1. Treatment Options for Postmenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Recent Trials and Future Directions Harold Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School

2. Key Issues

3. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Unanswered Questions  Duration of aromatase inhibitor (AI) therapy  Sequencing of aromatase inhibitor and tamoxifen  Treatment beyond 10 years?  Are all the aromatase inhibitors the same?  Long-term safety

4. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Initial diagnosis2-3 years after Tam 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Points ? ? ? ? ?

5. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Decision Points: Initial Therapy MA.27R Z1031 TEAM ? ? ? ? Initial diagnosis2-3 years after Tam 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years

6. NCIC MA.27

7. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies  Postmenopausal women  Histologically or cytologically confirmed, receptor-positive, adequately excised, primary breast cancer N = 6350* 5 years Exemestane 25 mg/day Anastrozole 1 mg/day Surgery ± RT ± chemo- therapy MA.27: Study Design Randomization *Closed to accrual.

8. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies MA.27  Randomized, phase III trial in postmenopausal women with receptor-positive primary breast cancer  Eligible patients have completely resected, histologically confirmed invasive breast cancer –Primary tumor is ER positive and/or PgR positive  Planned sample size: 5800 (90% power) –6350 accrued; study closed  Primary endpoint: event-free survival  Secondary endpoints: –Overall survival, time to distant recurrence, incidence of contralateral breast cancer, long-term clinical and laboratory safety

9. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Correlative Studies: MA.27 Bone  MA.27 patients who have a bone mineral density measurement (using dual energy x-ray absorptiometry [DEXA]) done within 12 weeks prior to randomization to the MA.27 core protocol  Eligible patients will be stratified according to their baseline bone mineral density measurement –Group A: BMD T-score > -2.0 SD of the mean value of peak bone mass in young normal women –Group B: BMD T-score < -2.0 SD of the mean value of peak bone mass in young normal women  Patients in group B must agree to begin bisphosphonate therapy at the time of registration to this study; specific bone biomarkers will be followed  Sample size: 408 eligible women

10. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies MA.27D: Changes in Breast Density  Objective: To investigate whether changes in breast density while on aromatase inhibitors are predictive of local recurrence of breast cancer and/or new primary contralateral breast cancer  Design: Within the MA.27 core protocol, obtain preregistration mammogram films –Nested case-control analysis in Year 5 of the study –To evaluate whether changes in breast density predict local recurrence of breast cancer and future contralateral breast cancer

11. ACOSOG Z1031 Neoadjuvant Therapy

12. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Randomization Anastrozole 1 mg qd Exemestane 25 mg qd Letrozole 2.5 mg qd Postmenopausal women (N = 375) Stage II or III ER positive Surgery Follow-up for 10 years, replace with standard endocrine therapy 16-18 weeks Z1031: Design

13. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies  Primary endpoint: response rate  Eligibility –Patients with T2-T4a-c, any N, M0 breast cancer –Patients must agree to undergo mastectomy or lumpectomy after neoadjuvant hormonal therapy  Exclusion criteria –Patients with inflammatory breast cancer –Patients who have received any prior treatment for breast cancer –Patients must not have had any hormone replacement therapy, megestrol acetate, or raloxifene within 1 week prior to study registration Z1031: Background

14. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Sequencing  Optimal sequencing: Studies have shown with remarkable consistency that incorporation of AI therapy has advantages over tamoxifen  However, no studies have directly compared 2-3 years of tamoxifen vs an AI as primary treatment for early-stage breast cancer –Laboratory models suggest that tamoxifen exposure might somehow prime the tumor

15. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies TEAM  Phase III, open-label, randomized trial of 5 years’ adjuvant exemestane vs adjuvant tamoxifen followed by exemestane  Postmenopausal women with hormone receptor– positive, early-stage breast cancer  Sample size = 1240; closed to accrual

16. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies ? BIG 1-98 ? ? ? Initial diagnosis2-3 years after Tam 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years Decision Point: 2-3 Years After Tamoxifen

17. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Tamoxifen 20 mg Tamoxifen n = 1530 Randomization 0 5 Years 2 (Following complete tumor resection) Tamoxifen 20 mg n = 2446 Letrozole 2.5 mg n = 2446 Letrozole n = 1530 Letrozole 2.5 mg Accrual interval: 3/98-5/03 Complete accrual: 8028 pts Companion Studies  Lipid metabolism  BMD Primary Endpoints  Disease-free survival  Overall survival BIG 1-98 Trial: Crossover Arms Letrozole vs Tamoxifen

18. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Decision Point: After 5 Years ? NSABP B-42 ? ? ? Initial diagnosis2-3 years after Tam 5 years after Tam or AI Beyond 10 years? Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years

19. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies AI x 5 yrs AI x 3-2 yrs Tam x 2-3 yrs Letrozole x 5 yrs Placebo x 5 yrs Letrozole vs placebo after 5 years; not yet enrolling NSABP B-42: Study Design

20. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Decision Point: After 10 Years ? ? ? ? MA.17R Tamoxifen Aromatase inhibitor 5 years total10 years total> 10 years

21. NCIC MA.17R

22. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Primary endpoint: DFS Secondary endpoints: OS/safety/QoL *n = 2575 (efficacy); 2154 (safety) in the letrozole arm. † n = 2582 (efficacy); 2145 (safety) in the placebo arm. Randomization (Disease-free) Tamoxifen Placebo qd † Letrozole 2.5 mg qd* 5 years’ early adjuvant5 years’ extended adjuvant Goss P, et al. N Engl J Med. 2003;349:1793-1802. MA.17: Original Design

23. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Primary endpoint: DFS Secondary endpoints: OS, incidence of contralateral breast cancer, long-term clinical and laboratory safety, overall QoL, menopausal QoL MA.17R: Design Rerandomization (Disease-free) Letrozole Placebo qd Letrozole 2.5 mg qd 5 years’ early adjuvant5 years’ extended adjuvant

24. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies MA.17R: Eligibility  Eligible patients must be free of recurrent breast cancer and have completed letrozole no more than 6 months prior to rerandomization  Bone mineral density measured by DEXA should be done within 4 weeks prior to rerandomization if not done within the previous 12 months, but the results do not affect eligibility

25. Ductal Carcinoma In Situ

26. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Results of NSABP B-24  Pivotal trial that looked at the role of endocrine therapy in patients with DCIS  Patients received lumpectomy and radiation therapy followed by either tamoxifen or a placebo  Adding tamoxifen to standard treatment reduced the risk of recurrence by approximately one half –Lower risk of ipsilateral breast cancer –Secondary benefit: lower risk of contralateral breast cancer

27. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies NSABP B-35: Study Design Randomization Tamoxifen 20 mg/day + placebo + breast radiation Anastrozole 1 mg/day + placebo + breast radiation 5 years  Postmenopausal women  DCIS treated by lumpectomy  Hormone-receptor positive by IHC  Stratified by < 60 years or ≥ 60 years of age

28. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies Summary  Sequencing  Duration –2-3 or 5 years of Tam, followed by AI –5 years of AI  All the same?  Late toxicity  Premenopausal

29. clinicaloptions.com/oncology Adjuvant Endocrine Therapy for Postmenopausal Women: Ongoing Studies For more information on this important clinical topic, go online to: www.clinicaloptions.com/postmenopausal  Free CME-certified virtual presentations with narration by the experts and more downloadable slidesets –Harold Burstein, MD, PhD: Recent Trials and Future Directions –Charles E. Geyer, Jr., MD: Overview of Aromatase Inhibitors  Sign up for a free CME-certified teleconference and present your questions to the experts!