NSABP B-14, NSABP B-33, NCIC-CTAG MA.17 Trial and MA.17 R Trial

• NSABP B-14:
  • Was a randomized, double-blind, placebo-controlled trial:
    • Comparing tamoxifen to placebo in women with node-negative ER positive invasive breast cancer
  • It demonstrated a statistically significant improvement in 10-year disease-free survival (DFS)with the use of 5 years of tamoxifen:
    • 69% vs. 57%, P<0.0001
  • Tamoxifen was also associated with a 37% reduction in contralateral breast cancers

• The results of B-14 raised questions about the benefit of administration of additional adjuvant hormonal therapy following completion of 5 years of tamoxifen:
  • More specifically, the administration of aromatase inhibitors after completion of tamoxifen therapy became of interest

• NSABP B-33:
  • Was developed to compare exemestane with placebo in recurrence-free postmenopausal women who completed 5 years of tamoxifen therapy
  • Accrual to this study was terminated prematurely when results of NCIC-CTG MA.17 showed:
    • A significant improvement with letrozole after 5 years of tamoxifen
    • With a median follow-up of 64 months:
      • The hazard ratios of letrozole after 5 years of tamoxifen compared to placebo after similar tamoxifen therapy were:
        • 0.52 (95% confidence interval [CI], 0.45 to 0.61; P<.001) for DFS
        • 0.51 (95% CI, 0.42 to 0.61; P<.001) for distant DFS
        • 0.61 (95% CI, 0.52 to 0.71; P<.001) for overall survival
  • The patients in NSABP B-33 were then unblinded and offered 5 years of exemestane:
    • The improvement in relapse-free survival observed in B-33 with exemestane was similar to that observed in the NCIC-CTG MA.17 trial with letrozole
  • To further examine the benefits of aromatase inhibitors as primary therapy or after 2 to 5 years of tamoxifen:
    • In women with early-stage, hormone receptor-positive breast cancer:
      • The MA.17 R trial analyzed prolonging duration of therapy to 10 years:
        • With DFS as the primary endpoint
    • The study randomized 1,918 women to placebo versus letrozole
    • After a median follow-up of 6.3 years:
      • DFS was 95% for the letrozole group and 91% for the placebo group
      • There was also an improvement in the annual incidence of contralateral breast cancer:
        • With the letrozole group at 0.21% versus 0.49% for the placebo group. 
      • These data support a new standard of care for this patient population, i.e., to improve DFS through 10-year treatment with aromatase inhibitors
• References:
  • Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93(9):684-690.
  • Fisher B, Jeong JH, Dignam J, Anderson S, Mamounas E, Wickerham DL, et al. Findings from recent National Surgical Adjuvant Breast and Bowel Project studies in Stage I breast cancer. J Natl Cancer Inst Monogr. 2001;93(30):62-66.
  • Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26(12):1965-1971.
  • Ingle JN, Tu D, Pater JL, Muss HB, Martino S, Robert NJ, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 2008;19(5):877-882.
  • Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30(7):718-721.
  • Lemieux J, Goss PE, Parulekar WR, Ingle JN, Pritchard KI, Robert NJ, et al. Patient-reported outcomes from MA.17R: a randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34(18 

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