1. SABCS 2012 Guy Jerusalem, MD, PhD

2. SABCS 2012: Clinical studies in HER2 negative disease Hunderds of oral and poster presentations to be covered (endocrine therapy, chemo, targeted therapy) Selection criteria for my presentation: phase 3 studies contributing to respond to important clinical questions

11. Impact of the ATLAS trial? Premenopausal patients (10% of study population) The new standard? Postmenopausal patients Use of AI

15. My opinion Postmenopausal patients I consider 5 years of TAM as an option in high risk patients after 5 years of AI (discussion with the patient indicating of course that this is not an evidence-based approach)

16. Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka, Roberto Torres, Igor N. Bondarenko, Rustem Khasanov, Didier Verhoeven, José L. Pedrini, Iva Smirnova, Mikhail R. Lichinitser, Kelly Pendergrass, Sally Garnett, Yuri Rukazenkov, Miguel Martin, on behalf of the CONFIRM investigators San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012 This presentation is the intellectual property of the author/presenter. Contact them at adileo@usl4.toscana.it for permission to reprint and/or distributeadileo@usl4.toscana.it

17. Trial design and main eligibility criteria X X Relapsing pts. X 1 st line HT X “de novo” advanced pts. Allowed prior hormonotherapy (HT) start adjuvant HT 5 yrs.12 mos. gap Post-menopausal Advanced disease ER+ Fulvestrant 250 mg (1 injection i.m.) + placebo (1 injection i.m.) days 0, 14 (2 placebo injections), 28, and every 28 days thereafter Fulvestrant 500 mg (2 injections 250 mg i.m.) days 0, 14, 28, and every 28 days thereafter San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012

18. Primary endpoint: progression-free survival 1.0 0.8 0.6 0.4 0.2 0 4812162024283236 40 4448 Proportion of patients progression-free Time (months) 216 199 163 144 113 85 90 60 54 35 37 25 19 12 12 4 7373 3131 21210 362 374 Patients at risk: 500 mg 250 mg Fulvestrant 500 mg Fulvestrant 250 mg HR = 0.80; 95% CI: 0.68, 0.94; p=0.006 Median PFS (months) Fulvestrant 500 mg 6.5 Fulvestrant 250 mg 5.5 0.0 Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600 CI, confidence interval; HR, hazard ratio; PFS, progression-free survival San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012 This presentation is the intellectual property of the author/presenter. Contact them at adileo@usl4.toscana.it for permission to reprint and/or distributeadileo@usl4.toscana.it

19. 1.0 0.8 0.6 0.4 0.2 04 812162024283236404448 Proportion of patients alive Time (months) 330 338 285 299 251 260 223 222 165 157 116 107 74 61 46 34 29 18 16 10 62620 362 374 HR = 0.84; 95% CI: 0.69, 1.03; p=0.091 Median time to death (months) Fulvestrant 500 mg 25.1 Fulvestrant 250 mg 22.8 0.0 Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600 Patients at risk: 500 mg 250 mg Fulvestrant 500 mg Fulvestrant 250 mg Secondary endpoint: overall survival (first analysis at 50% maturity – full analysis set) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012 This presentation is the intellectual property of the author/presenter. Contact them at adileo@usl4.toscana.it for permission to reprint and/or distributeadileo@usl4.toscana.it

20. 0.1 0 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 048121620242832364044485256606468727680 Fulvestrant 500 mg Fulvestrant 250 mg 36233328825422720217816314112311498816447302615810500 mg 37433829926122319116413711296877464483722148320250 mg Time (months) Proportion of patients alive Patients at risk: HR (95% CI)0.81 (0.69, 0.96) p-value0.016 a a Nominal value, cannot be claimed as statistically significant Median time to death (months) Fulvestrant 500 mg26.4 Fulvestrant 250 mg22.3 Overall survival (final analysis at 75% maturity – full analysis set) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012 This presentation is the intellectual property of the author/presenter. Contact them at adileo@usl4.toscana.it for permission to reprint and/or distributeadileo@usl4.toscana.it

21. First subsequent therapies Fulvestrant 500 N=362 Fulvestrant 250 N=374 % pts. with available information63 (N=230)64 (N=239) Type of 1 st subsequent therapy - % chemotherapy / anti-HER-259 / -59 / 0.4 - % endocrine therapy other than fulvestrant* 3531 - % objective response / clinical benefit8 / 338 / 41 * 8 out of 374 patients (2.1%) shifted from fulvestrant 250 mg to fulvestrant 500 mg either at the time of PD to 250 mg (4 pts.) or in absence of PD (4 pts.) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012

22. Conclusion and clinical impact This 4-month OS benefit is clinically relevant although surprising (only 1-month PFS benefit) A better endocrine therapy in first or second line ER positive breast cancer can improve survival (TAMRAD, trend in BOLERO 2 – mature OS results expected in 2013) 500 mg is already approved as the new standard dose and is used in our routine practice

28. Conclusion and clinical impact LEA is a negative trial although a small benefit (<31% reduction in PFS with bevacizumab) cannot be ruled out by this study; bev has no impact on OS More promising combined treatments (endocrine therapy and targeted therapy) are under evaluation

34. Conclusion and clinical impact First randomized phase 3 trial specifically in early TNBC; 3 year IDFS better than expected. The BEATRICE trial demonstrated no statistically significant improvement in invasive DFS Results are consistent with disappointing data observed in the adjuvant treatment of early colon cancer

36. q 2 wk (w/G-CSF)q 3 wk 22 weeks 14 weeks21 weeks 33 weeks Radiation therapy and tamoxifen followed as appropriate doxorubicin 60 mg/m 2 cyclophosphamide 600 mg/m 2 paclitaxel 175 mg/m 2 over 3 hours 2 x 2 Factorial Design In Node Positive Disease CALGB 9741 / Intergroup Trial Citron, et al. JCO 2003, 21:1431-1439

37. DFS by Dose Density (Q2 vs Q3) 11/30/2005 q2wk q3wk Disease-free survival Q2 n = 988 Events = 230p = 0.012 Q3 n = 984 Events = 278

38. OS by Dose Density (Q2 vs Q3) 11/30/2005 q2wk q3wk Overall survival Q2 n = 988 Events = 168p = 0.049 Q3 n = 984 Events = 202

42. Conclusion and my interpretation TACT trial : unable to confirm the results of the Citron trial Dose-dense epirubicine (4 cycles) does not improve TTR; actual delivered dose-intensity was OK Explanation ??? Role of taxanes? Lenght of follow-up?

43. Conclusion and my interpretation Should we stop using dose-dense chemo? The Citron trial is not the only success story of dose-dense chemotherapy (dose-dense adriamycine/cyclophosphamide in NHL, dose- dense paclitaxel in ovarian cancer) Good rationale (Norton-Simon hypothesis) for using dose-dense chemotherapy in highly proliferative tumors

50. Conclusion and my interpretation Interesting results; suggest that we can still improve our standard chemo regimens All parts of this regimen are different from current standards… Dose-density? Dose-intensity? Early use of dose-dense paclitaxel? I will not use this regimen…

56. Conclusion and my interpretation Capecitabine remains the standard of care in patients previously treated by anthracyclines and taxanes Erubiline has confirmed antitumor activity in breast cancer. It is a good treatment option for heavily pretreated patients (EMBRACE trial)