1. Programa InForMed 2006-2007 Programa de Información y Formación Médica Continuada Para el uso racional del medicamento

2. Jesus Alarcon Company Oncologia Mèdica HUSD

3. TAMOXIFENO

4. EBCTCG Metanàlisi 2005 ASSAJOS 1-2 anys TMX vs 044 5 anys TMX vs 012 Tct llarg vs curt15

5. TMX 5 a vs NO TCT RecurrènciaMortalitat 11,8%9,2%

6. TMX vs NO TTO RE+: reducció significativa del risc –Recidiva –Mortalitat Evidència indirecta: –5 anys > 2 anys RE ? Benefici < RE + No benefici a RE- EBCTCG Lancet 2005, 365; 1648-1717

7. TMX 5A vs NO TCT RE+; TMX 5a; als 15 anys… HR recurrència 0,59 HR mortalitat 0,66 RA 11,8% per recurrència i 9,2% per mortalitat Recidiva: benefici mantingut 10a Mortalitat: benefici mantingut 15a

8. RECURRÈNCIA SEGONS N 9,1%16,1%

9. SEGONS N+/N- DISMINUCIÓ RISC RECAIGUDA DISMINUCIÓ RISC MORT N+46%25% N- 43%28%

10. SEGONS EDAT 9,8% 12,3%

11. SEGONS EDAT EDAT REDUCCIÓ % RECAIGUDA REDUCCIÓ % MORT 50-5937%11% 60-6954%33% 7054%34%

12. 1-2 a vs 5 a Recurrència Mortalitat

13. LLARG(10a) vs CURT(5a) NSABP B14 –1272 pacients N- –Branques: –Benefici grup placebo SLE i SG En espera dATLAS i ATOM TMX 5a + placebo 5a TMX 5a + TMX 5a

14. CONCOMITANT O SEQÜENCIAL Seqüencial INT 100 GEICAM 9401 TOXICITAT Càncer dendometri Processos tromboembòlics Risc absolut 0,2% Menor que el benefici (5,3%N- i 12,2%N+) Altres: calrades, sequetat vaginal, nausees, hepatotoxicitat, catarates IN SITU Després de cirurgia + RT Reducció 50% recaigudes IN SITU i INFILTRANTS

15. Tamoxifé és actiu a pacients posmenopàusiques Reduccions del risc de recidiva i mortalitat més enllà dels 5 a La resistència (de novo/adquirida) pot esser responsable del fracàs a qualcunes pacients Ja no és el tractament estàndar a posmenopàusia RE+

17. Arimidex, Tamoxifen, Alone and in Combination (ATAC) Trial

18. Which Problems does ATAC Address? Is tamoxifen still the best adjuvant therapy for postmenopausal women with early breast cancer? How do we reduce recurrences in the first few years of treatment? Can we improve upon the tolerability problems associated with adjuvant tamoxifen? Is anastrozol superior to tamoxifen in the adjuvant setting?

19. 9366 postmenopausal women with invasive breast cancer Mean age 64 years; 84% hormone receptor-positive 61% node-negative; 64% with tumour 2cm in diameter Surgery radiotherapy chemotherapy Randomisation 1:1:1 for 5 years Anastrozol (n=3125) Tamoxifen (n=3116) Combination (n=3125) Regular follow-up Primary trial endpoints: Disease-free survival Safety/tolerability Secondary trial endpoints: Incidence of contralateral breast cancer Time to distant recurrence Overall survival Time to breast cancer death Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm ATAC Trial Design

20. ATAC: Analysis History 2001 analysis 1 Median follow-up: 33 months 2002 analysis 2 Median follow-up: 47 months 2004 analysis 3 Median follow-up: 68 months Women years follow-up: 49,941 Total events: 1867 1. The ATAC Trialists Group. Lancet 2002; 359: 2131–2139. 2. The ATAC Trialists Group. Cancer 2003; 98: 1802–1810. 3. ATAC Trialists Group. Lancet 2005; 365: 60–62.

21. Disease-free Survival (HR+ Population) ITT=intent to treat Follow-up time (years) 0123456 Absolute difference:1.6%2.6%2.5%3.3% Patients (%) Anastrozol (A) Tamoxifen (T) HR 0.83 0.87 HR+ ITT 95% CI (0.73, 0.94) (0.78, 0.97) p value 0.005 0.01 A 424 575 T 497 651 0 5 10 15 20 25

22. Analysis of Time to Recurrence for Subgroups Nodal status All patients 0.401.501.750.600.801.001.25 Tumour size Receptor status Previous chemotherapy +ve –ve 2cm >2cm +ve –ve unknown yes no Anastrozol (A) better Tamoxifen (T) better HR (A:T) and 95% CI Cuzick J. Lancet 2005; 365: 1308.

23. Segons receptors RE+ RP+: –HR 0,84 (p 0,07 n.s.) RE+ PR-: –HR 0,43 (p <0,001) RE- RP+: –HR 0,79 (p n.s.)

24. Time to Distant Recurrence (HR+ Population) Patients (%) 0 5 10 15 20 25 0123456 HR 0.84 0.86 HR+ ITT 95% CI (0.70, 1.00) (0.74, 0.99) p value 0.06 0.04 A 226 324 T 265 375 Follow-up time (years) Anastrozol (A) Tamoxifen (T)

25. Overall Survival (HR+ Population) Deaths (%) HR 0.97 HR+ ITT 95% CI (0.83, 1.14) (0.85, 1.12) p value 0.7 A 296 411 T 301 420 Anastrozol (A) Tamoxifen (T) 0123456 Follow-up time (years) 0 5 10 15 20 25

26. 0 10 20 30 40 50 60 Tamoxifen (T) (n=3116) Anastrozol (A) (n=3125) No. cases 27 invasive 8 DCIS 52 invasive 7 DCIS 35 59 p value 0.01 HR 0.58 A vs T 95% CI (0.38, 0.88) Incidence of New (Contralateral) Breast Primaries in ITT Population

27. HR (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 ITT population HR+ population Efficacy Analysis: ITT and HR+ Populations Anastrozol (A) betterTamoxifen (T) better

28. Predefined Adverse Events 0.20.40.60.81.02.01.5 Hot flushes Odds ratio (anastrozol/tamoxifen) In favour of anastrozol In favour of tamoxifen Joint disorders Vaginal bleeding Vaginal discharge Endometrial cancer Fractures Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events AEs on treatment or within 14 days of discontinuation

29. ATAC Summary The ATAC Completed Treatment Analysis extends and strengthens the evidence that 5 years of anastrozol is significantly more effective and better tolerated than 5 years of tamoxifen The overall risk:benefit profile remains clearly in favour of anastrozol The absolute benefits for anastrozol over and above those of tamoxifen continue to increase with time and extend beyond the completion of therapy

30. A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer The Breast International Group (BIG) 1-98 Collaborative Group N Engl J Med Volume 353;26:2747-2757 December 29, 2005

31. BIG 1-98 Compara TMX i LETROZOL en adjuvància a dones posmenopàusiques RE+ i/o RP+ 8010 pacients –4007 TMX –4003 LETROZOL MILLOR LETROZOL –HR de SLE 0,81 (IC 95% 0,7-0,93) –HR de recaiguda distància 0,73 (IC 95% 0,6- 0,88)

32. DISSENY DE LESTUDI Branques TMX x 3a LETROZOL x 3a LETROZOL x 2 anys TMX x 2 anys TAMOXIFE x 5 anys LETROZOL x 5 anys

34. Kaplan-Meier Estimates of Disease-free Survival The Breast International Group (BIG) 1-98 Collaborative Group N Engl J Med 2005;353:2747-2757 SUPERVIVÈNCIA LLIURE DE MALALTIA HR=0.81 (95 % CI, 0.70 to 0.93; P = 0.003)

35. Cumulative Incidence of a Breast-Cancer Relapse (Panel A); a Second, Nonbreast Cancer (Panel B); and Death without a Prior Cancer Event (Panel C) The Breast International Group (BIG) 1-98 Collaborative Group N Engl J Med 2005;353:2747-2757 PERCENTATGE DE RECURRÈNCIES HR=0.72 (05% CI, 0,61 to 0,86; p<0,001) Distant recurrence: HR=0.73 (95 %CI, 0.60 to 0.88; p=0.001)

36. Segons receptors i Her2 RE+ RP+ –HR= 0,84 (95% CI 0.69-1,03) RE+ RP- –HR= 0,83 (95% CI 0,62-1,10) N.S. RE+ Her2- –HR=0,72 (95% CI 0,56-0,91) RE+ Her2+ –HR=0.68 (95% CI 0,33-1,41) N.S.

37. Cox Proportional-Hazards Model Results of Primary, Secondary, and Additional End Points The Breast International Group (BIG) 1-98 Collaborative Group N Engl J Med 2005;353:2747-2757

38. More patients in the letrozole group than in the tamoxifen group reported at least one protocolspecified adverse event of any grade (2912 patientsvs. 2554 patients). Life-threatening or fatal protocol-specified adverse events was similar in the two groups (67 of 3975 [1.7 percent] and 69 of 3988 [1.7 percent], respectively). Letrozole: Thromboembolic events (1.5 % vs. 3.5 %, P<0.001) Cardiac events of grade >2 (2.1 % vs. 1.1 %) Vaginal bleeding (3.3 % vs. 6.6 %, P<0.001) Invasive endometrial cancers (0.1 % vs. 0.3 %, P = 0.18) Hypercholesterolemia (43.6 % vs. 19.2 %)

39. Incidence of Worst Grade of Adverse Events among Patients Included in the Safety Analysis The Breast International Group (BIG) 1-98 Collaborative Group N Engl J Med 2005;353:2747-2757

40. Conclusion In postmenopausal women with endocrine responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites. ATAC: benefit of ANASTROZOLE predominantly in: Not adjuvant CT N-. BIG 1-98 : greatest benefit of LETROZOLE in: Had received CT N+.

41. LETROZOLE: ER+ similar reduction in the risk of a disease-free–survival event irrespective of their progesterone-receptor status ANASTROZOLE: Mainly in patients with ER+ and PR- tumors. Letrozole>Tamoxifen DISTANT DISEASE: Anastrozole>Tamoxifen ??

43. A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer Coombes, R. et al. N Engl J Med 2004;350:1081-1092 N Engl J Med Volume 350;11:1081-1092 March 11, 2004

44. Study Overview This large randomized trial compared five years of therapy with tamoxifen, with two to three years of tamoxifen followed by therapy with exemestane. Disease-free survival was significantly better in the exemestane group than in the tamoxifen group This trial indicates that the sequential use of antiestrogen compounds with different mechanisms of action has the potential to obviate the problem of resistance that has been encountered in women treated only with tamoxifen

45. Coombes, R. et al. N Engl J Med 2004;350:1081-1092

46. End-Point Events Coombes, R. et al. N Engl J Med 2004;350:1081-1092

47. Kaplan-Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B) Coombes, R. et al. N Engl J Med 2004;350:1081-1092

48. Hazard Ratios in the Exemestane Group as Compared with the Tamoxifen Group Coombes, R. et al. N Engl J Med 2004;350:1081-1092

49. Subgroup Analysis of Disease-free Survival Coombes, R. et al. N Engl J Med 2004;350:1081-1092

50. Adverse Events Coombes, R. et al. N Engl J Med 2004;350:1081-1092

51. Conclusions Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment

52. Switching from Adjuvant Tamoxifen to Anastrozole in Postmenopausal Women with Hormone-responsive Early Breast Cancer: A Meta-analysis of the ARNO 95 Trial, ABCSG Trial 8, and the ITA Trial

53. 2–3 years prior tamoxifen (n=448) Study Designs ITA ABCSG 8 ARNO 95 3–2 years Tamoxifen (n=225) Randomisation 2 years prior tamoxifen (n=979) 2 years prior tamoxifen (n=2579) Tamoxifen (n=1282) Arimidex (n=1297) Randomisation Tamoxifen (n=490) Arimidex(n=489) Randomisation 05 Time (years) Switch analysis 3–2 years Arimidex (n=223)

54. Trial Populations The overall population included was representative of postmenopausal women with early breast cancer being treated with adjuvant tamoxifen

55. Key Differences Between the Trial Populations Node involvement, % Negative Positive Grading Prior chemotherapy Surgery, % Breast-conserving d Mastectomy d ABCSG 8 (n=2579) 75 25 a G1,2,x No 81 19 ARNO 95 (n=979) 74 26 G1,2,3,x No 69 31 ITA (n=448) <1 99 b G1,2,3,x Yes c 42 52 e a not recorded in two patients; b not recorded in three patients c 67% of patients received prior chemotherapy; d lumpectomy or quadrantectomy; e other surgery in 27 patients Gx = lobular carcinoma

56. Results: Follow-up (ITT Population) Total duration of follow-up (person-years) Median follow-up (months) Minimum (months) Maximum (months) Tamoxifen (n=1997) 5339 30 0 89 Anastrozol (n=2009) 5389 30 0 89 Total (n=4006) 10727 30 0 89

57. Results: Recurrence Events (ITT Population) Local recurrence, n (%) Distant recurrence, n (%) Contralateral breast cancer, n (%) Total recurrence events, n (%) Tamoxifen (n=1997) 35 (1.8) 102 (5.1) 22 (1.1) 159 (8.0) Anastrozol (n=2009) 19 (0.9) 59 (2.9) 14 (0.7) 92 (4.6) Total (n=4006) 54 161 36 251 Median follow-up 30 months (max 89 months)

58. Forest Plot: Disease-free Survival (ITT Population) 0.20.40.60.81.01.21.41.6 Hazard ratio (HR) and 95% confidence intervals (CI) ARNO 95 ITA Meta-analysis 0.68 0.62 0.41 0.59 HR 0.017 0.024 <0.001 <0.0001 p value ABCSG 8 2579 979 448 4006 Patients In favour of switching to anastrozol In favour of continued tamoxifen

59. Forest Plot: Overall Survival (ITT Population) 0.20.40.60.81.0 HR and 95% CI ARNO 95 ITA Meta-analysis ABCSG 8 1.21.41.6 0.726 0.026 0.094 0.038 p value 2579 979 448 4006 Patients 0.93 0.48 0.50 0.71 HR In favour of switching to anastrozol In favour of continued tamoxifen

60. Forest Plot: Summary of Efficacy (ITT Population) HR and 95% CI 0.20.40.60.81.0 Disease-free survival Time to any recurrence Time to distant recurrence Overall survival 1.21.41.6 0.0377 <0.0001 0.0015 p value 0.71 0.59 0.55 0.61 HR In favour of switching to anastrozol In favour of continued tamoxifen

61. Meta-analysis: Efficacy Summary Demonstrates that patients switched to anastrozol experience significantly fewer recurrences than those patients remaining on tamoxifen These advantages translate into a benefit in the long-term endpoint of overall survival Consistency of effect was seen between the three trials Switching to anastrozole results in a benefit in overall survival compared with continued tamoxifen

62. …més estudis de SWITCHING… Goss P, et al JNCI 2005; 97; 1262-71

63. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival.

65. DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confi dence interval [CI] = 0.45 to 0.76; P <.001. Distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P =.002. Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P =.3)

67. SLE

68. SG

69. TOXICITAT

70. CONCLUSIÓ Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease -free survival but not overall survival, except in node-positive patients. [J Natl Cancer Inst 2005;97:1262–71]

71. HR ATAC BIG 1-98 IES 031ARNOMA.17 SLE0,830,810,680,600,58 SG0,970,860,880,480,82

72. Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer 1.AI=superiors a TMX Tractament delecció a ER+ posmenopàusia. Si ja reben TMX switching 2.No dades de comparació inicial vs seqüencial 3.Duració òptima AI?? - Benefici 2-3 a dIA després de 5a TMX 4. Efectes adverses ginecològics amb IA 5.Problemes ossis dIA són predibles i contol.lables - Densitometria i bifosfonats si alt risc de fractura. 6.No evidència per contraindicar IA a cardiopatia isquèmica - Rel.lació no clara 7.No clara rel.lació IA amb tromboembòlia Buzdar A et al. Curr Med Res Opin 2006; 22(8): 1575-1585

73. S. Gallen: Low risk N- AND all: –pT 2 cm, –AND Grade 1 –AND Absence of peritumoral vascular invasion –AND HER2/neu gene neither overexpressed nor amplified –AND Age 35 Intermediate risk N- AND at least one: –pT >2 cm, –OR Grade 2-3, –OR Presence of peritumoral vascular invasion, –OR HER2/neu gene overexpressed or amplified, –OR Age <35 years N+ (1-3 involved nodes) AND HER2/neu gene neither overexpressed nor amplified High risk N+ (1-3 involved nodes) AND HER2/neu gene overexpressed or amplified N+ (4 or more involved nodes)

74. S. Gallen: Resposta endocrina incerta <10% of cells + or qualitatively insufficient PR- HER-2/neu overexpression high number of N high tumor levels of u-PA / PAI 1 proliferation markers. Should receive endocrine therapy, but the doubtful adequancy of such therapy alone suggests the need for the addition of adjuvant chemotherapy.

75. SAN GALLEN Resposta endocrina Baix riscRisc intermigAlt risc Certa Tam, or AI, or Nil* Tam, or AI, or CTTam, or CTAI Indication for switch to an AI after Tam: Exemestane or anastrozole after 2-3 years, and letrozole after 5 years. CTTam, or CTAI Indication for switch to an AI after Tam: Exemestane or anastrozole after 2-3 years, and letrozole after 5 years. Incerta Tam, or AI, or Nil* CTAI, or CTTam Indication for switch to an AI after Tam: Exemestane or anastrozole after 2-3 years, and letrozole after 5 years. CTAI, or CTTam Indication for switch to an AI after Tam: Exemestane or anastrozole after 2-3 years, and letrozole after 5 years.

76. MOLTES GRÀCIES