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The role of the Oncotype DX ® assay in breast cancer management.

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Presentation on theme: "The role of the Oncotype DX ® assay in breast cancer management."— Presentation transcript:

1 The role of the Oncotype DX ® assay in breast cancer management

2 2 Objectives Brief overview of the Oncotype DX ® assay and reports Review assay development strategy and supporting studies –Technical feasibility studies –Gene discovery and refinement studies –Analytical validation studies Review clinical validation studies in women with breast cancer –Prognostic studies –Predictive studies Discuss future development plans

3 3 Case study presentation A 55-year-old post-menopausal woman presents with an infiltrating ductal carcinoma –Tumor size 1.0 cm –ER/PR IHC positive –HER2 IHC negative –Sentinel lymph node negative –Excellent overall health How should this patient be evaluated for treatment? What is her risk of disease recurrence? How likely is she to benefit from hormonal or chemotherapy? How should this patient be evaluated for treatment? What is her risk of disease recurrence? How likely is she to benefit from hormonal or chemotherapy?

4 4 Breast cancer treatment in the United States (2009) Approximately 110,000 women with ER+, lymph node-negative breast cancer are diagnosed annually in the United States –This represents ~50% of newly diagnosed patients today –Many women are offered chemotherapy, but all do not receive substantial benefit Better identification of disease markers is needed to help make therapeutic decisions

5 5 Prognostic & predictive markers utilized in breast cancer management Prognostic (recurrence risk) Axillary node status Histologic type/grade Tumor size Patient age Lymphatic/Vascular invasion ER/PR status HER2 neu status Oncotype DX ® test Predictive (treatment benefit) ER/PR status HER2 neu status Oncotype DX ® test Cianfrocca and Goldstein. Oncologist. 2004;9(6): ; Lonning PE. Ann Oncol. 2007;18(suppl 8):viii3-viii7. These markers can be used to predict treatment benefit These markers can be used to estimate the risk of disease recurrence

6 6 The Oncotype DX ® assay Quantitatively predicts the likelihood of breast cancer recurrence in women with newly diagnosed, early stage, ER+ invasive breast cancer Assesses the likely benefit from both hormonal therapy and chemotherapy Is recommended by both ASCO and NCCN clinical practice guidelines Harris L, et al. J Clin Oncol. 2007;33(25): NCCN, National Comprehensive Cancer Network Adapted from NCCN Practice Guidelines in Oncology – v

7 7 Oncotype DX ® Report Samples Oncotype DX report provides valuable information on: –Clinical prognosis –Predicted chemotherapy benefit –Quantitative data on ER / PR / HER2 Node positive report contains an additional page with prognosis and predicted chemo benefit information specific to node-positive patients

8 88 Technical Feasibility Gene Discovery & Refinement Analytical Validation Clinical Validation (prognostic) Clinical Validation (predictive) Oncotype DX ® Technology Development Overview

9 9 Technical Feasibility Gene Discovery & Refinement Analytical Validation Clinical Validation (prognostic) Oncotype DX ® Technology Development Overview Clinical Validation (predictive)

10 10 Purpose of technical feasibility studies Technical feasibility studies were designed to assess: RNA yield and the quality of RNA after extraction from FPET tissues Gene expression differences and similarities between whole section and enriched tumor tissue sections –To establish criteria for manual microdissection Gene expression heterogeneity within breast tumor tissues –Assess within block and between block gene expression heterogeneity Selection of reference genes (important for normalization of pre-analytical factors) –Delay to fixation, duration of fixation, fixative

11 11 Importance of manual microdissection ER = estrogen receptor Differences in non-tumor tissue may impact single gene assessment ER Enriched Tumor ER Whole Section ER r = 0.73, p = Example from study of 16 breast cancer blocks for ER expression Most cases show minimal differences in ER expression between WS and ET Some tumors contain significant amounts of non- tumor elements (e.g., biopsy cavities, skin, smooth muscle) which require manual microdissection Thus, if < 50% invasive carcinoma, manual microdissection is always performed Most cases show minimal differences in ER expression between WS and ET Some tumors contain significant amounts of non- tumor elements (e.g., biopsy cavities, skin, smooth muscle) which require manual microdissection Thus, if < 50% invasive carcinoma, manual microdissection is always performed

12 12 Evaluation of tumor gene expression heterogeneity Example of the differences in gene expression within & among 3 FPET blocks from two patients Block 123 H&E PR+ ER+ HER2– The three FPET blocks were step sectioned at five different levels Quantitative RT-PCR was performed on all 15 samples 3 Blocks from spatially distinct tumor regions ER/PR/HER2 IHC Status Poster presented at: United States-Canadian Academy of Pathology 93 rd Annual Meeting; March, 2004; Vancouver, British Columbia.

13 13 Importance of standardized quantitative measurement using RT-PCR: minimal gene expression heterogeneity within & among tumor blocks Poster presented at: United States-Canadian Academy of Pathology 93 rd Annual Meeting; March, 2004; Vancouver, British Columbia. Expression by RT-PCR (relative to reference genes) Reproducibility Within block expression: standard deviation < 0.5 normalized expression units Among block expression: standard deviation < 1.0 normalized expression units Expression by RT-PCR (relative to reference genes)

14 14 Oncotype DX ® Technology Development Overview Technical Feasibility Gene Discovery & Refinement Analytical Validation Clinical Validation (prognostic) Clinical Validation (predictive)

15 15 Oncotype DX ® gene panel was developed from clinical trial evidence 250 cancer-related genes were selected Genes were analyzed for expression and relapse-free interval correlations across 3 independent studies of 447 breast cancer patients Study siteN Node status ER status Treatment NSABP B-20, Pittsburgh, PA 233N–ER+Tamoxifen (100%) Rush University, Chicago, IL positive nodes ER+/– Tamoxifen (54%) Chemotherapy (80%) Providence St. Josephs Hospital, Burbank, CA 136N+/–ER+/– Tamoxifen (41%) Chemotherapy (39%) Paik et al. SABCS Abstract #16. Cobleigh et al. Clin Cancer Res. 2005;11(24 Pt 1): Esteban et al. Proc ASCO Abstract #3416. From these studies, 21 genes were selected

16 16 Oncotype DX ® Recurrence Score ® result: calculated from 21 different genes 16 C ANCER RELATED GENES Paik et al. N Engl J Med. 2004;351: ER PR Bcl2 SCUBE2 ER PR Bcl2 SCUBE2 GRB7 HER2 GRB7 HER2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 Stromelysin 3 Cathepsin L2 Stromelysin 3 Cathepsin L2 GSTM1 CD68 BAG1 Beta-actin GAPDH RPLPO GUS TFRC 5 R EFERENCE GENES EstrogenProliferationHER2InvasionOthers

17 17 Oncotype DX ® Recurrence Score ® result calculation and risk categories Paik et al. N Engl J Med. 2004;351: Risk group Low risk Recurrence Score < 18 Intermediate risk High risk 31 Recurrence Score = × HER2 Group Score – 0.34 × Estrogen Group Score × Proliferation Group Score × Invasion Group Score × CD68 – 0.08 × GSTM1 – 0.07 × BAG1

18 18 The Oncotype DX ® Recurrence Score ® result is a continuous predictor of recurrence risk Dotted lines represent 95% CI Distant recurrence at 10 years L OWER R ISK H IGHER R ISK What is the 10-year probability of distant recurrence for a patient with a Recurrence Score of 30? Recurrence Score Recurrence Score 30 = 20% risk of distant recurrence at 10 years

19 19 Oncotype DX ® Technology Development Overview Technical Feasibility Gene Discovery & Refinement Analytical Validation Clinical Validation (prognostic) Clinical Validation (predictive)

20 20 The Oncotype DX ® assay is analytically validated Elements of analytic validation Analytical sensitivity (limits of detection and quantitation) Assay precision and linear dynamic range Analytical reproducibility PCR amplification efficiency Sample and reagent stability Reagent calibration Instrument validation and calibration Chau CH, et al. Clin Cancer Res. 2008;14(19): Analytical validation is the assessment of assay performance characteristics and the optimal conditions to generate accuracy, precision and reproducibility

21 Strand displacement and cleavage of probe Polymerization completion and signal detection R Q R Q R Q Forward Primer Reverse Primer Probe Reporter Quencher Oncotype DX ® uses RT-PCR technology RT-PCR provides > 65,000- fold range of measurement –Maximizes ability to discriminate the full range of gene expression differences among individual samples RT-PCR reactions can be repeated with high quantitative precision –Provides required reliability for individualized reporting RT-PCR works well with RNA from formalin-fixed paraffin-embedded tissue Cronin M, et al. Am J Pathol. 2004;164:

22 22 Oncotype DX ® assay process Cronin et al. Am J Pathol. 2004;164:35-42 Standardized RT-PCR –Optimized for the small RNA fragments extracted from fixed paraffin embedded tissue (FPET) –Optimized to be robust with regard to sources of pre- analytic variability such as Delay to fixation Duration of fixation Fixative type Sample age

23 23 Normalization accounts for all sources of pre-analytic variability Hollandes Formalin Delays to fixation, duration of fixation, different fixatives and sample age can affect RNA quality Reference normalization compensates for these differences in sample processing and sample age

24 24 Oncotype DX ® assay process steps 1)PRE-ANALYTIC –Pathology review of the FPET sample by a Board Certified Anatomic Pathologist with Breast Expertise –Determine whether manual microdissection for tumor enrichment is required (~40% of submissions are microdissected for tumor enrichment) 2)ANALYTIC –RNA extraction and quantitation (RiboGreen ® method) –qPCR test for residual genomic DNA –Reverse transcription –TaqMan PCR –Data quality control 3)POST-ANALYTIC –Calculation of Recurrence Score ® result –Report preparation and approval

25 25 Pre-analytic processing: all FPET blocks are bar-coded before entering histology

26 26 Pre-analytic processing: all tumors assessed by surgical pathologists with breast expertise Pathology review to assess: Is tumor present? Is there sufficient tumor?

27 27 Patient samples are barcode tracked from submission to report

28 28 Automation is central to laboratory processes

29 29 Patient FPET sample Material manager RNA extraction Primers Probe Pool 96-well plate 96-well Plate QPCR master mix 384-well plate 96-well Plate 96-well Plate 96-well Plate Material manager Reverse transcription cDNA plates QPCR reaction plate Plate layout template and assembly for primers and samples Assay detection system Patient sample tracking: LIMS bar-coding integrates reagents and robots for tracking and process control Reverse primer pool Oligo plate assembly SARP GEMTools Tecan Robotics

30 30 Patient report delivery: automated output and delivery Report distribution service PDF report w/ electronic signature approval Print FedEx Fax Web

31 31 Oncotype DX ® Technology Development Overview Technical Feasibility Gene Discovery & Refinement Analytical Validation Clinical Validation (prognostic) Clinical Validation (predictive)

32 Clinical validation of Oncotype DX ® breast cancer assay in node-negative disease

33 33 Oncotype DX ® clinical validation: NSABP B-14 Objective: Prospectively validate Recurrence Score ® result as predictor of distant recurrence in node- negative, ER+ patients Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Randomized Registered Placebonot eligible Tamoxifeneligible Paik S, et al. N Engl J Med. 2004;351:

34 34 Oncotype DX ® clinical validation: NSABP B-14, Distant Recurrence Distant recurrence over time 10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% Years Paik S, et al. N Engl J Med. 2004;351: % 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Proportion without distant recurrence RS < 18, n = 338 RS 18-30, n = 149 RS 31, n = 181 All Patients, n = 668 P < Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% *10-Year distant recurrence comparison between low- and high-risk groups: P < RS, Recurrence Score ® result

35 35 Analysis with Recurrence Score P valueHR < < Multivariate Cox proportional hazards regression of age, tumor size, tumor grade and Recurrence Score ® value in relation to likelihood of distant recurrence (NSABP B-14) Variable Age at surgery Clinical tumor size Tumor grade Moderately differentiated Poorly differentiated HER2 amplification Estrogen-receptor protein fmol/mg fmol/mg > 200 fmol/mg Recurrence Score Paik S, et al. N Engl J Med. 2004;351: Analysis without Recurrence Score P valueHR <

36 Oncotype DX ® assay NSABP B-14 subgroup analysis

37 37 20% 40% 60% 80% 100% % Distant recurrence-free at 10 years All patients N = 668 Well Moderate Poor Oncotype DX ® NSABP B-14: Recurrence Score ® result subgroups by tumor grade Paik S, et al. N Engl J Med. 2004;351: All patients Low risk (RS < 18) Int risk (RS 18-30) High risk (RS 31) RS, Recurrence Score result

38 38 Oncotype DX ® clinical validation: conclusions, NSABP B-14 Oncotype DX ® Recurrence Score ® result is validated as a predictor of recurrence in node-negative, ER+ patients Oncotype DX Recurrence Score performance exceeds standard measures (patient age, tumor size, and tumor grade) Oncotype DX Recurrence Score result (based on tumor gene expression) more accurately quantifies the risk of distant recurrence than do the NCCN guidelines (based on patient age, tumor size, and tumor grade) Paik et al. N Engl J Med. 2004;351:

39 39 Oncotype DX ® clinical validation: the Kaiser Permanente study Study designMatched case-control Study population (N = 4964) Kaiser Permanente patients < 75 years old in 14 Northern California hospitals diagnosed with node- negative breast cancer between , no adjuvant chemotherapy Cases: Deaths from BC (n = 220) Controls: Randomly selected, matched on age, race, diagnosis year, KP facility, tamoxifen (n = 570) Data sources Cancer registry, medical records, archived diagnostic slides, and tumor blocks Habel LA, et al. Breast Cancer Res. 2006;8(3):R25.

40 40 The Kaiser Permanente study: risk of BC death at 10 years: ER+, Tam-treated patients Risk classification (Recurrence Score ® group) 10-Year absolute risk 1 Kaiser 10-Year absolute risk 1 NSABP B-14 Low2.8%3.1% Intermediate10.7%12.2% High15.5%27.0% 1 Based on methods by Langholz and Borgan, Biometrics 1997;53: The Recurrence Score result has now been shown to be strongly associated with risk of breast cancer-specific mortality among node- negative, ER+, Tam-treated patients participating in a clinical trial and among similar patients from the community setting. Results from our study suggest that combining Recurrence Score result, tumor grade, and tumor size provides better risk classification than any one of these factors alone. Habel LA, et al. Breast Cancer Res. 2006;8(3):R25.

41 41 Oncotype DX ® Technology Development Overview Technical Feasibility Gene Discovery & Refinement Analytical Validation Clinical Validation (prognostic) Clinical Validation (predictive)

42 42 Tam Oncotype DX ® clinical validation: NSABP B-20 Objective: To determine the relationship between Recurrence Score ® value and chemotherapy benefit in node-negative, ER+ patients Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Randomized Tam + MF Tam + CMF Paik S, et al. J Clin Oncol. 2006;24:

43 High Recurrence Score ® result correlates with greater benefit from chemotherapy (NSABP B-20) 43 Paik S, et al. J Clin Oncol. 2006;24: RS, Recurrence Score result Proportion without distant recurrence Years % absolute benefit from tamoxifen + chemotherapy NEvents All patients Tamoxifen + chemotherapy Tamoxifen P = 0.02 RS Tamoxifen + chemotherapy Tamoxifen P = 0.39 RS < 18 Tamoxifen + chemotherapy Tamoxifen P = 0.61 NEvents RS 31 Tamoxifen + chemotherapy Tamoxifen P < PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy

44 44 Recurrence Score ® result can add prognostic discrimination not always provided by traditional prognostic factors Age –44% of patients < 40 years old had low Recurrence Score results (ie, there is a large fraction of younger patients for whom chemotherapy benefit may be minimal) Tumor size –46% of patients with large tumors (> 4 cm) had low Recurrence Score results –Some patients with small tumors (< 1 cm) had intermediate or high Recurrence Score results Tumor grade –Assessment by local pathologists revealed that, even for poorly differentiated tumors, 36% of patients had low Recurrence Score result –Approximately 20% of poorly differentiated tumors still had a low Recurrence Score result Paik S, et al. J Clin Oncol. 2006;24:

45 NSABP B-20: Many younger patients have low Recurrence Score ® results Paik S, et al. J Clin Oncol. 2006;24: P= % 24% 28% 19% 14% 21% 22% 21% 44% 55% 50% 60% N=63 N=226 N=166 N=196

46 46 NSABP B-20: Many small tumors have Intermediate to High Recurrence Score ® values Paik S, et al. J Clin Oncol. 2006;24: % 20% 19% 23%21% 46% N=110 N=318 N=196 N=24 Recurrence Score 1 cm cm cm>4 cm Clinical tumor size P= % 56% 46% 16% 25% 30%

47 NSABP B-20: Significant proportion of high-grade tumors have low Recurrence Score ® values Paik S, et al. J Clin Oncol. 2006;24: % 22% 42% 16% 22% 22% 73% 56% 36% N=77 N=339 N=163 P< % 12% 61% 12% 24% 19% 83% 64% 19% N=119 N=340 N=190

48 48 Tamoxifen benefit and the Oncotype DX ® assay NSABP B-14 tamoxifen benefit study in node-negative, ER+ patients Objective: determine whether the Oncotype DX assay provides information on 1)Prognosis (likelihood of recurrence) 2)Response to tamoxifen (change in likelihood of recurrence with tamoxifen) 3)Both Randomized Placebo-eligible Tamoxifen-eligible Paik S, et al. N Engl J Med. 2004;351:

49 49 All patients (N = 645) Years Proportion without distant recurrence Placebo Tamoxifen B-14 overall benefit of tamoxifen Paik S, et al. ASCO 2004; Abstract 510.

50 50 B-14 benefit of tamoxifen by Recurrence Score ® risk category D ISTANT RECURRENCE - FREE INTERVAL Paik et al. ASCO 2004; Abstract 510. RS < 18 Years N Placebo171 Tamoxifen142 P = *Results should not be used to indicate that tamoxifen should not be given to the high-risk group RS Years P = 0.02 N Placebo85 Tamoxifen69 RS 31* Years P = 0.82 N Placebo99 Tamoxifen79 Interaction P = 0.06 RS, Recurrence Score result

51 The Oncotype DX ® assay identifies patients for whom tamoxifen alone may be appropriate therapy TAMOXIFEN NO SYSTEMIC TREATMENT 10-Year absolute risk BC death (%) (95% CI) Tamoxifen benefit < Paik S, et al. ASCO. 2005; Abstract 510. Tamoxifen benefit Recurrence Score ® Result 51

52 The Oncotype DX ® assay can predict benefit from chemotherapy and tamoxifen 52 TAMOXIFEN + CHEMO TAMOXIFEN 10-Year absolute risk BC death (%) (95% CI) Chemotherapy benefit < Adapted from Paik S, et al. J Clin Oncol. 2006;24:3726. Recurrence Score ® Result

53 53 ASCO guidelines on the use of tumor markers in breast cancer Oncotype DX ® testing can be used to determine prognosis in newly diagnosed patients with node-negative, estrogen receptor-positive breast cancer who will receive tamoxifen Conclusions may not be generalizable to hormonal therapies other then tamoxifen or to other chemotherapy regimens Harris L, et al. J Clin Oncol. 2007;33(25): To predict risk of recurrence in patients considering treatment with tamoxifen To identify patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy Patients with high Recurrence Score ® result appear to achieve relatively more benefit from adjuvant chemotherapy (specifically CMF) than tamoxifen

54 NCCN® guidelines include Oncotype DX® testing in the treatment-decision pathway for node-negative and micrometastatic disease Adapted from NCCN Practice Guidelines in Oncology – v Tumor > 0.5 cm Consider Oncotype DX (Category 2A) Consider Oncotype DX (Category 2A) HR+, HER2– disease pT1, pT2, or pT3 and pN1mi ( 2mm axillary node metastasis) No test RS < 18 RS RS 31 Adjuvant endocrine therapy ± adjuvant chemotherapy (Category 1) Adjuvant endocrine therapy ± adjuvant chemotherapy (Category 1) Adjuvant endocrine therapy (Category 2B) Adjuvant endocrine therapy (Category 2B) Adjuvant endocrine therapy ± adjuvant chemotherapy (Category 2B) Adjuvant endocrine therapy ± adjuvant chemotherapy (Category 2B) Adjuvant endocrine therapy + adjuvant chemotherapy (Category 2B) Adjuvant endocrine therapy + adjuvant chemotherapy (Category 2B) RS, Recurrence Score® result NCCN is a trademark of the National Comprehensive Cancer Network. NCCN does not endorse any therapy or product.

55 Oncotype DX ® testing in node-positive disease

56 56 Oncotype DX ® clinical validation in node-positive patients (ECOG trial 2197) 776 samples with genomic data, including Recurrence Score ® results Paraffin blocks with cancer cells occupying < 5% of the section area excluded Manual micro-dissection RNA extraction 776 samples with genomic data, including Recurrence Score ® results Paraffin blocks with cancer cells occupying < 5% of the section area excluded Manual micro-dissection RNA extraction ECOG TRIAL 2197 Operable breast cancer 0-3 positive nodes T.1cm if node negative N = 2885 eligible patients AC Doxorubicin 60 mg/m 2 Cyclophosphamide 600 mg/m 2 Every 3 weeks × 4 cycles AC Doxorubicin 60 mg/m 2 Cyclophosphamide 600 mg/m 2 Every 3 weeks × 4 cycles AT Doxorubicin 60 mg/m 2 Docetaxel 60 mg/m 2 Every 3 weeks × 4 cycles AT Doxorubicin 60 mg/m 2 Docetaxel 60 mg/m 2 Every 3 weeks × 4 cycles Tamoxifen × 5 years If HR-positive (amended to allow Als) Plus RT if indicated Tamoxifen × 5 years If HR-positive (amended to allow Als) Plus RT if indicated Goldstein LJ, et al. ASCO Abstract 526. No difference between arms Median follow-up 76 months 96.8% reported follow-up until death or for at least 5 years Tamoxifen × 5 years If HR-positive (amended to allow Als) Plus RT if indicated Tamoxifen × 5 years If HR-positive (amended to allow Als) Plus RT if indicated

57 57 Patients with 1-3 positive nodes and low Recurrence Score ® result do well without chemotherapy* RSNodesRFI (%)DFS (%)OS (%) < 18 Negative Positive Negative Positive Negative Positive Low Recurrence Score results (< 18) in patients with 1-3 positive axillary nodes may eventually be used to select individuals for a short course of chemotherapy plus hormonal therapy Elevated Recurrence Score results ( 18) may eventually be used to select individuals for participation in clinical trials evaluating novel treatment strategies or for more aggressive chemotherapy regimens 5-Year event rates by nodal status & Recurrence Score result Goldstein LJ, et al. ASCO Abstract 526. *Including micrometastases (pN1mi) RS, Recurrence Score result

58 58 Superior disease-free survival and overall survival over 10 years Tamoxifen × 5 yrs n = 361 Tamoxifen × 5 yrs n = 361 CAF × 6 tamoxifen n = 566 CAF × 6 tamoxifen n = 566 CAF × 6 + tamoxifen n = 550 CAF × 6 + tamoxifen n = 550 SWOG 8814 Postmenopausal, node-positive, ER-positive breast cancer N = 1477 Patients with samples (n = 666) RT-PCR obtained (n = 601) Tamoxifen alone (n = 148) CAF + T (n = 243) CAF T (n = 219) Sample for primary analysis = 367 (40% of parent trial) Patients with samples (n = 666) RT-PCR obtained (n = 601) Tamoxifen alone (n = 148) CAF + T (n = 243) CAF T (n = 219) Sample for primary analysis = 367 (40% of parent trial) SUB ANALYSIS Oncotype DX ® clinical validation in node-positive patients (SWOG 8814 sub-analysis) 58 Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

59 59 Recurrence Score ® result is prognostic for node-positive patients (tamoxifen arm) RS < 18 (n = 55) RS (n = 46) RS 31 (n = 47) Stratified log-rank P = at 10 years RS < 18 (n = 55) RS (n = 46) RS 31 (n = 47) Stratified log-rank P = at 10 years DFS by risk group (tamoxifen-alone arm) OS by risk group (tamoxifen-alone arm) Years since registration 10-Year DFS: 60%, 49%, 43% 10-Year OS: 77%, 68%, 51% RS, Recurrence Score result Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

60 60 High Recurrence Score ® result predictive of chemotherapy benefit in node-positive patients DFS BY TREATMENT & RS GROUP RS < 18 RS RS Years since registration Stratified log-rank P = 0.97 at 10 years Years since registration Stratified log-rank P = 0.48 at 10 years Years since registration Stratified log-rank P = at 10 years CAF T (n = 91, 26 events) Tam (n = 55, 15 events) CAF T (n = 46, 22 events) Tam (n = 57, 20 events) CAF T (n = 47, 26 events) Tam (n = 71, 28 events) No benefit to CAF over time if low or intermediate RS Strong benefit if high RS Strong benefit if high RS RS, Recurrence Score result Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

61 Risk of Distant Recurrence Using Oncotype DX ® Assay in Postmenopausal Primary Breast Cancer Patients Treated with Anastrozole or Tamoxifen: a TransATAC Study Dowsett M et al on behalf of the ATAC Trialists Group San Antonio Breast Cancer Symposium. 2008; Abstract 53.

62 62 Study overview Secondary analyses: –Determine whether the relationship between continuous Recurrence Score ® result and time to distant recurrence differs by nodal status or treatment arm –Determine the relationship of predefined Recurrence Score groups with time to distant recurrence by nodal status and treatment arm –Evaluate whether Recurrence Score result adds to the Adjuvant! Online estimate of risk Dowsett M, et al. SABCS 2008; abstract 53. Tamoxifen Anastrozole Tamoxifen + Anastrozole ATAC study population (N = 9366) (combination arm not examined) Primary Analysis: To determine whether Oncotype DX ® assay significantly adds to a proportional hazards model for time to distant recurrence (age, tumor size, grade, treatment) in node-negative, HR+, patients with no adjuvant chemotherapy

63 63 Number of evaluable patients and distant events by nodal status Node negative Node positive Node unknown Total All Adjuvant chemo–9–55–1–65 HR negative–4–0 –4 Didnt start T or A–5–2–1–8 Evaluable patients 872 (71%) 306 (25%) 53 (4%) 1231 (100%) Number of distant events Dowsett M, et al. SABCS 2008; abstract 53. Distributions of the clinical variables in the 1231 evaluable (non-N Am) patients were similar to those in the 2929 ATAC (non-N Am) patients who were not included in this study

64 64 Primary analysis: time to distant recurrence and Recurrence Score ® value adjusted for clinical covariates (node-negative patients, both treatment arms) VariableHR (95% CI)*P value Recurrence Score / 50*5.25 (2.84, 9.73)< Tumor Size: > 2 vs 2 cm2.78 (1.70, 4.57)< Central grade Moderate vs Well Poor vs Well 1.70 (0.75, 3.86) 2.06 (0.82, 5.17) Dowsett M, et al. SABCS 2008; abstract 53. Multivariate analysis adjusted for treatment arm and patient age *Hazard Ratio for a 50-point increment in Recurrence Score value Multivariate analysis confirms that the Oncotype DX ® Recurrence Score result as a continuous variable is a highly significant predictor of time to distant recurrence

65 65 Time to distant recurrence by Recurrence Score ® group Dowsett M, et al. SABCS 2008; abstract 53. RS groupHR* (95% CI) High vs Low5.2 ( ) Int vs Low2.5 ( ) RS groupHR* (95% CI) High vs Low2.7 ( ) Int vs Low1.8 ( ) Node negative (n = 872) (both treatment arms) *Hazard ratio for RS group adjusted for tumor size, grade, age and treatment Years Proportion distant recurrence-free % 88% 75% N (%) Events Low 513 (59%) 20 Int 229 (26%) 24 High 130 (15%) 28 Log-rank P < Node positive (n = 306) (both treatment arms) 83% 72% 51% Years Proportion distant recurrence-free N (%) Events Low 160 (52%) 25 Int 94 (31%) 25 High 52 (17%) 24 Log-rank P < RS, Recurrence Score result

66 All patients, int. RS (n = 229) All patients, low RS (n = 513) All patients, high RS (n = 130) All patients (n = 872) All anastrozole (n = 440) Anastrozole, low RS (n = 268) Anastrozole, high RS (n = 60) Anastrozole, int. RS (n = 112) No. of events Percent with distant recurrence at 9 years Tamoxifen, low RS (n = 245) Tamoxifen, high RS (n = 70) Tamoxifen, int. RS (n = 117) All tamoxifen (n = 432) Dowsett et al., SABCS 2008, Abstract # 53 Percent with distant recurrence at 9 years (node negative) RS, Recurrence Score ® result

67 All patients, int. RS (n = 94) All patients, low RS (n = 160) All patients, high RS (n = 52) All patients (n = 306) All anastrozole (n = 154) Anastrozole, low RS (n = 81) Anastrozole, high RS (n = 26) Anastrozole, int. RS (n = 47) No. of events Percent with distant recurrence at 9 years Tamoxifen, low RS (n = 79) Tamoxifen, high RS (n = 26) Tamoxifen, int. RS (n = 47) All tamoxifen (n = 152) Dowsett et al., SABCS 2008, Abstract # 53 Percent with distant recurrence at 9 years (node positive) RS, Recurrence Score ® result

68 68 Rate of distant recurrence increases with the number of positive nodes for all Recurrence Score ® results Year risk of distant recurrence (%) Recurrence Score value Node negative 1-3 Positive nodes 4 Positive nodes 95% CI Mean Dowsett M, et al. SABCS 2008; abstract 53.

69 69 ATAC conclusions Confirms performance of Oncotype DX ® Recurrence Score ® result in postmenopausal HR+ patients treated with tamoxifen in a large contemporary population Demonstrates for the first time that the Oncotype DX Recurrence Score result is an independent predictor of distant recurrence in node negative and node positive HR+ patients treated with anastrozole The established relationship between Oncotype DX Recurrence Score result and distant recurrence for tamoxifen may be applied for anastrozole with adjustment for the lower risk of distant recurrence with the aromatase inhibitor Dowsett M, et al. SABCS 2008; abstract 53.

70 70 Reproducible clinical validation essential in changing standard of care: more than 4000 patients studied in 12 trials *Published studies StudyTypeNo. Pts Nodal status ProvidenceExploratory136Neg Rush*Exploratory78Pos NSABP B-20Exploratory233Neg NSABP B-14*Prospective668Neg MD Anderson*Prospective149Neg Kaiser Permanente*Prospective case-control790 cases/controlsNeg NSABP B-14Prospective placebo vs Tam645Neg Milan*Exploratory89Neg/Pos NSABP B-20*Prospective Tam vs Tam+Chemo651Neg ECOG 2197*Exploratory and prospective776Neg/Pos SWOG 8814Prospective Tam vs Tam+Chemo367Pos ATACProspective Tam vs AI1231Neg/Pos

71 71 TAILORx study Trial Assigning Individualized Options for Treatment Primary objective is to determine whether adjuvant hormonal therapy is not inferior to adjuvant chemohormonal therapy for patients with a Recurrence Score ® result –Correlates with 10-20% risk of distance recurrence at 10 years Potential implications –Reduce chemotherapy overtreatment in those likely to be treated with hormonal therapy alone –Reduce inadequate treatment by identifying individuals who derive great benefit from chemotherapy –Evaluate benefit of chemotherapy where uncertainty still exists about its utility

72 72 TAILORx schema Trial Assigning Individualized Options for Treatment Patients with node-negative, hormone- positive breast cancer Oncotype DX ® assay Recurrence Score ® result 10 Hormone therapy registry Recurrence Score result 11-25* Randomize to either hormone therapy or chemotherapy + hormone therapy Recurrence Score result > 25 Chemotherapy + hormone therapy Register specimen banking *Primary study group: Recurrence Score result correlates with a 10-20% risk of distance recurrence at 10 years (upper 95% CI)

73 Single-gene reporting Quantitative hormone receptor analysis

74 74 Oncotype DX ® assay also provides quantitative data for ER, PR, HER2 ER score PR score HER2 score Provides additional insight into the biology of individual tumors

75 Continuous measurement of ER/PR is reflective of tumor biology Reproducibility of the assay has a standard deviation of less than 0.4 units ER expression by RT-PCR (relative to reference genes; log 2) PR expression by RT-PCR (relative to reference genes; log 2) NSABP B-14 (N = 645) ER– PR+ ER– PR– ER+ PR– ER+ PR+ Overall PR range 1000-fold ER+ range 200-fold Overall ER range 3000-fold Data on file compiled from Paik S, et al. N Engl J Med. 2004;351:

76 76 Oncotype DX ® clinical validation: NSABP B-14 Objective: Prospectively validate Recurrence Score ® result as predictor of distant recurrence in node- negative, ER+ patients Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Randomized Registered Placebonot eligible Tamoxifeneligible Paik S, et al. N Engl J Med. 2004;351:

77 77 Quantitative ER expression is not strongly prognostic but is predictive of tamoxifen benefit in ER+ patients Placebo – highest ER tertile105 Placebo – mid ER tertile117 Placebo – lowest ER tertile 113 N Years Proportion without distant recurrence Quantitative ER expression in ER+, placebo-treated patients is not strongly prognostic (P = 0.54) Large tamoxifen benefit in highest / mid-ER tertiles Little tamoxifen benefit in lowest ER tertile Tamoxifen – highest ER tertile 99 Tamoxifen – mid ER tertile 88 Tamoxifen – lowest ER tertile 94 Baehner FL, et al. SABCS Abstract #510.

78 78 Quantitative PR expression is strongly prognostic in ER+, placebo-treated patients P value = Years Placebo – highest ER tertile127 Placebo – mid-ER tertile 94 Placebo – lowest ER tertile 114 N DRFI Baehner FL, et al. SABCS Abstract #510.

79 Concordance between RT-PCR and IHC for estrogen & progesterone receptors E2197 and Northern California Kaiser Permanente Studies

80 80 ECOG 2197 & Kaiser studies: methods for ER/PR assessment ECOG 2197 Nested, case-control study N = 769 Used tissue microarrays with mm cores per tumor Contained ER+ and ER– tumors ER antibody was 1D5 (Dako Cytomation) PR antibody was 636 (Dako Cytomation) ECOG central laboratory did IHC staining Staining assessed by 2 expert anatomic breast pathologists Quantitation used Allred Score (0-8) with positive AS 3 Kaiser study Case-control study N = 607 Used fixed paraffin whole-tumor tissue sections Confined to ER+ tumors ER antibody was SP1 (LabVision) PR antibody was 636 (Dako Cytomation) Phenopath central laboratory did IHC staining Staining assessed by 2 expert anatomic pathologists Quantitation used semiquantitative scoring method: 0%, 0-25%, 25-75%, > 75%

81 81 Badve SS. ASCO Breast Cancer Symposium Abstract #87. Baehner FL, et al. ASCO Breast Cancer Symposium Abstract #88. High degree of concordance between RT-PCR and IHC for ER/PR status Central IHC vs Oncotype DX ECOG study (n = 769) concordance (95% CI) Kaiser study (n = 607) concordance (95% CI) ER status 93% (91-94%) 96% (94-97%) PR status 90% (88-92%) 90% (87-92%) Hormone receptor status 93% (91-95%) 95% (93-97%) ER, estrogen receptor; PR, progesterone receptor; IHC, immunohistochemistry; RT-PCR, reverse transcriptase-polymerase chain reaction; ECOG, Eastern Cooperative Oncology Group; CI, confidence interval ER and PR concordance between central IHC vs RT-PCR Oncotype DX ® assay

82 82 E2197: ER & PR expression by central RT-PCR & central IHC 14% of ER-negative cases by IHC are ER positive by RT-PCR For these discordant cases, RT-PCR measurements range from 6.5 to 10.4 units 15% of PR-positive cases by IHC are PR negative by RT-PCR For these discordant cases, RT-PCR measurements range from 2.4 to 5.4 units ERPR Badve SS. ASCO Breast Cancer Symposium Abstract #87.

83 83 Kaiser: ER & PR expression by central RT-PCR & central IHC ERPR Of the 7 discordant pairs ER positive by IHC but ER negative by RT-PCR, 6 (86%) are within 1 unit of the 6.5 cutoff. Of the 20 discordant pairs ER negative by IHC but ER positive by RT-PCR, 17 (85%) are within 1 unit of the 6.5 cutoff. Of the 22 discordant pairs PR positive by IHC but PR negative by RT-PCR, 19 (86%) are within 1 unit of the 5.5 cutoff. Of the 38 discordant pairs PR negative by IHC but PR positive by RT-PCR, 23 (61%) are within 1 unit of the 5.5 cutoff. Baehner FL, et al. ASCO Breast Cancer Symposium Abstract #88.

84 Concordance between RT-PCR and IHC/FISH for HER2 receptor E2197 and Northern California Kaiser Permanente Studies

85 85 ECOG 2197 & Kaiser studies: methods for HER2 assessment ECOG 2197 Used tissue microarrays HER2 assessed using HercepTest ECOG central laboratory Positive result defined by ASCO guidelines Kaiser study Used fixed paraffin whole-tumor tissue sections HER2 assessed using Vysis PathVysion HER2/neu DNA Probe Kit Phenopath central laboratory Positive result defined by ASCO guidelines

86 86 HER2 distribution by RT-PCR, IHC & FISH *By IHC: Neg: 0 or 1+ staining, Equiv: 2+ staining or 3+ staining in 30% cells ** By RT-PCR: Neg: < 10.7, Equiv: 10.7-< 11.5, Pos: 11.5 E2197 study Kaiser study

87 87 Patients had continuous expression levels for HER2 and ER (E2197 study) The overall range of HER2 expression in this study is approximately 1000-fold Range of HER2 expression for HER2 positive is approximately 16-fold Separate reproducibility studies indicate that standard deviation for the assay is less than 0.4 units HER2+ by IHC (3+ with > 30 staining) HER2– or equivocal by IHC (0-3+ with < 30% staining) HER2 (by RT-PCR – log2) ER by RT-PCR (expression units) + HER2+/HR-HER2+/HR+ HER2-/HR+HER2-/HR

88 88 Patients had continuous expression levels for HER2 and ER (Kaiser study) HER2 expression (relative to ref genes) The overall range of HER2 expression in this study is approximately 500-fold Range of HER2 expression for HER2 positive is approximately 16-fold Separate reproducibility studies indicate that standard deviation for the assay is less than 0.4 units HER2+/HR- HER2+/HR+ HER2-/HR+ HER2-/HR- HER2+ by FISH HER2– by FISH + ER by RT-PCR (expression units) Cutoff = 2.2

89 89 High degree of concordance between RT-PCR and FISH for HER2 ECOG 2197Central IHC +Central IHC – Total Oncotype DX +94 (78%)4 (1%)98 Oncotype DX –27 (22%)439 (99%)466 Total HER2 concordance 2×2 Equivocal cases excluded by both assays (according to ASCO/CAP guidelines) Kaiser StudyCentral FISH +Central FISH –Total Oncotype DX +55 (98%)11 (3%)66 Oncotype DX –1 (2%)408 (97%)409 Total Sparano JL, et al. ASCO Breast Cancer Symposium. 2008; Abstract 13. Baehner FL, et al. ASCO Breast Cancer Symposium. 2008; Abstract 41. Wolff AC, et al. J Clin Oncol. 2007;25: CONCORDANCE 95%* [95% CI (92%,96%) Kappa 83%, 95% CI (77%,88%)] *Concordance calculated as (94+439)/564 CONCORDANCE 97%* [95% CI (96%,99%), Kappa 89%, 95% CI (82%,95%)] *Concordance calculated as (55+408)/475

90 Single-Gene Testing in the Oncotype DX ® assay addresses limitations with current methodologies Both IHC and FISH are associated with variability that can affect the accuracy of test results. The impact of variability can be minimized by normalization strategies used in quantitative gene expression assessment as performed by quantitative RT-PCR in the Oncotype DX assay. By minimizing variability, hormone-receptor status can be more accurately reported, and treatment decisions that depend on ER or HER2 status can be made with greater confidence. 90

91 Single-Gene Testing in the Oncotype DX ® assay addresses limitations with current methodologies There is a high degree of overall concordance between local and central IHC and central RT-PCR for ER, PR, and hormone-receptor status. The relatively high incidence of IHC-negative hormone- receptor status positive by RT-PCR is notable and deserves further study. Quantitative RT-PCR using the Oncotype DX assay is an alternative method for determining hormone-receptor status. 91

92 Single-Gene Testing in the Oncotype DX ® assay addresses limitations with current methodologies For HER2 status, there is a high degree of overall concordance between central FISH for gene amplification and central RT-PCR for quantitative gene expression. For HER2 status, there is a high degree of overall concordance between central IHC for protein expression and central RT-PCR for quantitative gene expression. Quantitative RT-PCR by the Oncotype DX assay for HER2 status is an alternative to FISH. Quantitative Single-Gene Testing results may be used by local pathology laboratories as an external concordance standard for ER, PR, and HER2. 92

93 Prospective Multi-center Study of the Impact of Oncotype DX ® Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /JCO

94 94 Background A multi-center study was designed to prospectively examine whether the Oncotype DX ® Recurrence Score ® result can affect medical oncologist and patient adjuvant treatment selection Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /JCO

95 95 Methods 17 medical oncologists at 1 community and 3 academic practices participated. Each medical oncologist consecutively offered enrollment to eligible women with node-negative, ER-positive breast cancer. Each medical oncologists and consenting patient completed pre- and post-Oncotype DX ® questionnaires. Medical oncologists stated their adjuvant treatment recommendation and confidence in it pre- and post-Oncotype DX testing. Patients indicated treatment choice pre- and post-Oncotype DX testing. In addition, patients completed measures for quality of life, anxiety, and decisional conflict pre and post assay. Oncotype DX results were returned to the medical oncologist and shared with patients for routine clinical care. Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /JCO

96 96 Change in medical oncologist treatment recommendation by Recurrence Score ® result Treatment recommendation Pre- Recurrence Score Post- Recurrence Score Number (%) Mean RS Number (%) Mean RS CHT42 (47.2)2123 (25.8)29 HT alone46 (51.7)1860 (67.4)16 Equipoise1 (1.1)196 (6.7)19 Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /JCO CHT, chemo and hormonal therapy; HT, hormonal therapy; equipoise defined as either chemo and hormonal therapy, hormonal therapy alone, or enrollment onto the TAILORx clinical trial; RS, Recurrence Score result

97 97 Medical oncologist treatment recommendations changed 31.5% of the time Medical oncologist treatment recommendation pre- to post-Oncotype DX ® assay Number of cases (%) CHT HT20 (22.5) HT CHT3 (3.4) CHT or HT Equipoise5 (5.6) Treatment plan did not change61 (68.5) Total89 (100) Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /JCO Treatment recommendation changed for 28 (31.5%) cases after results of the Oncotype DX assay were known The most common change was recommendation from CHT to HT (22.5% of cases) Treatment recommendation changed for 28 (31.5%) cases after results of the Oncotype DX assay were known The most common change was recommendation from CHT to HT (22.5% of cases)

98 98 Clinical summary Oncotype DX ® assay Oncotype DX assay provides: –An individualized prediction of 10-year distant recurrence risk for patients who receive 5 years of tamoxifen –An individualized prediction of tamoxifen benefit –An individualized prediction of chemotherapy benefit to inform adjuvant treatment decisions in women with early stage breast cancer Quantitative RT-PCR for ER/PR/HER2 is highly concordant with both IHC and FISH (using ASCO/CAP guidelines for determination of concordance). –93-96% concordant with IHC for ER –90% concordant with IHC for PR –95% and 97% concordant with IHC and FISH for HER2, respectively Oncotype DX assay is the only multi-gene expression assay recommended in both ASCO and NCCN clinical practice guidelines.

99 99 Reproducible clinical validation essential in changing standard of care: more than 4000 patients studied in 12 trials *Published studies StudyTypeNo. Pts Nodal status ProvidenceExploratory136Neg Rush*Exploratory78Pos NSABP B-20Exploratory233Neg NSABP B-14*Prospective668Neg MD Anderson*Prospective149Neg Kaiser Permanente*Prospective case-control790 cases/controlsNeg NSABP B-14Prospective placebo vs Tam645Neg Milan*Exploratory89Neg/Pos NSABP B-20*Prospective Tam vs Tam+Chemo651Neg ECOG 2197*Exploratory and prospective776Neg/Pos SWOG 8814Prospective Tam vs Tam+Chemo367Pos ATACProspective Tam vs AI1231Neg/Pos

100 100 Case study revisited A 55-year-old post-menopausal woman presents with an infiltrating ductal carcinoma –Tumor size 1.0 cm –ER/PR IHC positive –HER2 IHC negative –Sentinel lymph node negative –Excellent overall health How should this patient be evaluated for treatment? What is her risk of disease recurrence? How likely is she to benefit from hormonal or chemotherapy? How should this patient be evaluated for treatment? What is her risk of disease recurrence? How likely is she to benefit from hormonal or chemotherapy?

101 Oncotype DX® Recurrence Score ® result CLINICAL EXPERIENCE RESULTS 11 Recurrence Score = Patients with a Recurrence Score of 11 in clinical validation study had an Average Rate of Distant Recurrence at 10 years of 7.4% (95% CI: 4.9%, 9.8%) 101

102 Oncotype DX ® assay: quantitative hormone receptor analysis 102


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