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De beste aromataseremmer? Natuurlijk exemestaan! J.W.R.Nortier 4e jaarlijks mammacarcinoom symposium 29 juni 2005 AROMATASE INHIBITION androstenedione testosterone "steroidal inhibitor" catalytic site NADPH "non-steroidal inhibitor" NADP estrone estradiol Molecule structure aromatase inhibitors steroidal / aromataseinactivator androsteendion exemestane non-steroidal / aromataseinhibitors anastrozol letrozol Lecture Outline •Sequential studies •Sequential vs upfront studies •Safety Postmenopausal HR+ breast cancer: Studies of adjuvant aromatase inhibition Primary randomisation trials Switching trials Extension trials ATAC ITA MA-17 BIG 1-98 (FEMTA) ABCSG/ARNO IES HR+: hormone receptor-positive ITA: Design T (2–3 years) R A N D O M I S E T (2–3 years) A (2–3 years) • n=440 • DFS: HR 0.40, p=0.0002 in favour of anastrozole • Serious adverse events more common in women continued on tamoxifen (29 vs 14) A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003. No. and distribution of events TAM n=45 ANA n=17 13 2 19 10 10 5 contra lateral breast 2 1 endometrium 5 1 other 3 3 Deaths Breast cancer related 7 4 Deaths without relapse 3 - Local-regional (includes ipsilateral breast recurrences, relapses in localregional nodes) Distant metastases (with or without local-regional recurrences) Second primaries Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003. Event-free survival ANA TAM TAM ANA N° pts. Obs 225 45 223 17 p= 0.0002 Years Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003. Postmenopausal HR+ breast cancer: Studies of adjuvant aromatase inhibition Primary randomisation trials Switching trials Extension trials ATAC ITA MA-17 BIG 1-98 (FEMTA) ABCSG/ARNO IES HR+: hormone receptor-positive ABCSG/ARNO: Design T (2 years) R A N D O M I S E T (3 years) (n=1,606) A (3 years) (n=3,224) • Median follow-up 28 m • No preceding CT • Tumour size <2 cm: 70%; grade 1/2: 95% • LN–: 75% • HR+: 100%; ER+/PgR+: 81%; ER–/PgR+: 0.6%; ER+ /PR–: 18.3% • n=3,224 (T=1,606 and A=1,618) A: anastrazole; DFS: disease-free survival; HR: hazard ratio; T: tamoxifen Jakesz R. et al. San Antonio Breast Cancer Symposium 2004. Event-free survival Event- 100 free survival 95 (%) ANA 90 TAM 85 80 ANA vs TAM p=0.0009 HR 0.60 [95% CI 0.44-0.81] 75 0 0 At risk: TAM ANA 1 2 3 4 5 343 375 176 178 EFS time in years* 1606 1618 1217 1243 *Zero point = 2 years after surgery 858 874 593 623 Jakesz R. et al. San Antonio Breast Cancer Symposium 2004. Localization of events Events Locoregional Contralateral BC Distant recurrences Total n=3,224 TAM n=1,606 ANA n=1,618 177 44 28 121 110 24 16 75 67 20 12 46 events occuring simultaneously are included twice Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004. ABCSG/ARNO: Summary • Efficacy results favour switch to anastrozole • EFS: HR 0.60 (95% CI: 0.44, 0.81); p=0.0009 with: • 20% fewer locoregional recurrences • 20% less contralateral breast cancer • Distant RFS: HR 0.61 • Regardless of nodal stage or age • Switch especially beneficial in ER+/PgR– Serious adverse events more common in women continued on tamoxifen (29 vs 14) CI: confidence interval; EFS: event-free survival; RFS: recurrence-free survival Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004. Postmenopausal HR+ breast cancer: Studies of adjuvant aromatase inhibition Primary randomisation trials Switching trials Extension trials ATAC ITA MA-17 BIG 1-98 (FEMTA) ABCSG/ARNO IES HR+: hormone receptor-positive IES: Design Diagnosis and initial treatment of early breast cancer Tamoxifen therapy for 2-3 years R A N D O M I S A T I O N Exemestane 2-3 y 25 mg po qd (n=2,352)* Tamoxifen 2-3 y 20 mg po qd (n=2,372)* 5 Years Total Hormone Treatment * Intent to treat population Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: demographics Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: DFS DFS (%) 100 Exemestane (262 events) Tamoxifen (353 events) 75 50 25 Hazard ratio: 0.73 (95% CI: 0.62, 0.86) Log-rank test: p=0.0001 0 0 1 2 3 Years from randomisation 4 No. events/at risk Exemestane 0 / 2,352 57 / 2,233 65 / 2,081 75 / 1,413 41+24† / 661 Tamoxifen 0 / 2,372 82 / 2,243 105 / 2,062 96 / 1,359 47+23† / 650 †Events occurring more than 4 years after randomisation Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: Subgroup analysis Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: Overall survival Exemestane (152 deaths) ‘women alive’ (%) 100 Tamoxifen (187 deaths) 75 50 25 Hazard ratio: 0.83 (95% CI: 0.67, 1.02) Log-rank test: p=0.08 0 0 1 2 3 Years from randomisation 4 No. events/at risk Exemestane 0 / 2,352 Tamoxifen 0 / 2,372 †Events 18 / 2,270 23 / 2,300 41 / 2,137 41 / 1,469 37+15† / 690 53 / 2,165 49 / 1,465 41+21† / 701 occurring more than 4 years after randomisation Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: Causes of death Exemestane Tamoxifen Total 152 187 339 95 124 219 11 12 23 Intercurrent (without recurrence/CLB) 57 63 120 Vascular 15 7 22 Cardiac 13 12 25 Other cancer 13 22 35 Other 11 14 25 Unknown 5 8 13 Total number of deaths Breast cancer deaths Inc. other COD in patients with recurrence/CLB CLB: contralateral breast cancer; COD: cause of death . Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: Safety profile – CV events and MI Exemestane Tamoxifen n (%) n (%) 775 (32.9) 729 (30.7) All myocardial infarction 20 (0.9) 8 (0.4) Myocardial infarction on treatment 14 (0.7) 7 (0.3) Cardiac deaths on study 13 (0.5) 12 (0.6) Cardiovascular medical history p-values not statistically significant; Coombes et al. San Antonio Breast Cancer Symposium 2004. IES: Comparison of adverse events In favour of tamoxifen In favour of exemestane Pain in limb 2.5 Thromboembolic disease -1.4 Cramps -2.1 Diarrhoea 2.3 Arthralgia 6.7 Gynaecologic symptoms -6 -3.5 -4 -2 0 2 4 6 8 Difference between statistically significant adverse events (%) Presentation of events where the difference between treatment groups (in either incident case analysis or treatment emergent analysis) p<0.01; Coombes et al. San Antonio Breast Cancer Symposium;2004. IES: Efficacy conclusions • Switching to exemestane reduces the risk of: • Distant metastases by 34% (p=0.0001) • Contralateral breast cancer by 50% (p=0.04) • Switching to exemestane reduces the chances of dying (p=0.08) but, although more convincing than the March 2004 analysis (p=0.41), is not yet significant at the 0.05 level Coombes et al. San Antonio Breast Cancer Symposium;2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. IES: Safety conclusions • No excess of intercurrent deaths • Endocrine effects similar to tamoxifen • Musculoskeletal side effects more common in exemestane arm • No significant difference in the incidence of fractures: Exemestane 3.1%, tamoxifen 2.3% p=0.08 • Cardiovascular – more data are required but serious events are very rare • Exemestane associated with a reduction in gynaecological and thromboembolic side effects Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092. Summary SWITCH studies AIs vs tamoxifen Study AI Number of Design patients IES-031 ITA Exemestane Anastrozole 4712 426 Number of Patient countries Double-blind, randomised 37 randomised 1 population N: +, - CT: +, - N: + only CT: +, ARNO/ ABCSG Anastrozole 3224 Retrospective, pooled analysis 2 N: +, - (neg: 74%) CT: not allowed Switch vs. Upfront - level A2 evidence studies IES: 5 yr tamoxifen 2-3 yr tamoxifen 3-2 yr exemestane ATAC: 5 yr tamoxifen 5 yr anastrozole 5 yr tamoxifen & anastrozole BIG 1-98: 5 yr tamoxifen 5 yr letrozole 2 yr letrozole 3 yr tamoxifen 2 yr tamoxifen 3 yr letrozole Disease Free Survival (DFS) Parameter UPFRONT SWITCH BIG 1-98 ATAC* IES (F vs.T) (A vs. T) (E vs. T) DFS – relative risk reduction HR 0.81 (P=0.003) HR 0.83 (P=0.005) HR 0.73 DFS – absolute risk reduction 2.6% Distant Recurrences HR 0.73 HR 0.84 E: N= 150 (P=0.006) (P=0.06) T: N= 208 *** 0.4% vs 0.7% HR 0.47 HR 0.50 (p=0.125) (P=0.001) (p=0.04) Contralateral BC (p=0.0001) 3.3% 30,6 months: 4,7%** 37,4 months: NA •ATAC: mediane FU: 68 months; only HR+ population •** FU: 37.4 months (NEJM) *** HR not reported Retrospective analysis of time to recurrence for ER/PgR subgroups (Howell T et al, ATAC, SABCS 2004) Patient group HR+ ER+PgR+ ER+PgR- Hazard ratio 0.79 0.84 0.43 Patients (%) 25 Anastrozole (A) Tamoxifen (T) 20 ER+/PgR- 15 10 5 0 0 At risk: A 451 T 429 1 2 3 4 5 6 347 276 124 96 Follow-up time (years) 435 412 417 375 400 353 390 327 Annual hazard rates (%) Smoothed hazard rates for recurrence HR+ patients Which patients are these? •HER2neu+++? •Should have been treated with CT? •ER+PgR-? 3.0 2.5 2.0 1.5 1.0 Anastrozole Tamoxifen 0.5 0 0 1 2 3 4 5 6 Follow-up time (years) Howell T. et al., ATAC trial , San Antonio Breast Cancer Symposium 2004. Overall Survival UPFRONT SWITCH BIG I-98 ATAC IES (F vs.T) (A vs. T) (E vs. T) Mediane FU: Mediane FU: Mediane FU*: 26 months 68 months 37,4 months HR 0.86 HR 0.97 HR 0.83 (NS; p=?) (p=0.7) (p=0.08) * after randomisation after Tam IES: Model effect addition AI after 3 years Tam in PR+ 1,0 AI % recurrence -free 0,9 tamoxifen 0,8 0,7 0 2 4 6 8 10 12 Presentation of K. Osborne, St. Gallen Conference January 2005 14 jaar Safety Upfront and Switch - Summary of fracture risk Healthy Postmenopausal Volunteers Subar M. et al. Oral presentation ASCO 2004, abstract # 8038 Objective: To compare the effects of a steroidal or a nonsteroidal aromatase inhibitor on serum biomarkers of bone resorption and bone formation Study subjects were randomized at two investigative sites in Germany to one of four single-blind treatment groups (target enrollment = 80) Treated for 24 weeks Re-assessed at 36 weeks Primary Endpoint: Percent change from baseline in bone turnover markers at assessment week Secondary Endpoints: Baseline-adjusted area under the curve (AUC) for 0-12 weeks and 0-24 weeks of treatment calculated for all bone turnover markers, Percent change from baseline in bone turnover makers at assessment weeks 12 and 36, Percent change from baseline in lipid profiles at assessment weeks 12, 24 and 36, Percent of baseline estrogen concentrations at assessment weeks 12, 24 and 36 and safety Anastrozole 1 mg po qd Exemestane 25 mg po qd Letrozole 2.5 mg po qd Placebo po qd Bone Resorption Marker: % Change Week 24 from Baseline serum CTX-I Median with 95% CI 70.00 60.00 50.00 40.00 30.00 20.00 10.00 0.00 -10.00 Anastrozole Exemestane Letrozole Placebo Treatment *p = 0.182 *Difference across active treatment groups Subar M. et al. Oral presentation ASCO 2004, abstract # 8038 Bone Formation Marker: %Change Week 24 from Baseline Serum PINP Median with 95% CI 35.00 30.00 25.00 20.00 15.00 10.00 5.00 0.00 -5.00 -10.00 Anastrozole Exemestane Letrozole Placebo Treatment *p = 0.093 *Difference across active treatment groups Subar M. et al. Oral presentation ASCO 2004, abstract # 8038 027: Study design A total of 128 BMD-evaluable postmenopausal women with early breast cancer at low risk of relapse not given adjuvant therapy routinely during inclusion period or DCIS Exemestane 25 mg po daily for 24 months Placebo po daily for 24 months • Patients were followed up for a total of 36 months for BMD and 5 years for DFS. The study data were reviewed yearly by a Data Monitoring Committee. • Primary endpoint: Mean annual BMD loss • Secondary endpoints: lipid metabolism parameters / cardiovascular risk parameters, bone metabolism markers, coagulation parameters, sex hormones profile, DFS • BMD, bone markers, hormones, lipids, coagulation markers were measured at 0, 6, 12, 18, 24 and 36 months (follow-up) Lonning PE et al. ASCO 2004:Abstract 518. 027: BMD Lumbar spine 1.2 1.1 BMD (g/cm2) 1.0 Placebo Exemestane 0.9 0.8 Placebo 0.7 Exemestane 0.6 Femoral neck 0.5 0 6 12 Months Lonning PE et al. ASCO 2004:Abstract 518. 24 027: T-score mean changes from baseline at 2 years Exemestane n=62 Placebo n=66 Difference Lumbar spine –0.30 –0.21 0.09 Femoral neck –0.21 –0.11 0.10 4 fractures in exemestane group; 5 fractures in placebo group Lonning PE et al. ASCO 2004:Abstract 518. % BMD Change from Baseline (Mean, 95% CI) 027: 1-yr follow-up Lumbar Spine Placebo Exem estane Femoral Neck Placebo Exem estane 0 -1 -2 -3 -4 -5 -6 NS p=0.0003 24 months NS NS 36 months (1-yr FU) Lonning PE et al. ASCO 2005: poster # 531 027: Conclusions • Exemestane moderately increases bone loss in the lumbar spine (non-significant) and the femoral neck. • No patient with normal BMD at baseline became osteoporotic on either treatment. • There was no difference in the frequency of osteopenic patients becoming osteoporotic. “We conclude that pharmacodynamic effects of exemestane therapy on bone are mostly reversible within one year after treatment withdrawal. This suggests exemestane adjuvant therapy should not have long-term detrimental effects on bone metabolism.” Lonning PE et al. ASCO 2004: Abstract 518. Lonning PE et al. ASCO 2005: poster # 531 Molecule structure aromatase inhibitors steroidal / aromataseinactivator androsteendion exemestane non-steroidal / aromataseinhibitors anastrozol letrozol The metabolite of exemestane is weak androgenic. Effect of Estrogen Concentration on Androgen Sensitivity in Bone AIs: Consensus guidelines ASCO assessment of aromatase inhibitors (Journal of Clinical Oncology, 20 Jan 2005) “Optimal adjuvant hormonal therapy for a postmenopausal woman with hormone receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen.” AIs: Consensus guidelines St. Gallen consensus panel (January 2005) Tamoxifen 2–3 years Tamoxifen 5 years AI 2–3 years 72% AI in high risk 93% AI irrespective of risk 50% Upfront tamoxifen 58% ER+, PR+ upfront tamoxifen 65% ER+, PR– upfront tamoxifen 14% HER2 overexpression upfront tamoxifen 10% Final conclusions • Exemestane is superior in the sequential studies after tamoxifen. • Exemestane has the most favourable tolerability profile, in particular on the skeleton. • The TEAM trial will answer the question whether 5 years of exemestane is superior to the sequence tamoxifen followed by exemestane. Back up slides