1. Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate This program is supported by an educational grant from

2. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Early Days: Alkylating Agents and Antimetabolites  In 1976, Bonadonna and colleagues from Milan, Italy, reported that postoperative CMF improved DFS and OS in women with node-positive breast cancer  At the same time, the NSABP was evaluating adjuvant L-phenylalanine mustard and fluorouracil  In Scandinavia, Nissen Meyer was evaluating adjuvant cyclophosphamide

3. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate 0 0.51.0 1.5 Entry Age and Nodal Status 40-49 yrs 50-59 yrs 60-69 yrs 70+ yrs Total Allocated Polychemo Allocated Control Events/Women Log Rank O-E Variance of O-E Ratio of Annual Event Rates Polychemo:Control Polychemo Events 784/2480 (31.6%) 1843/4880 (37.8%) 1812/4886 (37.1%) 158/570 (27.7%) 4973/13776 (36.1%) Heterogeneity between 5 categories:  2 = 25.4; P =.00004 4 954/2391 (39.9%) 2220/5143 (43.2%) 2063/4967 (41.5%) 209/610 (34.3%) 5909/14019 (42.1%) -150.4 -196.8 -125.3 -8.6 -567.3 367.8 770.6 733.4 56.3 2095.2 < 40 yrs376/960 (39.2%) 463/908 (51.0%) -86.2167.040% (SE 6) 34% (SE 4) 23% (SE 3) 16% (SE 3) 14% (SE 12) 23.7% (SE 1.9) reduction 2P <.00001 Polychemo BetterPolychemo Worse Treatment effect 2P <.00001 2.0 99% or 95% Cl Polychemotherapy vs No Polychemotherapy: Recurrences EBCTCG. Lancet. 2005;365:1687-1717.

4. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Anthracyclines  FarmItalia Research developed these compounds in 1960s  Derivatives of soil microbe, Streptomyces peucetius (rhodomycin)  Daunomycin (R = CH 3 ), doxorubicin (R = CH 2 OH)

5. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Anthracyclines (cont’d)  Inhibition of DNA and RNA synthesis –By intercalation between DNA base pairs –Block DNA repair by inhibition of topoisomerase II  In the 1980s, RCTs were initiated to evaluate the role of anthracycline-containing adjuvant regimens

6. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate NSABP B-15: AC x 4 vs CMF x 6  > 1400 women with node-positive breast cancer  No difference in 3-year DFS (62% vs 63%)  No difference in 3-year OS (83% vs 82%)  Different toxicity profiles Fisher B, et al. J Clin Oncol. 1990;8:1483-1496.

7. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Epirubicin and Doxorubicin O O O O OCH 3 OOH O O NH 2 HO CH 3 O O O O OCH 3 OOH O O NH 2 HO CH 3 Epirubicin Doxorubicin

8. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Epirubicin and Doxorubicin Structural Considerations FeatureConsequence Epirubicin has lower pKa than doxorubicin More lipophilic and better able to penetrate cells Glucuronidation of epirubicin and epirubicinol to inactive metabolites Terminal half-life  Epirubicin: 30 hours  Doxorubicin: 45 hours

9. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Doxorubicin : Epirubicin Dose Ratios With Similar Toxicities  Hematologic 1.0:1.2  Nonhematologic 1.0:1.5  Cardiac 1.0:1.8 Launchbury AP, et al. Cancer Treat Rev. 1993;19:197-228.

10. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Node-positive, pre- and perimenopausal patients with lumpectomy or mastectomy from 1985-1993 (N = 710) C 75 mg/m 2 PO QD Days 1-14 E 60 mg/m 2 IV Days 1 and 8 every 4 weeks x 6* F 500 mg/m 2 IV Days 1 and 8 C 100 mg/m 2 PO QD Days 1-14 M 40 mg/m 2 IV Days 1 and 8 every 4 weeks x 6 F 600 mg/m 2 IV Days 1 and 8 *Plus prophylactic antibiotics. NCIC CTG MA.5 Trial

11. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Endpoint, % CEF (n = 351) CMF (n = 359) P Value DFS6353.009 OS7770.03 Levine MN, et al. J Clin Oncol. 1998;16:2651-2653. MA.5 Trial: 5-Year DFS and OS

12. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Anthracycline Regimens vs CMF StudyTreatmentsNDFS, %OS, % SWOGCAF vs CMF269185 vs 82*92 vs 90 DanishFEC 60 vs CMF119563 vs 58*70 vs 65* *Statistically significant (P <.05).

13. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate NIH Consensus Statement 2000  “Adjuvant chemotherapy regimens that include an anthracycline (such as doxorubicin or epirubicin) result in a statistically significant improvement in survival compared to nonanthracycline regimens”

14. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Poole et al UK Trial (2006)  4 cycles of epirubicin every 3 weeks followed by 4 cycles of CMF vs 8 cycles of CMF alone  Median follow-up: 48 months  A priori specified combination of the results of NEAT and BR9601 Poole CJ, et al. N Engl J Med. 2006;355:1851-1862.

15. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Copyright © [2006] Massachusetts Medical Society. All rights reserved. Poole CJ, et al. N Engl J Med. 2006;355:1851-1862. UK Trial: Survival by Treatment No. at Risk Epirubicin plus CMF CMF 1189 1202 1166 1172 1082 1044 851 797 Years Since Surgery 012345 0 25 50 75 100 560 521 293 257 OS (%) HR = 0.67; P <.001 82 75 95 92 Epirubicin plus CMF CMF

16. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Levine MN, et al. J Clin Oncol. 2005;23:5166-5170. HR = 0.80; P =.007 MA.5 Trial: 10-Year Recurrence-Free Survival—CEF vs CMF No. at Risk CEF CMF 351 359 212 193 Years 0510 0 20 40 60 84 80 10-Year Survival Rate (%) 80 CEF CMF 100

17. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate MA.5 Trial: 10-Year OS—CEF vs CMF HR = 0.85; P =.047 No. at Risk CEF CMF 351 359 269 253 Years 0510 0 20 40 60 98 106 80 100 CEF CMF 10-Year Survival Rate (%) Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Levine MN, et al. J Clin Oncol. 2005;23:5166-5170.

18. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate EBCTCG: 15-Year Mortality Reprinted from The Lancet, Vol. 365. pp1687-1717. © 2005, with permission from Elsevier. Anthracycline Better 0.84 (SE 0.033) 2P <.00001 Treatment effect 2P <.00001 0 0.51.0 1.5 CMF Better 2.0 Anthracycline:CMF Ratio of Annual Death Rates Deaths/WomenAnthracycline Deaths AnthracyclineCMFLog rank O-EVariance of O-E (95% CI) -133.0761.9 Total1809/72282038/7243 (25.0%)(28.1%)

19. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Summary  DFS and OS are improved with anthracycline-containing adjuvant chemotherapy compared with CMF  These data are robust as they are based on trials with 15 years of follow-up in > 15,000 women  Anthracycline-containing adjuvant chemotherapy is the standard

20. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Adjuvant Chemotherapy of Primary Breast Cancer: What We Know  Low-risk category – ER(+), PR (+), axillary lymph nodes (-), Size<1 cm, histologic grade 1, or 1-2 cm hormone receptor-positive tumor with tubular or mucinous histologic types.

21. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Ushering in a New Era: The Taxanes  Anthracyclines are still the backbone; taxanes are studied in sequence or concurrent  Perhaps because 4 cycles of AC every 3 weeks is not enough? O O O NH OH HO O OH H H O O O O O O O NH OH O O O O O O O H O Docetaxel Paclitaxel O

22. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate StudyNTreatmentsDFS, OS Improve With: CALGB 9344 [1] 3121AC vs AC → TAC → T CALGB 9741 [2] 2005AC → T: sched, combDose-dense AC → T PACS 01 [3] 1999FEC vs FEC → T d FEC → T d BCIRG 001 [4] 1491FAC vs T d ACT d AC 1. Henderson IC, et al J Clin Oncol. 2003;21:976-983. 2. Citron ML, et al. J Clin Oncol. 2003;21:1431-1439. 3. Roche H, et al. J Clin Oncol. 2006;24:5664-5671. 4. Martin M, et al. N Eng J Med. 2005;352:2302-2313. Trials Incorporating Taxane Therapy

23. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Safety of Anthracyclines: Cardiotoxicity  Clinical CHF is rare (< 1%)  In EBCTCG analysis, mortality from heart disease was 0.08% vs 0.06% per year [1]  Decrease risk by screening patients  Use safer anthracyclines, eg, epirubicin 1. EBCTCG. Lancet. 2005;365:1687-1717.

24. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Safety of Anthracyclines: Leukemia  Leukemia is a rare event and typically occurs early in contrast to the late occurrence with alkylating agents  Leukemia occurs with most every chemotherapy agent

25. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Risk vs Benefit of Anthracyclines in Preventing Breast Cancer Benefits Toxicity

26. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Adjuvant Trastuzumab StudyRxEfficacySafety B-31/9831 [1] (n = 3351) AC (Q3) → T(Q1) AC → TH DFS: HR = 0.48 OS: HR = 0.67 Cardiac: 4.1% vs 0.8% HERA [2] (n = 3387) Chemo* Chemo* → H DFS: HR = 0.54 Cardiac: 0.5% vs 0% 1. Romond EH, et al. N Engl J Med. 2006;353:1673-1684. 2. Piccart-Gebhart MJ, et al. N Engl J Med. 2005;353:1659-1672. *A/E + taxane in 30%, A/E alone in 70%. ↔

27. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate NSABP B-31: Cardiac Update Rastogi P, et al. ASCO 2007. Abstract 513.  At 5 years, rate of cardiac events unchanged (3.8%)  Recovery in LVEF noted in patients who had clinically relevant declines  Symptoms of CHF resolved in most women but many remained on meds for LV dysfunction  None of 175 patients randomized to AC → TH who initiated trastuzumab after completing paclitaxel has developed a cardiac event

28. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Summary  Adjuvant anthracyclines in > 40,000 women  15-year follow-up with anthracyclines  Dose and schedule of anthracyclines are important  Cardiac events are very rare  Avoidance of breast cancer deaths far outweighs toxicity

29. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Summary (cont’d)  Trastuzumab adds significant benefit to anthracycline- based adjuvant chemotherapy  Serious cardiac toxicity was considerably higher in B-31/9831 than in HERA likely due to sequencing of trastuzumab relative to anthracyclines

30. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate What Evidence Is Required to Change Current Therapy?  Require level 1 evidence: “Beyond a reasonable doubt that the proposed new treatment is better than or as good as current treatment”  Large RCT showing a statistically significant difference  Adequately powered noninferiority trial ACCP Guidelines. Chest. 2008;133:123S-121S.

31. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate What Methodologic Criteria Need to Be Satisfied?  Results of the trial should be published in a peer-reviewed journal  Sample size should be large enough to rule out a clinically important difference  Treatment should be safe  Results should be consistent over the long term  Results should be reproducible

32. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate BCIRG 006  3225 women with HER2-positive (FISH), high-risk, node- positive, or node-negative breast cancer  Randomized to –AC x 4 → T d x 4 (ACT) –AC x 4 → T d x 4 + trastuzumab x 1 year (AC → TH) –T d Carbo x 6 + trastuzumab x 1 year (TCH)  Phase II data for T d Carbo regimen in metastatic disease

33. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Slamon D, et al. SABCS 2006. Abstract 52. Years From Randomization Disease Free (%) 0.5 0.6 0.7 0.8 0.9 1.0 012345 83% 82% AC → TH 1074 128 Arm Pts Events TCH 1075 142 270 HR = 0.9 (0.7-1.2) BCIRG 006: DFS—2nd Interim Analysis AC → TH TCH

34. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate US Oncology 9735  AC every 3 weeks x 4 vs T d C every 3 weeks x 4  HR = 0.67, P =.01 in favor of TC  AC every 3 weeks is not standard adjuvant chemotherapy  Standard therapy is DD ACT or CEF Jones SE, et al. J Clin Oncol. 2006;24:5381-5387.

35. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate How Do These Studies Match Criterion? CriterionBCIRG 006 USO 9735 Completed and publishedAbstract J Clin Oncol 2006 UnderpoweredYes (at this point)No Safety?Yes Long-term follow-upNo (3 years)No (5 years) ReproducibleNo

36. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate Criteria to Use to Choose a Regimen Based on Biomarkers  Demonstrated prediction, not just association  Validated prospectively in large numbers of patients

37. clinicaloptions.com/oncology Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate + + + + ++ + + + + Prediction Not Amplified Amplified 0 20 40 60 80 100 OS (%) Years 6810024 0 20 40 60 80 100 OS (%) Years 6810024 + +++ + + + + + + ++ + + ++ + ++ + ++ +++ + + + + + + + + + + + ++ +++ ++ ++++ ++ ++ ++++++ ++++++++ +++++++++ ++++++ + ++ + + +++ ++ ++ + + + + + + + + + +++ +++ ++++++ Interaction + + + + + Bartlett JMS, et al. J Clin Oncol. 2008;26:5027-5035. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.