2. 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 DXÂŽ
Breast Cancer Assay
⢠Explain the Oncotype DX Recurrence Score Ž
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. 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
Source: American Cancer Society and National Cancer Institute
4. 4
Breast Cancer Progress Report
⢠Breast Cancer
mortality rates have
decreased by 2.3%
annually since 1990
Source: Breast Cancer Facts and Figures 2005-2006
National Center for Health Statistics data as analyzed by NCI
⢠The decline in
mortality is primarily
due to early
detection and new
treatment methods
5. 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. 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. 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
9. 9
Genetics Help us Identify Patients at
High Risk of Developing Breast Cancer
Genetics
â 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
Source: Understanding Cancer Series: Gene Testing,
National Cancer Institute
10. 10
Genomics Help us Look at the Patients
Individual Tumor Biology
Genomics
â 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
â How aggressive is the cancer (prognosis)
â What is the likely benefit from treatment
(prediction)
11. 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 DXŽ
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).
13. 13
Hormonal Therapy
If 100 women with ER+, N- disease are treated with
hormonal therapy how many will recur within 10
years?
â Based on the Landmark NSABP B-14 Study using Tamoxifen
85
15 Recurrence
Disease free
Fisher et al. N Engl J Med 1989;320(8):479-84
14. 14
Chemotherapy and Hormonal Therapy
If all 100 women with ER+, N- disease are treated with
chemotherapy and hormonal therapy, how many will
benefit from the addition of chemotherapy?
â Based on the Landmark NSABP B-20 Study using Tamoxifen +
Chemotherapy
4
85
11
Benefited from
Chemotherapy
Relapsed despite
Chemotherapy
Disease free
regardless of
Chemotherapy
Fisher et al. J Natl Cancer Inst 1997;89:1673-82
15. 15
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?
16. 16
How Do We Assess Risk
in Breast Cancer Patients?
Classic Pathological
Criteria
Oncotype DXÂŽ
New tools in the
Genomic EraâŚ
Age
Tumor
Size
Lymph Node
Status
ER/PR
HER2
Tumor
Grade Adjuvant!
Computer-based model
17. 17
With Genomic Tools We Can Now Analyze
Cancer at the Molecular Level
1. Patientâs tumor
4. Oncotype DXÂŽ
Report
3. Analyze expression of tumorâs genes
2. Oncotype DXÂŽ
Assay
5. Shared Decision Making
19. 19
Oncotype DXÂŽ 21-Gene
Recurrence ScoreÂŽ (RS) Assay
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN
ER
PR
Bcl2
SCUBE2
INVASION
Stromelysin 3
Cathepsin L2
HER2
GRB7
HER2
BAG1GSTM1
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Paik et al. N Engl J Med. 2004;351: 2817-2826
20. 20
Oncotype DXÂŽ 21-Gene
Recurrence ScoreÂŽ (RS) Assay
Calculation of the Recurrence Score Result
Category RS (0-100)
Low risk RS <18
Int risk RS âĽ18 and <31
High risk RS âĽ31
Paik et al. N Engl J Med. 2004;351: 2817-2826
RS =
Coefficient x Expression Level
+ 0.47 x HER2 Group Score
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1
21. 21
The Oncotype DXÂŽ
Assay is for N-, ER+
Breast Cancer Patients
Invasive
Breast
Cancer
Stage I Stage II Stage III Stage IV
ER- ER+ N- N+
ER- ER+
22. 22
The Oncotype DXÂŽ 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 Exploratory 78 Clin Cancer Res 2005; 11: 8623-31
NSABP B-20 Exploratory 233 SABCS 2003; Abstract 16
NSABP B-14 Prospective 668 NEJM 2004; 351:2817-26
MD Anderson Prospective 149 Clin Cancer Res 2005; 11: 3315-19
Kaiser Permanente Prospective
Case-Control
790
Cases/
Controls
Breast Cancer Res 2006; 8: R25
NSABP B-14 Prospective
Placebo vs Tam
645 JCO 2005; 23 (16S): Abstract 510
Instituto Nazionale
Tumori, Milan
Exploratory
Pathologic CR
89 JCO 2005; 23: 7265-77
NSABP B-20 Prospective
Tam vs Tam+Chemo
651 JCO 2006; 24: 3726-34
ECOG 2197 Exploratory and Prospective 776 JCO 2007; 25 (18S): Abstract 526
39,000+ Commercial Assays as of September 30, 2007
23. 23
NASBP B-14 Validation Trial for the
Oncotype DXÂŽ
Assay
⢠Purpose: To evaluate the Oncotype DX 21-gene panel and
its Recurrence ScoreÂŽ (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:
â 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
â Blinded, triplicate analysis by RT-PCR of 10 Îźm fixed
tumor block sections
Paik et al. N Engl J Med. 2004;351: 2817-2826
24. 24
Paik et al. N Engl J Med. 2004;351:2817-2826
The Recurrence ScoreÂŽ Result Stratifies
Patients by their 10-Year Distant
Recurrence-Free Survival
25. 25
The Recurrence ScoreÂŽ Result Quantifies the
Risk of Distant Recurrence (Prognosis)
P < 0.00001 668 patients
Paik et al. N Engl J Med. 2004;351:2817-2826
26. 26
The Recurrence ScoreÂŽ is a Continuous
Predictor of the Risk of Distant Recurrence
Paik et al. N Engl J Med. 2004;351:2817-2826
27. 27
Summary of the NASBP B-14 Trial
⢠Clinical validation study for the Oncotype DXŽ
assay showing that the Recurrence ScoreÂŽ
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
Paik et al. N Engl J Med. 2004;351:2817-2826
28. 28
NASBP B-20 Chemotherapy Benefit Trial
for the Oncotype DXÂŽ
Assay
⢠Purpose: To determine whether the Oncotype DX assay
and its Recurrence ScoreÂŽ
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:
â 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
â Blinded, triplicate analysis by RT-PCR of 10 Îźm fixed
tumor block sections
Paik et al. J Clin Oncol. 2006;24:3726-3734
29. 29
The Oncotype DXÂŽ
Assay: Patients Do Not
Benefit Equally from Chemotherapy
Paik et al. J Clin Oncol. 2006;24:3726-3734
28%
Absolute
Benefit
Little, if
any,
benefit
All patients Low RS
High RSIntermediate RS
30. 30
Int
RS18-30
Absolute Increase in Distant Recurrence Free Survival at 10 Yrs (mean Âą SE)
Low
RS<18
High
RS âĽ31
0 10% 20% 30% 40%
n = 353
n = 134
n = 164
Patients with High RS Derive Significant
Benefit from Chemotherapy (Prediction)
Paik et al. J Clin Oncol. 2006;24:3726-3734
31. 31
Summary of the NASBP B-20 Trial
⢠The Recurrence ScoreŽ (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
Paik et al. J Clin Oncol. 2006;24:3726-3734
33. 33
The Oncotype DXÂŽ
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:
â Predict risk of recurrence
â Identify patients who are predicted to obtain the most therapeutic
benefit from tamoxifen and may not require chemotherapy
â 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
35. 35
The Oncotype DXÂŽ
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 Âľm each) to Genomic Health using the
OncotypeÂŽ Specimen Kit
⢠Turnaround time: 10-14 days
⢠Customer Service: 1-866-ONCOTYPE
1-866-662-6897
36. 36
Reimbursement Support for Your
Practice for the Oncotype DXÂŽ
Assay
â Genomic Health helps your patient and
practice by taking assignment of benefits and
managing the billing and claims process
â The Genomic Access Program (GAP) performs
comprehensive benefits investigations and
informs patients of their coverage and potential
financial responsibility within 2 business days
37. 37
The Oncotype DXÂŽ
Assay Is Widely
Covered in the United States
â Oncotype DX is covered by several insurance
plans representing 165+ million lives in the USš
⢠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
â GAP also provides a generous financial
assistance to qualifying patients
š 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 Healthâs California facility
38. 38
Procedure for Ordering the
Oncotype DXÂŽ
Assay
1. Patient Education and Reimbursement Information
â Ensure that each patient that is considering the Oncotype DX assay has a copy âA Patientâs
Guide to Oncotype DXâ
2. Requisition Form
â Fill out form completely, have an authorized Healthcare Provider sign form
â 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
â Select Specimen Retrieval service option
â FAX completed form to Genomic Health Customer Service (650-556-1073)
3. Acknowledgement of Referral Form
â You will receive a FAX from GAP confirming the receipt of your Benefits Investigation
4. Benefits Summary
â If you have selected a Benefits Investigation, within 2 business days you will receive a FAX
entitled âBenefits Summaryâ and a GAP representative will call your patient to explain their
laboratory benefits and any financial responsibility resulting from performing the assay
â If you selected, âYES Investigate â Proceed pending patient confirmationâ, Genomic Health
Customer Service will be contacting you on how the test should proceed
39. 39
Oncotype DXÂŽ
Patient Report
⢠The patient report includes:
â Recurrence ScoreÂŽ (RS)
â Average 10-year distant
recurrence rate for
that RS
â Graph of 10-year recurrence
risk as a function of RS in
tamoxifen-treated patients
⢠The report is sent to:
â Treating physician
â Submitting pathologist
40. 40
How Can Nurses be Involved with
the Oncotype DXÂŽ
Assay?
⢠Identify appropriate patients
â 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
41. 41
Oncotype DXÂŽ
Resources for Nurses
⢠Patient Education Brochure
â English and Spanish
⢠My Breast Cancer Coach
â 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
⢠www.MyTreatmentDecision.com
â Patient website providing an overview of
invasive breast cancer and the tools used to
determine recurrence risk and help make
treatment decisions
42. 42
Genomic Healthâs 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
44. 44
Patient Cases
⢠Patient was identified
as low risk by
Oncotype DXÂŽ
with a
Recurrence Score ÂŽ
result of 4
⢠Patient received
hormonal therapy
since she was in a
group in which
chemotherapy does
not provide benefit
46. 46
⢠Patient was identified
as high risk by
Oncotype DXÂŽ
with a
Recurrence ScoreÂŽ
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
Patient Cases
48. 48
⢠Patient was identified
as intermediate risk by
Oncotype DXÂŽ
with a
Recurrence ScoreÂŽ
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
Patient Cases
50. 50
Trial Assigning IndividuaLized Options for
Treatment (Rx) (TAILORx)
⢠Premise
â Integration of a new cancer test, the Oncotype DXÂŽ
assay, into the clinical decision-making process
⢠Implications
â Reduce chemotherapy over-treatment in those likely to
be optimally treated with hormonal therapy alone
â Reduce inadequate treatment by identifying individuals
who likely will derive great benefit from chemotherapy
â Evaluate benefit of chemotherapy where uncertainty
still exists about its utility
Trial sponsored by NCI. Participating cooperative groups include ECOG, SWOG,
NCCTG, CALGB, NCIC, ACOSOG, and NSABP
51. 51
Node N-, ER+ Breast CancerNode N-, ER+ Breast Cancer
RS <10
Hormone
Therapy
Registry
RS <10
Hormone
Therapy
Registry
RS 11-25
Randomize
Hormone Rx
vs
Chemotherapy
+ Hormone Rx
RS 11-25
Randomize
Hormone Rx
vs
Chemotherapy
+ Hormone Rx
RS >25
Chemotherapy
+
Hormone Rx
RS >25
Chemotherapy
+
Hormone Rx
Oncotype DXÂŽ AssayOncotype DXÂŽ Assay
Register
Specimen
banking
Primary study group
TAILORx Schema
52. 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
âprimary study groupâ (Oncotype DXÂŽ RS 11-25)
⢠To create a tissue and specimen bank for patients
enrolled in this trial to learn more about breast
cancer
53. 53
TAILORx: Key Points
⢠Participating groups
â Major North American cooperative groups, including ECOG, SWOG,
NCCTG, CALGB, NCIC, ACOSOG, and NSABP
⢠Adjuvant therapy
â Choice of hormonal and/or chemotherapy regimen is at discretion of
treating physician
â Permissible options are outlined in protocol, and are generally consistent
with NCCN guidelines
⢠Other trials
â May enroll on other CTSU or other cooperative group studies if treatment
assignment on other trial is consistent with PACCT-assigned treatment
⢠Cost
â Genomic Health will assist in securing reimbursement for patients who
have health insurance
â 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 DXÂŽ assay
54. 54
TAILORx Information Resources
Protocol and General Information
⢠Clinical Trials Support Unit
â 1-888-823-5923
â CTSUcontact@westat.com
â www.ctsu.org
Eligibility Questions
⢠Eastern Cooperative Oncology Group
â ecog.tailorx@jimmy.harvard.edu
â www.ecog.org
TAILORx Patient Education Materials
⢠Eastern Cooperative Oncology Group
â http://www.ecog.org/general/tailorx.html
Oncotype DXÂŽ Information
⢠Genomic Health Customer Service
â 1-866-ONCOTYPE (1-866-662-6897)
â www.oncotypedx.com
56. 56
Recurrence ScoreÂŽ
in N-, ER+ patients
Oncotype DXÂŽ is a Standardized and
Quantitative Assay
1) Paik et al. NEJM 2004, 2) Habel et al. Breast Cancer Research 2006
3) Paik et al. JCO 2006, 4) Gianni et al. JCO 2005
Lower RSâs
⢠Lower likelihood of recurrence
⢠Minimal, if any, chemotherapy benefit
Higher RSâs
⢠Greater likelihood of recurrence
⢠Clear chemotherapy benefit
57. 57
Oncotype DXÂŽ
Summary
ď§ The Oncotype DX Recurrence ScoreÂŽ
assay
predicts likelihood of recurrence (prognostic)
and magnitude of adjuvant treatment benefit
for chemotherapy (predictive)
ď§ The Oncotype DX Recurrence Score assay
shows consistent results across multiple
independent studies
Hinweis der Redaktion
Today we are going to discuss the role genomics is currently playing in breast cancer clinical practice
&lt;number&gt;
Statistics from 2007
&lt;number&gt;
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.
Example of Genetic test: BRCA1 and BRCA2 look at specific gene mutations on the patientâs 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 patientâs tumor tissue and correlates that information with the likelihood of distant recurrence in 10 years and the magnitude of chemotherapy benefit.
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?
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.
&lt;number&gt;
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 patientâs individual disease.
The major challenge in current management of patients with N-, ER+ breast cancer, is indeed the selection of patients for adjuvant chemotherapy.
&lt;number&gt;
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 individualâs risk of assessment and responsiveness to treatment would enable better tailored therapeutic intervention.
* Image from NCI
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 patientâs 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)
Oncotype DX allow us to look at your patientâs tumor and help inform decision-making about treatment that is right for her.
&lt;number&gt;
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.
&lt;number&gt;
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 &lt;18
An intermediate-risk group with an RS between 18 and 30
A high-risk group with an RS of ďł31
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.
Extensive evidence supporting Oncotype DXâs 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):8623-8631.
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):2817-2826.
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):3315-3319
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):7265-7277.
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;24:3726-3734.
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 1982-1988. 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.
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.
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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 &lt;0.00001).
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):2904-15).
For each risk-based cohort, the 95% confidence interval error bands have little to no overlap.
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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.
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.
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 GHIâs 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.
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;89:1673-1682) 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 &gt;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 &lt;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.
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.
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
Letâs transition over and talk about how health care professionals like yourself get access to Oncotype DX and the process surrounding ordering within your institution.
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 Âľm 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 patientâs tumor specimen.
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)
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 â up to 3 levels to include independent medical review if available
Communication with physicianâs 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
Procedure as of September 2007
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.
TAILORx trial to be discussed later
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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.
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This is the schema of the TAILORx trial. The eligible patients for this trial are Nâ, 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 dealerâs choiceâtype 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%.
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This study has a non-inferiority design. The working premise is that patients in the mid-range Recurrence Score risk group will do âno worseâ 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 &lt;11, chemotherapy will not be given. For a patient with a RS &gt;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):2817-2826.
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 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):7332-7341.
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 â 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.
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)