Presentation on theme: "Oncotype DX® Breast Cancer Assay Clinical Data Review"— Presentation transcript:
1Oncotype DX® Breast Cancer Assay Clinical Data Review Post-SABCS 2011 UpdateGHI10102_0112
2Agenda SABCS 2011 Meeting Overview Clinical Validation of the Oncotype DX® Breast Cancer Assay for DCIS PatientsECOG 5194 Podium PresentationNew Data for Patients with Invasive Breast CancerOncotype DX reveals underlying biology in the neoadjuvant settingTraditional clinical pathologic measures cannot predict the Recurrence Score®Assay quality assurance is criticalOncotype DX Changes Treatment Decision in Node Negative and Node Positive Breast CancerAdvances in New Technology: Next Generation SequencingClosing Remarks
3SABCS 2011 Meeting Overview Understanding and treating the underlying biologyQuantifying recurrence risk in DCISNew therapeutic regimens in ER-positive breast cancerCombination antibody therapy for HER-2 positive diseaseContinual advances in basic research and technology
4Clinical Validation of the Oncotype DX® Breast Cancer Assay for DCIS Patients
5A QUANTITATIVE MULTIGENE RT-PCR ASSAY FOR PREDICTING RECURRENCE RISK AFTER SURGICAL EXCISION ALONE WITHOUT IRRADIATION FOR DUCTAL CARCINOMA IN SITU (DCIS): A PROSPECTIVE VALIDATION STUDY OF THE DCIS SCORE FROM ECOG E Solin LJ, Gray R, Baehner FL, Butler S, Badve S, Yoshizawa C, Shak S, Hughes L, Sledge G, Davidson N, Perez EA, Ingle J, Sparano J, Wood W Eastern Cooperative Oncology Group (ECOG) North Central Cancer Treatment Group (NCCTG) Genomic Health, Inc (GHI) San Antonio Breast Cancer SymposiumSolin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
6PRESPECIFIED STUDY OBJECTIVES Primary: To determine whether there is a significantassociation between the DCIS Score and the risk ofan ipsilateral breast event (IBE)Secondary: To determine whether the DCIS Score provides value beyond standard clinical and pathologic factorsConditional (if DCIS Score validated):To evaluate the Recurrence Score as a predictor of risk of an ipsilateral breast event (IBE)Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
7DCIS SCORE: 10-YEAR IPSILATERAL BREAST EVENTS (IBE) BY RISK GROUP ANY IBEINVASIVE IBESolin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
8DCIS SCORE: 10-YEAR RISK OF AN IPSILATERAL BREAST EVENT (IBE) ANY IBEINVASIVE IBESolin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
9SUMMARY: DCIS SCOREPresent study validates the DCIS Score as a predictor of an ipsilateral breast event (IBE) and invasive IBEDCIS Score quantifies 10-year risk of IBE - Continuous variable or 3 risk groupsDCIS Score provides independent information on IBE risk beyond clinical and pathologic variables - Including tamoxifen, grade, and negative margin width - Identifies underlying tumor biologyDCIS Score provides a new clinical tool to guide treatment selection for patients with newly diagnosed DCISSolin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-6.
10Oncotype DX® Reveals Underlying Biology in the Neoadjuvant Setting
11Previous Studies Evaluating the Recurrence Score as a Predictor of Neoadjuvant Chemotherapy Response Neoadjuvant Anthracyline-Taxane Treatment1(N=89)Neoadjuvant Docetaxel Treatment2 (N=72)P=0.005P=0.00791Gianni L, et al. J Clin Oncol Chang JC, et al. Breast Cancer Res Treat
12Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER2-Negative Breast Cancer with Exploratory Oncotype DX® Assessments: A Sarah Cannon Research Institute Phase II TrialYardley DA,1,2 Peacock NW,1,2 Hendricks C,3 Huh SY,4 Ketchum S,5 Chao C,6 Yoshizawa C,6 Burris HA,1,2 Hainsworth JD1,21Sarah Cannon Research Institute, Nashville, TN; 2Tennessee Oncology, PLLC, Nashville, TN; 3Center for Cancer and Blood Disorders, Bethesda, MD; 4Providence Medical Group, Terre Haute, IN; 5Mercy Hospital, Portland, ME; 6Genomic Health, Inc.®, Redwood City, CAYardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P
13Study ObjectivesTo correlate the baseline Oncotype DX® Recurrence Score® withpCR rate to neoadjuvant ixabepilone/cyclophosphamideClinical response rate to neoadjuvant ixabepilone/cyclophosphamideTo compare Recurrence Score results determined at baseline to those determined after completion of neoadjuvant ixabepilone/cyclophosphamideYardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P
14Clinical Characteristics and Neoadjuvant Treatment Results in Patients with Baseline Recurrence Score® ResultsCharacteristic (N=138)Number of PatientsMedian age, years (range)51 (30-79)Hormone receptor statusER+ 75 (54%)PR+ 61 (44%)ER-/PR- 62 (45%)Baseline Oncotype DX Recurrence ScoreLow (<18) 20 (14%)Intermediate (18-30) 23 (17%)High (≥31) 95 (69%)Completed 6 cycles of neoadjuvant chemotherapy112Definitive surgery performed108Clinical response to neoadjuvant treatment (N=112)CR 30 (27%)CR + PR 70 (63%)Pathologic Complete Response (N=108)19 (18%)Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P
15Baseline Recurrence Score (N=108) Logistic Regression of Continuous RS Correlation of Pathologic Complete Responses and Baseline Recurrence Score® ResultsBaseline Recurrence Score (N=108)Baseline RS GroupLow(RS<18)Intermediate(RS 18-30)High(RS≥31)Proportion (%) with pCR0/19 (0%)0/17 (0%)19/72 (26%)Mantel-Haenszel Chi-square p=0.002Logistic Regression of Continuous RSVariableOdds Ratio95% CIP-valueContinuous RS57.9(9.5,583)<0.001There were NO pCRs in tumors with either “Low” or “Intermediate” baseline Recurrence Scores (RS≤30).A high Oncotype DX® Recurrence Score, analyzed either by RS group or as a continuous variable, was strongly associated with a pCR to neoadjuvant chemotherapy.Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P
16Paired Baseline and Post-treatment Recurrence Score® Results o ER+ by IHC (n=44)o ER- by IHC (n=28)Spearman correlationOverall: 0.82 (95% CI )ER+: 0.60 (95% CI )ER-: 0.55 (95% CI )Lin’s concordance: correlation Overall: 0.76ER+: 0.72ER-: 0.44N=72 samplesPaired baseline and post-treatment Recurrence Scores demonstrated concordance.ER negative tumors demonstrated higher Recurrence Scores at baseline and after neoadjuvant chemotherapy.13 of 40 tumors (33%) with a high RS at baseline had residual tumor with low or intermediate RS after neoadjuvant chemotherapy. No tumors with initial low or intermediate RS had high risk RS after neoadjuvant chemotherapy.Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P
17Summary and Conclusions Baseline Oncotype DX® Recurrence Score ® Results were highly predictive of the likelihood of achieving a pCR with neoadjuvant ixabepilone/cyclophosphamide.All pCRs occurred in patients with baseline high risk Recurrence Scores (≥31).There was high concordance (Spearman coefficient = 0.82) and agreement (Lin’s concordance correlation = 0.76) in Recurrence Scores determined at baseline and after neoadjuvant chemotherapy, suggesting that most tumors retain the same molecular characteristics.Further follow-up is necessary to confirm that Oncotype DX Recurrence Scores correlate with survival endpoints in addition to pCR rate.Oncotype DX Recurrence Scores may provide important prognostic information in patients who are candidates for neoadjuvant chemotherapy. Identification of patients unlikely to achieve pCR with current regimens may be useful in the design of future clinical trials.Yardley DA et al, San Antonio Breast Cancer Symposium 2011; Abstract P
18Traditional Clinical Pathologic Measures Cannot Predict the Recurrence Score®
19Prospective Comparison of Risk Assessment Tools in Early Breast Cancer (Recurrence Score®, uPA/PAI-1, Central Grade, and Luminal Subtypes): Final Correlation Analysis from the Phase III WSG planB TrialGluz O,1,2 Kreipe HH,³ Degenhardt T,1 Christgen M,³ Kates R,1Liedtke C, 1,4 Shak S,5 Clemens M,6 Markmann S,7 Uleer C,8Augustin D,9 Thomssen C,10 Nitz U,1,2 and Harbeck N 1,11on behalf of the planB investigators1West German Study Group, Moenchengladbach, Germany; 2Bethesda Hospital, Moenchengladbach, Germany; ³Institut of Pathology, Medical College, Hanover, Germany; 4University Hospital Muenster, Muenster, Germany; 5 Genomic Health, Redwood City, CA.; 6Hospital Mutterhaus, Trier, Germany; 7University Hospital Suedstadt, Rostock, Germany; 8Gynecological Practice, Hildesheim, Germany; 9Hospital Deggendorf, Deggendorf, Germany; 10University Halle, Halle, Germany; 11 Breast Center, University of Cologne, Cologne, GermanyGluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.
20Plan B Trial Design HER2-negative Primary Breast Cancer HR-RANDOMIZATIONT75C600 x 6*pT1-4free marginspN+pN0 high riskRECURRENCESCORE0-3 LN andRS>11or ≥ 4 LNE90C600x4 Doc100 x4*pT>2cmG2-3uPA/PAI-1↑HR-age <35 yearsHR+0-3 LN andRS<11Endocrine therapy** Endocrine therapy and RT according to national guidelinesGluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.
21Patient Characteristics Recurrence Score® populationn=2549*Central tumor bank populationn=3033Age< 50> 50Median33%67%56 yearsNodal statuspN0pN1pN2/362%5%Tumor size< 20 mm> 20 mm55%45%Central gradeG1G2G363%32%57%39%*Baseline data not available for two patientsGluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.
22Risk Distribution by Recurrence Score® Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.
23Recurrence Score ® by Ki-67 Plan B Cut-offs high riskhigh risk(>25)(>25)intermediateintermediaterisk (12-25)risk (12-25)low risklow risk(0-11)(0-11)9%67%24%32%55%13%11%68%22%41%48%11%Ki-67 <14Ki-67 14Ki-67 <20Ki-67 20Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..
24Recurrence Score ® by Ki-67 Standard Cut-offs high riskhigh risk(≥31)(≥31)intermediateintermediaterisk (18-30)risk (18-30)low risklow risk(<18)(<18)3%36%61%19%43%38%3%38%59%26%44%30%Ki-67 <14Ki-67 14Ki-67 <20Ki-67 20Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..
25Recurrence Score® by Central Grade Plan B Cut-offs high risk(>25)intermediateConcordance is limitedIf the RS is high it is quite likely that central grade is high.However, the converse is not true.risk (12-25)low risk(0-11)4%72%24%12%67%21%43%46%11%123Central gradeGluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..
26Recurrence Score® by Central Grade Standard Cut-offs high risk(≥31)intermediateConcordance is limitedIf the RS is high it is quite likely that central grade is high.However, the converse is not true.risk (18-30)low risk(<18)37%63%5%39%56%30%39%31%123Central gradeGluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3..
27ConclusionsLarge phase III prospective study comparing two CT regimens. Data presented: correlation between RS and uPA/PAI-1, central grade, and Ki-67in patients with HR+, N+/- early stage breast cancer at baseline.RS data available in large cohort of 2,549 patients.This study demonstrated only a moderate correlation between RS and Ki-67 and RS and central grade. Weak concordance was observed between RS and uPA/PAI-1.As previously demonstrated in multiple studies, Oncotype DX® provides an individualized RS result that cannot be predicted by traditional clinicopathologic measures.Gluz O et al, San Antonio Breast Cancer Symposium 2011; Abstract S4-3.
29Consistency and Control in Clinical Assay Technology over Time: The Oncotype DX® Recurrence Score® and Assessment of Single Gene Expression Levels Baehner FL,1,2 Butler S,1 Anderson J,1 Ballard J,1 Tan V,1 Tharayanil A,1 Shak S1 1Genomic Health, Inc., Redwood City, CA; 2University of California, San Francisco, San Francisco, CABaehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
30BackgroundThe American Society of Clinical Oncology® and College of American Pathology® have highlighted the importance of consistency and control in clinical assay technology.1-2The Genomic Health clinical laboratory quality assurance and quality control programs and biannual proficiency testing ensures consistency and reproducibility for the RS and quantitative single gene results for ER, PR, and HER2.1Wolff A et al, J Clin Oncol Hammonds E et al, J Clin Oncol 2010.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
31MethodsAll tumors successfully analyzed in the Genomic Health laboratory from January 1, 2005 to March 31, 2011 were included.Descriptive statistics for the Recurrence Score® value, the average reference gene expression level, and expression levels for quantitative single genes ER, PR and HER2 were calculated for each calendar year.Single gene reporting (ER, PR, HER2) began in 2008.The associations by year between HER2 and GRB7, ER and HER2, and ER and PR expression levels were characterized using scatterplots and correlation statistics.Subgroup analyses were conducted by histological tumor type, core biopsy versus excision, and whether micro-dissection was done.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
32Recurrence Score® Distribution Over Time RS distribution is consistent over time.The average and median RSs are 19.5 and 17, respectively.Approximately 50% of cases have a RS between 12 and 24.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
33Reference Gene Distributions The distribution of the average non-normalized level of expression for the five reference genes remained consistent over time, with non-systematic variation in the median value within approximately 0.5 units.The middle 50% of cases were within one unit, indicating consistently low variation in reference gene expression levels.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
34ER Quantitative Gene Distributions The distribution of quantitative ER and PR expression was consistent over time.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
35HER2 Quantitative Gene Distributions % HER2 positive: % % % %The distribution of quantitative HER2 expression was consistent over time, with a wide range of HER2 expression noted.The majority of cases show HER2 expression levels consistent with HER2 normal status.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
36HER2 and GRB7 Quantitative Gene Distributions YearPearson Correlation, Regression Slope20080.80, 0.7620090.79, 0.7520100.77, 0.742011HER2 and GRB7 gene expression are highly correlatedHigh degree of similarity over time in the distributions of HER2 and GRB7Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
37ConclusionsThis study evaluated consistency of RS and single gene expression levels for ER, PR, and HER2 over a 6 year period (2005 to 2011) in 207,691 patient cases.Multiple quality control and quality assurance processes have resulted in consistent performance of the Oncotype DX® Breast Cancer Assay.A high degree of consistency and no systematic change in expression level for reference genes, RS, ER, PR, or HER2 was observed.Baehner FL et al, San Antonio Breast Cancer Symposium 2011; Abstract P
38Oncotype DX® Changes Treatment Decision in Node Negative and Node Positive Breast Cancer
39Impact of the Recurrence Score® on Adjuvant Decision-Making in ER-positive Early Breast Cancer - Results of a Large Prospective Multicentre Decision Impact Study in Node-negative and Node-positive DiseaseRezai M,1 Eiermann W,2 Kümmel S,3 Kühne T,4 Warm M,5 Friedrichs K,6 Schneeweiss A,7 Markmann S,8 Eggemann H,9 Hilfrich J,10 Jackisch C,11 Witzel I,12 Eidtmann H,13 Kaufmann M,14 Blohmer J151 Luisenkrankenhaus, Düsseldorf, 2Rotkreuzkrankenhaus, München, 3Kliniken Essen Mitte, Essen, 4Klinikum, Esslingen, 5Krankenhaus Holweide, Köln, 6Mammazentrum, Hamburg, 7Nationales Tumorcentrum, Universität Heidelberg,, 8Universitätsklinikum, Rostock , 9Universitätsklinikum, Magdeburg ,10Eilenriedeklinik, Hannover, 11Klinikum, Offenbach, 12Universitätsklinikum, Hamburg , 13Universitätsklinikum, Kiel 14Universitätsklinikum, Frankfurt, 15Sankt Gertrauden-Krankenhaus, BerlinRezai M et al, San Antonio Breast Cancer Symposium 2011; Abstract P
40Changes in Treatment Recommendations Based on the Oncotype DX® Results PatientsNOverall Change RatePre- to Post-Oncotype DXCHT to HTHT to CHTOtherAll evaluable36612133.1% (95% CI 28.3 – 38.1)7921.6%3910.7%30.8%Node-negative2447430.3% (95% CI 24.6 – 36.5)4518.4%2811.5%1+0.4%Node-positive1224738.5% (95% CI 29.9 – 47.8)3427.9%119.0%2*1.6%95% confidence intervals calculated using Clopper-Pearson method+Observation to CHT *Observation to HT, CT to CHTRezai M et al, San Antonio Breast Cancer Symposium 2011; Abstract P
41de Boer RH,1 Baker C,2 Speakman D,3 and Mann GB4 Australian Decision Impact Study: The impact of Oncotype DX® Recurrence Score® (RS) on Adjuvant Treatment Decisions in Hormone Receptor Positive (HR+), Node-negative (N0) and Node-positive (N+) Early Stage Breast Cancer (ESBC) in the Multidisciplinary Clinic (MDC)de Boer RH,1 Baker C,2 Speakman D,3 and Mann GB41Royal Melbourne Hospital, Melbourne, Victoria, Australia; 2Austin Hospital, Melbourne, Victoria, Australia; 3Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; 4Royal Melbourne and Royal Women’s Hospital, Melbourne, Victoria, Australiade Boer RH et al, San Antonio Breast Cancer Symposium 2011; Abstract P
42Changes in Treatment Recommendations Based on the Oncotype DX® Results PatientsNOverall Change RatePre- to Post-Oncotype DXCHT to HTHT to CHTAll evaluable1513624%2415.9%127.9%Node-negative1012322.8%11.9%1110.9%Node-positive511326%12%de Boer RH et al, San Antonio Breast Cancer Symposium 2011; Abstract P
43ConclusionsThere were multiple decision impact studies presented at SABCS in both node-positive and node-negative patients.1-3Changes in treatment decisions ranged from 23.8% to 33.1%.These results are consistent with previous studies performed worldwide showing that the RS changes treatment decisions approximately a third of the time.41Rezai M et al, San Antonio Breast Cancer Symposium 2011; 2de Boer RH et al, San Antonio Breast Cancer Symposium 2011; 3Holt S et al, San Antonio Breast Cancer Symposium 2011; 4 Hornberger J et al, St Gallen International Breast Cancer Conference 2011
44Advances in New Technology: Next Generation Sequencing
45Breast Cancer Recurrence Risk Probed by Whole Transcriptome Next Generation Sequencing in 136 PatientsBaker J,1 Liu ML,1 Crager M,1 Stephans J,1 Pho M,1 Jeong J,1 Scott A,1 Ambannavar R,1 Morlan J,1 Pelham R,1 Qu K,1 Mena R,2 Esteban J,2 Collin F,1 and Sinicropi D11Genomic Health, Inc.®, Redwood City, CA; 2Providence Saint Joseph Medical Center, Burbank, CABaker J et al, San Antonio Breast Cancer Symposium 2011; Abstract PD45
46Summary and Conclusions Genomic Health reported on the technical performance of whole transcriptome next generation sequencing compared to the 21-gene RT-PCR Oncotype DX® Breast Cancer Assay.Whole transcriptome RNA-Seq identified more than 1800 new coding, intronic, and intergenic transcripts that were strongly associated with breast cancer recurrence risk.This technology has sensitivity and selectivity comparable to RT-PCR, can provide a vast increase in the number of interrogated transcripts, can reveal new biological relationships, and has excellent performance suitable for the discovery of RNA biomarkers.Baker J et al, San Antonio Breast Cancer Symposium 2011; Abstract PD
47Closing RemarksThese studies support the importance of understanding cancer biology to advance the treatment of breast cancer patients.Oncotype DX® is the first clinically validated commercial genomic assay quantifying the risk for local recurrence in DCIS patients.Data from a large phase III prospective study confirms that the Recurrence Score® cannot be predicted by clinical and pathological variables.A growing body of evidence suggests that the Recurrence Score may help guide neoadjuvant treatment decisions.
48Closing RemarksGenomic Health’s quality assurance and quality control programs ensure consistency and reproducibility for the Recurrence Score® and quantitative single gene results for ER, PR, and HER2.Multiple decision impact studies demonstrate that the Recurrence Score changes treatment decisions in node negative and node positive breast cancer.Genomic Health is committed to performing cutting edge research to better serve the oncology community (physicians and patients).