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


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

    1. 1. ESO BALKAN MASTERCLASS IN CLINICAL ONCOLOGY<br />Dubrovnik, Croatia, 11-15 May 2011<br />Hormone therapy: best options for pre and postmenopausal patients<br />F. Cardoso, MD<br />ESO Breast Cancer Program Coordinator<br />Head, Breast Cancer Unit - Champalimaud Cancer Center<br />Lisbon, Portugal<br />
    3. 3. MAJOR PUBLISHED STUDIES OF ADJUVANT ENDOCRINE THERAPY WITH AN AROMATASE INHIBITOR IN POSTMENOPAUSAL WOMEN<br />Tamoxifen x 5y<br />N=<br />8010<br />N=<br />6241<br />N=<br />4742<br />Anastrozole x 5 years<br />N=<br />3123<br />Letrozole x 5 years<br />N=<br />5187<br />and<br />N=<br />856<br />Tamoxifen x 2-3y<br />Exemestane x 3-2y<br />Tam x 2y<br />Anastrozole x 3y<br />Letrozole x 5y<br />Anastrozole x 3y<br />Tamoxifen x 5y<br />N=28177<br />
    4. 4. TRIALS OF AROMATASE INHIBITORS IN THE EARLY ADJUVANT SETTING<br />Randomization<br />2 years<br />3 years<br />2 years<br />3 years<br />ATAC*<br />5 years<br />TAMOXIFEN<br /> 5 years†<br />5 years<br />ANASTROZOLE<br />5 years<br />BIG 1-98*<br />5 years<br />LETROZOLE<br />EXEMESTANE<br />TEAM<br />5 years ‡<br />PLACEBO<br />5 years<br />IES*<br />2–3 years<br /> 2–3 years<br />2–3 years <br />ABCSG-8/ARNO**<br />2 years<br /> 3 years<br />3 years <br />2–3 years<br /> 2–3 years<br />ITA<br />2–3 years <br />*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<br />Courtesy of R. Gelber<br />
    5. 5. Oxford Overview (Meta-Analysis) on Adjuvant Aromatase Inhibitors<br />
    6. 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<br />Cohort 1: Direct comparison as monotherapy<br />Trials<br />ATAC<br />BIG 1-98/BCSG 18-98<br />R<br />5 years<br />Cohort 2: Comparison after 2-3 years of tamoxifen<br />Trials<br />GABG/ARNO IES/BIG 2-97 ITA ABCSG VIII<br />R<br />2-3 years<br />2-3 years<br />5 years<br />Tamoxifen<br />Aromatase inhibitor<br />Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12.<br />
    7. 7. Reduction <br /> 3yrs > 2yrs<br />Meta-Analysis: Recurrence<br />Cohort 1: Monotherapy 23% proportional reduction<br />Cohort 2: Switching 29%proportional reduction<br />AI-treated patients had statistically significant improvements in recurrence-free survival in both cohorts<br />Note: These data cannot answer the question if “switching” is better<br />Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12.<br />Dowsett M, et al. J Clin Oncol. 2010;28(3):509-518.<br />
    8. 8. Oxford Overview Upfront Tamoxifen vs AI Survival Summary <br />Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12.<br />Dowsett M, et al. J Clin Oncol. 2010;28(3):509-518.<br />
    9. 9. Oxford Overview Delayed AI vs TamoxifenSurvival Summary <br />Ingle JN, et al. Cancer Res. 2009;69(Suppl 2): Abstract 12. Dowsett M, et al. J Clin Oncol. 2010;28(3):509-518.<br />
    11. 11. BIG 1-98 Overall Design<br />2-Arm Option<br />RANDOMI<br />ZE<br />N=1,828<br />Enrolled<br />1998-2000<br />A<br />N=911<br />Tamoxifen<br />B<br />N=917<br />Letrozole<br />SURGERY<br /> Stratify<br /><ul><li>Institution
    12. 12. CT (Adjuvant/ Neoadjuvant)</li></ul> -Prior<br /> -None<br /> -Concurrent<br />4-Arm Option<br />N=8,010*<br />A<br />RANDOMI<br />ZE<br />N=1548<br />Tamoxifen<br />B<br />*ITT: excludes 18 patients who withdrew <br />consent and did not receive study treatment<br />N=1546<br />N=6,182<br />Enrolled<br />1999-2003<br />Letrozole<br />C<br />N=1548<br />Letrozole<br />Tamoxifen<br />D<br />N=1540<br />Letrozole<br />Tamoxifen<br />0<br />2<br />5<br />YEARS<br />Previous Analyses: <br />Is 5 years Let superior to 5 years Tam as initial therapy?<br /><ul><li> Primary Core Analysis (PCA), Median follow-up 26 months
    13. 13. Monotherapy Arm Analysis, Median follow-up 51 months</li></li></ul><li>BIG 1-98 Monotherapy UpdateMedian Follow-up 76 months<br />*Let:Tam: breast cancer events, 321:363<br /> second (non breast) malignancy, 101:115<br /> deaths without prior cancer event, 87:87<br />
    14. 14. Sequential Treatment ComparisonsMedian Follow-up 71 months<br />Tam->Let vs.Let<br />Let->Tamvs. Let<br />
    15. 15. ATAC trial design<br />Postmenopausal women with invasive breast cancer <br />(n = 9366)<br />Surgery  radiotherapy  chemotherapy<br />Randomisation 1:1:1 for 5 years<br />Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm<br />Tamoxifen (n = 3116)<br />Anastrozole <br />(n = 3125)<br />Combination<br />n=3125<br />ITT population n = 3125 <br />Safety population<br />n = 3092<br />HR+ subpopulationn = 2618<br />ITT population n = 3116 <br />Safety population<br />n = 3094<br />HR+ subpopulationn = 2598<br />ITT, intent-to-treat; HR+, hormone receptor-positive<br />The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53<br />
    16. 16. Hazard ratio<br />Hazard ratio<br />Favoursanastrozole (A)<br />Favourstamoxifen (T)<br />All patients (ITT)HR+ patients<br />Allpatients<br />HR+patients<br />Disease-free survival<br />0.90<br />0.85<br />Time to recurrence<br />0.81<br />0.76<br />Time to distant recurrence<br />0.86<br />0.84<br />Contralateral breast cancer<br />0.68<br />0.60<br />Death − all causes<br />1.00<br />0.97<br />Death after recurrence<br />0.91<br />0.90<br />Death without recurrence<br />1.12<br />1.05<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.5<br />2.0<br />Hazard ratio (A / T) and 95% CI<br />Efficacy endpoints for all patients and HR+ patients<br />The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53<br />
    17. 17. Annual hazard rates (%) <br />4.0<br />4.0<br />3.0<br />3.0<br />2.0<br />2.0<br />Tamoxifen (T)<br />Anastrozole (A)<br />1.0<br />1.0<br />0.0<br />0.0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />8<br />9<br />Follow-up time (years)<br />Time to recurrence: smoothed hazard estimatesHR+ patients<br /><ul><li>In the HR+ subgroup, the absolute difference in recurrence increased from 2.8% after 5 years to 4.8% after 9 years
    18. 18. There is a statistically significant larger carryover effect for anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01)</li></li></ul><li>Fracture episode rates throughout the study<br />4<br />Annual fracture episode rates (%)<br />Anastrozole (A)Tamoxifen (T)<br />3<br />2<br />1<br />0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />8<br />9<br />Time since randomization (years)<br />At risk:<br />2984<br />2976<br />A<br />T<br />2859<br />2824<br />2745<br />2699<br />2640<br />2572<br />2496<br />2419<br />2306<br />2208<br />2077<br />2000<br />1713<br />1645<br />702<br />659<br />
    19. 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<br />N = 9775 accrued<br />IES Positive Results <br />RANDOMIZATION<br />Postmenopausal receptor-positive women<br />Diagnosis and adequate primary therapy of early breast cancer<br />Tamoxifen<br /> Exemestane<br />Exemestane<br />Total of 5 years’ treatment<br />Co-primary endpoints <br />DFS at 2.75 years<br />DFS at 5 years<br />TEAM Trial: Revised Design 2004<br />Rea D, et al. Cancer Res. 2009;69(Suppl): Abstract 11.<br />
    20. 20. RESULTS AT 5 YEARS<br />Rea D, et al. Cancer Res. 2009;69(Suppl): Abstract 11.<br />
    21. 21. DFS ITT and Censored Analyses<br />BIG 1-98, ABCSG 8, and TEAM all had compliance issues and crossover to the AI<br />van de Velde C, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 2BA.<br />
    22. 22. BIG 1-98 Monotherapy Update<br />Including Inverse Probability of Censoring Weighted Analysis (IPCW) Analyses<br />Regan MM, et al. Cancer Res. 2009;69(Suppl): Abstract 16.<br />
    23. 23. MA.27 Study Design<br />Open-label<br />RANDOMIZE<br />Anastrozole1 mg/day x 5 years<br />Eligibility:<br /><ul><li>Postmenopausal
    24. 24. ER-positive
    25. 25. Early breast cancer</li></ul>Stratification<br /><ul><li>Lymph node status
    26. 26. Adjuvant chemotherapy
    27. 27. Trastuzumab use
    28. 28. Celecoxib use
    29. 29. Aspirin use</li></ul>N = 7576 patients<br />May 2003 – July 2008<br />Exemestane25 mg/day x 5 years<br />Study Objectives:<br /><ul><li>Primary: Event-free survival (EFS)
    30. 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</li></ul>Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1.<br />
    31. 31. MA.27: EFFICACY OUTCOMES<br /><ul><li>Exemestane is comparable to anastrozole and provides a new option for 5 years of up-front adjuvant therapy
    32. 32. Compliance is equally poor for both agents
    33. 33. End-organ/toxicity profiles are different</li></ul>Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-1.<br />Similar results in neo-adjuvant studies; other adjuvant AI vs. AI studies ongoing (FACE trial: letrozole vs anastrozole)<br />
    35. 35. ADJUVANT HT: PRE-MENOPAUSAL BC PATIENTS<br />STILL MANY UNANSWERED QUESTIONS<br />TAM is the mainstain of treatment!<br />Role of ovarian suppression in the presence or absence of adjuvant CT still controversial (SOFT trial) :<br />In the absence of CT: Tam + OA/OS seems to be superior to each drug alone<br />In the presence of CT: data unclear<br />Optimal duration of ovarian suppression<br />Role of AIs (SOFT and TEXT trials)<br />Optimal duration of adjuvant HT <br />More than 5 years of Tam (Final results of ATLAS, aTTom and Overview)<br />AI after Tam if pts become post-menopausal (recent MA-17 data)<br />What to offer to patients with c.i. or intolerance to tamoxifen (OA/OS alone is a good option)<br />
    36. 36. Suppression of Ovarian Function Trial (SOFT): Study Design<br />Target accrual: 3000<br />Enrolled as of 06/09: 2387<br />Eligibility:<br />Premenopausal<br />Estradiol (E2) in the premenopausal range either after or without chemotherapy<br />ER ≥10% and/or PgR ≥10%<br />Tamoxifen 20 mg/day<br />Randomization<br />OFS* + tamoxifen<br />OFS + exemestane 25 mg/day<br />5 Years<br />*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.<br />Study Chairs: Prudence Francis, MD, and Gini Fleming, MD<br />
    37. 37. Tamoxifen and Exemestane Trial (TEXT): Study Design<br />Target accrual: 2639<br />Enrolled as of 06/09: 2061<br />Eligibility:<br />Premenopausal<br />ER ≥10% and/or PgR ≥10%<br />Candidates to begin GnRH analogue from the start of adjuvant therapy<br />Randomization<br />GnRH* + tamoxifen ± <br />chemotherapy<br />GnRH* + exemestane ± <br />chemotherapy<br />5 Years<br />*GnRH = triptorelin 3.75 mg by injection every 28 days for 5 years, but oophorectomy or radiation is allowed after 6 months.<br />Study Chairs: Barbara Walley, MD, and Olivia Pagani, MD<br />
    39. 39. Long-Term Risk of Breast Cancer Recurrence Remains High in ER/PR+ Patients<br />0.3<br />ER/PgR+ (n = 2257)<br />ER/PgR– (n = 1305)<br />0.2<br />Recurrence Hazard Rate<br />0.1<br />0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />8<br />9<br />10<br />11<br />12<br />Years<br />PgR = progesterone receptor<br />Saphner T, et al. J Clin Oncol. 1996;14(10):2738-2746.<br />
    40. 40. MA.17: Trial Design <br />Randomization<br />(Disease-free)<br />Letrozole 2.5 mg qd*<br />Tamoxifen<br />Placebo qd†<br />5 years early adjuvant<br />5 years extended adjuvant<br />Primary endpoint: DFS<br />Secondary endpoints: OS/safety/QOL<br />*n = 2575 (efficacy); 2154 (safety) in the letrozole arm†n = 2582 (efficacy); 2145 (safety) in the placebo arm<br />Goss PE, et al. N Engl J Med. 2003;349(19):1793-1802.<br />
    41. 41. MA.17 RESULTS: DFS BY TREATMENT DURATION<br />Longer duration is associated with greater benefit<br />93%<br />P= 0.00008<br />87%<br /><ul><li>Increasing benefit in estimated DFS with treatment duration</li></ul>Goss et al. N Engl J Med. 2003;349:TBD.<br />
    42. 42. Overall Survival <br />Node Positive<br />Node Negative<br />p = 0.04<br />p = 0.34<br />
    43. 43. MA.17: Menopausal Status at Primary Diagnosis<br />Premenopausal n = 889<br /><ul><li> <50 years of age with menses but underwent subsequent bilateral oophorectomy when tamoxifen started OR
    44. 44. <50 years of age with menses when tamoxifen started but became ammenhoreic during adjuvant chemotherapy or on tamoxifen</li></ul>Menopausal Status at Primary Diagnosis<br />Postmenopausal n = 4277<br /><ul><li> ≥50 years of age without menses at diagnosis OR
    45. 45. <50 years of age without menses and considered postmenopausal at diagnosis OR
    46. 46. Considered postmenopausal by virtue of menopausal LH/FSH</li></ul>Goss PE, et al. Cancer Res. 2009;69(Suppl): Abstract 13.<br />
    47. 47. Among Untreated (Placebo) WomenPremenopausal Had Greater Disease Recurrence<br />HR = 2.06<br />P = .09<br />HR = 0.78<br />P = .78<br />HR = 0.67<br />P = .05<br />% Event-Free (4-Year)<br />Premenopausal placebo (n = 465)<br />Postmenopausal placebo (n = 2010)<br />Goss PE, et al. Cancer Res. 2009;69(Suppl): Abstract 13.<br />
    48. 48. The Principle of Extended Adjuvant Therapy<br />Unanswered questions:<br />1) Optimal duration<br />2) What about patients who have already received an AI as part of their 1st 5 years of HT?<br />
    49. 49. Extending Duration of Adjuvant AI Therapy<br />NCIC CTG - MA.17R (10 vs 5 Years) <br />PLAC 5y<br />ANY AI 5y<br />TAM 2-5 y<br />0-2 y<br />LET 5y<br />NSABP B-42 <br />PLAC 5y<br />LET 5y<br />SALSA (ABCSG 16) <br />ANA 2y<br />Endocrine therapy 5y<br />(±1 y)<br />ANA 5y<br />3-2y AI<br />2-3yTAM<br />
    50. 50. S LE<br />After 4 to 6 years of prior adjuvant endocrine therapy<br />Postmenopausal, HR-positive, Node-positive<br />Continuous letrozole x 5 years <br />R<br />ANDOMIZE<br />Stratify<br />Institution<br />Prior ET:<br /> SERM<br /> AI<br /> Both<br />Intermittent letrozole over 5 years<br />9 mos.<br />9 mos.<br />9 mos.<br />9 mos.<br />12 mos.<br />0<br />6<br />12<br />18<br />24<br />36<br />30<br />42<br />48<br />54<br />60<br />Extended Adjuvant Endocrine Therapy<br />A: Continuous letrozole 2.5 mg daily for 5 years<br />B: Intermittent letrozole 2.5 mg daily for the first 9 months of years 1 through 4, followed by 12 months in year 5<br />
    51. 51. QUALITY OF LIFE & HT<br />KEY TAKE HOME MESSAGES:<br />1) Different HT agents have different toxicity profiles/side effects<br />2) Overall, compliance is low to all agents and worse for longer durations<br />2) ALWAYS adapt to patients’ co-morbidities and tolerance<br />UNANSWERED QUESTIONS:<br />1) Arthralgias: Mechanism and solutions<br />2) Cognitive function: Reason for unexpected results<br />
    52. 52. ADVERSE EVENTS: TAMOXIFEN VS AIS<br /> Compared with tamoxifen, AIs associated with an increased risk of cardiovascular events and bone fractures, decreased risk of venous thromboembolism and endometrial cancer<br />Amir E, et al. SABCS 2010. Abstract S2-7.<br />
    53. 53. BIG 1.98 Trial: Cognitive Functioning<br />Ribi K, et al. J Clin Oncol. 2009;27(15S): Abstract 510.<br />
    54. 54. Results<br />Ribi K, et al. J Clin Oncol. 2009;27(15S): Abstract 510.<br />
    55. 55. TEAM Trial: Cognitive Functioning<br />After one year therapy:<br /><ul><li>Tamoxifen users performed worse than healthy controls on ‘verbal memory’ and ‘executive functioning’
    56. 56. Tamoxifen users scored lower on ‘information processing speed’ compared to exemestane users
    57. 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</li></ul>No difference between exemestane and healthy controls on any of the 8 cognitive domains after 1 year of therapy<br /><ul><li>SAME RESULTS SEEN IN COGNITIVE SUBSTUDY OF BIG 1-98
    58. 58. UNEXPECTED
    59. 59. IMPORTANT CLINICAL IMPLICATIONS</li></ul>Schilder C, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 5013.<br />
    60. 60. THE ROLE TRANSLATIONAL RESEARCH<br />Biomarkers of response<br />Pharmacogenetics & pharmacogenomics<br />
    61. 61. Potential Predictive Markers for Endocrine Therapy<br /><ul><li>ER and PgR
    62. 62. For tamoxifen and AIs
    63. 63. Only ones with LEVEL 1 evidence
    64. 64. But NOT discriminative between tamoxifen and AI
    65. 65. HER2
    66. 66. Seems associated with lower endocrine responsiveness
    67. 67. NOT discriminative between tamoxifen and AI
    68. 68. PROLIFERATION (Ki67): Maybe!
    69. 69. 21-gene recurrence score (OncotypeDx®)
    70. 70. Predictive of response for both tamoxifen and AIs
    71. 71. But NOT discriminative between tamoxifen and AI
    72. 72. Others:
    73. 73. For tamoxifen: Bcl-2, AIB-1, ER-beta, MTA1s, Cyclin E: none proven
    74. 74. For AIs: Intratumoral aromatase: not proven
    75. 75. Gene Signatures: All preliminary</li></li></ul><li>The Role of Pharmacogenomics <br />CYP2D6 for prediction of adjuvant HT benefit STILL CONTROVERSIAL<br /><ul><li>CYP2D6 associated with recurrence
    76. 76. Goetz et al. 2005, 2007 (USA)
    77. 77. Schroth et al. 2007 (Germany)
    78. 78. Kiyotani et al. 2008 (Japan)
    79. 79. Newman et al. 2008 (UK)
    80. 80. Xu et al. 2008 (China)
    81. 81. Goetz et al. SABCS 2008
    82. 82. Aubert RE et al. ASCO 2009
    83. 83. CYP2D6 not associated with recurrence
    84. 84. Wegman et al. 2005, 2007 (Sweden)
    85. 85. Nowell et al. 2005 (USA)
    86. 86. Dezentje V et al. ASCO 2009 (Netherlands)
    87. 87. Goetz et al. SABCS 2009</li></li></ul><li>TAKE HOME MESSAGES<br />
    88. 88. ADJUVANT HT: POST-MENOPAUSAL BC PATIENTS<br /><ul><li> Both TAM and AIs are valid options
    89. 89. Both upfront and sequential (Tam-> AI & AI -> Tam) are valid options
    90. 90. Benefit of AI over Tam is small and mainly in DFS
    91. 91. Apparently all AIs were born equal!
    92. 92. Toxicity profiles are different
    93. 93. Rates of non-compliance are high (e.g. AIs >30%)
    94. 94. ALWAYS take into account co-morbidities & tolerance
    95. 95. Crucial role of patient education & physician-patient communication(some type of Ht is better than non compliance!!)
    96. 96. The LONGER the treatment duration, the HIGHER/LONGER benefit (carryover effect) </li></li></ul><li>ADJUVANT HT: PRE-MENOPAUSAL BC PATIENTS<br /><ul><li>TAMOXIFEN is the main therapy
    97. 97. OA/OS should be offered in addition to Tam in the absence of CT
    98. 98. Role of OA/OS in the presence of CT still controversial
    99. 99. AI must NOT be used in pre-menopausal early BC pts, outside clinical trials (if used ALWAYS with OA/OS)
    100. 100. CAUTION: peri-menopausal patients!!!
    101. 101. The LONGER the treatment duration, the HIGHER/LONGER benefit (carryover effect) </li></li></ul><li>ADJUVANT HT: TRANSLATIONAL RESEARCH<br /><ul><li> Urgent need for BIOMARKERS to predict benefit from different types of HT agents (Tam vs. AIs)
    102. 102. ER still the most important biomarker. LEVELS OF ER do matter!
    103. 103. CYP2D6 polymorphisms SHOULD NOT be used in clinical practice in treatment decisions</li></li></ul><li>BACK-UP<br />
    104. 104. Early Peak of Recurrences and Distant Metastases Despite Tamoxifen Treatment<br />3,614 postmenopausal women with ER+ operable breast cancer, all treated with tamoxifen<br />5%<br />Overall<br />Locoregional<br />Distant<br />Contralateral<br />4%<br />3%<br />Annual Recurrence Rate<br />2%<br />1%<br />0%<br />0<br />1<br />2<br />3<br />4<br />5<br />Years From Diagnosis<br />Mansell J et al. Breast Cancer Res Treat 2008; Dec 27 [Epub ahead of print].<br />
    105. 105. Benefits of Adjuvant Tamoxifen<br />Tamoxifen 5 Years vs Not<br />RECURRENCES<br />Tamoxifen 5 Years vs Not<br />ALL DEATHS<br />Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005:365(9472):1687-1717.<br />
    106. 106. ZIPP: Subgroup Analysis Adjuvant Goserelinvs Tam vs Both<br />*First Event<br />Sverrisdottir SABCS 2010.<br />