100 women with ER+, N- disease are treated with hormonal therapy how many will recur within 10 years?
85 women are disease free with hormonal therapy alone (shown in trials conducted by the NSABP as well as other cooperative groups). How can we know who are these women?
Fisher et al. N Engl J Med 1989;320(8):479-84

14. Chemotherapy and Hormonal Therapy
Based on the Landmark NSABP B-20 Study using Tamoxifen + Chemotherapy
If all 100 women with ER+, N- disease are treated with chemotherapy and hormonal therapy, how many will benefit from the addition of chemotherapy?
By treating 100 women with chemotherapy and hormonal therapy only 4 would derive a benefit from chemotherapy treatment and 85 would have done well with hormonal therapy alone.
Today, we are treating nearly all women to benefit a few.
Fisher et al. J Natl Cancer Inst 1997;89:

15. Does she need chemotherapy after surgery for her cancer type?
Your Patient Needs Better Tests to Assess Her Risk of Recurrence and Optimize Her Treatment
Will her cancer spread?
Does she need chemotherapy after surgery for her cancer type?
What are the benefits and side effects of chemotherapy for her?
Are there any new drugs for her cancer?
Will she survive?
These are all questions you receive when patients come in to your center/office after being diagnosed.
As a patient, the decision to take adjuvant chemotherapy can be difficult, particularly given its side effects. Therefore we need better tests to evaluate risk of recurrence and chemotherapy benefit to customize treatment for the patient’s individual disease.
The major challenge in current management of patients with N-, ER+ breast cancer, is indeed the selection of patients for adjuvant chemotherapy.

16. How Do We Assess Risk in Breast Cancer Patients?
Oncotype DX®
New tools in the Genomic Era…
Classic Pathological Criteria
Age
Tumor Size
Lymph Node Status
ER/PR HER2
Tumor Grade
Adjuvant! Computer-based model
In the past, studies showed that age, size and tumor grade were the best available tools to predict which patients were at high risk. With the advent of computer models such as Adjuvant Online we have been able to aggregate classical pathologic criteria and help nurses and physicians better asses risk. Today, in the Genomic Era, we have better tests, such as the Oncotype DX assay, to help us identify patients whose tumor biology make them likely to recur.
*A robust assay that could characterize an individual’s risk of assessment and responsiveness to treatment would enable better tailored therapeutic intervention.
* Image from NCI

17. With Genomic Tools We Can Now Analyze Cancer at the Molecular Level
1. Patient’s tumor
4. Oncotype DX® Report
3. Analyze expression of tumor’s genes
2. Oncotype DX® Assay
5. Shared Decision Making
With Genomic tools, such as the Oncotype DX assay, we can now analyze cancer at the molecular level.The behavior of cancer is dependent on many different genes, how they interact, and the conditions they create for disease to occur. Oncotype DX analyzes the expression level of a key set of genes in the patient’s tumor to quantitatively assess the likelihood of breast cancer recurrence and prediction of benefit from therapy.
Gene expression looks at the mRNA abundance for a particular gene (i.e. number of copies of mRNA per nanoliter of homogenized tissue)

18. Oncotype DX®: A Genomic Assay
Oncotype DX allow us to look at your patient’s tumor and help inform decision-making about treatment that is right for her.

19. 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
INVASION
Stromelysin 3
Cathepsin L2
HER2
GRB7
BAG1
GSTM1
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
CD68
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.
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.
Paik et al. N Engl J Med. 2004;351:

20. Oncotype DX® 21-Gene Recurrence Score® (RS) Assay
Calculation of the Recurrence Score Result
RS =
Coefficient x Expression Level
x HER2 Group Score
x ER Group Score
x Proliferation Group Score
x Invasion Group Score
x CD68
x GSTM1
x BAG1
Category
RS (0-100)
Low risk
RS <18
Int risk
RS ≥18 and <31
High risk
RS ≥31
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 significant effect on the RS. 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
Paik et al. N Engl J Med. 2004;351:

21. The Oncotype DX® Assay is for N-, ER+ Breast Cancer Patients
Oncotype DX is only validated for patients with early stage breast cancer Stage I-II, node negative, ER+ patients.
As a reminder, in Stage I the cancer has spread from lobules or ducts to nearby tissue in the breast. At this stage and beyond, breast cancer is considered invasive. The tumor is 2 cm or less in diameter and has not spread to the lymph nodes. In Stage IIA, the tumor can range from 2 cm to less than 5 cm in diameter and has not spread to the lymph nodes.

22. The Oncotype DX® Assay Has Been Extensively Studied in 3,300+ Patients
Study
Type
No. Pts
References
Providence
Exploratory
136
Proc Am Soc Clin Oncol 21: 2002 Abstract 3017
Rush 78
Clin Cancer Res 2005; 11:
NSABP B-20
233
SABCS 2003; Abstract 16
NSABP B-14
Prospective
668
NEJM 2004; 351:
MD Anderson
149
Clin Cancer Res 2005; 11:
Kaiser Permanente
Case-Control
790
Cases/ Controls
Breast Cancer Res 2006; 8: R25
Placebo vs Tam
645
JCO 2005; 23 (16S): Abstract 510
Instituto Nazionale Tumori, Milan
Pathologic CR 89
JCO 2005; 23:
Tam vs Tam+Chemo
651
JCO 2006; 24:
ECOG 2197
Exploratory and Prospective
776
JCO 2007; 25 (18S): Abstract 526
Extensive evidence supporting Oncotype DX’s utility in multiple studies involving over 3,300 patients and more than 39,000 commercial assays performed in the past 3 years.
We are going to look in the next couple of slides at two pivotal trials: NASBP B-14 and NASBP B-20.
The references for the fully published studies are as follows from top to bottom:
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:
39,000+ Commercial Assays as of September 30, 2007

23. NASBP B-14 Validation Trial for the Oncotype DX® Assay
Purpose: To evaluate the Oncotype DX 21-gene panel and its Recurrence Score® (RS) result as predictors of the likelihood of distant recurrence
Population: Tumor tissue from 668 N-, ER+, tamoxifen-treated patients enrolled in the NASBP B-14 study
Design:
Multi-center study using a pre-defined panel of 21 genes with prospectively-defined endpoints, analysis plan and algorithm for calculation of the RS result
Blinded, triplicate analysis by RT-PCR of 10 μm fixed tumor block sections
The NASBP B-14 validation trial for Oncotype DX is a prospectively designed trial using archival tissue. The laboratory was blinded to the clinical outcomes.
This NSABP study was performed to clinically validate the prespecified 21 gene RT-PCR assay and the 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 B-14 study.
The original B-14 trial had 2828 N-, ER+ patients who were randomized 1:1 to tamoxifen or placebo in a double-blind fashion from An additional 1335 patients were registered to Tamoxifen in the 10-month period following closure of this trial in 1988, making 2617 clinically eligible tamoxifen-treated patients.
Patients who were treated with tamoxifen in the randomized portion or the registered portion were eligible for the Genomic Health study.
Paik et al. N Engl J Med. 2004;351:

24. Paik et al. N Engl J Med. 2004;351:2817-2826
The Recurrence Score® Result Stratifies Patients by their 10-Year Distant Recurrence-Free Survival
Of the 675 available blocks in the NSABP library, 668 underwent successful evaluation with RT-PCR, representing a 99% success rate.
This graph demonstrates the difference in DRFS over time for the different risk categories. The distant recurrence-free survival for the high- and low-risk groups were statistically significantly different; the 10-year distant recurrence-free survival for the low-risk category was 93% compared to 69% for the high-risk category.
Paik et al. N Engl J Med. 2004;351:

25. The Recurrence Score® Result Quantifies the Risk of Distant Recurrence (Prognosis)
668 patients
The graph presented in this slide indicates that the proportion of patients in the low-risk group who were 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 (Bonadonna et al. Cancer 1977;39(6 Suppl): ).
For each risk-based cohort, the 95% confidence interval error bands have little to no overlap.
Paik et al. N Engl J Med. 2004;351:

26. The Recurrence Score® is a Continuous Predictor of the Risk of Distant Recurrence
The recurrence score is a continuous predictor of tumor biology. Risks groups have been developed for statistical analysis in the clinical trials. However, each individual RS has a distinct risk of recurrence associated with it. As an example, the risk of recurrence for a patient with a RS of 20 is closer to a patient with a RS of 17 in the low risk group than to one with a RS of 29 in the intermediate risk group.
Paik et al. N Engl J Med. 2004;351:

27. Summary of the NASBP B-14 Trial
Clinical validation study for the Oncotype DX® assay showing that the Recurrence Score® result quantifies the likelihood of distant recurrence in N- ER+, tamoxifen-treated breast cancer patients (prognosis)
The Recurrence Score result identified a large subset of patients with low risk of recurrence
The Recurrence Score result was a consistent predictor of distant recurrence independent of patient age, tumor size and tumor grade
Using the prospectively defined 21-gene expression assay and endpoints, the RS predicted the likelihood of distant recurrence in N-, ER+ tamoxifen treated breast cancer patients.
The RS provides accuracy and precision in predicting the likelihood of distant recurrence. The performance of the RS exceed standard measures such as age, tumor size and tumor grade in prognostic power and reproducibility.
Overall, 50% of the patients were reclassified by the RS when compared to NCCN or St. Gallen (not shown)
The RS (based upon tumor gene expression) more accurately quantifies the risk of distant recurrence than do the NCCN guidelines (based upon size, age and grade).
Although all patients enrolled in B-14 were later treated with Tamoxifen, which as implications for interpretration of RS for individual patients, the tissue that was archived for analysis was taken from tumors before any systemic therapy was administered.
Paik et al. N Engl J Med. 2004;351:

28. NASBP B-20 Chemotherapy Benefit Trial for the Oncotype DX® Assay
Purpose: To determine whether the Oncotype DX assay and its Recurrence Score® result could predict magnitude of chemotherapy benefit
Population: Tumor tissue from 651 N-, ER+ patients from the NASBP B-20 study treated with either tamoxifen alone (n=227) or with tamoxifen plus CMF or MF chemotherapy (n=424)
Design:
Multi-center, randomized trial using a pre-defined panel of 21 genes with prospectively-defined endpoints, analysis plan and algorithm for calculation of the RS result
Blinded, triplicate analysis by RT-PCR of 10 μm fixed tumor block sections
The NASBP B-20 chemotherapy benefit study for Oncotype DX is a prospectively designed trial using archival tissue.
The objective of this trial is listed above along with the schema of the protocol.
In secondary analyses, similar results were seen when the patients treated with CMF or with MF were examined separately.
The analysis by NSABP shows GHI’s B-20 study subjects were similar to all B-20 patients in the cohort and the loss of cases was principally due to blocks never being collected.
Again this trial had prospectively define endpoints and the laboratory was blinded to the clinical outcomes.
Paik et al. J Clin Oncol. 2006;24:

29. The Oncotype DX® Assay: Patients Do Not Benefit Equally from Chemotherapy
28% Absolute Benefit
Little, if any, benefit
All patients
Low RS
High RS
Intermediate RS
These results indicate that not all women benefit equally from chemotherapy.
(A)- shows all 651 patients within this trial showing the overall benefit of chemotherapy in these evaluable patients of 4.4% absolute benefit from tamoxifen + chemotherapy. 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?
(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 helped open the door to widespread use of adjuvant cytotoxic therapy for this population.
(D)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.
(B) 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.
(C)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 and remains unclear. We will be addressing this intermediate risk group later in our discussion (TAILORx)
This type of assay helps to 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 to unwanted toxicities associated with chemotherapy.
Paik et al. J Clin Oncol. 2006;24:

30. Patients with High RS Derive Significant Benefit from Chemotherapy (Prediction)
Low
RS<18
High
RS ≥31
% % % %
n = 353
n = 134
n = 164
Int
RS18-30
Shown here is the absolute increase in DRFS by the addition of chemotherapy in each of the Recurrence Score risk groups.
The high-risk patients gain a clear large benefit from chemotherapy, with the absolute risk of recurrence decreased by 28%.
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.
This intermediate group we will be discussing further when we get to the TAILORx NCI sponsored trial that is ongoing.
Absolute Increase in Distant Recurrence Free Survival at 10 Yrs (mean ± SE)
Paik et al. J Clin Oncol. 2006;24:

31. Summary of the NASBP B-20 Trial
The Recurrence Score® (RS) result not only quantifies the risk of recurrence in women with N-, ER+ breast cancer, but also predicts the magnitude of chemotherapy benefit (predictive)
Patients with a low RS have minimal, if any benefit, from chemotherapy while patients with a high RS have a significant benefit from chemotherapy
Benefits of adjuvant treatment differ by Recurrence Score risk category:
Benefits of tamoxifen are greater in patients with low risk or intermediate risk tumors (Paik et al. JCO, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, 2005: 510)
Benefits of chemotherapy are greater in patients with high risk tumors
Paik et al. J Clin Oncol. 2006;24:

32. The Oncotype DX® Assay in Clinical Practice
Let’s transition over and talk about how health care professionals like yourself get access to Oncotype DX and the process surrounding ordering within your institution.

33. The Oncotype DX® Assay Recommended in ASCO Clinical Practice Guidelines
The Oncotype DX assay is recommended on the ASCO Clinical Practice Guidelines for use in newly diagnosed patients with N-, ER+ breast cancer to:
Predict risk of recurrence
Identify patients who are predicted to obtain the most therapeutic benefit from tamoxifen and may not require chemotherapy
Identify patients with high RS scores who appear to derive greater benefit from chemotherapy (specifically CMF) than from tamoxifen
Conclusions may not be generalizable to hormonal therapies other than tamoxifen, or to other chemotherapy regimens
The Oncotype DX assay is the only multi-parameter gene expression assay found to show clinical utility in breast cancer
Harris et al. J Clin Oncol. 2007; published online ahead of print

34. The Oncotype DX® Assay Recommended for Consideration in NCCN Clinical Practice Guidelines

35. The Oncotype DX® Assay in Clinical Practice
The Oncotype DX assay has been offered by Genomic Health, Inc., since January 2004
Genomic Health has a CLIA-certified and CAP-accredited reference lab
Send tumor block or 6 fixed, paraffin-embedded sections (10 µm each) to Genomic Health using the Oncotype® Specimen Kit
Turnaround time: days
Customer Service: ONCOTYPE
The Oncotype DX assay has been available since January 2004.
Genomic Health has a Clinical Laboratory Improvement Act/Amendment (CLIA)- certified reference lab.
The assay requires sending a tumor block or 6 fixed, paraffin-embedded sections of 10 µm each to Genomic Health.
The turnaround time for the assay is 10 to 14 days calendar days from the time that Genomic Health receives the patient’s tumor specimen.

36. Reimbursement Support for Your Practice for the Oncotype DX® Assay
Genomic Health helps your patient and practice by taking assignment of benefits and managing the billing and claims process
The Genomic Access Program (GAP) performs comprehensive benefits investigations and informs patients of their coverage and potential financial responsibility within 2 business days
Well trained client service and reimbursement staff are available and willing to work one-on-one with offices/accounts/ and patients as needed.
There is a full brochure available to the patients outlining all of these services. (Refer to patient education brochure located on slide 40)

37. The Oncotype DX® Assay Is Widely Covered in the United States
Oncotype DX is covered by several insurance plans representing 165+ million lives in the US¹
Plans include: Medicare², Aetna, United Healthcare, Kaiser Permanente, Cigna, WellPoint, Highmark BC, Harvard Pilgrim, BC/BS of Michigan, BC/BS FEP, CareFirst BC/BS, BC/BS of Minnesota, BC/BS of Alabama, BC/BS of New Jersey and others
GAP also provides a generous financial assistance to qualifying patients
Covered lives: number of lives with coverage either by policies or contracts.
GAP- Genomic Access Program- patient education brochure completely outlines the services these professionals provide (these include):
Services provided:
Benefit Investigations
Prior Authorizations when needed
Processing of Claims
Appeals – up to 3 levels to include independent medical review if available
Communication with physician’s office and patient throughout the reimbursement process (GAP Brochure provided to patients)
Uninsured Patient Assistance Program
Financial Assistance for insured patients who meet eligibility requirements
¹ As of September 2007
² Through a local coverage decision developed by the National Heritage Insurance Company which applies to all testing billed by Genomic Health’s California facility

38. Procedure for Ordering the Oncotype DX® Assay
Patient Education and Reimbursement Information
Ensure that each patient that is considering the Oncotype DX assay has a copy “A Patient’s Guide to Oncotype DX”
Requisition Form
Fill out form completely, have an authorized Healthcare Provider sign form
If the authorized Healthcare Provider would like a Benefits Investigation done, complete the Benefits Investigation section by selecting service options and adding a Statement of Medical Necessity
Select Specimen Retrieval service option
FAX completed form to Genomic Health Customer Service ( )
Acknowledgement of Referral Form
You will receive a FAX from GAP confirming the receipt of your Benefits Investigation
Benefits Summary
If you have selected a Benefits Investigation, within 2 business days you will receive a FAX entitled “Benefits Summary” and a GAP representative will call your patient to explain their laboratory benefits and any financial responsibility resulting from performing the assay
If you selected, “YES Investigate – Proceed pending patient confirmation”, Genomic Health Customer Service will be contacting you on how the test should proceed
Procedure as of September 2007

39. Oncotype DX® Patient Report
The patient report includes:
Recurrence Score® (RS)
Average 10-year distant recurrence rate for that RS
Graph of 10-year recurrence risk as a function of RS in tamoxifen-treated patients
The report is sent to:
Treating physician
Submitting pathologist
A detailed report is generated, showing the assay result as a Recurrence Score (RS). The report also provides an interpretation of the RS as the average 10-year distant recurrence rate for that RS in the clinical trial population (including 95% confidence interval) and the position of that RS on a graph of RS as a continuous variable.
The report is sent by fax, overnight mail, or secure online transfer to the treating physicians and submitting pathologist and any additional physicians named on the requisition form.
The Oncotype DX™ report is not directly distributed to patients.

40. How Can Nurses be Involved with the Oncotype DX® Assay?
Identify appropriate patients
Stage I/II, lymph node negative, ER positive, who need to make decisions regarding adjuvant chemotherapy
Not for DCIS patients
Not for lymph node positive patients
Educate patients on the Oncotype DX assay
Help inform and assist with enrollment
of eligible patients on the TAILORx
trial
TAILORx trial to be discussed later

41. Oncotype DX® Resources for Nurses
Patient Education Brochure
English and Spanish
My Breast Cancer Coach
Interactive online program developed with the Breast Cancer Network of Strength. This program enables newly diagnosed women to personalize their online search for breast cancer information by answering a series of eight questions about their diagnosis, based on the information contained in their pathology reports
Patient website providing an overview of invasive breast cancer and the tools used to determine recurrence risk and help make treatment decisions

42. Genomic Health’s Commitment to Nursing
Offer educational programs and activities on Genomics at both local and national levels
Provide accurate medical and clinical information in a timely manner, including one on one assistance from our medical team
Provide valuable assay results that are reliable, sensitive and reproducible
Deliver actionable insights that can improve decision making for breast cancer patients
Address reimbursement concerns
Provide patient education and support
Partner with advocacy groups to support breast cancer efforts

43. Patient Cases

44. Patient Cases
Patient was identified as low risk by Oncotype DX® with a Recurrence Score ® result of 4
Patient received hormonal therapy since she was in a group in which chemotherapy does not provide benefit

45. Patient Cases

46. Patient Cases
Patient was identified as high risk by Oncotype DX® with a Recurrence Score® result of 34
The Recurrence Score helped convince the patient on the likely benefits of taking chemotherapy given the biology of her disease
Patient received chemotherapy and hormonal therapy

47. Patient Cases

48. Patient Cases
Patient was identified as intermediate risk by Oncotype DX® with a Recurrence Score® result of 25
Is there benefit from chemotherapy for this patient? The TAILORx trial evaluates the utility of chemotherapy in the mid-range risk group

49. Integration of New Tests in Clinical Decision-Making: TAILORx

50. Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx)
Premise
Integration of a new cancer test, the Oncotype DX® assay, into the clinical decision-making process
Implications
Reduce chemotherapy over-treatment in those likely to be optimally treated with hormonal therapy alone
Reduce inadequate treatment by identifying individuals who likely will 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 will benefit from chemotherapy and women who will have little or no benefit from chemotherapy. Therefore, the implications of this premise for the study are that many women are currently being overtreated and could benefit from hormonal therapy alone, and other patients are getting inadequate treatment and could benefit from chemotherapy.
Through this trial many of these patients will now be appropriately treated based upon their risk of recurrence and likelihood of chemotherapy benefit. However, there are some woman for whom uncertainty still exists about the likelihood of benefit from chemotherapy, and these women will be randomized to determine if there is a group that largely receives chemotherapy plus hormone therapy now but may do no worse with hormonal therapy alone.
Trial sponsored by NCI. Participating cooperative groups include ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP

51. Node N-, ER+ Breast Cancer Chemotherapy + Hormone Rx
TAILORx Schema
Node N-, ER+ Breast Cancer
RS <10
Hormone
Therapy
Registry
RS 11-25
Randomize
Hormone Rx vs
Chemotherapy Hormone Rx
RS >25
Chemotherapy +
Oncotype DX® Assay
Register
Specimen banking
Primary study group
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). Also, HER2+ patients are not eligible for this trial.
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%.
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. However, the cutoffs for the TAILORx trial were picked for different reasons from those involved with the selection of cutoffs for the validation trial and the Oncotype DX™ report. The cutoffs in the study were selected to correspond with specific risk levels. For instance, the TAILORx investigators concluded that it was not ethical to deprive a women of chemotherapy if she had a risk level above 20%.

52. Primary Objectives TAILORx
To determine whether adjuvant hormonal therapy (i.e. 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 working premise is that patients in the mid-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 directly assess the validity of the Oncotype DX™ assay. In fact, this trial design is predicated on the assumption that the assay is fully validated. For a patient with a RS <11, chemotherapy will not be given. For a patient with a RS >25, chemotherapy will be given. In other words, 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 multi-gene 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):

53. TAILORx: Key Points Participating groups Adjuvant therapy Other trials
Major North American cooperative groups, including ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP
Adjuvant therapy
Choice of hormonal and/or chemotherapy regimen is at discretion of treating physician
Permissible options are outlined in protocol, and are generally consistent with NCCN guidelines
Other trials
May enroll on other CTSU or other cooperative group studies if treatment assignment on other trial is consistent with PACCT-assigned treatment
Cost
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 co-payments or deductibles will not be responsible for the cost of the Oncotype DX® assay
Financial Considerations
Costs associated with treating the patient and any supportive care will be billed by local practices in the normal manner.
Genomic Health will submit claims to relevant health plans for the cost of 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.

54. TAILORx Information Resources
Protocol and General Information
Clinical Trials Support Unit
Eligibility Questions
Eastern Cooperative Oncology Group
TAILORx Patient Education Materials
Oncotype DX® Information
Genomic Health Customer Service
1-866-ONCOTYPE ( )

55. Conclusions

56. Oncotype DX® is a Standardized and Quantitative Assay
Recurrence Score® in N-, ER+ patients
Lower RS’s
Lower likelihood of recurrence
Minimal, if any, chemotherapy benefit
Higher RS’s
Greater likelihood of recurrence
Clear chemotherapy benefit
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)
Chemotherapy benefit (the higher the score, the greater the impact of chemotherapy on 10 year distant recurrence-free survival)
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. Oncotype DX® Summary
The Oncotype DX Recurrence Score® assay predicts likelihood of recurrence (prognostic) and magnitude of adjuvant treatment benefit for chemotherapy (predictive)
The Oncotype DX Recurrence Score assay shows consistent results across multiple independent studies