Best first ? The ATAC completed treatment analysis Professor Jack Cuzick Wolfson Institute of Preventive Medicine, London, UK

Aims of the ATAC trial Can we improve on tamoxifen as adjuvant therapy for early breast cancer? Is anastrozole superior to tamoxifen in the initial adjuvant setting? Can we improve the tolerability profile of adjuvant tamoxifen? Can we reduce recurrences, especially in the first few years of treatment?

ATAC trial design 9366 Postmenopausal women with invasive breast cancer mean age 64 years; 84% hormone receptor positive 61% node negative; 64% with tumour  2 cm in diameter Surgery  radiotherapy  chemotherapy Randomisation 1:1:1 for 5 years Anastrozole n=3125 Tamoxifen n=3116 Combination n=3125 Regular follow-up Primary trial endpoints: Disease-free survival Safety / tolerability Secondary trial endpoints: Incidence of contralateral breast cancer Time to distant recurrence Overall survival Time to breast cancer death Combination arm discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm

ATAC completed treatment analysis Follow-up: –data cut-off 31st March 2004 –68 months’ median follow-up – beyond completion of treatment –only 8% of patients remain on treatment the great majority of these nearing completion

Efficacy analysis

Disease-free survival (HR-positive population) A T At risk: Follow-up time (years) Absolute difference: 1.6%2.6%2.5%3.3% HR=hormone receptor; ITT=intent-to-treat Events (%) Anastrozole (A) Tamoxifen (T) HR HR+ 95% CI (0.73–0.94) (0.78–0.97) p-value ITT

Recurrence (HR-positive population) A T Follow-up time (years) At risk: Absolute difference: 1.7%2.4%2.8%3.7% Events (%) Anastrozole (A) Tamoxifen (T) HR HR+ 95% CI (0.64–0.87) (0.70–0.90) p-value ITT

Incidence of contralateral breast cancer (HR-positive population) Invasive* 54 Tamoxifen (n=2598) Anastrozole (n=2618) 26 6 DCIS 48 Invasive* No. of cases 5 DCIS *p=0.001 for invasive cancers HR HR+ 95% CI (0.29–0.75) (0.38–0.88) p-value ITT

Time to distant recurrence (HR-positive population) A T Follow-up time (years) At risk: Patients (%) HR HR+ 95% CI (0.70–1.00) (0.74–0.99) p-value ITT Anastrozole (A) Tamoxifen (T)

Time to breast cancer death (HR-positive population) Follow-up time (years) Anastrozole (A) Tamoxifen (T) HR HR+ 95% CI (0.70–1.09) (0.74–1.05) p-value 0.2 ITT A T A T At risk: Patients (%)

Overall survival (HR-positive population) A T Follow-up time (years) At risk: Includes non breast cancer deaths Patients (%) HR 0.97 HR+ 95% CI (0.83–1.14) (0.85–1.12) p-value 0.7 ITT A T Anastrozole (A) Tamoxifen (T)

Summary of efficacy endpoints In the HR + population, compared with tamoxifen, anastrozole lowers the risk of : –all events: 17% (p=0.005) –recurrence: 26% (p=0.0002) –distant recurrence: 16% (p=0.06) –contralateral tumours: 53% (p=0.001)

Yearly risk of recurrence in early breast cancer in untreated patients Adapted from EBCTCG meta-analysis. Lancet, 1998; 351: Years 5110

Event rates for recurrence ( HR-positive population ) Follow-up time (years) Annual hazard rate (%) Anastrozole Tamoxifen Substantial benefit with anastrozole in the first 3 years Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1

Tolerability analysis

Overview of adverse events Adverse events leading to withdrawal* Drug-related adverse events leading to withdrawal* All serious adverse events Serious adverse events leading to withdrawal Serious adverse events leading to death Drug-related serious adverse events leading to death p-value Tamoxifen (%) (n=3094) Anastrozole (%) (n=3092) *Adverse events on treatment or within 14 days of discontinuation

Pre-defined adverse events T A Completion analysis p-value < < Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer* Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures** *Excludes patients with prior hysterectomy and includes on- and off-therapy AEs; **Fractures occurring at anytime prior to recurrence (includes patients no longer receiving treatment); pink text indicates p-value in favour of anastrozole and blue text in favour of tamoxifen

Annual fracture rates over time Years Arimidex Tamoxifen Number at risk Years since randomisation *Calculated using Kaplan-Meier estimates Annual rates, %* Anastrozole 1 mg od Tamoxifen 20 mg od 0

Indirect fracture rate comparison HRT = 1.48 Placebo = 1.91 Healthy women Age = 63 WHI (n=16,608) Tamoxifen = 1.80 Placebo = 1.84 Breast cancer prevention Age >50 (61%) PI ( n=13,175) Anastrozole = 2.26 Tamoxifen = 1.56 Early breast cancer (adjuvant) Age = 64 ATAC (n=6,186) Annual Fracture rate (%) Setting Average age (years) Clinical study ATAC Trialists’ Group. Lancet 2005; 365: 60–62 Fisher et al. J Natl Cancer Inst 1998; 90: 1371–1388 Women's Health Initiative Writing Group. JAMA 2002; 288: 321–333

Tolerability summary Compared with tamoxifen, anastrozole is associated with significantly fewer: –SAEs, treatment-related AEs and withdrawals due to SAEs or AEs –potentially life threatening AEs such as endometrial cancer, thromboembolic, and cerebrovasular events No new safety concerns have emerged with long-term follow-up Anastrozole is the only AI that has a mature tolerability profile covering the full 5 year treatment period

ATAC Conclusions ATAC completed treatment analysis extends and strengthens the evidence that 5 years of anastrozole is significantly more effective and better tolerated than 5 years of tamoxifen Substantial benefits for anastrozole were seen within the first 3 years The efficacy benefit continues to increase with time and extends beyond the completion of therapy These data support using anastrozole as initial adjuvant therapy