1. Clinical Perspective

2. Screening/Prevention Who is at risk for what type Decision to Intervene: Risk Assessment normal Evidence of Disease Disability Death Opportunity #1: Fate Regression, Stability, Progression Opportunity #2: Rate Slow, Moderate, Fast Opportunity #3: intervention/reverse fate Targeted to biologic subtype Treatment What type and when Where Biomarkers Can Make a Difference

3. Problems/opportunities  Tumor heterogeneity  Along a spectrum of indolent to aggressive  From early to late risk for recurrence  Among patients with high risk for early recurrence  Within a given tumor  For those at risk, standard therapy has made a difference, but not all benefit equally or at all  There are hundreds of agents in the pipeline but limited ability to test them  Biomarkers/ Companion Diagnostics for targeted agents are lacking

4. Women at Risk for Early Systemic Recurrence of Breast Cancer Biomarker: 70 gene high risk  Are unlikely to be cured with surgery alone  Order of surgery, systemic therapy has no impact on survival outcomes  Neoadjuvant approach is an opportunity  Downstage tumors, refine local therapy options  Better understand response to therapy, prognosis  Accelerate targeted drug development to improve outcomes in highest risk women  Particularly relevant as a tool to sort out optimal treatments in the molecular era

5. Acceleration of Knowledge Turns Promising qualifying biomarker I-SPY 2 TRIAL amendment approved Continuous enrollment Drug graduates or is dropped Full Approval Accelerated Approval for Agent/ Approval for biomarker/PMA SCREENING PHASE Adapts on drugs (~60 patients) Agent Enters New agent/combination qualifies and is approved for I-SPY 2 pCR not confirmed MARKER PHASE CONFIRMATORY PHASE Adapts on biomarker (~300 patients)