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De beste aromataseremmer? Natuurlijk exemestaan!

De beste aromataseremmer? Natuurlijk exemestaan!. J.W.R.Nortier 4e jaarlijks mammacarcinoom symposium 29 juni 2005. AROMATASE INHIBITION. androstenedione. estrone. "steroidal inhibitor". testosterone. estradiol. catalytic site. NADPH.

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De beste aromataseremmer? Natuurlijk exemestaan!

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  1. De beste aromataseremmer?Natuurlijk exemestaan! J.W.R.Nortier 4e jaarlijks mammacarcinoom symposium 29 juni 2005

  2. AROMATASE INHIBITION androstenedione estrone "steroidal inhibitor" testosterone estradiol catalytic site NADPH "non-steroidal inhibitor" NADP

  3. Molecule structure aromatase inhibitors steroidal / aromatase-inactivator non-steroidal / aromatase-inhibitors androsteendion exemestane anastrozol letrozol

  4. Lecture Outline • Sequential studies • Sequential vs upfront studies • Safety

  5. Postmenopausal HR+ breast cancer:Studies of adjuvant aromatase inhibition HR+: hormone receptor-positive

  6. ITA: Design R A N D O M I S E T (2–3 years) 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.

  7. No. and distribution of events Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.

  8. Event-free survival ANA TAM % Surviving N° pts. Obs p= TAM 225 45 ANA 223 17 0.0002 Years Boccardo F et al. San Antonio Breast Cancer Symposium, December 2003.

  9. Postmenopausal HR+ breast cancer:Studies of adjuvant aromatase inhibition HR+: hormone receptor-positive

  10. ABCSG/ARNO: Design R A N D O M I S E T (3 years) (n=1,606) T (2 years) 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.

  11. Event-free survival Event-free survival (%) 100 ANA 95 90 TAM 85 80 ANA vs TAM p=0.0009HR 0.60 [95% CI 0.44-0.81] 75 0 0 1 2 3 4 5 EFS time in years* At risk: 858 1606 1217 343 176 TAM 593 874 1618 1243 375 178 ANA 623 *Zero point = 2 years after surgery Jakesz R. et al. San Antonio Breast Cancer Symposium 2004.

  12. Localization of events Total TAM ANA n=3,224 n=1,606 n=1,618 Events 177 110 67 Locoregional 44 24 20 Contralateral BC 28 16 12 Distant recurrences 121 75 46 events occuring simultaneously are included twice Jakesz R. et al. San Antonio Breast Cancer Symposium, December 2004.

  13. 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.

  14. Postmenopausal HR+ breast cancer:Studies of adjuvant aromatase inhibition HR+: hormone receptor-positive

  15. Exemestane2-3 y 25 mg po qd(n=2,352)* Tamoxifen 2-3 y20 mg po qd (n=2,372)* IES: Design R A N D O M I S A T I O N Diagnosis and initial treatment of early breast cancer Tamoxifen therapy for 2-3 years 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.

  16. IES: demographics Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

  17. IES: DFS 100 Exemestane (262 events) Tamoxifen (353 events) 75 DFS (%) 50 25 Hazard ratio: 0.73 (95% CI: 0.62, 0.86) Log-rank test: p=0.0001 0 0 1 2 3 4 Years from randomisation †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.

  18. IES: Subgroup analysis Coombes et al. San Antonio Breast Cancer Symposium 2004; Coombes et al. N Engl J Med. 2004;350:1081-1092.

  19. IES: Overall survival Exemestane (152 deaths) 100 Tamoxifen (187 deaths) 75 ‘women alive’ (%) 50 25 Hazard ratio: 0.83 (95% CI: 0.67, 1.02) Log-rank test: p=0.08 0 0 1 2 3 4 Years from randomisation †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.

  20. IES: Causes of death 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.

  21. IES: Safety profile – CV events and MI p-values not statistically significant; Coombes et al. San Antonio Breast Cancer Symposium 2004.

  22. -6 -4 -2 0 2 4 6 8 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 -3.5 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.

  23. 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.

  24. 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.

  25. Summary SWITCH studies AIs vs tamoxifen

  26. Switch vs. Upfront - level A2 evidence studies IES: ATAC: BIG 1-98: 5 yr tamoxifen 2-3 yr tamoxifen 3-2 yr exemestane 5 yr tamoxifen 5 yr anastrozole 5 yr tamoxifen & anastrozole 5 yr tamoxifen 5 yr letrozole 2 yr letrozole 3 yr tamoxifen 2 yr tamoxifen 3 yr letrozole

  27. Disease Free Survival (DFS) • ATAC: mediane FU: 68 months; only HR+ population • ** FU: 37.4 months (NEJM) *** HR not reported

  28. Anastrozole(A) Tamoxifen(T) 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 25 20 ER+/PgR- 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 451 435 417 400 390 347 124 T 429 412 375 353 327 276 96

  29. Smoothed hazard rates for recurrenceHR+ patients • Whichpatients are these? • HER2neu+++? • Should have been treated with CT? • ER+PgR-? 3.0 2.5 2.0 Annual hazard rates (%) 1.5 1.0 Anastrozole 0.5 Tamoxifen 0 0 1 2 3 4 5 6 Follow-up time (years) Howell T. et al., ATAC trial , San Antonio Breast Cancer Symposium 2004.

  30. Overall Survival * after randomisation after Tam

  31. 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 14 jaar Presentation of K. Osborne, St. Gallen Conference January 2005

  32. Safety

  33. Upfront and Switch - Summary of fracture risk

  34. 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

  35. Bone Resorption Marker: % Change Week 24 from Baseline serum CTX-IMedian 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

  36. Bone Formation Marker:%Change Week 24 from Baseline Serum PINPMedian 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

  37. 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.

  38. 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 027: BMD Lumbar spine Placebo Exemestane BMD (g/cm2) Placebo Exemestane Femoral neck 0 6 12 24 Months Lonning PE et al. ASCO 2004:Abstract 518.

  39. 027: T-score mean changes from baseline at 2 years 4 fractures in exemestane group; 5 fractures in placebo group Lonning PE et al. ASCO 2004:Abstract 518.

  40. 027: 1-yr follow-up Lonning PE et al. ASCO 2005: poster # 531

  41. 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 2005: poster # 531 Lonning PE et al. ASCO 2004: Abstract 518.

  42. Molecule structure aromatase inhibitors steroidal / aromatase-inactivator non-steroidal / aromatase-inhibitors androsteendion exemestane anastrozol letrozol The metabolite of exemestane is weak androgenic.

  43. Effect of Estrogen Concentration on Androgen Sensitivity in Bone

  44. 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.”

  45. AIs: Consensus guidelines

  46. 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.

  47. Back up slides

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