Breast Cancer: The Importance of a Treatment and ER Independent Assay

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Visit http://www.Agendia.com to learn more about MammaPrint, the only FDA approved breast cancer recurrence test.

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  • MammaPrint provides a binary result with no intermediate group; developed with oncologists’ input as to who was at sufficiently low risk, as to be best served by endocrine treatment alone vs. women who would benefit by the addition of chemotherapy.
  • The FDA was especially worried that so-called "MIA"s or multi-analyte index analysis tests had no transparency or ability to monitor proficiency as the data was fed into a "black box" and result (i.e. "high risk", "low risk", etc) came out the other end. How was the physician to know if this was correct? Companies that had a test like this all received a letter requesting their submission for clearance to the FDA.
  • Breast Cancer: The Importance of a Treatment and ER Independent Assay

    1. 1. The Importance of a Treatment and ER Independent Assay
    2. 2. MammaPrint® is treatment and ER-independent  Nearly half of patients (49%) of patients do not comply with 5 years of Tamoxifen therapy (Owusu et. al., JCO 2008)  Aromatase inhibitors are in use and untested in prognostic profiles and also have a compliance issue (Partridge et. al., JCO 2008)  Concern with “correctness” of ER interpretation by IHC (Badve et. al., JCO 2008)
    3. 3. MammaPrint® validated on an untreated patient population Gene expression profile identifies “low risk” and “high risk” tumors With MammaPrint there are no Tamoxifen compliance issues
    4. 4. Some patients may be masking as “low risk” 21 Gene Assay validated on Tamoxifen treated patients Profile identifies recurrence risk assuming 5 years of Tamoxifen compliance
    5. 5. What does “low risk” mean?  MammaPrint® “Low Risk”: 90% metastasis-free without any adjuvant treatment over the following 10 years (NEJM 2002/JNCI 2006).  The majority of “Low Risk” patients are ER positive, but a few actually have high risk profiles and can be expected to have a more ominous clinical course.  Interestingly, 5-6% of “Low Risk” patients are ER negative.  With ER+ patients receiving hormonal therapy, a further 50% risk reduction can be achieved in the “Low Risk” group, thus MammaPrint “Low Risk” means >95% 10 year metastasis-free survival.
    6. 6. 0% 10% 20% 30% 40% 0 10 20 30 40 50 100 For other signatures, “Low Risk” can be as high as 14% recurrence following Hormonal Treatment Rate of Distant Recurrence by 21-Gene Recurrence Score in the Clinical Validation Study Low Risk Intermediate Risk High Risk Rate 95% Confidence Interval AverageRateofDistantRecurrenceat10Years after5YearsofTamoxifenTreatment Recurrence Score MammaPrint “Low Risk”
    7. 7. MammaPrint® Delivers a Definitive High Risk or Low Risk Result CLASSIFICATION THRESHOLD Low Risk Signature High Risk Signature No Intermediate Results
    8. 8. Ease of Interpretation: MammaPrint® Test Result
    9. 9. Criteria for an Ideal Genomic Assay  Highest Integrity of genomic material  Selection of an unbiased gene set  Highest quality clinical data with assay performance independent of hormone receptor status or compliance with treatment  Risk parameters consistent with treatment thresholds for chemotherapy  Ease of interpretation  FDA compliance to insure safety and efficacy  Predictive data to provide clinical relevance to prognosis  Data from prospective randomized clinical trials showing effect on treatment outcomes
    10. 10. Regulatory Compliance – FDA IVDMIA
    11. 11. 231 reporter genes (incl. 70-gene profile) in nine-fold 465 normalization genes in three-fold 539 control genes in three-fold XPrint Software Algorithm Risk Assessment (“High” Risk or “Low” Risk) 5,600 sources MammaPrint® IVDMIA Microarray
    12. 12. What does FDA Regulation mean? FDA clearance entails:  Clinical (Claims) Validation  Clinical Utility  Technical Validation - Precision, Accuracy, Reproducibility  Software Validation Demonstration that the assay is both safe (to use) and effective (clinically valid and useful)
    13. 13. Alternative to FDA regulation “Home brew” exemption per CLIA  No assessment of clinical validity  No assessment of clinical utility  No assessment of assay reproducibility CLIA only means running your lab according to prescribed Federal standards
    14. 14. FDA Clearance of MammaPrint® Study Purpose Details Comments 1 Nature Development 70-gene profile 2002 78 patients, LN0, <55yrs 6.4% adjuvant treatment Within 5 year metastasis risk by profile multivariate OR 18 2 NEJM Validation 70-gene profile 2002 151 patients 5.2% adjuvant treatment Metastasis-free at 10 yrs: low risk 87%,high risk: 44% 5 yrs: low risk 93%,high risk 56% 3 MammaPrint Development MammaPrint 2006 reproducibility of (1) and (2) on MammaPrint Highly reproducible MammaPrint as a diagnostic tool 4 TRANSBIG Independent European validation 2006 302 patients no adjuvant treatment Metastasis-free at 10 yrs: low risk 88%,high risk: 71% 5 yrs: low risk 96%,high risk 83%
    15. 15. Reproducibility of 70-Gene Prognostic Assay – 99% 70-Gene Prognostic Assay Experiment 1 70-GenePrognosticAssayExperiment2
    16. 16. Clinical Reproducibility of 70-Gene Prognostic Assay – 99% 70-GenePrognosticAssayOutcome
    17. 17. FDA clears MammaPrint® & Agendia’s molecular fixative  February 2007: MammaPrint granted FDA first and only IVDMIA Clearance  June 2007: FDA Clears RNARetain molecular fixative enabling ambient temperature shipping These data led to the first FDA clearance for an IVDMIA.

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