ATAC trial

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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

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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

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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

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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

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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

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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?

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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

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Study population

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

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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

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Study design

• 9366 women
• International trial 381 centres in 21 countries
• Enrolled between 12/7/96--gt24/3/00
• Cut-off date for follow-up 29/6/01
• Planned duration of treatment 60 months
• Median follow-up was 33.3 months

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Study design

• Patients randomised centrally by computer in
  blocks of 6
• 111 ratio
• Anastrozole placebo / Tamoxifen placebo /
  Anastrozole Tamoxifen
• 1mg anastrozole 20mg tamoxifen
• 125 ineligible following randomisation

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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

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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

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Results

• Disease free survival
• significantly longer for anastrozole compared to
  tamoxifen (HR 0.83) p0.013 or anastrozole
  compared to combination (HR 0.81) p0.006
• Disease free survival estimates at 3 years
• anastrozole 89.4 tamoxifen 87.4 combination
  87.2

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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

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Results

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

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Results

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

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Results

• Side effects
• no difference between tamoxifen and combn
• anastrozole significant reduction when compared
  to tamoxifen alone
• hot flushes, vaginal discharge and bleeding
• ischaemic cerebrovascular events, venous
  thromboembolic events
• endometrial cancer

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Results

• Significantly more common in anastrozole gp
• musculoskektal disorders
• fractures especially in spine

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Discussion

• Randomised double blinded controlled trial
• Large study population (n9366)
• 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

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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

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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

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Conclusion

• Anastrozole effective for adjuvant treatment of
  early breast cancer following initial treatment
  in postmenopausal women