1. Adjuvant Chemotherapy of Early Breast Cancer: When, Why, Prognostic factors, Regimens Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty, Ljubljana ESO Masterclass; Dubrovnik 2011

2. Cancer Mortality Rates in EU Member States Levi F et al.,Ann Oncol2007;18.

4. 7 independent meta-analysis showed median decline in mortality of 30% (range: 25%-38%)

5. Due to screening: 15% (range: 7%-23%)

6. Due to adjuvant therapy: 19%(range: 12%-21%)Berry DA et al. NEJM 2005

8. 40% ↓ risk of recurrence

9. 32 % ↓ risk of breast cancer mortality

10. Polychemotherapy

11. 33% ↓ risk of recurrence

13. 2010 EBCTCG Overview: Anthracyclinevs CMF Recurrence BC mortality Any death A C X 4 ANTHRAC YCLINE M O R E

14. 2010 EBCTCG Overview: Taxane+anthracycline(A) vs A Recurrence BC mortality Any death T + A vs S a m e A T + A vs. M o r e A

15. Poly-chemotherapy: Impact on Recurrence Anthracycline (A) + Taxanevs A Anthracyclinevs CMF Early benefit of anthracycline Taxane benefit is durable EBCTCG 2010 (unpublished overview)

16. Benefit from Chemotherapy According to Subgroups Taxane + Anthracycline (A) vs A AnthracyclinevsNoCTX All subgroups benefit from CT EBCTCG 2010 (unpublished overview)

17. ER- ER+ Genotype Luminal-like A, B HER-like Basal-like Phenotype Triple negative ER-neg PR-neg HER2-neg HER2-pos ER-neg PR-neg ER-pos HER2-neg (mostly) A: low proliferation rate B: high proliferation rate A variety of disease types: should all respond to the same therapy? Adapted from Sotiriou et al,.PNAS, 2003.

18. How to Select Adjuvant Systemic Therapy for Each Individual patient? A major determinant is a Target not a Risk Molecular targets in breast cancer: Endocrine receptors (ER) HER2 receptor St.Gallen recommendations 2007

19. Adjuvant systemic therapy is recommended if a relevant absolute risk reduction of recurrence and can can be expected with an acceptable level of treatment –related adverse effects ! EFFICACY TOXICITY

21. The optimal duration of Cht is not known (4-6 cycles)

22. The addition of taxanes to anthracyclines improves survival rates significantly

24. CALGB 9344: Benefit of Paclitaxel by ER and HER2 Status Hayes DF, et al. N Engl J Med 2007

25. BIG 2-98: Sequential vs. Concomitant Doxorubicine-Docetaxel Di Leo A, et al. SABCS 2009. Abstract 601.

26. FinXX: CEF-Docetaxel vs CEX-Docetaxel/Capecitabine: RFS ER+ and/or PR+, HER2+ ER+ and/or PR+, HER2- 100 100 80 80 T/CEF P = 0.845 HR = 1.11 n = 163 P = 0.591 HR = 0.91 n = 1009 60 60 TX/CEX 40 40 20 20 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 ER- and PR-, HER2- ER- and PR-, HER2+ 100 100 80 80 60 60 P = 0.786 HR = 0.91 n = 122 P = 0.0177 HR = 0.48 n = 202 40 40 20 20 0 0 0 1 2 3 4 5 6 7 Joensuu et al. SABCS 2010. Abstract S4-1. 0 1 2 3 4 5 6 7

28. HER2-directed therapy is the mainstay of adjuvant systemic therapy in HER2-positive EBC;5/6 trials have shown substantial DFS and OS benefits of adding trastuzumab to Cht

30. Adjuvant Chemotherapy ± Trastuzumab Trials: Overall Survival Median FU yrs p Reference Difference at 4y/3ya HR Combined US (n=3969)b 0.63 3.2% 3 0.0004 Perez 2007 HERA (n=3401) 0.66 2.7%* 2 0.0115 Smith 2007 BCIRG AC-TH (n=1074) 0.59 6% 3 0.004 Slamon 2006 BCIRG TCarboH (n=1075) 3 0.017 0.66 5% Slamon 2006 FinHER (n=232) 5 0.09 6.6%* 0.55 Joensuu 2009 n.s. 1.27 –1.0% 4 Spielmann 2009 PACS-04 (n=528) 2 1 0 Favours trastuzumab Favours chemotherapy only *Benefit at 3y a Absolute difference in percentage of patients with OS at 4 or 3 years b Combined US: Joint analysis of NSABP B-31 and NCCTG N9831

32. HER-2 + tumors benefit from anthracycline treatment (Meta-analysis, Gennari et al., 2008; Watanabe T et al. ASCO 2009)

33. Demonstrated efficacy in randomized clinical trials (NSABP B-31 / NCCTG N9831 and BCIRG 006)

34. TCH:

36. BCIRG 006: DFS Benefit of Adjuvant Trastuzumab Treatment by TOPO II Coamplification and Treatment Arm (all patients, 2nd interim analysis) % disease free % disease free Slamon. 2006. www.bcirg A, anthracycline; C, cyclophosphamide; D, docetaxel; T, trastuzumab; Carbo, carboplatin

37. NCCTG N9831: DFS Sequential vs Concurrent Trastuzumab AC -> T + H -> H (138 events) 100 89.1 % 90 84.2 % 85.7 % 80 79.8 % AC -> T -> H (174 events) 70 Alive and Disease Free (%) 60 Log rank P = .0190 HR=0.77 50 949954 837830 788766 740705 676641 456418 No. at risk 40 5 1 2 0 3 4 Yrs From Randomization Perez EA, et al. SABCS 2009. Abstract 80.

39. A wide spectrum ranging from those at a low risk to those with high risk

40. Classical clinico-pathological factors

41. Number of positive nodes

42. Tumor size

43. ER/PR expression

44. Grade

45. Proliferationindex (Ki- 67)

46. Novel molecular tools

47. Multigene microarrays (Genomic signatures, Gene expression grade index)

49. HER2-positive

50. ER-positive Colleoni M et al, JCO 2010; 28: 2966

51. Benefits of Adjuvant Chemotherapy in Endocrine Responsive Disease

52. p = 0.39 Intermediate RS p = 0.61 Low RS Proportion without Distant Recurrence High RS p < 0.001 High Risk Patients (RS≥31) N Events TAM + Chemo 117 13 TAM 47 18 Int Risk Patients (RS 18-30) N Events TAM + Chemo 89 9TAM 45 4 Low Risk Patients (RS<18) N Events TAM + Chemo 218 8 TAM 135 4 B-20 Results: TAM vs Chemo + TAM Oncotype DX: N0 28% absolute benefit from Chemo - TAM Paik et al. J Clin Oncol. 2006

53. Postmenopausal women with N+ HR+ disease (n = 1470) TAM CAF-T CAFT SWOG 8814, INT0100 Trial Disease-Free Survival by Treatment Low risk (21-gene RS < 18) 1.00 0.75 Disease-free survival 0.50 Stratified log-rank p = 0.97 at 10 years 0.25 Tamoxifen (n=55, 15 events) CAF-T (n=51, 26 events) 0.00 0 2 4 6 8 10 Years since registration Intermediate risk (21-gene RS 18- 30) High risk (21-gene RS ≥ 31) 1.00 1.00 0.75 0.75 Disease-free survival Disease-free survival 0.50 0.50 Stratified log-rank p = 0.033 at 10 years Stratified log-rank p = 0.48 at 10 years 0.25 0.25 Tamoxifen (n=47, 26 events) CAF-T (n=71, 25 events) Tamoxifen (n=46, 22 events) CAF-T (n=57, 20 events) 0.00 0.00 0 2 4 6 8 10 0 2 4 6 8 10 Years since registration Years since registration Albain K, et. al. SABCS 2007.Abstract 10

55. Randomize chemo: yes or no (MiNDACT)Endocrine therapy Potential CT sparing in 10-15% pts

56. Predicting Sensitivity to Chemotherapy PCR Probability With Neoadjuvant Chemotherapy - 33% ER + 7% 3 26% GRADE 1 or 2 7% 20% 21% Ki67 <20% 5% (Colleoni M et al.)

58. Chromosome 17 polysomy…

59. HER2 status

60. TOPO2A and TIMP-1 ?

61. Taxane benefit

62. HER2 ?

63. P53 ?

66. Effective biomarkers are needed to optimize chemotherapy in two directions:

67. To identify patients that can be spared from toxic chemotherapy

68. To define the optimal Cht regimen for each individual patient

69. Better understanding of long term side effects of Cht might help us to further refine our strategies.