Genomic HealthOncotype DX

E25 Project Muthu Alagappan

Vaishnav Aradhyula

Pitch OutlineReview of Science

- Human Genome Project - Gene Expression and RT-qPCR

Introduction to Oncotype DXInnovations

- 21-gene panel including HER2

CLIA vs. FDAFuture Pipeline

Pitch OutlineReview of Science

- Human Genome Project - Gene Expression and RT-qPCR

Introduction to Oncotype DXInnovations

- 21-gene panel including HER2

CLIA vs. FDAFuture Pipeline

A Review of Personalized MedicineKnowledge of a patient’s genome can inform

treatmentCertain genomic traits predict the patient’s

susceptibility to diseaseSpecific treatments can be tailored to fit the

patient

From E25 Lecture 8

Gene ExpressionGene expression is the conversion of

information encoded by a gene into a functional gene product (usually proteins)”

Certain genes (and thus certain proteins) are often found to be overexpressed in several types of cancer E.g. HER2 overexpression is linked to breast

cancerThus, measuring levels of gene expression is

a essential technique in understanding cancer

Measuring Gene ExpressionRT-PCR + qPCR (or RT-qPCR)

Generate cDNA template from mRNA using reverse transcription

Pitch OutlineReview of Science

- Human Genome Project - Gene Expression and RT-qPCR

Introduction to Oncotype DXInnovations

- 21-gene panel including HER2

CLIA vs. FDAFuture Pipeline

Oncotype DX – An OverviewDeveloped by Genomic Health, a life science

company based in Redwood City and founded in 2000

Oncotype DX is a diagnostic test for breast cancer

Analyzes 21 genes from a breast cancer tumor to determine the likelihood of recurrence and the effectiveness of chemotherapy

Oncotype DX— BackgroundIncidence

270,000 cases of breast cancer per year in the U.S.

1.15 million per year worldwideTreatment

Previous treatments based mainly on understanding of chemical pathways

Tamoxifen and chemotherapy proven to be reasonably effective in clinical trials

However, chemotherapy overused because not possible to determine the risk of recurrence

Clinical Need for Oncotype DXPhysicians require a diagnostic tool that:

Quantitatively states the chances of recurrence (as opposed to “high” or “low”) Known as prognostic significance

Indicates whether the patient will significantly benefit from chemotherapy Known as predictive significance Important because of chemotherapy’s severe side

effectss

Pitch OutlineReview of Science

- Human Genome Project - Gene Expression and RT-qPCR

Introduction to Oncotype DXInnovations

- 21-gene panel including HER2

CLIA vs. FDAFuture Pipeline

How Oncotype DX Was Developed250 candidate genes (from ~25,000 genes in the

human genome) identified from literature and previous studies

The gene expression of these genes relative to control genes measured against recurrence in 477-patient sample

16 genes identified 21 gene test (16 cancer-related genes and 5

reference genes) developedAlgorithm developed to assign Recurrence Score

(0 to 100) based on expression of the 21 genes

The 21 Genes

From Paik et. al

HER2HER2 (human epidermal growth factor receptor 2) is a tyrosine

kinase receptor protein that is over-expressed in aggressive forms of breast cancerLocation: Long arm of chromosome #17Mechanism: HER2 and HER3 dimerize on cell membrane. Growth

factor binds and causes cell proliferation.Significance: 30% of breast cancers have an over-expression of

HER2. Also linked to ovarian and stomach cancer.Drug herceptin can reduce the expression of HER2

Impact: 1. patients with HER2 expression have decreased survival rates2. HER2 over-expression is more likely to signal tumor

reoccurrence after surgery (75% chance vs 86%) 3. Used as 1 of 21 genes on our genetic panel (out of a potential

25,000 genes)

Oncotype DX in PracticeSubmit tissue sampleGenomic Health sends back RS score and

dataDoctor and Patient make informed decision

Pitch OutlineReview of Science

- Human Genome Project - Gene Expression and RT-qPCR

Introduction to Oncotype DXInnovations

- 21-gene panel including HER2

CLIA vs. FDAFuture Pipeline

FDA ProcessFood and Drug administration used to evaluate and

approve new medical devices, drugs, and diagnostics test

1976: FDA passes amendments which allowed “homebrew in vitro diagnostics” to come to market without FDA approval (because all testing would be done by the company within their own laboratory)FDA approval requires 4 phases of clinical trials

1988: Companies that do in vitro diagnostic testing in their laboratory now need to get CLIA approval.

Advantages of CLIA

Validation of Oncotype DXDoes a high recurrence score actually correlate to

recurrence?Test Oncotype DX against large sample to ensure

that it worksData taken from

National Surgical Adjuvant Breast and Bowel Project (NSABP) trials B-14 and B-20 Trials assessed effectiveness of Tamoxifen 2892 patients randomly assigned to Tamoxifen or placebo

Statistical Analysis of recurrence score versus actual recurrence reveals that the Oncotype DX assay is a very good predictive tool

Recurrence Score is an Excellent Predictive Tool

From Paik et. al

Pitch OutlineReview of Science

- Human Genome Project - Gene Expression and RT-qPCR

Introduction to Oncotype DXInnovations

- 21-gene panel including HER2

CLIA vs. FDAFuture Pipeline

Genomic Health PipelineGenomic Health other products

Colon cancer

Bibliography Paik, S et. al. A Multigene Assay to Predict Recurrence of Tamoxifen-

Treated, Node-Negative Breast Cancer. N Engl J Med. 351;27. 30 Dec 2004

http://ecog.dfci.harvard.edu/general/gendocs/tailorx_oncodxfact.pdf http://www.oncotypedx.com/en-US/Breast/HealthcareProfessional/

Overview.aspx Sparano, JA and Paik, S. Development of the 21-Gene Assay and Its

Application in Clinical Practice and Clinical Trials. J Clin Oncol. 2008; 26:721-728.

http://en.wikipedia.org/wiki/Gene_expression http://www.genomichealth.com/en-US/Pipeline/NextGeneration.aspx http://www6.appliedbiosystems.com/support/tutorials/pdf/

rtpcr_vs_tradpcr.pdf http://www.genomichealth.com/en-US/Company.aspx