1. SYSTEMIC TREATMENT IN BREAST CANCER N. PAVLIDIS PROFESSOR OF MEDICAL ONCOLOGY UNIVERSITY OF IOANNINA GREECE ESO COURSE IOANNINA, JULY 2011

6. CHEMOTHERAPY IN BREAST CANCER

8. HORMONAL THERAPY IN BREAST CANCER

9. ENDOCRINE THERAPIES IN ADVANCED BREAST CANCER TREATMENTS EFFECTS ON ESTROGENS SERMs (Selective Estrogen,Receptor Modulators) Tamoxifen Toremifene Raloxifene Occupy estrogen receptors ERD (Estogen Receptor, Down regulators) Fulvestrant Reduce expression of estrogen receptor, progesterone receptor and proliferative and cell turnover PROGESTINS Occupy progesterone receptors (reducing estrogen receptors and estrogen action)

11. TARGETED THERAPY IN BREAST CANCER

13. NORMAL CELL BREAST CANCER CELL gene amplification and overexpression of HER2 protein (10-fold to 100-fold) HER2 HER2 gene HER2 protein HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2

15. BISPHOSPHONATES IN BREAST CANCER

20. All Breast Cancer ER + 65-75% Triple neg 15% HER 2+ 15-20% BREAST CANCER IS NOT ONE OF A KIND !

24. BREAST CANCERS IN YOUNG WOMEN ARE LARGER - WHAT ELSE ?

25. TRIPLE NEGATIVE BREAST CANCER IS MORE COMMON IN YOUNG WOMEN PATIENTS

26. BREAST CANCERS IN YOUNG WOMEN WHAT IS DIFFERENT ?

27. BREAST CANCERS IN YOUNG WOMEN WHAT IS DIFFERENT ?

28. ADJUVANT SYSTEMIC TREATMENT IN BREAST CANCER (ESMO CLINICAL RECOMMENDATIONS)

30. RISK CATEGORIES FOR PATIENTS WITH OPERATED BREAST CANCER Low risk Node-negative and all of the following features Estimated risk of recurrence in 10 years (%) pT ≤ 2 cm Grade 1 Absence of extensive peritumoral vascular invasion ER and /or PgR expressed HER2 gene neither overexpressed nor amplified Age ≥ 35 years < 10

31. RISK CATEGORIES FOR PATIENTS WITH OPERATED BREAST CANCER Intermediate risk Node-negative and at least one of the following features Estimated risk of recurrence in 10 years (%) pT > 2 cm Grade 2-3 Presence of extensive peritumoral vascular invasion ER and PgR expressed HER2 gene overexpressed or amplified Age ≥ 35 years < 10 Node - positive (1-3 involved nodes) AND ER and/or PgR expressed AND HER2 gene overexpressed or amplified 10 - 50

32. RISK CATEGORIES FOR PATIENTS WITH OPERATED BREAST CANCER High risk Node-positive (1-3 involved nodes) AND Estimated risk of recurrence in 10 years (%) ER and PgR absent OR HER2 gene overexpressed or amplified Node-positive (4 or more involved nodes) < 50

34. ADJUVANT CHEMOTHERAPY Recurrence < 50 Breast Cancer Mortality 50-69 EBCTCG, Sept 2006 On average, chemotherapy is good for you

35. TRASTUZUMAB IN ADJUVANT SETTING WHERE DO WE STAND TODAY ?

36. Summary of Trastuzumab Adjuvant Trials Study FU, yrs Pts HERA 1 3,387 2 3,401 NSABP B-31/ NCCTG 9831 2 3,351 4 3,968 NCCTG 9831 seq BCIRG 006 1.5 3 1,964 3,222 FinHer 3 231 PACS 04 4 528 0 1 2 In favor of T In favor of Obs. HR 0.54 0.64 0.48 0.48 0.87 0.61 0.42 0.86

37. The future …. Looking at the biological target

38. Sorlie, T et al: PNAS 2001; 98:10869-10874 Breast Cancer is a Heterogeneous Group of Diseases OS DFS

39. MOLECULAR CLASSIFICATION AND TREATMENT OF BREAST CANCER TYPE CHARACTERISTICS TREATMENT Luminal A ER+/PR+/HER-/GR I (Ki67 < 14%) Endocr Rx alone Luminal B ER+/PR+/HER-/GR III (Ki67 high) Chemo+Endocr Rx ER+/PR+/HER+/GR any Chemo+anti-HER2+Endocr Rx HER-2 overexpression HER (+), ER- PR Chemo+anti-HER2 Rx Basal-Like Triple negative Chemo Rx

41. Oncotype DX 21 Gene Recurrence Score (RS) Assay PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies Category RS (0 – 100) Low risk RS < 18 Int risk RS ≥ 18 and < 31 High risk RS ≥ 31 RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1

42. TAILORx Node Neg, ER (+), Breast Cancer RS < 10 Hormone Therapy Registry RS 11 – 25 Randomize Hormone Rx vs. Chemotherapy + Hormone Rx RS > 26 Chemotherapy + Hormone Rx Onco type DX Assay Register Specimen banking Primary study group

43. SYSTEMIC TREATMENT FOR METASTATIC DISEASE

44. C H E M O T H E R A P Y IN METASTATIC BREAST CANCER

45. ORGAN PREDILECTION FOR DISTANT METASTASES IN BREAST CANCER SITE PERCENTAGE (%) Lymph nodes 74 Thorax Lung Pleura Pericardium Heart 64 37 22 11 Abdomen Liver Adrenals Spleen Intestine Peritoneum Ovaries Uterus Kidney Pancreas 60 40 18 18 17 15 15 15 14 Bones 57 Skin 35 Brain 15

46. FACTORS AFFECTING PROGNOSIS IN METASTATIC BREAST CANCER FAVOURABLE UNFAVOURABLE ER/PR positive tumour ER/PR negative tumour Long disease free interval (> 2 years) Short disease free interval (< 1 year) Response to first line therapy No response to first line therapy No visceral involvement Visceral involvement Limited metastatic sites, no bulky disease Multiple metastatic sites and/or bulky disease HER-2 negative tumour HER-2 positive tumour

47. SYSTEMIC MANAGEMENT OF METASTATIC BREAST CANCER ACCORDING TO RISK SUBSETS RISK EVALUATION FAVORABLE SUBSETS UNFAVORABLE SUBSETS ENDOCRINE THERAPY CHEMOTHERAPY

48. COMBINED SYSTEMIC TREATMENT IN ABC A HISTORICAL OVERVIEW DECADE ( Drug – based ) REGIMEN RESPONSE ( % ) CR ( % ) OVERALL SURVIVAL ( m ) 1960 – 1970 (non-anthracycline) CMF, CMFP, CMFVP 50 – 60 5 – 10 15 – 18 1970 – 1990 (anthracycline) AC, FAC, FEC 50 – 80 5 – 20 17 – 25 1990 – 2000 (taxane) AT, ET, TAC 46 – 68 54 – 65 7 – 41 14 – 23

49. RESPONSES TO COMBINATION CHEMOTHERAPY AS FIRST LINE TREATMENT OF METASTATIC BREAST CANCER Partial or complete response 45 % to 80 % Complete response 5 % to 25 % Time to initial response (median) 4 to 8 wk Duration of response (median) 5 to 13 mos Survival of responders (median) 15 to 33 mos

50. ARE TAXANE - CONTAINING REGIMENS SUPERIOR TO NON TAXANE - CONTAINING ONES ?

52. H O R M O N O T H E R A P Y IN METASTATIC BREAST CANCER

53. RESPONSE OF HORMONAL THERAPIES IN METASTATIC BREAST CANCER Agent Response Rate (%) Range (%) Tamoxifen 32 16-52 Aromatase Inhibitors 32 16-43 LHRH Analogues 36 32-45 Progestins 30 9-67

54. TOXICITIES AND LONG – TERM EFFECTS OF ENDOCRINE THERAPY TAMOXIFEN Amenorrhea (>1/3), hot flashes, vaginal bleeding, thrombophlebitis, endometrial cancer. AROMATASE INHIBITORS Muscoloskeletal complaints. GnRH ANALOGUE Sexual dysfunction

56. TARGETED TREATMENT IN METASTATIC BREAST CANCER

57. TRASTUZUMAB COMBINATIONS FOR METASTATIC BREAST CANCER Combination Response Rate % H + Doxorubicin /Cyclophosphamide 60 H + Epirubicin / Cyclophosphamide 64 H + Liposomal doxorubicin 58 H + Cisplatin 26 H + Viborelbine 60-84 H + Gemcitabine 32-62 H + Capecitabine 47 H + Taxol 41-81 H + Taxotere 55-76 H + Taxol/Carbo 68 H + Taxotere /Carbo 56 H + Taxotere / Cisplatin 79

59. BEVACIZUMAB (Avastin) EFFICACY IN METASTATIC BREAST CANCER Response Rate (%) PFS (wks) Overall Survival (mos) Bevacizumab + Capecitabine vs Capecitabine 19.8 % 9.1 % 4.86 4.17 15.1 14.5 p value 0.001 NS NS Bevacizumab + Paclitaxel vs Paclitaxel 48.0 % 23.4 % 11.4 5.8 26.5 24.8 p value < 0.0001 < 0.0001 NS

61. LAPATINIB EFFICACY IN METASTATIC BREAST CANCER Response Rate (%) PFS (wks) Survival (mos) Lapatinib + Capecitabine vs Capecitabine 22.5 % 14 % 39.6 17.9 - p value NS p 0.001 NS Lapatinib + Paclitaxel vs Lapatinib 35 % 25.3 % No difference No difference p value p 0.008 Lapatinib + Trastuzumab vs Lapatinib 10.3 % 6.9 % 12.0 8.4 51.6 39.0 p value NS p 0.029 NS

64. Efficacy of PARP Inhibitors in BRCA 1 / 2 mutated Breast Cancers : Synthetic Lethality Tutt A et al. The Lancet, Volume 376, Issue 9737, 2010, Pages 235-244 Olaparib 400 mg twice daily (n=27) Olaparib 100 mg twice daily (n=27) Objective response 11 ( 41% ; 25-59) 6 ( 22% ; 11-41) Complete response 1 (4%; 1-18) 0 Partial response 10 (37%; 22-56) 6 (22%; 11-41) Stable disease 12 (44%; 28-63) 12 (44%; 28-63) Progressive disease 4 (15%;6-32) 9 (33%;19-53)

65. PARP 1 Inhibitors Compound Route Phase Ongoing Trials Iniparib (BSI-201) Intravenous I-III Breast Veliparib Oral I-II Breast, ovarian Olaparib Oral I-II Breast, ovarian

66. BISPHOSPHONATES IN METASTATIC BREAST CANCER

69. TREATMENT LINES IN METASTATIC BREAST CANCER SURVIVAL GAIN 1 st LINE CX, HOR, TARG 3 rd LINE CX, HOR, TARG 2 nd LINE CX, HOR, TARG 12 – 16 months 12 – 16 months 6-9 months 12 – 16 months 6-9 months 4-6 months TOTAL (maximum) 16 mos 25 mos 31 mos CX = chemotherapy, HOR = Hormonal treatment, TARG = Targeted treatment