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‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis. Tony Howell on behalf of the ATAC Trialists’ Group. 9,366 patients recruited from 381 centres in 21 countries. ATAC. Recruitment July 1996 – March 2000
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‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis Tony Howell on behalf of the ATAC Trialists’ Group 9,366 patients recruited from 381 centres in 21 countries
ATAC • Recruitment July 1996 – March 2000 • Median follow up 68 months (data cut 31st March 2004) • 8% of patients remain on trial therapy Tamoxifen (n=3,116) Surgery +/- RT +/- Chemo (20%) Anastrozole (n=3,125) Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm Arimidex + Tamoxifen (n=3,125) • 84% HR positive • 61% Node negative 5 years
Anastrozole (A) Tamoxifen (T) Disease-free survivalCurves shown for HR+ patients p-value 0.005 0.01 A 424 575 T 497 651 HR 0.83 0.87 95% CI (0.73–0.94) (0.78-0.97) 25 HR+ 20 ITT 15 Patients (%) 10 5 Absolute difference: 1.6% 2.6% 2.5% 3.3% 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 DFS includes all deaths as a first event
Anastrozole (A) Tamoxifen (T) A 2618 2540 2448 2355 2268 2014 830 Time to recurrence Curves shown for HR+ patients 25 p-value 0.0002 0.0005 A 282 402 T 370 498 HR 0.74 0.79 95% CI (0.64–0.87) (0.70-0.90) HR+ 20 ITT 15 Patients (%) 10 5 Absolute difference: 1.7% 2.4% 2.8% 3.7% 1.7% 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2516 2398 2304 2189 1932 774
Smoothed hazard rates for recurrenceHR+ patients 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)
Incidence of contralateral breast cancer HR+ patients HR 0.47 0.58 95% CI (0.29–0.75) (0.38-0.88) p-value 0.001 0.01 HR+ ITT 60 Number ofcases 53 5 DCIS 50 40 26 30 48 Invasive* 5 DCIS 20 21 Invasive* 10 0 Anastrozole (n=2618) Tamoxifen (n=2598) *p=0.001 for invasive cancers
Anastrozole (A) Tamoxifen (T) A 2618 2550 2464 2386 2309 2051 845 Time to distant recurrenceCurves shown for HR+ patients p-value 0.06 0.04 A 226 324 T 265 375 HR 0.84 0.86 95% CI (0.70–1.00) (0.74-0.99) 25 HR+ 20 ITT 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2533 2438 2361 2257 2005 816
Anastrozole (A) Tamoxifen (T) A 2618 2566 2505 2437 2377 2117 867 Time to breast cancer deathCurves shown for HR+ patients 25 p-value 0.2 0.2 A 152 235 T 172 265 HR 0.87 0.88 95% CI (0.70–1.09) (0.74-1.05) HR+ 20 ITT 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2549 2502 2430 2333 2080 855
Anastrozole (A) Tamoxifen (T) T 2598 2549 2502 2430 2333 2080 855 Overall survivalCurves shown for HR+ patients 25 p-value 0.7 0.7 A 296 411 T 301 420 HR 0.97 0.97 95% CI (0.83–1.14) (0.85-1.12) 20 HR+ ITT 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2566 2505 2437 2377 2117 867 Includes non breast cancer deaths
Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer* 1.5 0.2 0.4 0.6 0.8 1.0 1.2 2.0 ITT population Tamoxifen better Anastrozole better HR+ population Hazard ratio (A:T) and 95% CI * Odds Ratio computed instead of Hazard Ratio Efficacy summary
Additional effect of anastrozole on recurrences at 5 years 38% recurrences with no adjuvant treatment (EBCTCG) 50% risk reduction with tamoxifen Further 26% risk reduction with anastrozole
Analysis of time to recurrence for subgroups Nodal status +ve -ve Tumor size ≤2 cm >2 cm Receptorstatus +ve -ve unknown Previous chemotherapy yes no All patients 0.40 0.60 0.80 1.00 1.25 1.50 1.75 Tamoxifen better Anastrozole better Hazard ratio (A:T) and 95% CI
Anastrozole(A) Tamoxifen(T) Retrospective analysis of time to recurrence for ER/PgR subgroups 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
Overview of adverse events* (%) Anastrozole(n=3092) 60.9 4.7 11.1 Tamoxifen(n=3094) 68.4 9.0 14.3 p-value <0.0001 0.0001 0.0002 Drug-related: AEs SAEs AEs leading to withdrawal *Adverse events on treatment or within 14 days of discontinuation
Pre-specified adverse events (%) Hot flashes Vaginal bleeding Vaginal discharge Endometrial cancer Ischemic cerebrovascular Venous thromboembolic Joint symptoms Fractures* Hysterectomy A 35.7 5.4 3.5 0.2 2.0 2.8 35.6 11.0 1.3 T 40.9 10.2 13.2 0.8 2.8 4.5 29.4 7.7 5.1 p-value<0.0001 <0.0001 <0.0001 0.02 0.03 0.0004 <0.0001 <0.0001 <0.0001 * Patients 1 fracture occurring before recurrence, including patients no longer on treatment
Fracture rates over time 3 2.5 2 Annual rates % 1.5 1 Anastrozole Tamoxifen 0.5 0 0 1 2 3 4 5 6 Years since randomization Fracture rates per 1000 women years: anastrozole 22.6; tamoxifen 15.6; P1 control 18.4; WHI control 19.1
Summary • Anastrozole – • demonstrates superior efficacy to tamoxifen - reduces recurrence, distant recurrence and contralateral breast cancer • is better tolerated overall • benefit in the first 3 years justifies offering • treatment as early as possible
Conclusion • Anastrozole – • the initial treatment of choice for • hormone receptor positive early breast • cancer in postmenopausal women
Professor A HowellManchester, UK (Chairman) Professor J AdamsManchester, UK Professor M BaumLondon, UK Professor AR BiancoNaples, Italy Dr A BuzdarHouston, USA Professor D Cella Evanston, USA Dr M CoibionBrussels, Belgium Professor R ColemanSheffield, UK Dr M ConstenlaPontevedra, Spain Professor J CuzickLondon, UK Professor W DistlerDresden, Germany Professor M DowsettLondon, UK Dr G LockerEvanston, USA Dr J MackeyAlberta, Canada Professor RE Mansel Cardiff, UK Professor J-M Nabholtz Neuilly s/Seine, France Dr T NagykalnaiBudapest, Hungary Dr A NiccoluciChieta, Italy Dr U NylenStockholm, Sweden Mr R SainsburyLondon, UK Dr F SapunarAstraZeneca, UK Dr V Suarez-MendezAstraZeneca, UK Professor JS TobiasLondon, UK Mr N WilliamsLondon, UK Acknowledgements We would like to thank all the patients and investigators for their participation in the trial ATAC Steering Committee • Mr S DuffyLeeds, UK • Professor R EastellSheffield, UK • Professor L FallowfieldBrighton, UK • Professor J Forbes Newcastle, Australia • Professor WD GeorgeGlasgow, UK • Sister J GrayBelfast, UK • Dr J-P GuastallaLyon, France • Mr R HellmundAstraZeneca, US • Dr G Hoctin-BoesAstraZeneca, US • Mrs J HoughtonLondon, UK • Professor J KlijnRotterdam, Netherlands