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Paul E. Goss, MD, PhD Director of Breast Cancer Research

Preventing Relapse Beyond 5 Years: The MA.17 Extended Adjuvant Trial. Paul E. Goss, MD, PhD Director of Breast Cancer Research Massachusetts General Hospital Cancer Center Professor of Medicine Harvard Medical School Boston, Massachusetts.

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Paul E. Goss, MD, PhD Director of Breast Cancer Research

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  1. Preventing Relapse Beyond 5 Years: The MA.17 Extended Adjuvant Trial Paul E. Goss, MD, PhD Director of Breast Cancer Research Massachusetts General Hospital Cancer Center Professor of Medicine Harvard Medical School Boston, Massachusetts

  2. Antagonizing Estrogen-Dependent Breast Cancer Growth Postmenopausal Ovaries Fat tissue Tumor and peritumoral cells LH/FSH inhibitor Aromatase inhibitor Estrogen Exogenous estrogen Tamoxifen X • Resistance develops • Growth can be stimulated by tamoxifen • Endometrial cancer • DVT/PE LH/FSH = luteinizing hormone/follicle/stimulating hormone; DVT/PE = deep veinthrombosis/pulmonary embolism.

  3. More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen Recurrence Breast Cancer Mortality 60 60 50 50 45.0 38.3 40 40 34.8 26.5 30 30 33.2 Breast Cancer Mortality (%) Recurrence (%) 25.7 25.6 24.7 20 20 11.9 17.8 15.1 15-year gain 11.8% (SE 1.3) Logrank 2p<0.00001 10 10 15-year gain 9.2% (SE 1.2) Logrank 2p<0.00001 8.3 0 0 0 5 10 15 0 5 10 15 Years Years Control About 5 years of tamoxifen Early Breast Cancer Trialists Collaborative Group. The Lancet. Vol 365 May 14, 2005.

  4. Greater Absolute Risk Reduction With Tamoxifen in Node + vs Node - Disease Early Breast Cancer Trialists Collaborative Group Lancet 2005; 365:168

  5. Relapse-Free Survival Decreases Consistently Regardless of ER/PgR Status N- and N+ Patients 1.0 0.9 ER/PgR– (n=430) 0.8 Proportion disease-free 0.7 0.6 ER+ and/or PgR+ (n=778) 0.5 P<0.001 0.4 5 10 15 20 Years postdiagnosis • Late recurrences (>5 years) were more frequent in ER+ and/or PgR+ tumors Hortobagyi et al. Proc Am Soc Clin Oncol. 2004;23:23. Abstract 585.

  6. NSABP B-14: No Benefit of Extending Tamoxifen for 7 Years Beyond the Initial 5 Years • Tamoxifen demonstrated higher rates of endometrial cancer, ischemic heart disease, and cerebrovascular disease. Disease-Free Survival Survival 100 100 94% 90 90 91% 82% 80 P=0.07 80 P=0.03 % Surviving disease-free % Surviving 78% 70 70 Placebo Tamoxifen Placebo Tamoxifen 60 60 50 50 5 10 12 5 10 12 Years Years Fisher et al. J Natl Cancer Inst. 2001;93:684.

  7. Letrozole better Tamoxifen better Subgroup Viscera Bone Soft tissue Rec. unknown Rec. positive No antiestrogen Post Tam Whole study 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Hazard ratio Letrozole vs Tamoxifen in First-line Metastatic Breast Cancer Mouridsen et al. J Clin Oncol. 2003;21:2101.

  8. Extended Adjuvant Therapy: Letrozole (LET) Following 5 Years of Tamoxifen • >5 y of tamoxifen believed to add no benefit • Recurrence after tamoxifen is ~2% and ~4% per annum in node –ve and +ve pts, respectively • Late recurrences (>5 years) were more frequent in ER+ and/or PgR+ tumors • LET after tamoxifen shrinks existing tumors/ prevents tumors in animal models • LET after tamoxifen induces remissions in advanced breast cancer

  9. MA.17: Trial Design Randomization (all patients disease-free) 0-3months Letrozole 2.5 mg qd* n=2582 Tamoxifen Placebo qd† n=2586 Approx. 5 years adjuvant 5 years extended adjuvant Primary end point: DFS Secondary end points: OS/safety/QOL/rate of contralateral breast cancerSubstudies: BMD/bone markers, lipid profile *n=2582 (efficacy), 2563 (safety); †n=2586 (efficacy), 2573 (safety). QOL = quality of life; BMD = bone mineral density. Adapted from Goss et al. ASCO, 2004. Abstract 847 and slide presentation; and N Engl J Med. 2003;349:1793.

  10. MA.17: Primary End Point • Disease-free survival • Recurrence in • Ipsilateral breast • Chest wall • Locoregional nodal • Metastatic sites • Occurrence of contralateral new primary breast cancer Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  11. MA.17: Secondary End Points • Overall survival • Rate of contralateral breast cancer • Long-term safety/tolerability • Lipid profile • Cardiovascular morbidity/mortality • Bone fractures/BMD • Clinical/laboratory • QOL SF-36/MENQOL SF-36 = 36-item short-form health survey;MENQOL = menopause-specific quality of life questionnaire. Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  12. MA.17: Eligibility Criteria • Patients enrolled • Postmenopausal • ER+ and/or PgR+ or both unknown • Node–, node+, or node-unknown • Completed 4.5-6 years of initial tamoxifen • No evidence of recurrent cancer • ECOG PS 0-2 ER = estrogen receptor; PgR = progesterone receptor; ECOG = Eastern Cooperative Oncology Group; PS = performance status. Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  13. MA.17: Statistical Assumptions • Primary end point (DFS) • To detect an improvement in DFS of 22%, equivalent to reducing the estimated risk of relapse at 4 years by 2.5% (12%-9.5%) • Interim analyses • Prospectively planned at 171 and 342 events • Stopping boundary nominal significance, P=0.0008

  14. 5 Preplanned Subset Analyses • Tumor receptors +ve, unknown • Lymph node status +ve, –ve, unknown • Prior chemo Y/N • Menopausal status at start of tamoxifen • Prior tamoxifen < or > 5 years

  15. Interim Analysis (NEJM) DFS events: 207 Deaths: 73 No. of pts at 40 months: 384 Median follow-up: 2.4y Final Analysis (Publication Pending) DFS events: 247 Deaths: 113 No. of pts at 40 months: 1115 Median follow-up: 2.5y MA.17: Final Analysis Toxicity - Efficacy 2003 March Aug Oct 1998 2003 2004

  16. MA.17: Patient Demographics

  17. Disease-Free Survival in All Patients: Significant 42% Reduction in Relative Risk 100 80 60 Percent P=0.00004 Letrozole 40 Placebo 20 0 0 10 20 30 40 50 60 Months No. at risk: Letrozole 2583 2497 1905 1110 541 176 6 Placebo 2587 2489 1874 1075 519 164 8 Adapted fromGoss et al. ASCO, 2004. Abstract 847 and slide presentation.

  18. MA.17: DFS by Treatment Duration— Increasing Benefit With Treatment Duration % of Patients Letrozole Placebo(n=2582) (n=2586) Year Abs diff (%) 1 98.597.9 2 96.9 95.4 3 95.7 92.2 4 94.35 89.84 4.5 (CI, 2.1-6.9) Node – 96.3 93.6 2.7 Node + 92.3 84.8 7.5 Overall P=0.00004 Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  19. MA.17: Total Recurrences of Breast Cancer 175 155 Node+ Node– 150 125 Distant 102 Locoregional 94 92 100 New primary only No. of events 75 63 74 57 50 50 33 39 20 23 18 25 14 18 14 13 28 3 17 14 12 10 7 0 Placebo Letrozole Placebo Letrozole Placebo Letrozole Adapted fromGoss et al. ASCO, 2004. Abstract 847 and slide presentation.

  20. MA.17: Distant DFS—Letrozole Significantly Reduced the Risk of Distant Metastases by 40% Distant DFS: All Patients 100 80 P=0.002 60 % Disease-free 40 Letrozole Placebo 20 0 0 10 20 30 40 50 60 Months No. at risk: Letrozole 2583 2497 1905 1110 541 176 6 Placebo 2587 2489 1874 1075 519 164 8 Adapted fromGoss et al. ASCO, 2004. Abstract 847 and slide presentation.

  21. MA.17: Overall Survival—All Patients 100 80 P=0.30 60 % Surviving 40 Letrozole Placebo 20 0 0 10 20 30 40 50 60 Months No. at risk: Letrozole 2583 2523 1937 1138 556 182 6 Placebo 2587 2522 1928 1130 559 175 8 Adapted fromGoss et al. ASCO, 2004. Abstract 847 and slide presentation.

  22. MA.17: Overall Survival—Letrozole Decreased Mortality by 39% in Node-Positive Patients Node+ Node– 100 100 80 80 60 60 P=0.04 P=0.24 % Surviving % Surviving 40 40 Letrozole Letrozole 20 Placebo 20 Placebo 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Months Months While OS was not improved in node– patients, a similar reduction in local recurrences, new primaries, and distant recurrences occurred as in the node+ patients Adapted fromGoss et al. ASCO, 2004. Abstract 847 and slide presentation.

  23. Summary of Key End Points in Nodal Subgroups HR=1.52 (0.76-3.06) HR=0.45 (0.27-0.75) HR=0.63 (0.31-1.27) Node* –ve Node –ve Node –ve DistantDFS DFS* OS Node* +ve Node* +ve Node* +ve HR=0.61 (0.45-0.84) HR=0.61 (0.38-0.98) HR=0.53 (0.36-0.78) *Statistically significant.

  24. Letrozole: Effects on Women’s Health 1. Breast cancer Estrogen 2. End-organ and QOL Bone metabolism Lipid metabolism/CVD Thromboembolism/CVD Cognitive function Endometrial cancer Urogenital function Vasomotor symptoms Other cancers Other 800 Pmol/L ERT/HRT 200 Normal levels Aromatase inhibition Premenop Postmenop

  25. MA.17: Incidence of Adverse Events* (All Grades) *90% of AEs grade 1 or 2. Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  26. MA.17: Number of Patients Who Experienced Osteoporosis or Bone Fractures 209 200 (8%) Letrozole 155 Placebo 150 (6%) 137 119 (5.3%) No. of patients (4.6%) 100 50 0 New osteoporosis* Bone fractures* (P=0.003) (P=0.25) *Patient-reported. Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  27. MA.17: Bone Companion Trial Design(N=226) BMD Bone biomarkers Serum bone ALK phos Serum C-telopeptide Urine N-telopeptide 0 1 2 3 4 5 Year Letrozole 0-3months n=113 Tamoxifen Placebo n=113 Perez et al. SABCS, 2004. Abstract 404.

  28. MA.17 Bone Companion Trial: 2-Year Results • Percent change from baseline BMD in LS and TH after 2 y; osteoporosis documented by DEXA scan (unlike MA.17) • LS BMD, LET vs PLC: −5.35% vs −0.7% (P=0.008) • Reported osteoporosis (3.3% vs 0%; P=0.126) • TH BMD, LET vs PLC: −3.60% vs −0.71% (P=0.044) • No patient went below the absolute threshold for osteoporosis(≤−2.5 SD below peak bone mass) • Documented osteoporosis less than patient-reported (MA.17) • Difference in fracture rates not significant (LET: 1.65%; PLC: 6.73%; P=0.08) • Urine N-telopeptide significantly higher with LET at 1 and 2 years LS = lumbar spine; TH = total hipLET = letrozole; PLC = placebo. Update of Perez et al. Breast Cancer Res Treat. 2004;88(suppl 1):S36. Abstract 404.

  29. MA.17 Lipid Substudy (MA.17L) Trial Design Randomization (All patients disease-free) • 347 patients enrolled • 37 ineligible patients – (33 hyperlipidemic at baseline, 4 protocol violations) • Closed for accrual May 2002 0-3months Letrozole 2.5 mg qd* n=183 Tamoxifen Placebo qd† n=164 ~5 years adjuvant 5 years extended adjuvant Wasan et al. Ann Oncol. Epub ahead of print, April 7, 2005.

  30. MA.17L: Results • Letrozole did not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, or lipoprotein (a) compared with placebo in patients treated for up to 36 months following approximately 5 years of adjuvant tamoxifen Wasan et al. Ann Oncol. Epub ahead of print, April 7, 2005.

  31. MA.17: Efficacy Conclusions • LET significantly reduced the risk of recurrences (43%) regardless of nodal status and prior chemotherapy • LET significantly reduced the risk of distant metastases by 40% compared with placebo • LET reduced occurrences (37.5%) of new contralateral breast cancers • LET significantly improved OS in node-positive patients • OS was not improved in node-negative patients but a similar degree of reduction in local recurrences, new primaries, and distant recurrences occurred as in the node-positive patients

  32. MA.17: Safety and Tolerability Conclusions • Predictable but mild E2 deficiency symptoms occurred • Global QOL was unaffected; mild QOL changes were noted related to reported menopausal symptoms and joint and muscle pains • Bone metabolism was affected by LET as indicated by a minimal increase in osteoporosis detected over 4 years,but no significant difference in clinical fractures occurred • Evaluation of longer-term toxicities will be determined from MA.17 follow-up and re-randomization including sub-studies

  33. 2004 ASCO Guidelines on AIs in Postmenopausal Women With HR+ Breast Cancer • Optimal adjuvant therapy should include an AI as initial therapy or after treatment with tamoxifen in order to lower the risk of tumor recurrence • AIs are appropriate as initial treatment for women with contraindications to tamoxifen • For all other postmenopausal women, treatment options include 5 years of AI treatment or sequential therapy consisting of tamoxifen (for either 2-3 years or 5 years) followed by AIs for 2-3, to 5 years • Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options Winer et al. J Clin Oncol. 2004. Epub ahead of print.

  34. MA.17 Rerandomization Trial Tamoxifen Letrozole Placebo (n=900) (n=900) MA.17 MA.17 Extension 0 5 10 15 Years • As of May 2005, 81 patients have been re-randomized to MA.17R Goss et al. ASCO, 2004. Abstract 847 and slide presentation.

  35. Questions and Answers

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