1. Angelo Di Leo “Sandro Pitigliani” Medical Oncology Department Hospital of Prato Istituto Toscano Tumori, Prato, Italy Adjuvant hormone therapy in post-menopausal women

2. ApplicabilityCompany (1) Advisory roleYes AstraZeneca, Bayer, Lilly, Novartis, Pfizer, Roche (2) Stock ownership/profit None (3) Patent royalties/licensing fees None (4) Lecture feesYes AstraZeneca, Eisai, Genomic Health, Novartis, Pfizer, Roche (5) Manuscript feesNone (6) Scholarship fundNone (7) Other remunerationNone Conflict of Interest Disclosure

3. Aromatase inhibitors: Major adjuvant trials Study Study design Upfront treatment ATACtamoxifen (T) vs anastrozole (A) BIG 1-98T vs letrozole (L) TEAMT vs exemestane (E) Sequential treatment ARNO 95T  T vs T  A ABCSG-8T vs T  A IEST  T vs T  E TEAMT  E vs E BIG 1-98T vs L vs T  L vs L  T

4. Aromatase inhibitors versus Tamoxifen: Patient-level meta-analysis of the randomised trials A total of 31,920 post-menopausal patients was included in the analysis 5 yrs. TAM vs. 5 yrs. AI (N= 9,885 ) 5 yrs. TAM vs. TAMAI – total 5 yrs. (N= 11,798) TAMAI – total 5 yrs. vs. 5 yrs. AI (N= 12,799) EBCTCG, The Lancet, 386: 1341- 52, 2015

5. 5 yrs. TAM vs. 5 yrs. AI EBCTCG, The Lancet, 386: 1341- 52, 2015 RecurrenceBreast Cancer mortality

6. 5 yrs. TAM vs. 5 yrs. AI EBCTCG, The Lancet, 386: 1341- 52, 2015 Death without recurrenceDeath from any cause

7. 5 yrs. TAM vs. TAM AI – total 5 yrs. EBCTCG, The Lancet, 386: 1341- 52, 2015 RecurrenceBreast Cancer mortality

8. EBCTCG, The Lancet, 386: 1341- 52, 2015 Death without recurrenceDeath from any cause 5 yrs. TAM vs. TAM AI – total 5 yrs.

9. TAMAI – total 5 yrs. vs. 5 yrs. AI EBCTCG, The Lancet, 386: 1341- 52, 2015 RecurrenceBreast Cancer mortality

10. EBCTCG, The Lancet, 386: 1341- 52, 2015 TAMAI – total 5 yrs. vs. 5 yrs. AI Death without recurrenceDeath from any cause

11. AI vs. TAM in the adjuvant setting Bottom-line messages from the meta-analysis AI better than TAM (30% ↓ recurrence; 15%↓ breast cancer mortality) AI slightly better than TAM AI (10% ↓ recurrence; 11% ↓ breast cancer mortality, NS) AI = TAM in terms of “death without recurrence” rate - 5 yrs. AI upfront in the suggested strategy - 5 yrs. TAM or TAM AI are still valid options for low risk patients or in case of poor compliance to AI

12. Optimal treatment duration: 5 vs. 10 yrs. The ATLAS trial main result Davies C et al, Lancet 2013

22. Should we always extend treatment beyond 5 years? No! Consider for N+ patients or N- with adverse disease biology

24. Trials evaluating oral bisphosphonates in early breast cancer Hadji P et al, Ann Oncol 27:379-390, 2016

25. Trials evaluating i.v. Zoledronic acid in early breast cancer

26. Areas of strong consensus (> 80%) regarding adjuvant bisphosphonates to prevent metastases Should be considered because the data are conclusive Agree 20 (17 + 3; 83%) Disagree 2 (1+1; 8%)Neutral/abstain 2 (8%) Should be considered in post-menopausal women Agree 22 (14 + 8; 92%) Disagree 1 (0+1;4%)Neutral/abstain 1 (4%) Should not be considered in pre-menopausal women Agree 21 (17 + 4; 87%) Disagree 1 (0+1;4%)Neutral/abstain 2 (8%) Should be considered in pre-menopausal women receiving ovarian suppression therapy Agree 22 (11 + 11; 92%) Disagree 1 (0+1; 4%)Neutral/abstain 1 (4%) Zoledronic acid or oral clodronate are the agents of choice Agree 21 (16 + 5; 87%) Disagree 0 (0+0; 0%)Neutral/abstain 3 (12%) Hadji P et al, Ann Oncol 27:379-390, 2016

27. Acknowledgments