BALKAN MCO 2011 - F. Cardoso - Hormone therapy: best options for pre and postmenopausal patients

  • 928 views
Uploaded on

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
No Downloads

Views

Total Views
928
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
0
Comments
0
Likes
1

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • Colours don’t show correctly on my screen
  • For more information on this study, go online to:http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Breast%20Cancer%20Dec%202010/Tracks/Early%20Breast%20Cancer/Capsules/S2-7.aspx

Transcript

  • 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
  • 11. BIG 1-98 Overall Design
    2-Arm Option
    RANDOMI
    ZE
    N=1,828
    Enrolled
    1998-2000
    A
    N=911
    Tamoxifen
    B
    N=917
    Letrozole
    SURGERY
    Stratify
    • Institution
    • 12. CT (Adjuvant/ Neoadjuvant)
    -Prior
    -None
    -Concurrent
    4-Arm Option
    N=8,010*
    A
    RANDOMI
    ZE
    N=1548
    Tamoxifen
    B
    *ITT: excludes 18 patients who withdrew
    consent and did not receive study treatment
    N=1546
    N=6,182
    Enrolled
    1999-2003
    Letrozole
    C
    N=1548
    Letrozole
    Tamoxifen
    D
    N=1540
    Letrozole
    Tamoxifen
    0
    2
    5
    YEARS
    Previous Analyses:
    Is 5 years Let superior to 5 years Tam as initial therapy?
    • Primary Core Analysis (PCA), Median follow-up 26 months
    • 13. Monotherapy Arm Analysis, Median follow-up 51 months
  • BIG 1-98 Monotherapy UpdateMedian Follow-up 76 months
    *Let:Tam: breast cancer events, 321:363
    second (non breast) malignancy, 101:115
    deaths without prior cancer event, 87:87
  • 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
  • 17. Annual hazard rates (%)
    4.0
    4.0
    3.0
    3.0
    2.0
    2.0
    Tamoxifen (T)
    Anastrozole (A)
    1.0
    1.0
    0.0
    0.0
    0
    1
    2
    3
    4
    5
    6
    7
    8
    9
    Follow-up time (years)
    Time to recurrence: smoothed hazard estimatesHR+ patients
    • In the HR+ subgroup, the absolute difference in recurrence increased from 2.8% after 5 years to 4.8% after 9 years
    • 18. There is a statistically significant larger carryover effect for anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01)
  • Fracture episode rates throughout the study
    4
    Annual fracture episode rates (%)
    Anastrozole (A)Tamoxifen (T)
    3
    2
    1
    0
    0
    1
    2
    3
    4
    5
    6
    7
    8
    9
    Time since randomization (years)
    At risk:
    2984
    2976
    A
    T
    2859
    2824
    2745
    2699
    2640
    2572
    2496
    2419
    2306
    2208
    2077
    2000
    1713
    1645
    702
    659
  • 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.
  • 23. MA.27 Study Design
    Open-label
    RANDOMIZE
    Anastrozole1 mg/day x 5 years
    Eligibility:
    • Postmenopausal
    • 24. ER-positive
    • 25. Early breast cancer
    Stratification
    N = 7576 patients
    May 2003 – July 2008
    Exemestane25 mg/day x 5 years
    Study Objectives:
    • Primary: Event-free survival (EFS)
    • 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 life
    Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1.
  • 31. MA.27: EFFICACY OUTCOMES
    • Exemestane is comparable to anastrozole and provides a new option for 5 years of up-front adjuvant therapy
    • 32. Compliance is equally poor for both agents
    • 33. End-organ/toxicity profiles are different
    Goss 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.
  • 41. MA.17 RESULTS: DFS BY TREATMENT DURATION
    Longer duration is associated with greater benefit
    93%
    P= 0.00008
    87%
    • Increasing benefit in estimated DFS with treatment duration
    Goss et al. N Engl J Med. 2003;349:TBD.
  • 42. Overall Survival
    Node Positive
    Node Negative
    p = 0.04
    p = 0.34
  • 43. MA.17: Menopausal Status at Primary Diagnosis
    Premenopausal n = 889
    • <50 years of age with menses but underwent subsequent bilateral oophorectomy when tamoxifen started OR
    • 44. <50 years of age with menses when tamoxifen started but became ammenhoreic during adjuvant chemotherapy or on tamoxifen
    Menopausal Status at Primary Diagnosis
    Postmenopausal n = 4277
    • ≥50 years of age without menses at diagnosis OR
    • 45. <50 years of age without menses and considered postmenopausal at diagnosis OR
    • 46. Considered postmenopausal by virtue of menopausal LH/FSH
    Goss 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.
  • 55. TEAM Trial: Cognitive Functioning
    After one year therapy:
    • Tamoxifen users performed worse than healthy controls on ‘verbal memory’ and ‘executive functioning’
    • 56. Tamoxifen users scored lower on ‘information processing speed’ compared to exemestane users
    • 57. Patients ≤ 65 years old on tamoxifen performed worse than healthy controls on executive functioning while patients ≥65 years old performed worse on verbal control and information processing speed
    No difference between exemestane and healthy controls on any of the 8 cognitive domains after 1 year of therapy
    • SAME RESULTS SEEN IN COGNITIVE SUBSTUDY OF BIG 1-98
    • 58. UNEXPECTED
    • 59. IMPORTANT CLINICAL IMPLICATIONS
    Schilder C, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 5013.
  • 60. THE ROLE TRANSLATIONAL RESEARCH
    Biomarkers of response
    Pharmacogenetics & pharmacogenomics
  • 61. Potential Predictive Markers for Endocrine Therapy
    • ER and PgR
    • 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
    • 75. Gene Signatures: All preliminary
  • The Role of Pharmacogenomics
    CYP2D6 for prediction of adjuvant HT benefit STILL CONTROVERSIAL
    • CYP2D6 associated with recurrence
    • 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)
    • 87. Goetz et al. SABCS 2009
  • TAKE HOME MESSAGES
  • 88. ADJUVANT HT: POST-MENOPAUSAL BC PATIENTS
    • Both TAM and AIs are valid options
    • 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!!)
    • 96. The LONGER the treatment duration, the HIGHER/LONGER benefit (carryover effect)
  • ADJUVANT HT: PRE-MENOPAUSAL BC PATIENTS
    • TAMOXIFEN is the main therapy
    • 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!!!
    • 101. The LONGER the treatment duration, the HIGHER/LONGER benefit (carryover effect)
  • ADJUVANT HT: TRANSLATIONAL RESEARCH
    • Urgent need for BIOMARKERS to predict benefit from different types of HT agents (Tam vs. AIs)
    • 102. ER still the most important biomarker. LEVELS OF ER do matter!
    • 103. CYP2D6 polymorphisms SHOULD NOT be used in clinical practice in treatment decisions
  • BACK-UP
  • 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.