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The Present and Future of Genomics in DCIS On Demand Post-SABCS 2011 Update Steve Shak, MD Chief Medical Officer.

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Presentation on theme: "The Present and Future of Genomics in DCIS On Demand Post-SABCS 2011 Update Steve Shak, MD Chief Medical Officer."— Presentation transcript:

1 The Present and Future of Genomics in DCIS On Demand Post-SABCS 2011 Update Steve Shak, MD Chief Medical Officer

2 2 Agenda Background and Unmet Need Algorithm Development for the DCIS Score ™ Clinical Validation Clinical Applications Future Research Closing Remarks

3 DCIS Background and Unmet Need

4 4 DCIS Background Ductal carcinoma in situ (DCIS) is a pre ‐ invasive form of breast cancer –~45,000 new cases in 2010 in the U.S. Women diagnosed with DCIS are at risk for local recurrence, which may be either DCIS or an invasive breast cancer Approximately 70% of women with DCIS are treated with radiation following surgical excision The addition of radiation for DCIS has been shown in clinical trials to reduce local recurrence risk, but has not been demonstrated to prolong survival Viani GA et al. Radiat Oncol 2007; 2:28. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). J Natl Cancer Inst Monogr 2010;

5 5 Key Radiation Trials in DCIS Early Breast Cancer Trialists' Collaborative Group (EBCTCG). J Natl Cancer Inst Monogr 2010;

6 6 Unmet Need Reliable methods for making treatment decisions based upon patient specific tumor biology in DCIS have not been previously established There is a need to quantitatively assess the risk of invasive breast cancer recurrence in newly-diagnosed patients with DCIS There is a significant unmet need for validated tests that identify: –low risk disease which may be treated with surgery alone, avoiding toxicities and costs associated with radiation –high risk disease for which the addition of radiation may be considered

7 Algorithm Development: DCIS Score ™

8 8 DCIS Score ™ : Gene Selection and Algorithm Development DCIS Score developed from analysis of multiple correlative science studies Compared gene expression in invasive and DCIS –Recurrence Score ® tumor biology of invasive breast cancer and DCIS are similar 1 –Differences seen in the distribution of proliferation genes 1 Analyzed local and distant recurrence risk in published data in invasive breast cancer (NSABP B-14: randomized trial of tamoxifen vs. placebo in ER+ patients 2,3 and Kaiser: case-control study in ER+ tamoxifen-treated and untreated and ER- untreated patients 4 ) –Selected genes that predict local recurrence –Selected genes that predict recurrence risk regardless of tamoxifen treatment –Coefficients selected on multiple considerations from prior breast and colon studies Scaling and category cutpoints based on analysis of DCIS Score in separate cohort of DCIS patients 1. Baehner FL et al. San Antonio Breast Cancer Symposium 2008; Abstract Paik S et al. N Engl J Med. 2004; Mamounas EP et al. J Clin Oncol. 2009; Habel LA et al. Breast Cancer Res. 2006; R25.

9 9 PR Ki-67 STK15 Survivin Cyclin B1 MYBL2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 GSTM1 Beta-actin GAPDH RPLPO GUS TFRC Beta-actin GAPDH RPLPO GUS TFRC Hormone Receptor GroupProliferationReference DCIS Score: Continuous variable Number between 0 – 100 DCIS Score ™ : Gene Selection

10 Clinical Validation for DCIS Score ™

11 11 DCIS Score ™ Pre-specified for Validation All aspects of the study were pre-specified in a final protocol prior to initiation of sample processing for the E5194 clinical validation study. This included: –Pre-analytical and analytical methods –Gene coefficients for DCIS Score –Scaling and centering coefficients –DCIS Score risk groups Low < 39, Intermediate 39 – 54, High ≥ 55

12 A 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 E5194 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) 2011 San Antonio Breast Cancer Symposium

13 ECOG E5194 (PARENT STUDY) Prospective multicenter study (n = 670) Cohort 1: Low/intermediate grade, size < 2.5 cm Cohort 2: High grade, size < 1 cm Study treatment - Surgical excision - Minimum 3 mm negative margin width - No radiation - Tamoxifen option beginning May 2000 Reported outcomes at 5 and 7 years (Hughes, JCO, 2009) - Currently 10-year outcomes Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

14 PRESPECIFIED STUDY OBJECTIVES Primary: To determine whether there is a significant association between the DCIS Score and the risk of an ipsilateral breast event (IBE) Secondary: To determine whether the DCIS Score provides value beyond standard clinical and pathologic factors Conditional (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 S

15 METHODS FOR DCIS SCORE VALIDATION STUDY Prospective-retrospective study design Pre-specified: Study objectives, population, laboratory assays, endpoints, statistical methods Oncotype DX assay performed (n = 327; 49%) Standardized methods for 21 gene assay Central pathology review Calculated:DCIS Score and Recurrence Score Study endpoint: Ipsilateral breast events (IBE) 1 o Endpoint: Any IBE (DCIS or invasive carcinoma) 2 o Endpoints: Invasive IBE DCIS IBE Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

16 PATIENT AND TUMOR CHARACTERISTICS Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

17 PRIMARY ANALYSES OF THE RISK FOR AN IPSILATERAL BREAST EVENT (IBE) Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

18 DCIS SCORE: 10-YEAR IPSILATERAL BREAST EVENTS (IBE) BY RISK GROUP ANY IBE Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

19 DCIS SCORE: 10-YEAR IPSILATERAL BREAST EVENTS (IBE) BY RISK GROUP ANY IBEINVASIVE IBE Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

20 ANY IBE DCIS SCORE: 10-YEAR RISK OF AN IPSILATERAL BREAST EVENT (IBE) Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

21 ANY IBEINVASIVE IBE DCIS SCORE: 10-YEAR RISK OF AN IPSILATERAL BREAST EVENT (IBE) Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

22 MULTIVARIABLE MODELS OF RISK FOR IBE Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

23 EXPLORATORY ANALYSES OF DCIS SCORE: CONSISTENT ASSOCIATION ACROSS SUBGROUPS Overall 327 Pre Menopausal 79 Post Menopausal 248 Lesion Size ≤ Lesion Size > No. Negative Margins < 5 mm 113 Negative Margins ≥ 5 mm 214 Low/intermediate Grade 216 High Grade Tamoxifen Treated 96 Not Treated 231 Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

24 ASSOCIATION BETWEEN THE DCIS SCORE AND CLINICAL AND PATHOLOGICAL CHARACTERISTICS For each characteristic (including tumor grade, tumor size, margin width, patient age, menopausal status), a wide distribution of DCIS Score values was seen within each subgroup Although lesion size and menopausal status were, as expected, significantly associated with IBE risk, adjusting for these characteristics in multivariate models did not change the estimated association between the DCIS Score and IBE risk –This demonstrates that the DCIS Score provided additional information on IBE risk beyond these characteristics 24

25 SUMMARY: DCIS SCORE 1.Present study validates the DCIS Score as a predictor of an ipsilateral breast event (IBE) and invasive IBE Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

26 SUMMARY: DCIS SCORE 1.Present study validates the DCIS Score as a predictor of an ipsilateral breast event (IBE) and invasive IBE 2.DCIS Score quantifies 10-year risk of IBE - Continuous variable or 3 risk groups Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

27 SUMMARY: DCIS SCORE 1.Present study validates the DCIS Score as a predictor of an ipsilateral breast event (IBE) and invasive IBE 2.DCIS Score quantifies 10-year risk of IBE - Continuous variable or 3 risk groups 3.DCIS Score provides independent information on IBE risk beyond clinical and pathologic variables - Including tamoxifen, grade, and negative margin width - Identifies underlying tumor biology Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

28 SUMMARY: DCIS SCORE 1.Present study validates the DCIS Score as a predictor of an ipsilateral breast event (IBE) and invasive IBE 2.DCIS Score quantifies 10-year risk of IBE - Continuous variable or 3 risk groups 3.DCIS Score provides independent information on IBE risk beyond clinical and pathologic variables - Including tamoxifen, grade, and negative margin width - Identifies underlying tumor biology 4.DCIS Score provides a new clinical tool to guide treatment selection for patients with newly diagnosed DCIS Solin LJ et al, San Antonio Breast Cancer Symposium 2011; Abstract S

29 Clinical Applications for DCIS Score ™

30 30 The DCIS Score ™ Provides Clinical Insights Clinicians and patients desire objective evidence regarding risk of local recurrence (DCIS or invasive) to assist in treatment decision-making –In situations where clinicians and patients are uncertain about radiation –In situations where clinical and pathological parameters might indicate treatment and the patient does not wish to receive therapy –In situations where clinicians recommend forgoing therapy and the patient is not convinced

31 31 DCIS Sample Report: Local Recurrence

32 32 DCIS Sample Report: Local Recurrence

33 33 DCIS Sample Report: ER and PR Scores

34 Future DCIS Research

35 35 Future Research Additional research that provides confirmation and more experience in certain groups (e.g., higher risk DCIS and ER negative DCIS) Identification of predictive genes for radiation sensitivity and/or resistance Next Generation Sequencing to explore whether new genes might be identified that actually cause progression to invasive disease

36 36 Additional Information on DCIS The Oncotype DX ® Breast Cancer Assay for DCIS patients will be commercially available starting on December 28, 2011 For additional resources on DCIS visit US/Breast/HealthcareProfessional/DCIS.aspx If you have further questions, please contact Customer Service at or ONCOTYPE

37 37 Further Education In January 2012 you will receive an blast to register for our “On Demand Post-SABCS 2011 Update” summarizing the important developments in breast cancer

38 38 Closing Remarks Oncotype DX ® reveals the underlying biology that can help guide DCIS treatment decisions Oncotype DX is the first and only clinically validated commercial genomic assay for patients with DCIS Oncotype DX predicts the risk of any local recurrence (DCIS or invasive) and the risk of local invasive carcinoma Oncotype DX allows for personalized treatment based on tumor biology as determined by the DCIS Score™

39 Thank you


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