This document discusses Oncotype DX, a 21-gene diagnostic test for breast cancer recurrence developed by Genomic Health. It measures gene expression from tumor samples using RT-qPCR to determine a Recurrence Score predicting recurrence risk and chemotherapy benefit. Oncotype DX was validated using large clinical trials and provides a quantitative recurrence risk assessment to guide treatment decisions. Though regulated under CLIA, Oncotype DX avoids the lengthy FDA approval process required for diagnostic tests. Genomic Health continues developing additional cancer diagnostic tests.

1. Genomic HealthOncotype DX E25 Project MuthuAlagappan Vaishnav Aradhyula

6. A Review of Personalized Medicine Knowledge of a patient’s genome can inform treatment Certain genomic traits predict the patient’s susceptibility to disease Specific treatments can be tailored to fit the patient From E25 Lecture 8

7. Gene Expression Gene 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 cancer Thus, measuring levels of gene expression is a essential technique in understanding cancer

8. Measuring Gene Expression RT-PCR + qPCR (or RT-qPCR) Generate cDNA template from mRNA using reverse transcription

11. Oncotype DX – An Overview Developed 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

12. Oncotype DX— Background Incidence 270,000 cases of breast cancer per year in the U.S. 1.15 million per year worldwide Treatment 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

13. Clinical Need for Oncotype DX Physicians 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

16. How Oncotype DX Was Developed 250 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) developed Algorithm developed to assign Recurrence Score (0 to 100) based on expression of the 21 genes

17. The 21 Genes From Paik et. al

18. HER2 HER2 (human epidermal growth factor receptor 2) is a tyrosine kinasereceptor protein that is over-expressed in aggressive forms of breast cancer Location: Long arm of chromosome #17 Mechanism: 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: patients with HER2 expression have decreased survival rates HER2 over-expression is more likely to signal tumor reoccurrence after surgery (75% chance vs 86%) Used as 1 of 21 genes on our genetic panel (out of a potential 25,000 genes)

19. Oncotype DX in Practice Submit tissue sample Genomic Health sends back RS score and data Doctor and Patient make informed decision

22. FDA Process Food 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.

23. Advantages of CLIA

24. Validation of Oncotype DX Does a high recurrence score actually correlate to recurrence? Test Oncotype DX against large sample to ensure that it works Data 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

25. Recurrence Score is an Excellent Predictive Tool From Paik et. al

28. Genomic Health Pipeline Genomic Health other products Colon cancer

29. 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 ClinOncol. 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