OPTIMAL ENDOCRINE THERAPY IN EARLY BREAST CANCER

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1 OPTIMAL ENDOCRINE THERAPY IN EARLY BREAST CANCER STEPHEN E. JONES, M.D. US ONCOLOGY RESEARCH THE WOODLANDS, TX TOPICS PREMENOPAUSAL BREAST CANCER POSTMENOPAUSAL BREAST CANCER THE FUTURE TOPICS PREMENOPAUSAL BREAST CANCER POSTMENOPAUSAL BREAST CANCER THE FUTURE

2 Ovarian Ablation or Suppression vs. None in ER + or ER UK Breast cancer Recurrence Breast Cancer Mortality 4.3% 3.2% Lancet. 2005;365: yr 5 y OA/OS in Premenopausal ESBC Patients Does OA/OS add to standard tamoxifen in premenopausal ER+ ESBC pts?

3 Overall Survival HR+ Premenopausal First-Line MBC Pts Klijn J, et al, JNCI, 92:903, 2000 Chemoendocrine Therapy for Premenopausal Women E5188 INT 0101 CAF Premenopausal CAF -- Goserelin (Z) X 5 y Receptor-positive Node-positive n=1503 CAF -- Goserelin (Z) + (T) X 5 y < 35 10% % >39 71% Davidson, J Clin Oncol 2005 Proba ability Disease-Free Survival for Women Under 40 Years E5188 INT yr DFS 0.2 CAF CAFZ 48% 55% CAFZT 64% Disease-Free Survival (Years)

Disease-Free Survival for Women 40 Years or Over bility Proba 1.0 0.

0 6 7 8 9 10 Disease-Free Survival (Years) LHRH Agonist plus AI for

4 Disease-Free Survival for Women 40 Years or Over bility Proba yr DFS CAF 61% CAFZ 62% CAFZT 69% Disease-Free Survival (Years) LHRH Agonist plus AI for Early Breast Cancer? 75% T1 and 30% node + Gnant, M, et al. Lancet Oncology 9:840-9, 2008

5 Enrollment Completed!! Ovarian Function Suppression in Premenopausal Women Available data suggest that amenorrhea benefits premenopausal HR+ EBC patients in addition to tamoxifen Uncertain whether addition of LHRH agonist or oophorectomy adds to tamoxifen in women who have had adjuvant chemotherapy. May be some benefit in women under 40. Do premenopausal ER+ pts need long duration Endocrine Therapy as in MA-17 then AI? Meta-analysis Longer vs Shorter

6 Extended Adjuvant Endocrine Therapy in Premenopausal Early Stage Breast Cancer An analysis of younger women from NCIC CTG MA17 P. Goss, J. Ingle, S. Martino, N. Robert, H. Muss, R. Livingston, N. Davidson, E. Perez, D. Cameron, KI. Pritchard, T.Whelan, L. Shepherd, M. Palmer, D. Tu. Participating Collaborative Groups NCIC CTG, ECOG, SWOG, CALGB, NCCTG, BIG SABCS Premenopausal Women had a Greater Benefit rtion Disease Free Porpor # At Risk Pre-menopausal Abs Diff in 4 year DFS=10.1% HR=0.25 P< Pre - Letrozole Pre - Placebo Post - Letrozole Post - Placebo Post-menopausal Abs Diff in 4 year DFS=3.3% HR=0.69 P= Premenopausal Women did better than Postmenopausal HR=0.39, p= Time from randomization (months) # At Risk(Letrozole Pre-menopausal) # At Risk(Letrozole Post-menopausal) # At Risk(Placebo Pre-menopausal) # At Risk(Placebo Post-menopausal) Letrozole Pre-menopausal Placebo Pre-menopausal Letrozole Post-menopausal Placebo Post-menopausal Endocrine Therapy for Premenopausal HR+ EBC Patients: Summary Endocrine therapy of utmost importance in HR+ premenopausal EBC Premenopausal HR+ pts appear to benefit from amenorrhea in addition to tamoxifen - US/Canada guidelines don t recommend ovarian suppression Prolonged endocrine therapy with AI following tamoxifen of benefit in N- and N+ patients who have become postmenopausal

7 TOPICS PREMENOPAUSAL BREAST CANCER POSTMENOPAUSAL BREAST CANCER THE FUTURE Initial adjuvant trial Adjuvant Aromatase Trials Randomization Randomization Aromatase inhibitor Randomization Trial ATAC, BIG 1-98 Switching trial Randomization 2-3 years prior tamoxifen Aromatase inhibitor ARNO 95, ITA, IES ABCSG 8 Upfront vs. Switching Initial and sequencing trial Extended adjuvant trial Aromatase inhibitor Aromatase inhibitor Aromatase inhibitor Aromatase inhibitor Aromatase inhibitor Randomisation TEAM BIG 1-98 MA.17, ABCSG-6A, NSABP B-33 Aromatase inhibitor 5 years prior tamoxifen Placebo 0 Time (years) 5 TEAM Trial: Revised Design 2004 N = 9775 accrued Postmenopausal receptor-positive women Diagnosis and adequate primary therapy of early breast cancer R A N D O M I Z A T I O N Exemestane Total of 5 years treatment Co-primary end points DFS at 2.75 years DFS at 5 years IES Positive Results Exemestane 23

8 Disease Free Survival 5 y (ITT) HR = 0.97 (95% CI ) P = bility Probab T E 5yrs T E = 85.4% 0.0 Exe 5yrs Exe = 85.7% Numbers at risk T E: / / / / /2529 Exe: / / / / /2564 OVERALL SURVIVAL BY TREATMENT (ITT) HR = 1.00 (95%CI ) P = Overall Survival (ITT) ility Probab T E 5yrs T E = 90.6 % 0.0 Exe 5yrs Exe = 90.5 % Numbers at risk: T E: / / / / /2613 Exe: / / / / /2742 WHAT TO DO TODAY? THE FIRST 5 YEARS -Initial AI use: no survival advantage -TAM/AI switch: modest survival advantage -TEAM trial shows no difference in outcome between initial AI or TAM/AI switch (DFS and OS) C li d b h lth -Compliance and bone health LONGER TREATMENT -Compliance -Monitor bone health

9 Eligibility: Postmenopausal ER-positive Early breast cancer Stratification Lymph node status Adjuvant chemotherapy Trastuzumab use Celecoxib use Aspirin use MA.27 Study Design Open-label R A N D O M I Z E Anastrozole 1 mg/day x 5 years N = 7576 patients May 2003 July 2008 Exemestane 25 mg/day x 5 years Study Objectives: Primary: Event-free survival (EFS) 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 S MA.27 Event-Free Survival Stratified HR P All patients 1.02 ( ).85 Lymph node status Node-negative (71%) 1.04 ( ).726 Node-positive/unknown (29%) 0.99 ( ).896 Adjuvant chemotherapy use No (69%) 1.01 ( ).894 Yes (31%) 1.02 ( ).887 Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S MA.27: Secondary Efficacy Outcomes Number (%) of Events Stratified HR Outcome Exemestane Anastrozole (95% CI) P Value OS 208 (5.5) 224 (5.9) 0.93 ( ).64 DDFS 157 (4.1) 164 (4.3) 0.95 ( ).46 DSS 89 (2.4) 98 (2.6) 0.93 ( ).62 CI = confidence interval; DDFS = distant recurrence; DSS = disease-specific survival; HR = hazard ratio; OS = overall survival Goss PE, et al. Cancer Res. 2010;70(24 Suppl): Abstract S

10 FACE: Letrozole vs Anastrozole Clinical Evaluation Phase IIIb Head-to-Head Comparison Study Design EBC ER+ Postmenopausal Node+ Postmenopausal FSH/LH/E 2 levels De novo adjuvant ET R A N D O M I Z E l l Letrozole 2.5 mg/qd Anastrozole 1 mg/qd Primary end point DFS Secondary end points Safety OS Time to distant metastasis Time to contralateral disease Breast cancer specific survival N=~4000 FSH = follicle-stimulating hormone; LH = luteinizing hormone; ET = endocrine therapy. Extended Adjuvant Therapy with AIs After ~5 Years MA 17 (5000pts) 5 years 5 years Placebo Letrozole HR 4 Year DFS % Goss et al. JNCI NSABP-B33 (1598pts) 5 years 5 years Placebo Exemestane ABCSG-6a (856pts) 3 years 5 years Placebo + AG Anastrozole 0.44 p Mamounas et al. JCO ; p 0.05 Update of Jakesz et al. J Clin Oncol 2005;23(16S):10s. Current Clinical Trials of AIs: Duration of AI Therapy MA.17R Placebo (n=800) Letrozole* n=900 n=900 NSABP B42 Any AI x 5 Tam x 2 Any AI x 3 Placebo x 5 Letrozole x 5

HAVE WE MADE PROGRESS? Patients and Methods The TEAM ( Exemestane Adjuvant Multinational) trial is now a mature adjuvant endocrine study comparing a switch strategy ( to Exemestane) vs.

11 HAVE WE MADE PROGRESS? Patients and Methods The TEAM ( Exemestane Adjuvant Multinational) trial is now a mature adjuvant endocrine study comparing a switch strategy ( to Exemestane) vs. Exemestane alone for 5 years (Figure 1). Postmenopausal women with early stage breast cancer (N=9,766) R A N D O M I Z A T I O N Exemestane 25 mg po qd x 5 yrs Exemestane 20 mg po qd 25 mg po qd x yrs x yrs 34 Results 9,766 women have been followed for 5.14 years with 67% having at least 5 years of follow-up. 608 (6.2%) have died due to breast cancer and 435 (4.5%) from other causes. 5 years OS is 90.5% (95% CI ) 1) 35

12 Cumulative Probability of Dying from Breast Cancer or Other Causes All patients Cause-specific death P < Alive Other causes Breast cancer 36 Cumulative Probability of Dying by Axillary Lymph Node Status N positive N negative Cause-specific death P < Alive Other causes Breast cancer Cause-specific death P = Alive Other causes Breast cancer 37 Probability of Dying by Age-Group Age < 60 Age Cause-specif fic death P < Alive Other causes Breast cancer Cause-specif fic death P < Alive Other causes Breast cancer 38

13 Probability of Dying by Age-Group cont d Age >= 70 Cause-specific death P < Alive Other causes Breast cancer 39 TOPICS PREMENOPAUSAL BREAST CANCER POSTMENOPAUSAL BREAST CANCER THE FUTURE WE HAVE MADE PROGRESS!!! TAKE HOME MESSAGES FOR ENDOCRINE SENSTIVE BREAST CANCER, TAMOXIFEN REMAINS A POTENT LIFE-SAVING AGENT DON T FORGET ABOUT OVARIAN SUPPRESSION IN SELECTED PREMENOPAUSAL PATIENTS 3 AROMATASE INHIBITORS ARE SUPERIOR TO TAMOXIFEN 5 YEARS OF AN AI OR SWITCHING FROM TAM TO AN AI ARE EQUAL LONGER TREATMENT SHOULD BE CONSIDERED MOST WOMEN WITH ENDOCRINE SENSITIVE BREAST CANCER SURVIVE THE CANCER COMPLIANCE WITH TAKING LONGTERM MEDICATIONS STILL IS A CHALLENGE ADDING BIOLOGICS MIGHT FURTHER ADD TO OUTCOME 41

14 THANK YOU

Endocrine Therapy in Premenopausal Breast Cancer. Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology, PA US Oncology

Endocrine Therapy in Premenopausal Breast Cancer Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology, PA US Oncology Ovarian Ablation or Suppression vs. Not in ER + or ER UK Breast Cancer