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The final gene set used for the Onco type DX ™ assay includes the 16 cancer genes identified in the clinical trials: 5 genes are in the proliferation group, 2 in the HER2 group, 4 in the estrogen receptor group, 2 in the invasion group, and 3 are unaligned. Some of the genes are well known in the breast cancer literature; others are relatively new. The 5 reference genes are used for normalizing the expression of the cancer-related genes. As was previously stated, it is important to note that there are other genes linked to breast cancer (eg, the 250 candidate genes from which the 16 genes were selected). The 16 genes presented in this slide were selected for the Onco type 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. 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 dominant effect. For example, there is a 200-fold range of expression of ER in the quantitative RT-PCR assay. For individual tumors, the expression of any one gene can affect the Recurrence Score 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 If the right number of genes to address these questions had been 6 or 60, we would have designed the assay accordingly. As it turned out, The assay was designed to include expression of 16 genes because the development studies indicated these genes provided the most robust predictive score.
All hormone responsive patients receive endocrine therapy
Breast Cancer Early Locally advanced Metastatic
Early breast cancer 85 with No Distant Recurrence 15 with Distant Recurrence 100 women ; N - , ER+ After Surgery & Tamoxifen
Breast Cancer - Survival Pre-menopausal patients, lymph node negative time (years) survival ~30% die of breast cancer ~70% survive breast cancer
Prognistic and Predictive factors <ul><li>Lymph node involvement </li></ul><ul><li>Age </li></ul><ul><li>Tu size </li></ul><ul><li>Grade </li></ul><ul><li>Hormonal status </li></ul><ul><li>Her 2 status </li></ul>
Early Breast cancer <ul><li>Surgery </li></ul><ul><li>Chemotherapy </li></ul><ul><li>Radiotherapy </li></ul><ul><li>Hormonal Therapy </li></ul><ul><li>Biologic Therapy </li></ul>
Early breast cancer 85 with No Distant Recurrence 15 with Distant Recurrence 100 women ; N - , ER+ After Surgery & Tamoxifen “ at least 85 percent of patients would be over treated with chemotherapy if it were offered to everyone . ” Paik .S. et al. N Engl J Med 2004 ;351:2817-26
PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 Paik et al. N Engl J Med. 2004;351:2817-2826. 16 cancer genes and 5 reference genes make up the Oncotype DX gene panel. The expression of these genes is used to calculate the recurrence score: + 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 RS =
Results: Population distribution by Oncotype DX risk group A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer Paik .S. et al. N Engl J Med 2004 ;351:2817-26 Intermed. risk 27.0% Low risk 51.0% High risk 22.0%
Distant Recurrence-Free Survival (%) P < 0.00001 Paik .S. et al. N Engl J Med 2004 ;351:2817-26 93% 69% All patients Low Risk (RS < 18) Years 100 0 20 40 60 DRFS (%) 80 0 2 6 10 4 8 12 16 14 Intermediate Risk (RS 18 - 30) High Risk (RS 31)
Onco type DX ™ - TAILORx - Study Design Onco type DX™ Assay No Minimal Chemotherapy Benefit Group Recurrence Score <11 (~29% of Population) Uncertain Chemotherapy Benefit Group Recurrence Score 11-25 (~44% of Population) Established Chemotherapy Benefit Group Recurrence Score >25 (~27% of Population) <ul><li>Stratify </li></ul><ul><li>Tumor Size ≤2.0 cm vs. ≥ 2.1 cm </li></ul><ul><li>Post menopausal vs. Pre-or Peri-menopausal </li></ul><ul><li>Planned chemotherapy: Taxane-containing (i.e. paclitaxel, docetaxel) vs. </li></ul><ul><li>Non-taxane-containing </li></ul>Arm A Hormonal Therapy Randomize Arm D Chemotherapy Plus Hormonal Therapy Arm B Hormonal Therapy Arm C Chemotherapy Plus Hormonal Therapy
Conclusions: Onco type DX TM <ul><ul><li>Low RS associated with minimal chemotherapy benefit </li></ul></ul><ul><ul><li>High RS associated with large chemotherapy benefit </li></ul></ul><ul><li>The Onco type DX Recurrence Score provides precise, quantitative information for individual patients on prognosis across and statistically independent of information on patient age, tumor size, and tumor grade. </li></ul>
Old versus new diagnostics of cancer: from microscope to microarray High grade Low grade High risk Low risk MammaPrint
Prognosis Classifier for Breast Cancer based on Genomic Profiling Good signature Poor signature threshold Rows: 70 significant prognosis genes Columns: tumor samples Threshold set with 10% false negatives 91% sensitivity; 73% specificity Van ‘t Veer et al Nature 415, p530-536, 2002 Metastases: white = +
A Gene-Expression Signature as a Predictor of Survival in Breast Cancer Metastasis Free Survival Overall survival H.R. = 5.1 95% CI = 2.9 - 9.0 P < 0.001 H.R. = 8.6 95% CI = 4 - 19 P < 0.001 van de Vijver M.J. et al. N Eng J Med 2002 ;347(25):1999-2009. Results: all patients Good signature Poor signature Years 100 0 20 40 60 % patients metastasis free 80 0 2 4 6 8 10 12 Years 100 0 20 40 60 Overall survival (%) 80 0 2 4 6 8 10 12 85.2% 50.6% 94.5% 54.6%
Profiling vs. St Gallen selection (LN0, <53) <ul><li>improved prediction. </li></ul><ul><li>Significantly less women classified as having a bad prognosis </li></ul>van de Vijver M.J. et al. N Eng J Med 2002 ;347(25):1999-2009. St Gallen St Gallen: 15% in low risk 85% in high risk Profile Profiling: 40% in good profile 60 % in poor profile
MINDACT Design (Microarray in Node-Negative Disease May Avoid Chemotherapy Trial) All hormone responsive patients receive endocrine therapy Clinical pathological AND 70-gene signature HIGH risk Clinical pathological AND 70-gene signature LOW risk Discordant cases Clin-Path HIGH risk 70-gene LOW risk Clin-Path LOW risk 70-gene HIGH risk Evaluate clinico-pathological risk (Adjuvant!) AND 70-gene signature risk Buyse M et al, JNCI 2006 N=3300 55% 32% n=1920 N=780 13% Use Clin-Path risk to decide on adjuvant chemotherapy or not Use 70-gene risk to decide on adjuvant chemotherapy or not No chemotherapy chemotherapy R
<ul><li>Oncotype </li></ul><ul><li>Early breast cancer </li></ul><ul><li>Hormonal receptor positive </li></ul><ul><li>Her 2 Negative </li></ul><ul><li>Mammaprint </li></ul><ul><li>Early node negative breast cancer </li></ul>