1. SELECT: Selenium and Vitamin E Cancer Prevention Trial

2. Rationale for SELECT Study Supplements chosen based on secondary results for prostate cancer from other randomized controlled trials –63% risk reduction for selenized yeast (NPC) –32% risk reduction for α-tocopherol (ATBC) –Reduction in cancer mortality for combination of selenium, vitamin E and beta carotene (Nutrition intervention trials in Linxian, China) Results supported by epidemiologic and preclinical data

3. SELECT Schema Calendar Year 2001 - 2013 Randomized Pre-Randomization Period Follow - up Prostate cancer, other cancer, death Placebo + Selenium Placebo + Placebo Vitamin E + Placebo Vitamin E + Selenium Calendar Year 2001 – 2004 (Planned 2001 – 2006)

4. SELECT Study Supplements Selenium 200 μg/d from L-selenomethionine or matched placebo Vitamin E 400 IU/d all rac-α-tocopheryl acetate or matched placebo

5. Eligibility Criteria Age of ≥ 50 if African American, ≥55 otherwise Prostate health –No prior prostate cancer or high-grade PIN –PSA ≤ 4.0 ng/ml and DRE not suspicious for cancer within 1 year prior to randomization Concurrent supplements –Must not be taking, or planning to take, any vitamin E or selenium in addition to the Study Supplements

6. Eligibility Criteria Other health –No prior history of cancer (except basal and squamous cell skin cancers) unless no evidence of disease for at least 5 years –No current use of anticoagulant therapy other than <175 mg/day of aspirin or if taking Plavix < 81 mg/day –No history of hemorrhagic stroke; normal BP (SBP < 160 mm/Hg, DBP < 90 mm/Hg) –No diagnosis of retinitis pigmentosa

7. Statistical Elements Double-blind placebo-controlled Intent-to-treat analysis Time-to-event analysis for prostate cancers, other cancers, deaths –Cox model, Hazard rates Overall incidence rate for cardiovascular, diabetes, other adverse events –Χ 2 test, Relative risk

8. Follow-Up Schedule Followed twice yearly for men without prostate cancer, annually for those with prostate cancer Adherence and adverse event data collected every 6-months Annual limited physical exam including assessment of blood pressure, weight, smoking status –DRE and PSA per Study Site standard of care

9. Study Duration Assumed: 5 year uniform accrual Actual: 3 year accrual Follow-up: until unique calendar date Supplementation stopped in 2008

10. DSMC Recommendation On September 15, 2008, the independent SELECT DSMC met and made the recommendation to discontinue study supplementation –No evidence of benefit for prostate cancer incidence –Planned reduction in prostate cancer incidence extremely unlikely in all arms and would not be seen within the timeframe of the trial (p<.0001)

11. Eligibility Status Placebo (n=8856) Vitamin E (n=8904) Selenium (n=8910) Combination (n=8863) Excluded from Primary Analysis Participants from 2 sites removed due to poor site performance 155156155 Prior prostate cancer 1512 Randomized in error 4623 Included in Primary Analysis 8696 (98%) 8737 (98%) 8752 (98%) 8703 (98%)

12. Eligibility Status Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Clinically ineligible 134(1%) 128(1%) 113(1%) 113(1%) Insufficient baseline data 154(2%)151(2%)166(2%)169(2%)

13. Follow-Up Status Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Number On or Temporarily Off 7903791379527917 Median FU (yrs)5.46 Time since last contact 0 – 7 months 6913(87%)6910(88%)6925(87%)6978(88%) 7.1 – 13 months362(5%)382(4%)369(5%)337(4%) 13.1 – 19 months136(2%)149(2%)149(2%)148(2%) 19.1 – 24 months72(1%)87(1%)75(1%)75(1%) > 24 months420(5%)385(5%)434(5%)379(5%)

14. Follow-Up Status Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Endpoint reached793824800786 Number on or temporarily off supplements 7903791379527917 Median FU (yrs)5.46 Time since last contact 0 – 7 months 6913(87%)6910(88%)6925(87%)6978(88%) 7.1 – 13 months362(5%)382(4%)369(5%)337(4%) 13.1 – 19 months136(2%)149(2%)149(2%)148(2%) 19.1 – 24 months72(1%)87(1%)75(1%)75(1%) > 24 months420(5%)385(5%)434(5%)379(5%)

15. Baseline Characteristics Age Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Age (years) Median (Inter-quartile range) 62.6 (58.1 – 67.8) 62.3 (58.0 – 67.8) 62.6 (58.2 – 68.0) 62.4 (58.1 – 67.8) 50 – 543554%4025%3374%3854% 55 – 64507858%514359%507658%505258% 65 – 74270231%264130%273331%273131% ≥ 755616%5516%6067%5356%

16. Baseline Characteristics Race/Ethnicity Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Race/Ethnicity White686379%689079%694279%687479% African American107812%110713%105312%107612% Hispanic (non- African American) 4926%4775%4815%4846% Hispanic (African American) 761%1031%861%951% Other1872%1602%1902%1742%

17. Baseline Characteristics PSA Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) PSA, ng/ml 0.1 – 1.0412247%420848%421848%421348% 1.1 – 2.0272831%265330%266130%266631% 2.1 – 3.0116813%122814%121114%114913% 3.1 – 4.06668%6347%6527%6598% > 4.05<1%3 2 1 Unknown/missing7<1%11<1%8 15<1%

18. Baseline Characteristics Smoking Status Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Smoking Status Never368242%375243%378043%366642% Current6558%6598%6317%6708% Former420848%419448%421448%424249% Ever (current status unknown) 631%551%611%561% Unknown881%771%661%691%

19. Baseline Characteristics Education Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Education (highest level) ≤ High school grad or GED 199323%187522%191722%189822% Some college or vocational school 229126%238727%232727%234827% ≥ College graduate431750%439451%443051%437250% Unknown/missing951%811%781%851%

20. Adherence

21. Serum Selenium (μg/L) Data from the adherence cohort

22. α-tocopherol (μg/mL)* * Cholesterol-adjusted; Participants from adherence cohort

23. γ -tocopherol (μg/mL)* * Cholesterol-adjusted; Participants from adherence cohort

24. Drop-Ins

25. Prostate Cancer Incidence Per Study Design* and Actual * PCPT rates for years 1 – 3 and 1995 SEER rates thereafter.

26. Prostate Cancers Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) Total416473432437 5-year incidence 4.43%4.93%4.56% HR (99% CI) 1.00 1.13 (0.95 – 1.35) 1.04 (0.87 – 1.24) 1.05 (0.88 – 1.25) p - value---p = 0.06p = 0.62p = 0.52

27. Prostate Cancers 99% CI 0.95 – 1.35 p=0.06 99% CI 0.87 – 1.24 p=0.62 99% CI 0.88 – 1.25 p=0.52

28. Prostate Cancer Placebo Vitamin E Selenium Vitamin E + selenium

29. Prostate Cancer Method of Diagnosis Placebo (n=416) Vitamin E (n=473) Selenium (n=432) Combination (n=437) Diagnosed by biopsy40497%45897%41997%42096% Number of biopsies10201011982997 Reason for Biopsy (positive biopsies) Elevated PSA25964%32471%29671%26363% PSA Velocity123%102%133%164% Abnormal DRE6616%5813%4611%5613% PSA + DRE5514%4911%5613%7217%

30. Prostate Cancer - Gleason Score Placebo (n=416) Vitamin E (n=473) Selenium (n=432) Combination (n=437) Number graded365396361365 Gleason Score 2 - 624066%24963%21760%22060% 7 (3+4)8022%9724%105299125% 7 (4+3)216%277%195%247% 8 - 10247%236%206%308%

31. Prostate Cancer - Clinical Stage Placebo (n=416) Vitamin E (n=473) Selenium (n=432) Combination (n=437) T-Stage T1 a-c27870%34375%30173%28669% T2 a-b12230%11425%10826%12831% T3 a-b00%2 51%3 N-Stage N0109100%127100%12599%117100% N100%0 11%00% M-Stage M0124100%13499%12296%11998% M1a-b00%21%54%22%

32. Annual PSA Tests

33. Annual DRE Tests

34. Other Cancers Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) Any cancer (including prostate) 824 1.00 856 1.03 (0.91 – 1.17) 837 1.01 (0.89 – 1.15) 846 1.02 (0.90 – 1.16) Lung 67 1.00 67 1.00 (0.64 – 1.55) 75 1.12 (0.73 – 1.72) 78 1.16 (0.76 – 1.78) Colorectal 60 1.00 66 1.09 (0.69 – 1.73) 63 1.05 (0.66 – 1.67) 77 1.28 (0.82 – 2.00) Other primary 306 1.00 274 0.89 (0.72 – 1.10) 292 0.95 (0.77 – 1.17) 290 0.94 (0.76 – 1.16) All p-values > 0.15

35. Total Cancers 99% CI 0.91 – 1.17 99% CI 0.89 – 1.15 99% CI 0.90 – 1.16

36. Lung CancerColorectal Cancer All Other Primary CancersDeaths Placebo Vitamin E Selenium Vitamin E + selenium

37. Cumulative Death Rate Per Study Design* and Actual * Estimated for placebo arm based on PCPT for the first 4 years and then adjusted upwards to 1995 US rates for all races combined.

38. Deaths Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N HR N HR (99% CI) N HR (99% CI) N HR (99% CI) All deaths 382 1.00 358 0.93 (0.77 – 1.13) 378 0.99 (0.82 – 1.19) 359 0.94 (0.77 – 1.13) Cancer deaths 125 1.00 106 0.84 (0.60 – 1.18) 128 1.02 (0.74 – 1.41) 117 0.93 (0.67 – 1.30) Cardiovascular deaths 142 1.00 119 0.84 (0.61 – 1.15) 129 0.91 (0.66 – 1.24) 117 0.82 (0.60 – 1.13) Other deaths 115 1.00 133 1.15 (0.83 – 1.60) 121 1.05 (0.75 – 1.47) 125 1.08 (0.78 – 1.51)

39. Cardiovascular Events Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) All Cardiovascular events* 1050 1.00 1034 0.98 (0.88 – 1.09) 1080 1.02 (0.92 – 1.13) 1041 0.99 (0.89 – 1.10) * Grades 3 – 5 (includes deaths)

40. Cardiovascular Events Non-fatal Strokes Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) Hemorrhagic 11 1.00 7 0.63 (0.18 – 2.20) 11 0.99 (0.33 – 2.98) 12 1.09 (0.37 – 3.19) Ischemic 56 1.00 49 0.87 (0.51 – 1.44) 51 0.90 (0.55 – 1.49) 67 1.20 (0.75 – 1.90) NOS 25 1.00 14 0.56 (0.24 – 1.32) 11 0.44 (0.17 – 1.11) 20 0.80 (0.37 – 1.73)

41. Cardiovascular Events Other Non-fatal Events Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) Grade 3 626 1.00 642 1.02 (0.89 – 1.17) 685 1.09 (0.95 – 1.25) 624 1.00 (0.87 – 1.15) Grade 4 190 1.00 203 1.06 (0.82 – 1.38) 193 1.01 (0.78 – 1.31) 201 1.06 (0.82 – 1.37)

42. Diabetes Diagnoses Placebo (n=7156) Vitamin E (n=7215) Selenium (n=7210) Combination (n=7248) Number (%)669 (9.3%)700 (9.7%)724 (10.0%)660 (9.1%) Relative Risk (99% CI) 1.00 1.04 (0.91 – 1.18) 1.07 (0.94 – 1.22) 0.97 (0.85 – 1.11) p-value--p = 0.47p = 0.16p = 0.61 Based on self-report of diabetes or reported use of diabetes medications of the glitazone class. Excludes prevalent cases at randomization (n=3625) and participants not evaluated for diabetes because they either died or were lost to follow-up prior to the assessment (n=2434).

43. Events Known to Be Associated with Study Supplements Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) Alopecia 206 1.00 220 1.06 (0.83 – 1.36) 265 1.28 (1.01 – 1.62) 238 1.15 (0.91 – 1.47) Dermatitis Grades 1 – 2 516 1.00 591 1.14 (0.98 – 1.32) 605 1.17 (1.00 – 1.35) 554 1.07 (0.92– 1.25) Grades 3 – 4 8 1.00 12 1.49 (0.46 – 4.83) 14 1.74 (0.56 – 5.44) 16 2.00 (0.66 – 6.09) = p < 0.01

44. Events Known to Be Associated with Study Supplements Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) Halitosis 427 1.00 493 1.15 (0.97 – 1.36) 503 1.17 (0.99 – 1.38) 531 1.24 (1.06 – 1.46) Nail changes 1035 1.00 1041 1.00 (0.90 – 1.11) 1087 1.04 (0.94 – 1.26) 1075 1.04 (0.93 – 1.15) = p < 0.01

45. Events Known to Be Associated with Study Supplements Placebo (n=8696) Vitamin E (n=8737) Selenium (n=8752) Combination (n=8703) N RR N RR (99% CI) N RR (99% CI) N RR (99% CI) Fatigue Grades 1 – 2 586 1.00 604 1.03 (0.89 – 1.19) 645 1.09 (0.95 – 1.26) 612 1.04 (0.90– 1.20) Grades 3 – 4 24 1.00 29 1.20 (0.59 – 2.45) 21 0.87 (0.40 – 1.88) 20 0.83 (0.38 – 1.81) Nausea Grades 1 – 2 203 1.00 191 0.94 (0.72 – 1.21) 244 1.19 (0.94 – 1.52) 202 0.99 (0.77– 1.28) Grade 3 9 1.00 3 0.33 (0.06 – 1.85) 9 0.99 (0.30 – 3.34) 8 0.89 (0.25 – 3.10)

46. Study Strengths Robust statistical design –Ample power for 5 comparisons between arms –Very large study population, including African Americans –Baseline characteristics well balanced –Design assumptions largely met Rigorous implementation –SELECT Workbench –Web-based forms with detailed edit checks –Semi-annual staff training; targeted mentoring

47. Study Limitations Not designed to test different supplement formulations and doses Unable to assess effects in reducing advanced or fatal prostate cancer –Active annual screening reduced incidence of advanced disease across all study arms Unable to assess effects in a vitamin E and/or selenium deficient population –Study population well-nourished at baseline

48. Conclusion SELECT has definitively demonstrated that, in these doses and formulations, selenium, vitamin E, and selenium + vitamin E do not prevent prostate cancer in the generally healthy, heterogeneous population of men in SELECT.

49. Other Findings No difference in rates of lung, colon or other primary cancers No differences in deaths

50. Other Findings Vitamin E: Statistically nonsignificant increase in prostate cancer (HR 1.13, 99% CI 0.95 – 1.35, p=.06) Selenium: Statistically nonsignificant increase in type 2 diabetes mellitus (RR 1.07, 99% CI 0.94 – 1.22, p=.16) Neither difference seen in vitamin E + selenium group

51. Vitamin E: Why Not a Positive Finding? Dose –The higher dose (400 IU/day) may be less effective than the lower dose (50 IU/day) –Effect on suppression of γ-tocopherol may be greater with the higher dose Population – Vitamin E may be most effective in smokers; SELECT population is only 7.5% smokers compared to ATBC which was 100% Inherent problems with secondary/exploratory findings of other trials; it’s why we do carefully controlled trials to answer the question

52. Selenium: Why Not a Positive Finding? Formulation –l-selenomethionine was chosen over high-selenium yeast –Selenomethionine is the major component of the high- selenium yeast –Pilots showed large batch-to-batch variation in the yeast Population – Prior study had men chosen because they were deficient in selenium; selenium was most protective in those with the lowest levels – Our population were replete in baseline selenium Inherent problems with secondary/exploratory findings of other trials; it’s why we do carefully controlled trials to answer the question