ATAC trial

1. ATAC trial Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer : first results of the ATAC randomised trial

2. Introduction Many breast cancers depend on oestrogens for continued growth Tamoxifen current standard for adjuvant treatment of breast cancer especially hormone receptor positive disease Recent trial 5 yrs showed 47% reduction in recurrence and 26% reduction in death

3. Tamoxifen Tamoxifen : oestrogen receptor antagonist has some partial agonist action some protection against bone loss and ?IHD endometrial ca and thromboembolic complications ? Less effective anti-tumour agent

4. Introduction Aromatase inhibitors inhibit enzyme aromatase which controls the rate limiting step of oestrogen synthesis from androgens reduce systemic oestrogen concentrations Anastrozole :potent, orally active , highly selective, aromatase inhibitor

6. Introduction Anastrozole Previous trials : showed reduced time to progression for metastatic breast cancer ATAC trial : anastrozole as adjuvant treatment for postmenopausal women with early operative breast cancer

7. Study 3 main questions Is anastrozole as effective as tamoxifen ? Any benefit in reduction of side-effects? Does combination of anastrozole and tamoxifen confer additional benefit?

8. Study population Postmenopausal women with histologically proven operable breast cancer had completed primary surgery and chemotherapy were candidates for hormonal adjuvant therapy both hormone receptor positive and negative patients included

9. Study population Ineligible metastatic disease trial not entered into within 8 weeks of surgery/ chemotherapy previous hormonal therapy history of invasive malignant disease

10. Study design Primary endpoint - disease free survival time to first occurrence of local or distant recurrence, new primary breast ca, death from any cause occurrence of adverse events

11. Study design 9366 women International trial : 381 centres in 21 countries Enrolled between 12/7/96-->24/3/00 Cut-off date for follow-up 29/6/01 Planned duration of treatment 60 months Median follow-up was 33.3 months

12. Study design Patients randomised centrally by computer in blocks of 6 1:1:1 ratio Anastrozole + placebo / Tamoxifen + placebo / Anastrozole + Tamoxifen 1mg anastrozole; 20mg tamoxifen 125 ineligible following randomisation

14. Trial protocol Progress assessments entry, 3 months, 6 months, then 6 monthly to 5 years, then annually to 10 years recurrence : histology for local recurrence, imaging for distal recurrence patients asked if they had experienced adverse events Baseline characteristics across all 3 groups very similar

16. Results First events including local and distant recurrence; contralateral breast cancer; deaths before recurrence 10.1% in anastrozole gp; 12.2 % tamoxifen gp; 12.3% in combination

18. Results Disease free survival significantly longer for anastrozole compared to tamoxifen (HR 0.83) p=0.013 or anastrozole compared to combination (HR 0.81) p=0.006 Disease free survival estimates at 3 years anastrozole 89.4%; tamoxifen 87.4%; combination 87.2%

19. Results Difference in annual recurrence rates similar at 1 year between 3 gps at 2 and 3 year f/u anastrozole gp showed significantly lower recurrence compared to other 2 gps over 3 years reduced risk of recurrence by 22%

21. Results Subgroup analysis benefit of anastrozole compared to tamoxifen not seen in patients with receptor negative disease OR in those with previous chemotherapy

23. Results Contralateral breast cancer reduction in primary contralateral breast cancer as a first event in anastrozole gp risk reduced by 58% compared to tamoxifen

24. Results Side effects no difference between tamoxifen and comb’n anastrozole significant reduction when compared to tamoxifen alone hot flushes, vaginal discharge and bleeding ischaemic cerebrovascular events, venous thromboembolic events endometrial cancer

25. Results Significantly more common in anastrozole gp musculoskektal disorders fractures especially in spine

27. Discussion Randomised double blinded controlled trial Large study population (n=9366) Large number of centres Findings applicable to practice Unsure of safety over 5 years Role of sponsor funding and organisational support from the trial sponsor AstraZeneca

28. Discussion Overall anastrozole showed better disease free survival (more pronounced in hormone-receptor positive) marked reduction in contralateral breast ca. combination treatment equivalent to tamoxifen

29. Discussion anastrozole lower incidence of menopausal symptoms, endometrial ca. and thromboembolic disease higher incidence of musculoskeletal problems including a polyarthralgia and fractures especially spinal Trial ongoing - further analysis expected distant recurrence + breast cancer deaths

30. Conclusion Anastrozole effective for adjuvant treatment of early breast cancer following initial treatment in postmenopausal women