Adjuvant hormonal therapy for early stage breast cancer Beyond Tamoxifen

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Adjuvant hormonal therapy for early stage breast
cancerBeyond Tamoxifen

• Rama Suresh M.D.
• Fellow
• Division of Oncology

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Why 5 years of Tamoxifen?
EBCTCG overview of randomised trials, Lancet
351 1451-1467, 1998
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EBCTCG overview of randomized trials, Lancet
351 1451-1467, 1998
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JNCI Monographs 30 56-61, 2001
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ATAC trial 4 yr data. Cancer 98(9)1802-1810, 2003
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ATAC trial 4 yr data. Cancer 98(9)1802-1810, 2003
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Toxicity

• Tamoxifen More hot flashes, vaginal bleeding,
  vaginal discharge, endometrial malignancies,
  ischemic cardiovascular events, ischemic
  cerebrovascular events, all venous thromboembolic
  events, DVT
• Anastrazole More musculoskeletal disorders,
  fractures

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Study design

• Phase 3
• Randomized
• Double-blinded
• Placebo controlled
• Stratified for receptor status,nodal status, and
  chemotherapy

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Inclusion criteria

• gt 50 yrs
• lt 50yrs and postmenopausal
• Previous adjuvant tamoxifen for 4.5 to 6 yrs
• Histologically confirmed breast cancer
• ER or PR or both (10fmol/mg of protein or
  by IHC or by immunocytochemical analysis)
• Discontinued tamoxifen lt 3 M before enrollment
• ECOG PS of 0-2
• Imaging studies to r/o mets in pts with symptoms
  or abnormal lab tests

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Exclusion criteria

• Other investigational agents
• H/O of another cancer except skin cancer and
  ca-in situ of the cervix
• Concomitant HRT or estrogen receptor modulator
  except for intermittent vaginal estrogens

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Statistical analysis

• Sample size was calculated under the assumption
  of a four year DFS rate of 88 for placebo group
  and a detection of 2.5 difference in the 4 yr
  DFS (HR of 0.78)
• 80 power
• Two sided alpha level of 0.05
• Needed 4800 women over a 4 yr period with 2 yrs
  of follow up accounting for 515 events
• Two interim analysis at 171 and 342 events
  planned

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Statistical analysis

• Early termination would be considered at the
  time of the interim analysis if the P value of
  the stratified log-rank test was below a nominal
  significance level calculated with the use of the
  Lan-DeMets alpha spending function, with
  OBrien-Fleming boundaries that maintained the
  overall significance of the study at a two-sided
  alpha level of 0.05.

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Study population

• Between 8-98 and 9-02 , 5187 women were
  randomized
• Sub study focused on bone
• 30 women excluded
• 39 women deemed ineligible but were included in
  the analysis according to the intention to treat
  principle

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MA-17 Letrozole v Placebo after Tamoxifen in
Postmenopausal Breast Ca

• Toxicity
• Arthralgias, arthritis, myalgias, hot flashes
  more common with letrozole
• Less vaginal bleeding with letrozole
• More osteoporosis with letrozole but not
  statistically significant
• Conclusions
• Letrozole reduces breast cancer recurrence in
  postmenopausal women who have completed 5 years
  of tamoxifen
• No difference is survival to date

Goss P, et al. NEJM. Nov 6, 2003
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Ongoing AI Trials in Adjuvant Therapy
ATAC (Anastrozole)
TAMOXIFEN
AI
EXEM 031 (Examestane)
PLACEBO
BIG 1.98(BIG FEMTA) (Letrozole)

ARNO (Anastrozole)
NSABP B33 (Examestane)
TEAM EXE (Examestane)
Courtesy of P.E. Goss.
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Questions

• What is benefit for women who completed Tamoxifen
  gt3 months ago?
• Did the study get unblinded too early?
• Impact on survival?
• Should patients receiving anastrazole in ATAC
  trial continue beyond 5 years??
• Should patients receiving anastrazole be given
  letrozole, tamoxifen or exemestane after 5 years?
• Long term side effect of letrozole?
• Impact on QOL life pending
• Cost vs. benefit ratio