Aromatase Inhibitors vs Anti-Oestrogens in Treatment of Early Breast Cancer

1
Aromatase Inhibitors vs Anti-Oestrogens in
Treatment of Early Breast Cancer

• The Journal Club Meeting POWH
• 1 May 2006
• Presenter Alexander Koshman
• Mentor Professor Philip Crowe

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A Comparison of Letrozole and Tamoxifen in
Postmenopausal Women with Early Breast Cancer

• The Breast International Group (BIG) 1-98
  Collaborative Group
• The New England Journal of Medicine, Vol.353, No
  26, December 29, 2005
• The Writing Committee Belgium, Denmark, France,
  Italy, Switzerland, UK, USA University of
  Sydney, Cancer Council of Australia (Alan S.
  Coates) University of Newcastle, N.S.W. (John F.
  Forbes)

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Background

• The aromatase inhibitor L is a more effective
  treatment for metastatic breast cancer and more
  effective in the neoadjuvant setting than T
• Many reports suggest that as first-line treatment
  for metastatic breast cancer, 3rd generation
  aromatase inhibitors are equivalent or superior
  to T
• Adjuvant endocrine therapy with T significantly
  prolongs disease-free and overall survival in
  postmenopausal women with early-stage breast
  cancer

4
Background

• Question raised
• What is effectiveness of L comparing to T as
  adjuvant treatment for steroid-hormone-receptor-po
  sitive early breast cancer in postmenopausal
  women?

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Study design

• BIG 1-98 randomized, phase 3, double-blind trial
• Inclusion criteria
• Postmenopausal women with
• Operable invasive breast cancer
• ER-positive, PgR-positive, or both
• Primary surgery with resulting clear margins and
  adequate haematologic, RF, LFT tests

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Study design

• Exclusion criteria
• Evidence of metastatic disease
• Previous or concurrent cancer within 5 years of
  randomization
• Adjuvant antioestrogen therapy or systemic
  investigational drugs within 30 days of
  randomization

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Study design

• Patients were randomly assigned to 4 groups
• L only, T only, L-gtT, T-gtL
• Patients recruitment
• March 1998 -March 2000 - 1835 patients
• April 1999 - May 2003 - 6193 patients
• Primary end point
• Disease-free survival
• Secondary end points
• Overall survival survival free of systemic
  disease occurrence of 2nd Ca death from any
  cause safety

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Statistical Analysis

• Primary core analysis comparing L to T was
  designed to estimate hazard ratios, or relative
  hazards
• Cox proportional-hazards regression was used to
  adjust for various prognostic factors
• Survival curves calculated by the Kaplan-Meier
  method, were used to display the cumulative
  probability of an individual remaining free of
  the end point at any time after randomization
• Adverse event rates compared by Fishers exact
  test

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Results

• Study population
• 8010 patients enrolled,
• 4003 in the Letrozole group,
• 4007 in the Tamoxifen group
• Median follow-up for the primary core analysis
  25.8 months
• The baseline characteristics of the patients,
  tumours, and primary treatments were similar in
  the two groups

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Results Efficacy

• Disease-free survival was significantly greater
  in the L group than in the T group
• Especially reduced was recurrence at distant
  sites
• 5-y estimates of disease-free survival were 84.0
  in L group and 81.4 in the T group
• L significantly reduced the cumulative incidence
  of breast cancer relapse as compared to T
• Difference evident 1 y after randomization
  absolute difference of 3.4 at 5 years
• Secondary end-point analysis also favored L

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Results Safety

• More pts in L group reported adverse events 2912
  in L group vs. 2554 in T group
• Number of life-threatening or fatal adverse
  events was similar in both groups 1.7
• Fractures were significantly more frequent in L
  group, with a shorter time to a 1st
• L was associated with fewer thromboembolic
  events, lower rate of vaginal bleeding, fewer
  invasive endometrial cancers
• More pts in L group had adverse cardiac events

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Conclusions

• L is an effective option for standard adjuvant
  therapy, with a relatively favorable safety
  profile
• Aromatase inhibitors should be considered in the
  adjuvant treatment plan for postmenopausal women
  with endocrine-responsive breast cancer
• T and L have different safety profiles. In pts at
  low risk for breast cancer recurrence, the
  incidence, severity and duration of side effects
  are relevant in selecting treatment

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Limitations of the Study and Ideas for Future
Research

• Longer follow-up is required to determine whether
  L will continue to reduce risk of relapse for
  several years after cessation of treatment, as
  has been shown for T
• Effect of oestrogen deprivation and aromatase
  inhibitors on ischaemic heart disease requires
  further study
• The cause of increased incidence of cardiac
  events in the L group is unknown ? Due to a
  protective effect of T on the arteries

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Ideas for Future Research

• Statement issued by the American Society of
  Clinical Oncology in 2005
• Current information is insufficient to determine
  fully the effect of aromatase inhibitors on
  cardiovascular disease, especially coronary heart
  disease