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Edith A. Perez, MD Director, Cancer Clinical Study Unit Mayo Clinic Jacksonville, Florida

Welcome and Introductions. Edith A. Perez, MD Director, Cancer Clinical Study Unit Mayo Clinic Jacksonville, Florida. The Early Use of Adjuvant Aromatase Inhibitors for Early Breast Cancer: New Contributions from the BIG 1-98 Letrozole Trial. John F. Forbes, MB, BS, MS, FRACS

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Edith A. Perez, MD Director, Cancer Clinical Study Unit Mayo Clinic Jacksonville, Florida

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  1. Welcome and Introductions Edith A. Perez, MD Director, Cancer Clinical Study Unit Mayo Clinic Jacksonville, Florida

  2. The Early Use of Adjuvant Aromatase Inhibitors for Early Breast Cancer: New Contributions from the BIG 1-98 Letrozole Trial John F. Forbes, MB, BS, MS, FRACS Professor of Surgical OncologyUniversity of NewcastleDirector, Department of Surgical OncologyNewcastle Mater Misericordiae HospitalNewcastle, Australia

  3. Outline • Trial Design • Statistical Analyses • Population • Efficacy Endpoints • Subgroups • Safety • Conclusions • Perspective

  4. BIG 1-98 Worldwide Collaborative 8028 patients enrolled March 1998-May 2003

  5. BIG 1-98 Design R A N D O M I Z E A Tamoxifen B Letrozole C Tamoxifen Letrozole D Letrozole Tamoxifen 0 2 5 YEARS • Compares Letrozole versus Tamoxifen • Letrozole: Arms B and D • Tamoxifen: Arms A and C • Excludes events and FU beyond switch for C & D

  6. BIG 1-98 • New since St. Gallen (January 2005) - Medical review of all cerebrovascular, cardiac, unclear AEs (538 cases) and all deaths without prior cancer event (93 cases) - Overall survival outcome by subgroups - Identification of myalgia and arthralgia AEs • Still to come - Central review of ER, PgR, Her-2 - Update of safety and efficacy - Results of sequential treatment comparisons

  7. Primary Core Analysis 8028 Randomized 18 withdrew consent (no treatment / FU) 8010 Primary Core Analysis versus 4003 L 4007 T 133 (1.66%) ineligible cases included in primary core analysis Median Follow-Up=25.8 months

  8. Patient/Tumor Characteristics Receptor positivity was a study requirement: 99.8% of patients had receptor positive tumors

  9. Primary End Point: DFS Time from randomization to first of: Invasive recurrence in - Ipsilateral breast - Chest wall - Regional site (internal mammary/axilla) - Distant site (including ipsi supraclavicular) Contralateral breast (invasive) Second (non breast) malignancy Death without prior cancer event

  10. Secondary End Points • Overall survival (OS) • Systemic disease-free survival (SDFS)* • Distant disease-free survival (DDFS)** • Safety * Excluding locoregional and contralateral events ** Excluding locoregional and 2nd non-breast cancer

  11. 84.0 81.4 97.7 97.6 95.1 93.4 90.5 89.0 86.8 84.6 Yearly DFS % L Events N HR (95% CI) p 779 8010 0.81 (.70-.93) 0.003 No. at Risk 4003 4007 3892 3896 2964 2926 1261 1238 892 866 567 544 Disease-Free Survival 100 80 T 60 Percent Alive and Disease-Free 40 20 0 0 1 2 3 4 5 Years from Randomization

  12. Cumulative IncidenceBreast Cancer Event 20 5-year diff (L-T) = -3.4% (S.E. 1.2) Cum incidence P=0.0002 13.6% 15 T Proportion Failure (%) L 8.1% 10 10.2% 5 6.2% 0 0 1 2 3 4 5 Years from Randomization

  13. Treatment Failures *Regional includes axilla or internal mammary **SDFS ignores local and contralateral events

  14. Deaths

  15. Protocol Endpoints 0.81 DFS 0.86 OS 0.83 SDFS 0.5 0.75 1.0 1.33 2.0 Favors L Favors T Hazard Ratio (L:T)

  16. Other Endpoints 0.81 DFS 0.86 OS 0.83 SDFS 0.79 DFS (w/o 2nd malignancy) 0.73 Time to distant recurrence 0.72 Time to recurrence 0.5 0.75 1.0 1.33 2.0 Favors L FavorsT Hazard Ratio (L:T)

  17. Sub group Analyses • Subgroup analyses should concentrate on: differences from theaverage overall treatment effect (via tests of heterogeneity or interaction) • It is inappropriate to assess the effects of treatment on a single subgroup by examination of the 95% CI for that subgroup. Cuzick J 1982; Lancet 2005 365:1308

  18. Sub group Analyses Two types of error can occur 1. Attribution of an effect to a subgroup when there is no overall effectand no evidence for heterogeneity (more common) 2. To claim a lack of effect in a subgroup when the overall effect is significant Cuzick J 1982; Lancet 2005 365: 1308

  19. Sub group Analyses • Confidence intervals in subgroups are always wider than those for the main effect because of smaller numbers. • If the interval for a subgroup crosses the no effect point, this is widely misinterpreted as a lack of effect in the subgroup even when the overall effect is significant. • The correct approach is to determine whether the effect size for different subgroups varies significantly from the main effect by a test for heterogeneity. Cuzick J 1982; Lancet 2005 365: 1308

  20. 0.70 CT given (n=2024) 0.85 CT not given (n=5986) 0.71 N-positive (n=3311) 0.99 N-negative (n=4174) 0.84 ER+ / PgR+ (n=5055)* 0.83 ER+ / PgR- (n=1631)* Subgroups - DFS 0.5 0.75 1.0 1.33 2.0 Favors L Favors T Hazard Ratio (L:T) * Based on local assessment

  21. N-positive (n=3311) 0.82 N-negative (n=4174) 0.88 ER+ / PgR+ (n=5055)* 1.00 ER+ / PgR- (n=1631)* 0.79 Subgroup - OS CT given (n=2024) 0.76 CT not given (n=5986) 0.90 0.5 0.75 1.0 1.33 2.0 Favors L Favors T Hazard Ratio (L:T) * Based on local assessment

  22. Summary of Efficacy • Letrozole significantly decreased overall risk of recurrence (19% P=0.003) • Letrozole significantly reduced the risk of distant metastases (27% P=0.0012) • Letrozole was associated with a non significant decreased risk of death (14% P=0.16) • The results are consistent with a similar effect in all subgroups examined

  23. Adverse Events, Any Grade Letrozole Tamoxifen *Grade 1: 35.1% L,17.3% T; Grade 2+:8.5% L, 1.9% T Serial cholesterol levels are being reviewed.

  24. Cardiovascular Events, Grade 3-5

  25. Summary: Cardiovascular Events • Compared with tamoxifen - AIs reduce the risk of thromboembolic adverse events - Adjuvant treatment with AIs has been associated with some increase in the risk of CV events • Current information is conflicting and insufficient to fully determine the longer-term effect of AIs on CV health • It is not possible at present to assign different cardiovascular risk profiles to the individual AIs • Further analyses of ongoing AI trials is required

  26. Bone Fractures

  27. Endometrial Events *Excludes 1717 patients with hysterectomy at baseline

  28. Perspective Interpretation Predictions

  29. EBCTCG 2000 (2005) Mortality EBCTCG 2000 (2005) Recurrence 11.7 HR 0.44 0.74 9.2 0.70 7.9 0.70 3.6 HR Abs RRn 0.64 13.7 0.74 11.8 HR Abs RRn 0.57 10.4 14.8 RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown: 15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+) Lancet May 14 2005

  30. Smoothed hazard rates for recurrence?Start Early or Switch Letrozole: Prevention of early distant relapses Should translate into mortality reduction 3.0 2.5 Annual HR HR+ % 2.0 1.5 1.0 Anastrozole ? Acquired Tamoxifen resistance developing at ~ 2-3 years 0.5 Tamoxifen 0 0 1 2 3 4 5 6 Follow-up time (years)

  31. Fracture rates over time 3 2.5 2 Annual rates % 1.5 1 Anastrozole Tamoxifen 0.5 0 0 1 2 3 4 5 6 Years since randomization Fracture rates per 1000 women years: Anastrozole 22.6; Tamoxifen 15.6; P1 control 18.4; WHI control 19.1

  32. Cross trial Comparisons Cross trial (indirect) comparisons may be unreliable: - Different end-point definitions - Different populations - Different treatments - Non randomised comparisons They should be interpreted with caution both for efficacy and side effects comparisons But they may lead to new hypotheses

  33. Endpoint: ComparisonsBIG 1-98 and ATAC ATAC HR+ 68 mo1 33 mo2 - - 0.81 DFS 0.97 - 0.86 OS - - 0.83 SDFS 0.83 0.78 0.79 DFS (w/o 2nd malignancy) 0.84 - 0.73 Time to distant metastasis (DDFS) 0.74 0.73 0.72 Time to recurrence 0.5 0.75 1.0 1.33 2.0 Favors LET Favors TAM 1. Lancet. Jan 7, 2005. 2. Lancet. June 22, 2002. Hazard ratio (LET:TAM)

  34. Subgroups: OS CT given (n=2024) 0.76 CT not given (n=5986) 0.90 N-positive (n=3311) 0.82 N-negative (n=4174) 0.88 ER+ / PgR+ (n=5055)* 1.00 ER+ / PgR- (n=1631)* 0.79 0.5 0.75 1.0 1.33 2.0 Favors L Favors T Hazard Ratio (L:T) * Based on local assessment

  35. Anastrozole(A) Tamoxifen(T) Retrospective analysis of time to recurrence for ER/PgR subgroups Patient group HR+ ER+PgR+ ER+PgR- Hazard ratio 0.79 0.84 0.43 25 20 ER+/PgR- 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 451 435 417 400 390 347 124 T 429 412 375 353 327 276 96

  36. Protective Effect of Tamoxifenon cholesterol? • Cardiovascular risk substantially and progressively increases in women age >65 (Framingham study)1 • The cardio protective effect of tamoxifen has been studied in several trials • The data are conflicting, some studies showed a cardio protective effect2-4, others did not5. 1) http://www.nhlbi.nih.gov/about/framingham/index.html; 2) McDonald CC et al.: BMJ 1995;311:977–80; 3) Rutqvist LE et al.:J Natl Cancer Inst 1993;85:1398–406, 4) Bradbury BD et al, Cancer March 2005, 5) Reis SE et al.; J Natl Cancer Inst 2001, Vol 93, No 1, Jan 3:16-21

  37. EBCTCG 2000 (2005) Mortality EBCTCG 2000 (2005) Recurrence 11.7 HR 0.44 0.74 9.2 0.70 7.9 0.70 3.6 HR Abs RRn 0.64 13.7 0.74 11.8 HR Abs RRn 0.57 10.4 14.8 RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown: 15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+) Lancet May 14 2005

  38. Questions and Answers

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