1. ESO BALKAN MASTERCLASS IN CLINICAL ONCOLOGY Dubrovnik, Croatia, 11-15 May 2011 Hormone therapy: best options for pre and postmenopausal patients F. Cardoso, MD ESO Breast Cancer Program Coordinator Head, Breast Cancer Unit - Champalimaud Cancer Center Lisbon, Portugal

2. POST-MENOPAUSAL PATIENTS

3. MAJOR PUBLISHED STUDIES OF ADJUVANT ENDOCRINE THERAPY WITH AN AROMATASE INHIBITOR IN POSTMENOPAUSAL WOMEN Tamoxifen x 5y N= 8010 N= 6241 N= 4742 Anastrozole x 5 years N= 3123 Letrozole x 5 years N= 5187 and N= 856 Tamoxifen x 2-3y Exemestane x 3-2y Tam x 2y Anastrozole x 3y Letrozole x 5y Anastrozole x 3y Tamoxifen x 5y N=28177

4. TRIALS OF AROMATASE INHIBITORS IN THE EARLY ADJUVANT SETTING Randomization 2 years 3 years 2 years 3 years ATAC* 5 years TAMOXIFEN 5 years† 5 years ANASTROZOLE 5 years BIG 1-98* 5 years LETROZOLE EXEMESTANE TEAM 5 years ‡ PLACEBO 5 years IES* 2–3 years 2–3 years 2–3 years ABCSG-8/ARNO** 2 years 3 years 3 years 2–3 years 2–3 years ITA 2–3 years *Registration trials; †Combination arm discontinued at first analysis; ‡TEAM protocol altered to affect switch to Exem after 2–3 years Tam; **ABCSG, randomization immediately after surgery; ARNO, randomization up to 2 years after surgery Courtesy of R. Gelber

5. Oxford Overview (Meta-Analysis) on Adjuvant Aromatase Inhibitors

6. Aromatase Inhibitors (AIs) vs Tamoxifen as Adjuvant Therapy for Postmenopausal Women with Estrogen Receptor–Positive Breast Cancer: Meta-Analyses of Randomized Trials of Monotherapy and Switching Strategies Cohort 1: Direct comparison as monotherapy Trials ATAC BIG 1-98/BCSG 18-98 R 5 years Cohort 2: Comparison after 2-3 years of tamoxifen Trials GABG/ARNO IES/BIG 2-97 ITA ABCSG VIII R 2-3 years 2-3 years 5 years Tamoxifen Aromatase inhibitor Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12.

7. Reduction 3yrs > 2yrs Meta-Analysis: Recurrence Cohort 1: Monotherapy 23% proportional reduction Cohort 2: Switching 29%proportional reduction AI-treated patients had statistically significant improvements in recurrence-free survival in both cohorts Note: These data cannot answer the question if “switching” is better Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12. Dowsett M, et al. J Clin Oncol. 2010;28(3):509-518.

8. Oxford Overview Upfront Tamoxifen vs AI Survival Summary Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12. Dowsett M, et al. J Clin Oncol. 2010;28(3):509-518.

9. Oxford Overview Delayed AI vs TamoxifenSurvival Summary Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12. Dowsett M, et al. J Clin Oncol. 2010;28(3):509-518.

10. LESSONS FROM INDIVIDUAL TRIALS

14. Sequential Treatment ComparisonsMedian Follow-up 71 months Tam->Let vs.Let Let->Tamvs. Let

15. ATAC trial design Postmenopausal women with invasive breast cancer (n = 9366) Surgery  radiotherapy  chemotherapy Randomisation 1:1:1 for 5 years Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm Tamoxifen (n = 3116) Anastrozole (n = 3125) Combination n=3125 ITT population n = 3125 Safety population n = 3092 HR+ subpopulationn = 2618 ITT population n = 3116 Safety population n = 3094 HR+ subpopulationn = 2598 ITT, intent-to-treat; HR+, hormone receptor-positive The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53

16. Hazard ratio Hazard ratio Favoursanastrozole (A) Favourstamoxifen (T) All patients (ITT)HR+ patients Allpatients HR+patients Disease-free survival 0.90 0.85 Time to recurrence 0.81 0.76 Time to distant recurrence 0.86 0.84 Contralateral breast cancer 0.68 0.60 Death − all causes 1.00 0.97 Death after recurrence 0.91 0.90 Death without recurrence 1.12 1.05 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 Hazard ratio (A / T) and 95% CI Efficacy endpoints for all patients and HR+ patients The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53

19. Results of the First Planned Analysis of the TEAM (Tamoxifen Exemestane Adjuvant Multinational) Prospective Randomized Phase III Trial in Hormone Sensitive Postmenopausal Early Breast Cancer N = 9775 accrued IES Positive Results RANDOMIZATION Postmenopausal receptor-positive women Diagnosis and adequate primary therapy of early breast cancer Tamoxifen Exemestane Exemestane Total of 5 years’ treatment Co-primary endpoints DFS at 2.75 years DFS at 5 years TEAM Trial: Revised Design 2004 Rea D, et al. Cancer Res. 2009;69(Suppl): Abstract 11.

20. RESULTS AT 5 YEARS Rea D, et al. Cancer Res. 2009;69(Suppl): Abstract 11.

21. DFS ITT and Censored Analyses BIG 1-98, ABCSG 8, and TEAM all had compliance issues and crossover to the AI van de Velde C, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 2BA.

22. BIG 1-98 Monotherapy Update Including Inverse Probability of Censoring Weighted Analysis (IPCW) Analyses Regan MM, et al. Cancer Res. 2009;69(Suppl): Abstract 16.

24. ER-positive

26. Adjuvant chemotherapy

27. Trastuzumab use

28. Celecoxib use

30. Secondary: Overall survival (OS), distant disease-free survival (DDFS), time to distant recurrence, incidence of contralateral breast cancer, incidence of clinical fractures, evaluation of breast density, cardiovascular events, toxicities, quality of lifeGoss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1.

32. Compliance is equally poor for both agents

33. End-organ/toxicity profiles are differentGoss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1. Similar results in neo-adjuvant studies; other adjuvant AI vs. AI studies ongoing (FACE trial: letrozole vs anastrozole)

34. PRE-MENOPAUSAL PATIENTS

35. ADJUVANT HT: PRE-MENOPAUSAL BC PATIENTS STILL MANY UNANSWERED QUESTIONS TAM is the mainstain of treatment! Role of ovarian suppression in the presence or absence of adjuvant CT still controversial (SOFT trial) : In the absence of CT: Tam + OA/OS seems to be superior to each drug alone In the presence of CT: data unclear Optimal duration of ovarian suppression Role of AIs (SOFT and TEXT trials) Optimal duration of adjuvant HT More than 5 years of Tam (Final results of ATLAS, aTTom and Overview) AI after Tam if pts become post-menopausal (recent MA-17 data) What to offer to patients with c.i. or intolerance to tamoxifen (OA/OS alone is a good option)

36. Suppression of Ovarian Function Trial (SOFT): Study Design Target accrual: 3000 Enrolled as of 06/09: 2387 Eligibility: Premenopausal Estradiol (E2) in the premenopausal range either after or without chemotherapy ER ≥10% and/or PgR ≥10% Tamoxifen 20 mg/day Randomization OFS* + tamoxifen OFS + exemestane 25 mg/day 5 Years *OFS = ovarian function suppression using triptorelin 3.75 mg by injection every 28 days for 5 years from randomization x 5 years or surgical oophorectomy or ovarian irradiation. Study Chairs: Prudence Francis, MD, and Gini Fleming, MD

37. Tamoxifen and Exemestane Trial (TEXT): Study Design Target accrual: 2639 Enrolled as of 06/09: 2061 Eligibility: Premenopausal ER ≥10% and/or PgR ≥10% Candidates to begin GnRH analogue from the start of adjuvant therapy Randomization GnRH* + tamoxifen ± chemotherapy GnRH* + exemestane ± chemotherapy 5 Years *GnRH = triptorelin 3.75 mg by injection every 28 days for 5 years, but oophorectomy or radiation is allowed after 6 months. Study Chairs: Barbara Walley, MD, and Olivia Pagani, MD

38. THE PRINCIPLE OF EXTENDED ADJUVANT THERAPY

39. Long-Term Risk of Breast Cancer Recurrence Remains High in ER/PR+ Patients 0.3 ER/PgR+ (n = 2257) ER/PgR– (n = 1305) 0.2 Recurrence Hazard Rate 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years PgR = progesterone receptor Saphner T, et al. J Clin Oncol. 1996;14(10):2738-2746.

40. MA.17: Trial Design Randomization (Disease-free) Letrozole 2.5 mg qd* Tamoxifen Placebo qd† 5 years early adjuvant 5 years extended adjuvant Primary endpoint: DFS Secondary endpoints: OS/safety/QOL *n = 2575 (efficacy); 2154 (safety) in the letrozole arm†n = 2582 (efficacy); 2145 (safety) in the placebo arm Goss PE, et al. N Engl J Med. 2003;349(19):1793-1802.

42. Overall Survival Node Positive Node Negative p = 0.04 p = 0.34

45. <50 years of age without menses and considered postmenopausal at diagnosis OR

46. Considered postmenopausal by virtue of menopausal LH/FSHGoss PE, et al. Cancer Res. 2009;69(Suppl): Abstract 13.

47. Among Untreated (Placebo) WomenPremenopausal Had Greater Disease Recurrence HR = 2.06 P = .09 HR = 0.78 P = .78 HR = 0.67 P = .05 % Event-Free (4-Year) Premenopausal placebo (n = 465) Postmenopausal placebo (n = 2010) Goss PE, et al. Cancer Res. 2009;69(Suppl): Abstract 13.

48. The Principle of Extended Adjuvant Therapy Unanswered questions: 1) Optimal duration 2) What about patients who have already received an AI as part of their 1st 5 years of HT?

49. Extending Duration of Adjuvant AI Therapy NCIC CTG - MA.17R (10 vs 5 Years) PLAC 5y ANY AI 5y TAM 2-5 y 0-2 y LET 5y NSABP B-42 PLAC 5y LET 5y SALSA (ABCSG 16) ANA 2y Endocrine therapy 5y (±1 y) ANA 5y 3-2y AI 2-3yTAM

50. S LE After 4 to 6 years of prior adjuvant endocrine therapy Postmenopausal, HR-positive, Node-positive Continuous letrozole x 5 years R ANDOMIZE Stratify Institution Prior ET: SERM AI Both Intermittent letrozole over 5 years 9 mos. 9 mos. 9 mos. 9 mos. 12 mos. 0 6 12 18 24 36 30 42 48 54 60 Extended Adjuvant Endocrine Therapy A: Continuous letrozole 2.5 mg daily for 5 years B: Intermittent letrozole 2.5 mg daily for the first 9 months of years 1 through 4, followed by 12 months in year 5

51. QUALITY OF LIFE & HT KEY TAKE HOME MESSAGES: 1) Different HT agents have different toxicity profiles/side effects 2) Overall, compliance is low to all agents and worse for longer durations 2) ALWAYS adapt to patients’ co-morbidities and tolerance UNANSWERED QUESTIONS: 1) Arthralgias: Mechanism and solutions 2) Cognitive function: Reason for unexpected results

52. ADVERSE EVENTS: TAMOXIFEN VS AIS Compared with tamoxifen, AIs associated with an increased risk of cardiovascular events and bone fractures, decreased risk of venous thromboembolism and endometrial cancer Amir E, et al. SABCS 2010. Abstract S2-7.

53. BIG 1.98 Trial: Cognitive Functioning Ribi K, et al. J Clin Oncol. 2009;27(15S): Abstract 510.

54. Results Ribi K, et al. J Clin Oncol. 2009;27(15S): Abstract 510.

56. Tamoxifen users scored lower on ‘information processing speed’ compared to exemestane users

58. UNEXPECTED

59. IMPORTANT CLINICAL IMPLICATIONSSchilder C, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 5013.

60. THE ROLE TRANSLATIONAL RESEARCH Biomarkers of response Pharmacogenetics & pharmacogenomics

62. For tamoxifen and AIs

63. Only ones with LEVEL 1 evidence

64. But NOT discriminative between tamoxifen and AI

65. HER2

66. Seems associated with lower endocrine responsiveness

67. NOT discriminative between tamoxifen and AI

68. PROLIFERATION (Ki67): Maybe!

69. 21-gene recurrence score (OncotypeDx®)

70. Predictive of response for both tamoxifen and AIs

71. But NOT discriminative between tamoxifen and AI

72. Others:

73. For tamoxifen: Bcl-2, AIB-1, ER-beta, MTA1s, Cyclin E: none proven

74. For AIs: Intratumoral aromatase: not proven

76. Goetz et al. 2005, 2007 (USA)

77. Schroth et al. 2007 (Germany)

78. Kiyotani et al. 2008 (Japan)

79. Newman et al. 2008 (UK)

80. Xu et al. 2008 (China)

81. Goetz et al. SABCS 2008

82. Aubert RE et al. ASCO 2009

83. CYP2D6 not associated with recurrence

84. Wegman et al. 2005, 2007 (Sweden)

85. Nowell et al. 2005 (USA)

86. Dezentje V et al. ASCO 2009 (Netherlands)

89. Both upfront and sequential (Tam-> AI & AI -> Tam) are valid options

90. Benefit of AI over Tam is small and mainly in DFS

91. Apparently all AIs were born equal!

92. Toxicity profiles are different

93. Rates of non-compliance are high (e.g. AIs >30%)

94. ALWAYS take into account co-morbidities & tolerance

95. Crucial role of patient education & physician-patient communication(some type of Ht is better than non compliance!!)

97. OA/OS should be offered in addition to Tam in the absence of CT

98. Role of OA/OS in the presence of CT still controversial

99. AI must NOT be used in pre-menopausal early BC pts, outside clinical trials (if used ALWAYS with OA/OS)

100. CAUTION: peri-menopausal patients!!!

102. ER still the most important biomarker. LEVELS OF ER do matter!

104. Early Peak of Recurrences and Distant Metastases Despite Tamoxifen Treatment 3,614 postmenopausal women with ER+ operable breast cancer, all treated with tamoxifen 5% Overall Locoregional Distant Contralateral 4% 3% Annual Recurrence Rate 2% 1% 0% 0 1 2 3 4 5 Years From Diagnosis Mansell J et al. Breast Cancer Res Treat 2008; Dec 27 [Epub ahead of print].

105. Benefits of Adjuvant Tamoxifen Tamoxifen 5 Years vs Not RECURRENCES Tamoxifen 5 Years vs Not ALL DEATHS Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005:365(9472):1687-1717.

106. ZIPP: Subgroup Analysis Adjuvant Goserelinvs Tam vs Both *First Event Sverrisdottir SABCS 2010.