1. Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know June 7, 2010 Neal J. Meropol, M.D. Chief, Division of Hematology and Oncology University Hospitals Case Medical Center Associate Director for Clinical Research Case Comprehensive Cancer Center Case Western Reserve University Cleveland, Ohio

2. QUASAR Survival – Stage II (92% of patients enrolled, N=2963) QUASAR Collaborative Group, Lancet, 2007 RR=0.84 P=0.05

3. Sargent, D. et al. J Clin Oncol; 2009 N = ~7000 5% benefit at 8 years ACCENT pooled analysis: benefit of adjuvant therapy in stage II colon cancer

4. The Data Not all patients with stage II colon cancer have the same risk In unselected patients –5-FU improves survival by a few percent –Oxaliplatin does not improve survival –Capecitabine as effective as 5-FU Clinical risk factors include –T4, obstruction, lymphovascular invasion, lymph node retrieval

5. Risk stratification is critical to decision making in stage II colon cancer Predictive: explains variability in response to treatment Prognostic: explains variability irrespective of treatment Variability exists in the host (germline) and tumor (somatic)

6. A Common Assumption The risk reduction associated with adjuvant therapy is consistent across the spectrum of risk Risk Relapse No Rx Adj Rx

7. The use of adjuvant therapy for stage II colon cancer requires a decision on the part of physicians and patients

8. What makes a good decision? Adequate understanding of alternatives Adequate understanding of potential risks and benefits Freedom from coercion “Rational” weighing of risks and benefits –consonant with individual values and preferences –“rational” does not imply that we would make the same decision Results in satisfaction

9. How do patients weigh decisions? Side effects - Intensity - Duration Cost Inconvenience Delay recurrence Reduce recurrence

10. What are the key issues? Potential benefit Potential harm –Short-term –Long-term Patient preferences

11. Decision making considerations

12. Relative vs. Absolute Risk Reduction 100 50 75 25 Survival % Time 5% RRR = 25% ARR = 5% “I can improve your chances by 5%” “I can reduce your risk by 25%” “I have to treat 100 people like you to save 5”

13. Patients are not Mathematicians Weinfurt et al. Cancer 2003 The following question involves a hypothetical situation in which your doctor is describing a new treatment. Imagine that your doctor says this new treatment controls cancer in 40% of cases like yours. How do you interpret what the doctor is saying? 14%The doctor is 40% confident that the treatment will control my cancer. 72%For every 100 patients like me, the treatment will work for 40 patients. 3%The new treatment will reduce my disease by 40%. 4%I am not sure what this information means. 3%Other 5%Don’t know/unsure

14. What is Rational? Or What is the minimum absolute benefit that you would require to feel comfortable offering (or receiving) adjuvant therapy?

15. Weinfurt, K. P. J Clin Oncol; 25:223-227 2007 Prospect Theory: People Care More About Outcomes Close to Their Reference Point

16. Weinfurt, K. P. J Clin Oncol; 25:223-227 2007 Prospect Theory: People Care More About Loss Than Gain Shifting Reference Point

17. People weight probabilities differently depending on where they fall on the probability curve The “Russian Roulette” experiment (Zeckhauser; Kahneman and Tversky) –You’d pay more to remove 1 bullet if the chamber is full, than if it only has 3 or 4 bullets to begin –You’d pay more to remove the final bullet, than to remove 1 bullet from a chamber with 3 or 4 bullets Do patients with stage II colon cancer weight absolute benefits of adjuvant therapy differently based upon their baseline underlying risk of recurrence?

18. Age may be an appropriate consideration %AC 85% 52% 35% Earle et al. J Surg Oncol, 2009

19. Should age matter? ACCENT: No benefit for combinations on survival in elderly (stage II/III) McCleary et al. ASCO 2009

20. Molecular Risk Stratification Mismatch repair is ready for clinical use –MSI vs. IHC –Prognostic and ?predictive –Implications for hereditary predisposition Oncotype DX is a validated platform –Establishes prognosis –Relative benefit of 5-FU is consistent across risk spectrum –Does not address benefit of oxaliplatin –Peer-reviewed publication is awaited ?Other molecular risk classifiers

21. Classifier discovery and validation DiscoveryValidation assay technology patient population characterized samples representative training and validation sets Prospective randomized trial is gold standard Retrospective randomized trial may be acceptable if: –a priori hypothesis and statistical design –samples available from vast majority of patients –adequate follow up and annotation Adapted from D. Sargent, ISGIO 9/07

22. QUASAR Recurrence Score There a significant relationship between the risk of recurrence and the pre- specified continuous Recurrence Score in stage II colon cancer patients randomized to surgery alone The relative risk reduction with 5-FU is consistent across Recurrence Score risk levels STROMAL FAP INHBA BGN CELL CYCLE Ki-67 C-MYC MYBL2 REFERENCE ATP5E GPX1 PGK1 UBB VDAC2 GADD45B RECURRENCE SCORE Calculated from Tumor Gene Expression Kerr et al. ASCO 2009

23. QUASAR : Clinical/Pathological Covariates and Recurrence Pre-specified Multivariate Analysis, Surgery Alone Patients (n=605) Kerr et al. ASCO 2009

24. QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery Kerr et al. ASCO 2009

25. Recurrence Score, T Stage, and MMR Deficiency are Independent Predictors of Recurrence in Stage II Colon Cancer 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 010203040506070 Recurrence Score Risk of recurrence at 3 years MMR deficient (11%) T4 stage (13%) T3 and MMR proficient (76%) Kerr et al. ASCO 2009

26. E5202: Stage II Colon Cancer Accrual Goal: 3438 Arm A: FOLFOX Arm B: FOLFOX + Bevacizumab Tumor block risk assessment based on biology (18q/MSI) High-risk (MSS and 18q LOH) Low-risk (MSI + or no loss 18q) Observation Surgery

27. NCCN Recommendations 2010 Ask the patient how much they’d like to know Discuss risks and benefits Consider clinical features that confer risk Consider comorbidities and life expectancy If considering fluoropyrimidine alone, MMR testing recommended

28. Proposed Stage II Algorithm Today MMR Clinical Risk No Adjuvant DeficientIntact Not HighHigh No Adjuvant Or Adjuvant *all decisions require discussion with patient

29. Proposed Stage II Algorithm Soon MMR Clinical & Molecular Risk No Adjuvant Deficient Intact Very small benefit from adjuvant therapy ?<3% No Adjuvant Or Adjuvant No Adjuvant *all decisions require discussion with patient More than very small benefit from adjuvant therapy ?3+%

30. What we need Models that integrate clinical and molecular risk assessment Improved methods of communicating risk (and risk reduction) to patients Formal modeling of impact of molecular vs. clinical tools on adjuvant therapy use, recurrence, survival, QOL, and cost Decision tools that go beyond simple calculations of 3 or 5 year clinical endpoints, and integrate comorbidities and life expectancy, i.e. will I gain or lose QALYs by taking adjuvant therapy?

31. What we need Recurrence Risk Life Expectancy Low High LowHigh DON’T TREAT TREAT ?

32. Our new cancer hospital